CA1180011A - Imidazobenzodiazepines - Google Patents

Abstract

- 1 - 4-13694/CGC 961/+

Imidazobenzodiazepines Abstract of the disclosure The invention concerns psychoactive and antihistaminic compounds of the formula I

(I)

Description

4-13694/CGC 961/~

IMIDAZOBENZODI~Z~PINES

The invention concerns 5-diazacycloalkyl-imidazo~1,2-c]~1,3]benzo-diazepines of formula I

6\ / 7 \i / \ .~ \.-R (I) n ~

wherein each of the symbols Rl and R2 is hydrogen, lower alkyl, lower alkanoyl, halogen, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, sulfamoyl, mono- or di-lower alkyl-(carbamoyl or sulfamoyl); C H2 is lower alkylene separating both nitrogen atoms by 2 or 3 carbon atoms; R3 is hydr~)gen~ lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, aryl lower alkyl, lower alkoxycarbonyl, phenyl lower alkoxycarbonyl or (hydroxy, lower alkanoyloxy, aryloxy or lower alkoxy) lower alkyl having at least two carbon atoms; R4 and R5 in-dependently represent hydrogen, lower alkyl, lower alkoxy, lower ~^``i alkylthio, halogen, trifluoromethyl, hydroxy, lower alkanoyloxy, sulfamoyl, mono- or .li-lower alkylsulfamoyl; and R6 and R7 represent h~7drogen or lower alkyl; tle N-oxides, lower alkyl quaternary derivatives, and salts, especially pharmaceutically acceptable salts i:hereof, process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application.

l'he term ~lower~ referred to above and hereinafter in connec~ion with organic radicals or compounds respectively deEines e.g. such alkyl, alkenyl und aLkynyl radicals with up to and including 7, preferably #

up and including 4 and advantageously one or two carbon atoms.

Halogen is preferably fluoro or chloro, but may also be bromo or iodo.

A lower alkyl group or sucll present in said alkoxy, alkylthio or other alkylated groups, is above all methyl, but also ethyl, n- or i-(propyl, butyl, pentyl, hexyl or heptyl), e.g. 2-methylpropyl or 3-methylbutyl, lower alkenyl is preferably allyl and lower alkynyl is preferably propargyl.

Aryl lower alkyl is preferably benzyl, 1-, 2~ or 3-phenylpropyl9 1- or 2-phenylethyl, said radicals being optionally substituted on the phenyl ring preferably by e.g. halogen, lower alkoxy or lower alkyl.

A lower alkoxy group preEerably contains 1 to 4 carbon atoms and represents for example ethoxy, propoxy, isopropoxy or advantageously methoxy.

A lower alkylthio group preferably contains 1 to 4 carbon atoms and represents for example ethylthio, propylthio or advantageously methylthio.

The term "acyl" represents for example lower alkanoyl, lower alkoxy carbonyl, carbamoyl, sulfamoyl, mono- or di-lower alkyl (carbamoyl or sulfamoyl), halosulfonyl5 phenyl lower alkoxycarbonyl and the like, I.owe~ allcalloyl is preferably acetyl or propionyl. Lower alkanoyloxy is preferably ace~yloxy or propionyloxy.

A lower alkoxycarbonyl, mono- or di-lower alkyl (carbamoyl or sulfamoyl) group is preferably methoxycarbonyl or ethoxycarbonyl;
mono- or dimethyl(carbamoyl or sulfamoyl).

A phenyl lower alkoxycarbonyl group represents preferably phenylmethoxycarbonyl or phenylethoxycarbonyl.

A lower alkylene group C H2 is especially ethylene; but also 1,2-or 1,3-propylene, 1,2-, 1,3- or 2,3-butylene; thus forming with both adjacent nitrogen atoms a piperaæinyl or homopiperazinyl moiety.

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

A lower alkanoyloxy lower alkyl group represents preferably lower alkanoyloxy (ethyl, propyl or butyl), e.g. 2-acetyloxy- or 2-propion-yloxy (ethyl, propyl or butyl) 7 3-acetyloxy- or 3-propionyloxy-(propyl or butyl), 4-acetyloxy- or 4-propionyloxybutyl and the like.

A lower alkyloxy lower alkyl group represents preferably lower alkyloxy-(ethyl, propyl or butyl), e.g. 2-methoxy- or ethoxy-(ethyl, propyl or butyl), 3-methoxy- or 3-ethoxy-(propyl or butyl), 4-methoxy- or 4-ethoxybutyl and the like.

An aryloxy lower alkyl group represents preferably phenyloxy-(ethyl, propyl or butyl), said radicals being optionally substi-tuted on the phenyl ring preferably by e.g. halogen, lower alkoxy or lower alkyl.

Lower alkyl quaternary salts of compouncls of formula I are pre-Eerably, e,g. methyl, ethyl or propyl quaternary salts derived from reactive es~ers of lower alkcmols having preEerably from l ~o 4 carbon a~oms, e.g. methanol, ethanol or propanol. The anions of said quaternary salts are preferably those corresponding to pharma-ceutically acceptable acids such as halide, e.g. bromide or iodide;sulfate; or lower alkylsulfonate, e.g. methylsulfonate.

Although N-oxides or lower alkyl quaternary salts of compounds of formula I may represent such functionalized at one or more of any of the depicted ring nitrogen atoms ;n formula I9 said N-oxides, lower alkyl quaternary salts of the compounds of formula I are pre~
ferably derived from those wherein R3 is lower alkyl, aryl lower alkyl, or (hydroxy, lower alkanoyloxy, aryloxy or lower alkoxy) lower alkyl having at least 2 carbon atoms in the lower alkyl group and wherein only the nitrogen atom 'bearing said R3 substituent is thus functionalized.

Said compounds of Formula I form acid addition salts, which are preferably such of pharmaceutically acceptable inorganic or organic acids, such as strong mineral acids, for example hydrohalic9 e.g.
hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g.
formic,acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, hydroxymaleic, pyruvic, phenyl-acetic, benzoic, 4-aminobenzoic, anthrani'lic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic; methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogeno benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; or ascorbic acid.

Compounds oE formula I with RL and/or R2 being carboxy also form salts with 'lases, preferably with such bases which yield pharmaceutically acceptable salts, for example, ammonium salts, mono, dl- or tri-lower alkyl amines, lower alkylene amines, morpholine, piperazine, piperidine, or lower a]kyl deriva~:ives of said cyclic bases, alkali or alkaline earth metal salts.

The compounds of the invention exhibit valuable pharmacological properties, psychoactive, e.g. neuroleptic, as well as antiallergic, e.g. antihistaminic effects. Such are demonstrable in animal tests using advantageously mammals, e.g. mice, rats, guinea pigs or monkeys, as test objects. Said compounds can be applied to them enterally or parenterally, advantageously orally, or subcutaneously, intra-venously or intraperitoneally, for example, within gelatin capsules or in the form of starchy suspensions or aqueous solutions respec-tively.

The applied dosage may range between about 0.1 and 100 mg/kg/day, preferably between about 0.5 and 50 mg/kg/day, advantageously between about 1 and 30 mg/kg/day.

Said neuroleptic properties can be demonstrated in adult rats or squirrel monkeys, which were trained to press a lever to avoid the onset of an electric foot shock. Each lever press postpones the shock for 30 seconds. I~henever the animal fails to press the lever once within said period, brief (0.5 sec.) shocks are delivered at 15 second intervals until the animal again presses the lever.
Under control conditions the animals press the lever at a moderately steady rate and seldom receive more than five or six shocks during a 25-minute (rats) and up to 4-hour experimental session. Said compounds are administered to the animals 30, 90, 210 minutes prior to the experimental session and block the learned conditioned avoidance behavior, manifested by a decrease in avoidance responding with a marlced increase in shocks taken by the animal. Both the avoidance responses and Eailures (shocks receivecl) are recorded separa~ely for evaluation.

Finally, said antihistaminic properties can be shown in vitro, e.g., according to Chasin et al., J. Neurochem. 22, 1031 (1974). Vesicles Erom a cell free preparation of guinea pig cerebal cortex are preincubated with H-adenine to Eorm endogenous H-adenosine ~'~8~

triphosphate. The vesicles are then incubated with 50 micromolar histamine to activate H-cyclic adenosine monophosphate synthesis in the absence or presence of the test compound at a concentration between 0.01 and 100 micromolar. When said compound is active, it inhibits the histamine activation of adenylate cyclase. The IC50 represents the concentration at which histamine activation is in-hibited by 50%.

Accordingly, the compounds of the invention are useful neuroleptic and antihistaminic agents, for example, in the treatment or management of psychotic manifestations, e.g., aggression, agitation, schizophrenia, and/or allergic conditions in mammals, including man.
They are also useful intermediates in the preparation oE other valuable products, especially of pharmacologically active compositions.

Preferred embodiments of this invention relate to compounds of formula I wherein each of Rl and R2 is hydrogen, lower alkyl, cyano, carboxy, lower alkoxycarbonyl or carbamoyl; n represents the integer

2 to 4; R3 is hydrogen, lower alkyl~ lower alkoxycarbonyl, or hydroxy lower alkyl of 2 to 4 carbon atoms; R4 represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl;
R5 represents hydrogen; and R6 and R7 represent hydrogen or lower alkyl; the N-oxides; lower alkyl quaternary salts; or salts, especially pharmaceutically acceptable salts thereof.

~lighly preEerred are compounds of formula I wherein each of Rl and R2 is hyclrogen, methyl, ethyl, cyano, carboxy, alkoxycarbonyl Oe 1 to 3 carbon atoms in the alkoxy portion or carbamoyl; n re-presents the integer 2 or 3; R3 is hydrogen, alkyl of 1 to 3 carbon atoms, alkoxycarbonyl of 1 to 3 carbon atoms in the alkoxy portion, hydroxyethyl or hyclroxypropyl; R4 represents hydrogen, methyl, methoxy, methylthio, chloro or trifluoromethyl; R5 represents hydro-gen; R6 and R7 represent hydrogen or methyl; the N-oxides; methyl ~L8~

quaternary salts; and salts, especially pharmaceutically acceptable salts thereof.

Especially useful are compounds of formula II

R (II) N\ ~ 3 CnH2n wherein Rl and R2 independently represent hydrogen or lower alkyl;
R3 represents hydrogen, lower alkyl or hydroxy lower alkyl wherein the hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms; R4 represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl; C H2 represents ethylene or propylene; the N-oxides; and salts, especially pharma-ceutically acceptable salts thereof.

Of particular interest are compounds of formula II wherein Rl and R2 independently represent hydrogen or methyl; R3 represents hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl or 3-hydroxypropyl; R4 is hydrogen, methyl, methoxy, fluoro,chloro or trifluormethyl; C ~12 represents ethylene or propylene; the N-oxides and salts, especially pharmaceutically acceptable salts thereof.

Further preferred are compounds of formula II wherein Rl and R2 independeTltly represent hydro~en or methy:l; R3 represents hydrogen, methyl, ethyl, propyl or 2-hydroxyethyl; R~ is hydrogen, methyl, ~luoro, c.hloro or trifllloromethyl and C H2 is ethylene, and salts, especially pharmaceutically acceptable salts thereof.

~L8~
-- 8 ~

Indicative of the antipsychotic utility of the compounds of this invention, e.g., the compound of example 1, namely 5-(4-methyl-1-piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine disrupts avoidance behavior, e.g. decreases avoidance responses in rats and monkeys at an oral dose of 30 mg/kg or lower.

Illustrative of the antihistaminic activity, 5-(4-methyl-1- ~
piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine, the compound of example 1, inhibits histamine activation of adenylate cyclase, with an IC50 of about 1 x 10 ~.

Furthermore, 5-(4-methyl-1-piperazinyl)-llH-imidazo[1,2-c][1,3]-benzodiazepine, the compound of example 1, an illustrative example of this invention, is essPntially free of extrapyramidal side effects, e.g. dyskinesias and dystonias in the monkey (dyskinetic movements and dystonic postures) and shows only minimal ~-adrenergic blocking activity in vitro.

The compounds of, the invention are prepared according to methods known per se, advantageous]y by a) condensing a compound of formula III

6\ / 7 \ / \.~ \~/ 1 (III) ~ =u ~ \R

20 Whereirl X iY a group detachable together with hydrogen or an alkali metal and the remaining symbols have meaning as deEined Eor formula I; with a compound o~ formula IV

_ 9 _ HN\ ~ -R3 (IV) Cn 2n or an alkali metal derivative thereof wherein R3 has meaning as defined for formula I; and, if desired, convertitlg any resulting compound of formula I into another compound of the invention.

A group detachable together with hydrogen or an alkali metal atom is for example in particular a free or preferably etherified mercapto group, also an optionally functionally modified reactive hydroxy group, the cyanato, thiocyanato or the nitroamino group. An etherified mercapto group is especially a mercapto group etherified by an optionally substituted hydrocarbon, particularly one of ali-phatic character. It is especially lower alkylthio, for example methylthio, ethylthio or butylthio, or phenyl-lower-alkylthio, for example phenylthio or benzylthio. An optionally functionally modified reactive hydroxy group is a free hydroxy group or, for example, a corresponding esterified hydroxy group. This is for example halogen, such as chlorine or bromine, or lower alkylsulfonyl-oxy, for example methanesulfonyloxy. An etherified hydroxy group is for example a lower alkoxy group, such as methoxy or ethoxy.

Said condensation is advantageously carried out with an excess of the compound IV, or with equivalent amounts of said metal deri-vcltives prepared in situ therefrom, preferably when X in Eortnula III
is halogeno, lower alkylthio or thiocyanato, advantageously and depending on the nature oE said X, at temperatures between about 0 and 150, flnd preeerably in an appropriate solvent e.g. a lower alkanol such as amyl alcohol7 dimethylformamide, hexamethylphosphor-amide or toluene. Said condensation of a compound of formula III
with a compound oE formula IV may also be carried out in thc pre-sence of an acid, e.g., a hydrohalic acid such as hydrochloric acid.

., :

The novel llH-imidazo[1,2-c][1,3]benzocliazepine starting materials of formula III are prepared according to ring closure methods known per se. Advantageously by condensing compounds of formula V

R 6\./ 7 ~ \./ \.~ \./ 1 (V) R~ ~ H2 H R2 wherein Rl, R2, R~-R7 have meaning as previously defined for Eormula I with reactive carbonic acid derivatives such as phosgene~
thiophosgene, l,l~-carbonyldiimidazole, cyanogen bromide or phenyl chloroformate.

Compounds of formula III wherein X is hydroxy can be converted to compounds wherein X is sulfhydryl by conventional sulfurating agents, such as phorphorus pentasulfide.

These compounds of formula III can be further derivatized to com-pounds of formula III above wherein X has the meaning given above, analogous to the procedures illustrated by the examples herein.

Starting materials of formula V are preferably prepared by reduction of the corresponding variously substituted 2-(o-nitrobenzyl)imidazoles, which are in turn preferably prepared from the correspondingly substituted o-nitrobenzylnitriles and 2-aminoacetals (or ketals) 9 e.g. aminoacetald~tlyde dimethyl acetal, by known methods illu-~0 s~rated in the examples herein.

Eurther process Eor the preparation of the compounds of generalEormula I consists in b) cyclizing a compound of formula VI

~ \ ~ IN- 3 Rl (VI) Rs ~ C~ R3 wherein Z is oxygen, sulfur, or NH, and the other symbols have the above-given meaning, under dehydrating, dehydrosulfurating or deamination conditions, and if desired converting any resulting compound into another compound of the invention.

Said cyclization is preferably carried out at temperatures between 0 and 120, with a reagent such as a phosphorus halide, for example, phosphorus pentachloride and/or phosphorus oxychloride or a 10 cyanogen halide, with or without a crown ether catalysator, for example 8-crown-6-ether, with or without basic catalysts such as triethylamine or potassium carbonate, advantageously in an inert solvent, such as acetonitrile or tolueneO

The starting materials of Fo~nula VI ~an be obtained according to methods known per se. For example they can be prepared from percursors of Formula III or tautomers thereof, wherein X is hydroxy, thio or amino by condensing them with compounds of Formula IV in the presence or absence of other bases, e.g. those listed above, preferably in an inert solvent, such as methylene chloride or toluene at temperatures between 0 and 150 advantageously between 10 and 50. The ring opening reaction is preEerably carried out at low temperature to minimiæe side reactions when R
and R2 represent reactive functional groups.

~lternately, starting materials of formula VI, wherein R3 is lower alk~moyl, lower alkoxycarbonyL or phenyl lower alkoxycarbonyl, are prepared by condensing a cornpound of formula V above with a compound of formula VII

Yl-N\ \N ~ R (VII) CnH2n wherein Y' represents halocarbonyl, halothiocarbonyl or cyano, preferably in an inert solvent, at temperatures between about 0 and 150, with or without basic catalysts such as triethylamine or potassium carbonate.

Starting materials of formula VII are preferably obtained by reacting compounds of formula IV wherein R3 has the meaning given for formula VII, or advantageously e.g. the N-trimethylsilyl derivative thereof, with phosgene, thiophosgene or cyanogen bromide in an inert solvent such as ethyl ether, methylene chloride or dimethoxyethane at temperatures of about -70 to -~50 with or without basic catalysts such as triethylamine or potassium carbonate.

The compounds of the invention so obtained can be converted into other compounds of Formula I according to known methods. Thus, for example, those with R3 being hydrogen or alkali metal, e.g., sodium or lithium salts thereof, can be reacted with substituted or un-substituted oxiranes, such as ethylene oxide, or reactive esters of unsubstituted or correspondingly substituted aliphatic or arali~
phatic alcohols such as methanol, ethanol, methoxyethanol, phenoxy-ethanol, allyl alcohol, propargyl alcohol, e.g. such esteriEied by a strong inorganic or organic acicl, above all hydrohalic acids~ e.g.
hydrochloric, hydrobromic or hydriodic acid; sulfuric or an aromatic sulfonic acid, e.g. p-toluene or m-bromobenzene sulfonic acid, in order to obtain the corresponding N-substituted compounds or quaternaries respectively, depending on the molar amount of the alkylating agent employed. Intermediates of formula I wherein R3 i9 alkali metal or alkali metal derivatives of compounds of formula IV are obtained by metallation with reactive organometallic agents such as lithium diisopropylamide, with alkali metal alkoxides such as sodium methoxide, or alkali metal hydrides such as sodium or potassium hydride.

Unsaturated compounds, such as those with R3 being lower alkenyl, lower alkynyl may be hydrogenated with catalytically activated hydrogen to obtain compounds wherein R3 is the corresponding lower alkyl. Conversely, resulting N-alkylated compounds can be converted into N-unsubstituted compounds, e.g. by catalytic hydrogenolysis of N-benzyl compounds, or reaction of N-lower alkyl derivatives with lower alkyl haloformates, e.g. ethyl chloroformate, to yield N-acy:L
derivatives which, in turn, may be hydrolyzed to said unsubstituted compounds, those with R3 = H, for example with aqueous bases, such as alkali metal hydroxides, e.g. aqueous sodium hydroxide solutionO

Compounds of formula I wherein R3 is hydroxy lower alkyl can also be prepared by first reacting corresponding compounds of Formula I, wherein R3 represents hydrogen, with reactive derivatives of corres-ponding glycols, glycolic acids or dicarboxylic acids, such as lower alkyl esters, halides or anhydrides thereof, or reactive esters of said glycols or glycolic acid derivatives, for example with hydrohalic or aromatic sulfonic acids, 1,2-dibromoethane or -propane, ethyl bromoacetate or -propionate, ethyl tosyloxyacetate;
diethyl oxalate or malonate or ethyl oxalyl chloride. The inter-mediates so obtained are either hydrolyzed or reduced with simpleor complex light metal hydrides such as lithium alumlnium hydride, alone or with diborane to compounds of Eormula I wherein R3 is hydroxyalkyl.

Compounds of formula I wherein R3 is lower alkyl, e.g. methyl carl be prepared by reacting the corresponding compounds Oe Eormula I wherein R3 represents hydrogen with lower alkyl or phenyl lower alkyl halo-formates, such as ethyl chloroformate, to obtain compounds of for-mula I wherein R3 is lower alkoxycarbonyl or lower phenylalkyloxy-carbonyl, and reducing said acyl derivatives with simple or complex light metal hydrides such as lithium aluminium hydride~ sodium tri~
t-butoxy or sodium bis-(2-methoxyethoxy) aluminium 'hydride.

N-acylated derivatives of formula I wherein R3 is lower alkanoyl can preferably be obtained from compounds of Formula I with R3 being hydrogen and corresponding reactive carboxylic acid derivatives, e.g.~ halides, simple or activated esters, such as alkyl or cyano-alkyl esters, anhydrides or isocyanates. ~hese in turn can be re-duced as above to the compounds of formula I wherein R3 is lower alkyl. Compounds of formula I wherein R3 is hydroxy lower alkyl may be acylated as above to the compounds wherein R3 is lower alkanoyloxy lower alkyl.

Compounds of Formula I with Rl and/or R2 being hydrogen~ may be converted to the corresponding compounds with Rl and/or R2 being halogen or acyl, e.g. by halogenation, preferably with chlorine in acetic acid or under Friedel Crafts conditions ~y'acylation with a trihaloacetyl halide or a halosulfonic acid optionally followed by treatment with an alkali metal lower alkoxide, hydroxide or amide. Any resulting carboxylic or sulfonic acid derivatives may then be hydrolyzed in known fashion, preferably under alkaline conditions and/or amidi~ed with ammonia, mono- or di-lower alkyl~
amines; the resulting primary carbo~amides may in turn be dehydrated to th~ corresponding ni~riles according to conventional methods.
Compounds o~ ~he Eormula I in which Rl and/or R2 represents carboxy, can be preparecl, ior example, by hydro'lysis of compounds wherein R
cmd/or R2 represen~s cyano, lower alkoxycarbonyl or carbamoyl.

- 15 ~

Tertiary amines in which R3 differs from hydrogen and is e.g. lower alkyl or aryl lower alkyl, can be converted into the N-oxides, for example with hydrogen peroxide or organic peracids, such as lower peralkanoic or perbenzoic acids, e.g. peracetic or m-chloroperbenzoic acid, advantageously at temperatures at or below room temperature with the latter, or up to 100 with hydrogen peroxide in the pre-sence of lower alkanoic acids, e.g. acetic acid. If only a mono N-oxide is desired, care should be taken in order to prevent further oxidation.

Finally, the compounds of the invention are either obtained in the free form, or as a salt thereof. Any resulting base can be conver-ted into a corresponding acid addition salt, preferably with the use of acids which yield a pharmaceutically acceptable salt or with anion exchange preparation, or any resulting salt can be converted into ]~ the corresponding free base, for example, with the use of a stronger base, such as a metal or ammonium hydroxide or a basic salt, e.g.
an alkali metal hydroxide or carbonate, or a cation exchange preparation. Said acid addition salts are preferably such of pharmaceutically acceptable inorganic or organic acids described previously.

Compounds of formula I with Rl and/or R2 being carboxy can be con-verted into the corresponding metal or ammonium salts by e.g.
treatment with the alkaline or alkaline earth metal hydroxides or carbonates, ammonia or the amines listed previously.

These or other salts, for exmaple, the picrates, can also be used for purif;ca~ion of the bases obtained; the bases are conver~ed into salts, the sal~s are separated and the bases are liberated from ~he salts.

In view of the close relatiollship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

In case mixtures of geometrical or optical isomers of the above compounds, e.g. I to VII are obtained, these can be separated into the single isomers by methods in themselves known, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the antipodes, for example, by se-paration of diastereomeric salts thereof, e.g. by the fractionalcrystallization of the salts formed with d- or l-tartaric acid.

The above-mentioned reactions are carried out according to standard methods9 in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, preferably at the boiling point of the solvents used, at atmospheric or superatmospheric pressure.

The invention further includes any variant of the present process, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes. Mainly those starting materials should be used in said reactions, that lead to the formation of those compounds, indicated above as being especially valuable, e.g.
those of Formula II.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with exci-pients suitable for either enteral or parenteral application.
Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also c) binders, e.g.
magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinyl-pyrrolidone, if desired, d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures and/or e) absorbents, colorants9 flavors and sweeteners. Injectable compo-sitions are preferably aqueous isotonic solutions or suspensions,and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are pre-pared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%~ preferably about 1 to 50%, of the active ingredient. ~ unit dosage for a mammal of about 50 to 70 kg weight may contain between about 25 and 200 mg of the active ingredient~

The following Examples a) to e) are intended to illustrate ~ome typical forms of application, but in no way do they represent the only embodiments thereof. SpeciEic demonstrations are given in the ~xamples.

0~

a) 100.0 g of active substance are mixed with 610.0 g of lactose and 442.0 g of potato starch; the mixture is then moistened with an alcoholic solution of 8 g of gelatine, and is granulated through a sieve. The granulate is dried, and 60.0 g of talcum, 10.0 g of S magneisum stearate and 20.0 g of colloidal silicon dioxide are mixed in; and the mixture is subsequently pressed to form 10,000 tablets~ each weighing 125 mg and each containing 10 mg of active substance. The tablets can, if desired, be provided with grooves for a more precise adjustment of the dosage amount.

b) A grallulate is prepared from 100.0 g of active substance, 379 g of lactose and the alcoholic solution of 6.0 g of gelatine; after drying, the granulate is mixed with 10.0 g of colloidal silicon dioxide, 40.0 g of talcum, 60.0 g of potato starch and 5.0 g of magnesium stearate, and the mixture is pressed out to form 10,000 dragée cores. These are subsequently coated with a concentrated syrup prepared from 533.5 g of crystallised saccharose, 20.0 g of shellac, 75.0 g of gum arabic, 250.0 g of talcum, 20.0 g of colloidal silicon dioxide and 1.5 g of colouring agent, and finally dried. The dragees obtained each weigh 150 mg and each contain 10 mg of active substance.

c) 10.0 g of active substance and 1990 g of finely ground supposi tory foundation substance (for example cocoa butter) are thoroughly mixed and then melted. The melt is maintained homogeneous by fitirring whilst 1000 2.0 g suppositories each containing 25 mg oE active substance are being poured.

d) To prepare a syrup having a content oE active substance of 0.25%, there are disso~Lved in 3 litres of distilled water, 1.5 litres of glycerin, 42 g oE p-hydroxybenzoic ac-id methyl ester, 18 g of p-hydroxybenæoic acid-n-propyl ester ancl, with slight warming, 25.0 g of active substance; to this solution are then added 4 litres of 70% sorbitol solution, 1000 g of crystallised saccharose, 350 g of glucose and an aroma substance, for example 250 g of "Orange Peel Soluble Fluid", Eli Lilly and Co., Indianapolis, or 5 g of natural lemon aroma and 5 g of "half and half" essence, both from Haarmann and Reimer, Holzminden, Germany; the solution obtained is filtered, and the filtrate is subsequently made up with distilled water to 10 litres.

e) To prepare a drip solution containing 1.5% of active substance, 150.0 g of active substance and 30 g of sodium cyclamate are dissolved in a mixture of 4 litres of ethanol (96%) and 1 litre of propylene glycol. A mixture of 3.5 litres of 70% sorbitol solution and 1 litre of water is prepared separately and is then added to the above solution of active substance An aroma substance, for example 5 g of cough-sweet aroma or 30 g of grapefruit essence, both from Haarmann and Reimerg Holzminden, Germany, is added; the whole is well mixed, filtered, and made up with distilled water to 10 litres.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Tempera-tures are given in degrees Centigrade, and all parts wherever givenare parts by weight. If not mentioned otherwise, all evaporations are performed under reducecl pressure, preferably between about 15 and 100 mm Hg.

~xample 1: ~myl alcohol (5100 ml) and 913.35 g (9.17 moles) of N-nlethyl-.. . . ~.
piperaæine are charged into a 12 Liter 3-necked reaction Elask fitted with a Dean-Stark adapter. The solution is stirred under nitrogen atmosphere ancl 989 ~1 of lON ethanolic hydrogen chloride solution are added rapidly. The reaction mixture is heated to reflux and the distillate is collected in the Dean-Stark adapter. When the tempera-ture of the reaction mixture reaches 131 the Dean-Stark adapter is removed and an additional 918.35 g ~9.17 moles) of N-methylpiperazine followed by 1045.0 g (4.56 moles) of 5-methylthio-llH-imidazo[1,2-c]-[1,3]benzodiazepine are added. The mixture is heated at reflux under nitrogen atmosphere for 20 hours. Amyl alcohol is then removed under reduced pressure at a water bath temperature of 80. The viscous residual oil is dissolved in 10,000 ml of dichloromethane, washed with 3 x 4,000 ml of 4N sodium hydroxide and 6 x 4,000 ml of water.
The dichloromethane solution is then extracted with 3 x 2,000 ml of 6N hydrochloric acid. The aqueous solution is back washed with 2 x 2,000 ml of dichloromethane, treated with 100 g of activated carbon and filtered. The clear filtrate is adjusted to pH 9-10 with 1,500 ml of ammonium hydroxide solution ~29%). The oil which separates is extracted with 3 x 4,000 ml of dichloromethane, the extracts are dried over 1,000 g of sodium sulfate and the solvent removed at reduced pressure with a water bath temperature of 60. An oil is obtained which rapidly solidifies and after drying further (5 mm Hg/40) yields crude product, m.p. 113-120. The crude product is dissolved in 8,000 ml of hot ~60-70~) isopropanol. The solutiGn is decolorized with 200 g of activated carbon and filtered. To this solution is added a solution of 760.7 g (8.28 moles) of maleic acid in 2,500 ml of warm (30) isopropanol and the maleate salt begins to precipitate. The suspension is stirred overnight at ambient tempera--ture to complete crystallization and the solid is collected by fil~ration. The product is washed with 3 x 500 ml of cold iso-propanol and dried (0.5 mm/50). This i8 recrystallized from ethanol, the resulting product is washed first with ethanol and then with ether and then dried to give 5-(4-methyl-1-piperazinyl)-llh-imidazo[l,2-c~[1,3]benzodiazeplne monomaleate, m.p. 204-205 (decomposition).

A solution of 2,246 g of the above maleate salt in 9000 ml of water is treated with 100 g of activated carbon and filtered. The aqueous solution is adjusted to pH 9 with 1000 ml of 29% ammonium hydroxide and the free base separated as an oil. The oil is extracted with 5 3 x 2000 ml of dichloromethane, the extract is dried over sodium sulfate, filtered and the solvent is removed under reduced pressure at a water bath temperature of 40. The solid obtained is recrystal-lized from 14,130 ml of heptane. The light yellow solid is collected and washed with 2 x 500 ml of heptane and dried (0.01 mm/50) to 10 give 5-(4-methyl-1-pipera~inyl)-llH-imidazo[1,2-c][1,3]benzodiazepine, m.p. 123-4.

The starting material is prepared as follows: Absolute ethanol (24,000 ml) and 3,240 g (60.0 moles) of sodium methoxide are charged into a 70 litre reaction flask. The solution is stirred under 15 nitrogen while a solution of 8228.4 g (60.0 moles) of o-nitrotoluene and 8768.4 g (60.0 moles) of diethyl oxalate is added all at once.
The resulting solution is heated at reflux ~or 25 minutes, cooled to 60 with an ice-bath and 18,000 ml of water are cautiously added. Heat is then applied and the mixture is held at the reflux 20 temperature for 1 hour. Most of the ethanol is then removed. The turbid solution is cooled at 50 and a solution of 4,140 g (59.6 moles) of hydroxylamine hydrochloride in 6,000 ml of water is added all at once.The temperature is maintained at 50, the pH is adjusted to 7.0 with 6,000 ml of 10 N sodium hydroxide solution 25 and the reaction mixture stirred overnight at ambient temperature~
The suspension is cooled to 10 and the pH is ad~justed to 1.0 wlth 6,000 ml of 12 N hydrochlorid acid. The stirring is contin~led over-night at 10 to complete the liberation of the Eree acid. The solid is collected, washed wi~h 6 x 4,000 ml of water, air dried overnight and suspellded in 20,000 ml of toluene. The suspension is stirred for 1 hour under nitrogen atmosphere. The product is collected, washed with 4 x 2,000 ml of toluene followed by 4 x 2,000 ml of petroleum ether and dried (5 mm llg/60) to give 2-nitrophenylpyruvic acid oxime, m.p. 158-60 (decomposition).

Water (50,000 ml), 2,940 ml of glacial acetic acid and (22.22 moles) of 2-nitrophenylpyruvic acid oxime are charged into a 70 litre reactor. The stirred suspension is heated over two hours under nitrogen atmosphere to 90 and this temperature is maintained for 2 hours. The dark solution is allowed to cool slowly and is stirred overnight at ambient temperature. The suspension is extracted with 5 x 4,000 ml of methylene chloride, washed with 3 x 3,000 ml of water, dried over magneisum sulfate and filtered. The filtrate is treated with activated carbon, filtered and the solvent is removed under reduced pressure. The solid residue is recrystallized from 1,000 ml of isopropanol to give 2-nitrophenylacetonitrile, m.p.
~2-84~

Absolute ethanol (2,250 ml) and 1,500 g (9.25 moles) of o-nitro-phenylacetonitrile are charged into a 22 liter flask. The suspension is cooled to 5-10 and hydrogen chloride is bubbled into the mixture for 2.5 hours. The reaction mixture is stirred at 10 under nitrogen atmosphere overnight. It is then diluted with 16,000 ml of ether and stirred for 1 hour; the solid is collected by filtration, washed with 4 x 1,000 ml of ether, dried (5 mm Hg/40), to give ethyl 2-(2-nitrophenyl)acetimidate hydrochloride, m.p. 122-123 (de-composition).

Ethanol (2,200 ml) and 5,15~ g (8.81 moLes) oE ethyl 2-(2~nitro-phenyl)acetimida~e hydrochloride are charged into a 22 liter Elask.
The suspension is stirrecl under nitrogen ac room temperature and 1022.9 g (9.73 moles) of aminoacetaldehyde dimethylacetal are added all at once. The mixtllre is stirred for 1 hour and 1,693 ml of 12N hydrochloric acid are added all at cnce to cause a gentle exotherm reaction (to 40). Heat is then applied and the temperature is maintained at 70-80 for 30 minutes. The solution is cooled to 20 (ice-water bath) and diluted with 2,700 ml of lON sodium hydroxide solution to precipitate the product. The suspension is stirred at 10 for 1 hour under nitrogen atmosphere, the solid collected by filtration and washed with 3 x 2,000 ml of water to give 2-(2-n;tro-benzyl)-imidazole, m.p. 155-157.

50% Aqueous ethanol (5,672 ml) and 2,890 g (1~.22 moles) of 2-(2-nitrobenzyl)-imidazole are charged into a 22 liter flask. The sus-pension is stirred under nitrogen atmosphere and 2,400 g (42.97 moles) of iron powder (100 mesh) are added all at once. The mixture is then warmed to 70 and a solution of 1~7 ml of 12N hydrochloric acid in 8.3 ml absolute ethanol are added. ~ vigorous exotherm reaction lS results and a strong reflux occurrs that persists for 1.5 hoursO
When the exotherm reaction subsides, a mixture of 290 ml of 12N HCl and 1400 ml of absolute ethanol are added over 30 minutes. Heat is applied and the mixture is refluxed for 2 hours, diluted with 6,500 ml of absolute ethanol and adjusted to pH 8-9 with 700 ml of lON sodium hydroxide. The suspension is stirred for 1 hour and filtered. The cake is washed with 1,000 ml of absolute ethanol, the filtrates are combined and the solvent is removed. The remaining solid is then suspended in 10,000 ml of water, stirred under nitrogen atmosphere for two hours, collected, washed with 2,000 ml of water, and dried to yield 2-(2-aminobenzyl)-imidazole, m.p. 153-155o Di.chloromethane (42,000 ml) and 5,120 g (50,65 moles) of triethyL-amine are charged into a 70 litre Elask. The solution is stirred under nitrogen atmosphere and 4,370 g (25.23 moles) of 2-(2-aminobenzyl)-imidazole are aclded. The suspension is cooled to 0-5 and 3,~21 g (29.75 moles) of 85% thiophosgene in carbon tetrachloride are added over 3 hours, during which time the reaction temperature rises slowly - 2~ -to 15D. The suspension is then stirred at 10 for 4 hours and at ambient temperature overnight. The precipitated product is collectedg washed with 2 x 3000 ml of dichloromethane and 5 x 4000 ml of water, and dried (5 mm llg/60) to give llH-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-thione, m.p. 182-183.

Absolute ethanol (20,000 ml) is charged into a 70 litre flask and stirred under nitrogen atmosphere; 517,62 g (9.58 moles) of sodium methoxide are added. ~fter stirring for 30 minutes there is complete solution and 2,063 g (~.58 moles) of llH-imidazo[1,2-c]El,3]benzo-diazepine-5(6H)-thione are added. There is complete solution after stirring at room temperature for 1 hour. The solution is then cooled to 1, and 1.360 g (9.58 moles) of methyl iodide are added over 30 minutes. The reaction mixture is stirred at 5 for 4 hours and at ambient temperature overnight. The turbid solution is then cooled to 5 and diluted with 50,000 ml of water. The resulting suspension is stirred for 4 hours at 5. The solid is collected, and dried (5 mm Hg/60) to give 5-methylthio-llH-imidazo[1,2-c][1,3]benzodiazepine, m.p. 87-88.

Similarly prepared from 4-chloro~2-nitrophenyl-acetonitrile is 8-chloro-llH-imidazorl,2-c]El,3]benzodiazepine-5(6H)-thione, m.p.
200-201 and 8-chloro-5-methylthio-llH-imidazo[1,2-c][1,3]benzo-diazepine hydrochloride, m.p. 255-257.

The following starting materials are similarly prepared Erom the correspondingly su~stituted 2-nitrophenylacetonitriles:
a) 8-methyl-5-methyl~hio-llH-imidQzoEl,2-c]~1,3]-benæQdiazepine;
~) 8-Eluoro-5-methylthio-llH-imidazoEl,2-c][1,3]-benzodiazepine;
c) 8-methoxy-5-methylthio~ 1-;midazQEl,2-c][1,3]benzodiQzepine.

~:~L8`~

~xample 2: To a suspension of 2.46 g of 1-[2-(2-imidazolylmethyl)-phenylcarbamoyl]-4-methylhomopiperazine in l9.4 ml of phosphorus oxychloride is added at once 1.66 g of phosphorous pentachloride and the mixture is stirred at room temperature for 4 hours. The mixture is evaporated to dryness, the residue is suspended in 45.2 ml of methylene chloride, the suspension is cooled to 0 and 21.4 ml of triethylamine are added dropwise with stirring over a period of 15 minutes. The mixture is allowed to warm up to room temperature, stirred for 1.5 hours and poured into 10% aqueous potassium carbonate.
The methylene chloride layer is separated, the aqueous layer is washed with methylene chloride and the combined methylene chloride extracts are dried over magnesium sulfate, decolorized with charcoal and evaporated to dryness. The residue is purified by column chromato-graphy with 50 g of silica gel, using methylene chloride-methanol-conc. ammonium hydroxide (300:50:1) as eluent to give 5-(4-methyl-1-homopiperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine as an oil.
This free base is dissolved in acetone and treated with maleic acid to give 5-(4-methyl-1-homopiperazinyl)-llH-imidazo[1,2-c][1,3]benzo-diazepine monomaleate, m.p. 160-163.

5-(4-Methyl-l-piperazinyl)-llH-imidazo[1,2-c][1,3]-benzodiazepine monomaleate of example 1 is similarly prepared from 1-[2-(2-imidazolyl-methyl)phenylcarbamoyl]-4-methyl-piperazine.

The starting materials are prepared as follows:
A solution of 32.4 g of phenyl chloroformate in 100 ml of aceto-nitrile is added dropwise under nitrogen while stirring to a mixture oE 34.6 g oE 2-(2-aminobenzyl)-imidazole ancl 71 g of triethylamine in 600 ml of acetonitrile A~ room temperature. After addition is com-ulete, the reac~ion mixture is heated under reflux for 12 hours, and allowed to cool to room temperature. Water (150 ml) is added, the mixture is stirred at roo-m temperature for 0.5 hour and cooted to 5. The resulting precipitate is filtered off, washed first twice with 50 ml of water, then 3 times with 33 ml of cold acetone and dried to give llH-imidazo[1,2-c][1,3]benzodiazepin-5(6H)-one, m.p. 255-257.

Alternately, 0.75 g of l,l'-carbonyldiimidazole is added at once to a suspension of 0.79 g of 2-(2-aminobenzyl)-imidazole in 38 ml of methylene chloride and the mixture is stirred at room temperature overnight. The resulting precipitate is collected and recrystallized from methylene chloride to give the crude llH-imidazo[1,2-c][1,3]
benzodiazepin-5(6H)-one, m.p. 238-240.

In analogous fashion, or by using phosgene as the reagent for cyclization, the following intermediates are obtained.
a) 2,3-dimethyl-11l1-imidazo[1,2-c][1,3]benzodiazepin-5-(6H)-one;
b) 8-chloro-llH-imidazo[1,2-c][1,3]benzodiazepin-5(6H)-one;
c) 8-methyl-llH-imidazo[1,2-c][1,3]benzodiazepin-5-(6H)-one;
d) 8-methoxy-llH-imidazo[1,2-c][1,3]benzodiazepine-5 (6H)-one.

To a suspension of 0.76 g of llH-imidazo[1,2-c][1,3]benzodiazepin-5-(6H)-one in 9 ml oE methylene chloride is added at once 0.41 g of N-methylhomopiperazine and the mixture is stirred at room temperature for 2~ hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. Recrystallization of the residue from methylene chloride-ether gives 1-[2-(2-imidazolyl-methyl)-phenylcarbamoyl]-4-methylhomopiperazine, melting at 139-1~3.

Similarly prepared from ~-methylpiperazine is 1-[2-(2-imidazolyl metllyl)-phellylcRrbamoyl~ methylpiperazine, rn.p. 172-17~.

'rhe follo~ing compounds are prepared ac.cording to the above proce-dures:
a) '1-[2-(~,S~dimethyl-2-imidazoly'l.methyl)-pllenylcarbamoy'L]-~-me~hyl-piperaæine; and b) l-[2-(2-imidazolylmethyl) 5-chlorophenylcarbamoyl]-~ methyl-piperazine.

Example 3: A solution of 2.~i g of 5-cyanomercapto-llH-imidazo~1,2-c]--[1,3]benzodiazepine in 5 ml of hexamethylphosphoramide is cooled to ~5 and 2.1 g of N-methylpiperazine is added dropwise with efficient mechanical stirring and under nitrogen, over a period of 5 minutes.
Stirring is continued for 10 minutes at -5 and another 10 minutes after removal of the cooling bath. The mixture is diluted with 100 ml of ethyl acetate and the solution washed twice with brine, dried over magnesium sulfate, and evaporated to dryness. To the residue, a solution of 1.2 g of maleic acid in 3 ml acetone is added and the mixture is diluted with ether. The crude product crystallized, m.p.
183-186, and is recrystallized to give the 5-(4-methyl-1-piperaziny~-llH-imidaæo[1,2-c][1,3]benzodiazepine monomaleate of example lo It melts at 204-205 (decomposition)~

The starting material is prepared as follows:
l$ Sodium hydride (50~ in mineral oil9 1.44 g,) is washed with dry ether and suspended in 100 ml of dry tetrahydrofuran7 6c45 g of llH-imidazo[l~c]~1,3]benzodiazepine-5(6H)-thione is added in por-tions to the suspension of sodium hydride, with stirring and under nitrogen7 over a period of 2 minutes. The mixture is stirred at room temperature for 1.5 hours. The white suspension, which was formed by the end of this time, is cooled to 0 and 3.5 g of cyanogen bromide dissolved in 10 ml of dry tetrahydrofuran is added dropwiese. The mixture is stirred at room temperature for 0.5 hour and evaporated under reduced pressure at 45. The residue is dissolved in methylene chloride, the solution is washed with water, dried over ma~lesi-lm sulfate, decolorized with charcoal, and evclporated to a small volume. 5-Cyanomercapto-llll-imidazo[1,2-c]-~1,3]benzodiazepine~ m.p. 111-113, crystallized on dilution with ether.

Example 4: To a solution oE 8.9 g of 1-~2-(2-imidazolylmethyl)-phenylthiocarbamoyl]-4-ethoxycarbonylpiperazine in 70 ml of aceto-nitrile, cooled to 0, is added 2.4 g of solid potassium carbonate while stirring, followed by dropwise addition of a solution of 2.5 g of cyanogen bromide in 10 ml of acetonitrile; the mixture is allowed to warm up to room temperature overnight. The solids are filtered off, washed with ethyl acetate, and the filtrate is evaporated to dryness. The residue is dissolved in methylene chloride, the solution is washed with water, dried over magnesium sulfate, decolorized with charcoal and evaporated to dryness. The residue is chromatographed with 250 g of silica gel using ethyl acetate-methanol (9:1) as eluant to give 5-(4-ethoxycarbonyl-1-piperazinyl)-llH-imidazo[1,2-c][1,3]-benzodiazepine, m.p. 137-139.

The starting material is prepared as follows- A solution of 20 g of l-ethoxycarbonylpiperazine in 400 ml dry tetrahydrofuran is cooled to -65 and 6105 ml of 2.1M solution of n-butyllithium in hexane is added dropwise over a period of 15 minutes. The mixture is stirred for 15 minutes and a solution of 16.44 ml of chlorotrimethyl-silane in 68 ml of tetrahydrofuran is added dropwise over a period of 15 minutes. The mixture is then allowed to warm up to room tem-perature overnight and evaporated to dryness. Ethyl ether is added, the solids are filtered off9 the filtrate is evaporated to dryness and the residue is distilled to give l-ethoxycarbonyl-4-trimethyl-silylpiperazine, b.p. 102-107/0.1 mm Hg.

To a solution of 4.66 ml of 85% thiophosgene in 200 ml of ethyl ether, cooled ~o -/6~ is aclded7 while stirring and under nitrogen, a solu~-on of 7 g of 1-ethoxycarbonyl-4-trimethylsilylpiper~æine in 35 ml of ethyl ether over a period oE 20 minutes. The mixture i9 allowed to warm up to room temperature overnight. The suspension is ~a~8~

filtered and the filtrate is evaporated to dryness. The residue is crystallized from methylene chloride-hexane to give ~-ethoxycarbonyl-l-piperazinyl-thiocarbonyl chloride, m.p. 107~111.

To a suspension of 3.8 g of 2-(2-aminobenzyl)-imidazole in 38 ml of tetrahydrofuran and 3.23 ml of triethylamine is added dropwise a solution of 5.5 g 4-ethoxycarbonyl-1-piperazinyl-thiocarbony]
chloride in 10 ml of methylene chloride at room temperature. The mixture is stirred for 1 week and the suspension filtered. The filtrate is washed with first 10% aqueous potassium carbonate, then with water, dried and evaporated to dryness to give amorphous 1-~2~
(2-imidazolylmethyl)-phenylthiocarbamoyl]-4-ethoxycarbonylpiperazine, characterized by NMR.

Example 5: According to the methods illustrated by the previous .
examples, the following compounds of formula I, especially II wherein Rl and R2 represent hydrogen, and C H2 represents 1,2-ethylen were obtained from equivalent amounts of the corresponding starting materials.

No. R3 R4 Salt m.p.
1 CH2CH20H H __ 143-4 20 2 CH2CH20H Cl HCl 225 (decompo-sitlon)

3 CH3 Cl 2HC1 226-8 tdec.)

4 CH3 H 2HC1 ~250 (dec.) CH3 H HCl 217-220.

Example 6: The mixture oE 315 mg of 1-~2-(2 imidazolylmethyl)phenyl-thiocarhamoyl~-4-metllylpiperazineJ 3.3 ml of dimethylformamide, 276 mg of potassium carbonate, 116 mg of cyanogen bromide and 50 mg of 8-crown-6 ether is stirred at room temperature under nitrogen for 3 hours. It is diluted with ethyl acetate~ washed with saturated aqueous sodium chloride, dried and evaporated. The residue is dis-solved in acetone, the solution treated with 116 mg of maleic acid and diluted with diethyl ether, to yield 5-(4-methyl-1-piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine monomaleate. The product is identical with that of Example 1.

The starting material is prepared as follows:
The mixture of 2.1 g of llH-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-thione, 23 ml of methylene chloride and 1.0 g of l-methylpiperazine is stirred at room temperature for 15 hours. The crystalline product formed is filtered off and washed with methylene chlorideS to yield 1-[2-(2-imidazolylmethyl)-phenylthiocarbamoyl]-4-methylpiperazine~

Example 7: A mixture of 9.5 g of 5-methylthio-llH-imidazo[1,2-c~[1,3]--benzodiazepine hydrochloride, 3.~2 g of piperazine, and 350 ml of amyl alcohol is refluxed with stirring and under nitrogen for 20 hours. The solvent is evaporated under vacuum, the residue is triturated with methylene chloride, washed with 2N sodium hydroxide solution, dried over magnesium sulfate, and evaporated to dryness.
The residue is dissolved in 10 ml of methanol and treated with 2N
ethereal hydrochloric acid solution to give 5-(4H-l-piperazinyl)-llH-imidazo[l~2-c][1,3]benzodiazepine dihydrochloride.

Examples 8: To a solution of 0.2 g of 5-(4-carboethoxy-1-piperazinyl-llH-imidazo[1,2-c][1,3]benzodiazepine in 2 ml of dry tetrahydrofuran, 100 mg of lithium aluminium hydride are added at once and the mixture is ref]uxed under nitrogen for ~8 hours. The mixtllre is cooled to room temperature, stirred with 0.2 ml of 30% aqueous sodium hydroxide, and filtered. The fi.ltrates are evaporated to dryness and the product is purified to give 5-(4~methyl-1-piperazinyl]-llH-imidazo[1,2 c][1,3]benzodiazepine, which is identical wi~h the procluct of example 1. It melts at 123-124.

~8~

Example 9: To a solution of 82 mg of 5-~4-methyl-1-piperazinyl)-llH-imidazo[l,2-c][1,3]benzodiazepine in 1 ml of methylene chloride, 74 mg of m-chloroperbenzoic acid are added at 0. The mixture is stirred at 0 overnight; this is diluted with 1 ml of ether, one equivalent of

5 ethereal hydrochloric acid solution is added and the resulting precipitate is collected. Recrystallization gives 5-(4-methyl-4-oxi-lo-l-piperazinyl-llH-imidazo[1,2-c][1,3]benzodiazepine hydrochloride.

Example 10: To a solution of 100 mg of 5-(4-benzyloxycarbonyl-1-piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine in 0.3 ml of 10 acetic acid are added 0.35 ml of a 2N solution of hydrobromic acid in acetic acid. The mixture is heated at 100 for 1 hour and stirred at room temperature overnight. Ether is added, and the 5-~4H-l-piperazin-yl)-llH-imidazol192-c][1,3]benzodiazepine hydrobromide precipitatesO

The starting material is prepared similarly to starting material of 15 exm~ple 4 by replacing l-ethoxycarbonylpiperazine with the equivalent amount of l-benzyloxycarbonylpiperazineO

Example 11: A mixture of 265 mg of 5-~4H-l-piperazinyl)-llH-imidazo--[1,2-c][1,3]benzodiazepine 0.5 g of potassium carbonate, 0.142 g of methyl iodide and 2 ml of acetone is stirred at room temperature over-20 night and evaporated. Water is added to the residue, and the mixtureis extracted with methylene chloride. The extracts are dried over magnesium sulfate, evaporated, and the residue is purified to give 5-(4-methyl-l-piperazinyl)-llH-imidazo[192-c][1,3]benzodiazepineO

~xample L2: The following compounds of formula I (R -R =~1) are n______ _ 5 7 25 prepared according to the methods illustrated by the previous examples and are obtained from equivalent amounts oP the corresponding substi-tuted starting materials.

No. Rl R2 R3 R4 n 2n 1 CH3 H CH3 H (CH2)2 2 CH3 CH3 C113 H (CH2)2 3 H H C~13 8-CF3 (CH2)2 5 4 ll H CH3 8-F (CH2)2 H H CH3 8-OCH3 (CH2)2

6 H H CH3 8~0H (CH2)2

7 H H CH30CH2CH2 H (CH2)2 3 H H CH3COOCH2CH2 H (CH2)2 10 9 H H CH3 8-CH3 (CH2)2 Examples 13: Preparation of 10,000 tablets each containing 25 mg of the active ingredient:

Formula:
5-(4-methyl-1-piperazinyl)-llH-imidazo[1,2-c][1,3]-15 benzodiazepine 250.00 g Lactose 957 0O g Corn Starch 75.00 g Polyethylene glycol 6,000 75 00 g Talcum powder 75.00 g 20 Magnesium stearate 18.00 g Purified water q.s.

Procedure: All the powders are passes through a screen with openings . _ of 0 6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half o~ the starch are mixed in a suitable mixer. Tile other half of the starch is suspended in 40 ml of water and the sus-pension added to the boi-Ling solution of polyethylene glycol in 150 ml water. The paste formed is added to the powders which are granlllated, if necessary, with an additional amount of water. The granulate is dried overnight at 35, broken on Q screen with 1.2 mm openings and compressed into tablets using concave punches with 6.4 mm diameter, uppers bisected.

_ 33 -Example 14: Preparation of lO,000 capsules each containing 50 mg of the active ingredient:

Eormula:
5-(4-methyl-1-piperazinyl)-llH-imidazo[1,2-c][1,3]- 500.0 g 5 benzodiazepine monomaleate Lactose 1,400.0 g Talcum powder lOOoG g Procedure: All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer 10 and mixed first with the talcum, then with the lactose until homogenous. No. 34 capsules are filled with 200 mg, using a capsule filling machine, Analogously tablets or capsules are prepared from the remaining compounds of the invention, e.g. those illustrated by the other 15 examples herein.

Example 15: A mixture of 10 g of 1-[2-(4-methyl-2-imidazolylmethyl)-phenylcarbamoyl]-4-methylpipera~ine, 86 ml of phosphorous oxychloride and 7.24 g of phosphorous pentachloride is stirred at room temperature for 4 hours and evaporated to dryness. The residue is suspended in 20 186 ml of methylene chloride and 55.2 ml of triethylamine is added dropwise at 0 over a period of 15 minutes. The mixture is stirred at room temperature overnight, poured into cold water, basified with 10% aqueous potassium carbonate and extracted with methylene chloricle.
Tlle methylene chloride extracts are re-extracted with 2N aqueous 25 hydrochloric acid. The acidic extracts are basified with 2N aqueous sndium hydroxide and extracted three times with methylene chloride.
The organic extracts are clried over magnesium sulfate~ decolorized with charcoal and evaporated to dryness. The residue is chromato-~80~

graphed from 180 g of silica gel using methylene chloride-methanol-ammonium hydroxide (300:50:1) as eluant to give a foamy material which is dissolved in acetone and treated with an equivalent amount of maleic acid to give on dilution with ether the 2-methyl-5-~4-methyl-1-piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine mono-maleate, m.p. 195-197.

The starting material is prepared as follows: A solution of ethanolic sodium ethoxide, prepared by desolving 4.48 g of sodium metal in 112 ml of absolute ethanol, is added dropwise to a suspension of 47.84 g of ethyl 2-(2-nitrophenyl)-acetimidate hydrochloride in 224 ml of ethanol and the mixture is stirred at room temperature for one hourc The sodium chloride formed is filtered, 22.82 g of the ethylene ketal of l-amino-2-propane is added to the filtrates and the mixture is stirred at room temperature overnight. The insoluble material is filtered off and the filtrates are evaporated to dryness. The residue is dissolved in 470 ml of concentrated hydrochlorid acid and the solution is re-fluxed for 1 hour. The mixture is washed once with ether, basified with 2N sodium hydroxide and extracted three times with ethyl acetate.
The extracts are dried over magnesium sulfate, decolorized with charcoal and evaporated. The residue is crystallized from methylene chloride-ether to give 4-methyl-2~(2-nitrobenzyl)-imidazole, m.p.
125-128.

A mixture of 23044 g of 4-methyl-2-(2-nitrobenzyl)-imidazole, 2.34 g of 10% pallaclium on charcoal and 234 ml of ethanol is hydrogenated at ~2 psi (3 atmospheres) at room temperature for 4 hours. The catalyst is f;ltered ancl the filtrates are evaporated to dryness to give 4-methyl-2-t2-aminobenzyl)-imidadole showing signals in the NMR spectrum at ~ 2.09, 3.78, 6,08.

A mixture of 18.61 of ~-methyl-2-(2 aminobenzyl)-imidazole, 16.12 g of l,l~-carbonyldiimidaæole and 375 ml of methylene chloride is stirred at room temperature overnight. The mathylene chloride is evaporated to a small volume, the mixture is cooled to 0 and the solids are filtered and washed with ether to give ~-methyl-llH-imidazo[1,2 c]~l,3]benzodi-azepine-5(6H)-one, m.p. 23~.5-236.5.
A mixture of 16 g of 2-methyl-llH-imidazo[1,2-c][1,3]benzodiazepine-5-(6H)-one, 9.58 g of N-methylpiperazine and 160 ml of methylene chloride is stirred at room temperature overnight. The mixture is decolorized with charcoal and evaporated to dryness. The residue is crystallized from methanol-ether to give l-[2-(4-methyl-2-imidazolylmethyl)-phenylcarbamoyl]-4-methylpiperazine, m.p.
]77-179.
Example 16: To a solution of 5 g of 5-~4-methyl-1-piperazinyl)-llH-imidazo[l,2-c][1,3]benzodiazepine in 50 ml of methylene chloride is added in portions 3.75 g of m-chloroperbenzoic acid with stirring at 0. The mixture is then stirred at room temperature overnight and evaporated to dryness. The foamy residue is passed through 100 g of Amberlite IRA-400* ion exchange resin using water as eluent. Evaporation of the eluent gives 5-(4-methyl-4-oxido-1-pipera--zinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine as foamy material having Rf = 0.173 on silica gel plates using methylene chloride-methanol-ammonium hydroxide (150:50:1) as eluent, which is identicaL with product obtained in Example 9.
Example 17: A mixture of 8.67 g of 5-methylthio-11~ idazo[1,2-c~-~1~3]benzodiazepine,-3.38 g of piperazine and 326 ml of amyl alcohol is refluxed under nitrogen for 6 days and evaporated to dryness under reduced pressure.
The residue is dissolved in methylene chloride and the solution is washed succossively with 10% aclueous potassium carbonate and brine, driocl over magnesium sul~ate~ decolorized with charcoal cmd evaporated. T1le residue is chromatographed with 300 g o~ silica gel using methylene chloride-methanol-ammonium hydroxicle (150:50:1~ as eluent to give S-~ L-piperazinyl)-ll~l-imidazo[1,2-c][1,3]benzncli-azepine as an oil. The oil is trcatccl with 2.74 g o~ maleic acid in acetone to give 5-(~ll-1-piperazinyl)-ll~l-imidazo[1,2-c~-*Trade Mark O~

[1,3]benzodiazepine bis-maleate, m.p. 171.5-173.5.

Example 18: A mixture of 0.2 g of 5-(4-ethoxycarbonyl-1-piperazinyl)-. ... . , . _ _ llH-imidazo[1,2-c]~1,`3]-benzodiazepine, 10 ml of tetrahydrofuran and 50 mg of lithium aluminium hydride is refluxed overnight with 5 stirring. The mixture i9 cooled to 0, and the excess of the lithium aluminium hydride is destroyed with ethyl acetate, and the mixture s then poured into cold water and extracted with ethyl acetate. The extracts are dried and evaporated to give after purification 5-(4-methyl-l-piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine of 10 example lo Example 19o A mixture of 0.1 g of 5-(4H-l-piperazinyl)-llH-imidazo ~ .
~192-c][1,3]benzodiazepine, 0.058 g of methyl iodide, 0016 g of potassium carbonate and 1 ml of dimethylformamide is stirred at room temperature overnight. The mixture is poured into water and 15 extracted three times with ethyl acetate. The extracts are washed with brine, dried and evaporated to give 5-(4-methyl~l-piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine of example 1.

Sidman aroidance data in the rat -In teh test-procedure described above a selection of the new compounds 20 gives the following data . . . _. .
Compound of Dose n Number of Avoidance Failures mg/kg (difference from vehicle) example ~ _ _ __ __ p.o. 30 min 90 min 210 min . . _, I ~ .. __ . ..
1 10 6 ~31 ~13 +14 1 30 6 ~44 +49 -~40 255/2 30 3 ~22 +1~ + 8 S/3 10 3 ~ +14 _ ~ _ _ n ~ number oE rats A decrease in the avoidance response is indica~ive of neuroleptic activity and is characterized by an increase in the number of avoidance 30 failures.

Claims (10)

Claims

1. Process for the manufacture of 5-diazacycloalkyl-imidazo[1,2-c]-[1,3]benzodiazepines of formula I

(I) wherein each of the symbols Rl and R2 is hydrogen, lower alkyl, lower alkanoyl, halogen, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, sulfamoyl, mono- or di-lower alkyl-(carbamoyl or sulfamoyl); CnH2n is lower alkylene separating both nitrogen atoms by 2 or 3 carbon atoms; R3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, aryl lower alkyl, lower alkoxycarbonyl, phenyl lower alkoxycarbonyl or (hydroxy, lower alkanoyloxy, aryloxy or lower alkoxy) lower alkyl having at least two carbon atoms; R4 and R5 in-dependently represent hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, trifluoromethyl, hydroxy, lower alkanoyloxy, sulfamoyl, mono- or di-lower alkylsulfamoyl; and R6 and R7 represent hydrogen or lower alkyl; the N-oxides, lower alkyl quaternary derivatives, and salts thereof, which consists in a) condensing a compound of formula III

(III) wherein X is a group detachable together with hydrogen or an alkali metal and the remaining symbols have meaning as defined for formula I; with a compound of formula IV

(IV) or an alkali metal derivative thereof wherein R3 has meaning as defined for formula I; or b) cyclizing a compound of formula VI

(VI) wherein Z is oxygen, sulfur, or NH, and the other symbols have the above-given meaning, under dehydrating, dehydrosulfurating or deamination conditions, and/or 1) if a compound of the formula I is required in which R3 is lower alkyl, introducing such a radical into a compound of the formula I
in which R3 is hydrogen or an alkali metal atom, and/or, 2) if a compound is required in which R3 is lower alkyl, reducing in a compound having a lower alkenyl or lower alkynyl group instead of a lower alkyl group, and/or, 3) if a compound is required in which R3 is hydroxy-lower alkyl, reacting a compound in which R3 is hydrogen or an alkali metal atom with a corresponding oxirane or with a reactive ester of a mono-esterified lower alkanediol, and/or, 4) if a compound is required in which R3 is hydroxy-lower alkyl, reacting a compound in which R3 is hydrogen with a reactive deriva-tive of a corresponding glycol, glycolic acid or a dicarboxylic acid and hydrolyzing or reducing the compound so obtained to a product in which R3 is hydroxy-lower alkyl, and/or, 5) if a compound is required in which R3 is lower alkoxycarbonyl, converting in a product in which R3 is lower alkyl into a lower alkoxycarbonyl group, and/or, 6) if a compound is required in which R3 is an acyl radical named above, acylating a product in which R3 is hydrogen, and/or, 7) if a compound is required in which R3 represents hydrogen, hydro-lyzing a compound in which R3 is an acyl radical, and/or, 8) if a compound is required in which R3 represents methyl, reducing in a product in which R3 is lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl to obtain a compound in which R3 is methyl, and/or, 9) if a compound is required in which R1 and/or R2 is halogen, halo-genating a product in which R1 and/or R2 is hydrogen, and/or, 10) if a compound is required in which R1 and/or R2 is carboxy, lower alkoxycarbonyl or a carbamoyl residue named above, reacting a compound in which R1 and/or R2 is hydrogen, with a trihaloacetyl halide and treating the compound obtainecl with an alkali metal lower alkoxide, alkali metal hydroxide or alkali metal amide, and/or, 11) if a compound is required in which R1 and/or R2 is sulfamoyl, mono- or di-lower alkylsulfamoyl, reacting a product in which R1 and/
or R2 is hydrogen with a halosulfonic acid and treating the compound obtained with ammonia, a mono- or di-lower alkylamino, and/or, l2) if a compound is required in which Rl and/or R2 is cyano, dehydrating a product in which Rl and/or R2 is carbamoyl, and/or, 13) if a compound is required in which Rl and/or R2 is carboxy, hydro-lyzing a product in which Rl and/or R2 is cyano, lower alkoxycarbonyl or carbamoyl, and/or, 14) if an N-oxide is required, oxidizing a product in which R3 is different from hydrogen, and/or, 15) if a lower alkyl quaternary derivative is required, reacting a product in which R3 is different from hydrogen or represents hydrogen, with a reactive esterified lower alkanol, and/or, 16) if required, converting a resulting compound of formula I into another compound of the invention, and/or, if required, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt, and/or, if required, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if required, resolving a racemate obtained into the optical antipodes.

2. Process according to claim l, wherein there are prepared compounds of formula I shown in claim l, wherein each of Rl and R2 is hydrogen, lower alkyl, cyano, carboxy, lower alkoxycarbonyl or carbamoyl;
n represents the integer 2 to 4; R3 is hydrogen, lower alkyl, lower alkoxycarbonyl, or hydroxy lower alkyl of 2 to 4 carbon atoms;
R4 represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl; R5 represents hydrogen; and R6 and R7 represent hydrogen or lower alkyl; the N-oxides; lower alkyl quaternary salts; and salts thereof.

3. Process according to claim 1, wherein there are prepared compounds of formula I shown in claim 1, wherein each of Rl and R2 is hydrogen, methyl, ethyl, cyano, carboxy, alkoxycarbonyl of 1 to 3 carbon atoms in the alkoxy portion or carbamoyl; n re-presents the integer 2 or 3; R3 is hydrogen, alkyl of 1 to 3 carbon atoms, alkoxycarbonyl of 1 to 3 carbon atoms in the alkoxy portion, hydroxyethyl or hydroxypropyl; R4 represents hydrogen, methyl, methoxy, methylthio, chloro or trifluoromethyl; R5 represents hydro-gen; R6 and R7 represent hydrogen or methyl; the N-oxides; methyl quaternary salts; and salts thereof.

4. Process according to claim 1, wherein there are prepared compounds of formula II

(II) wherein Rl and R2 independently represent hydrogen or lower alkyl;
R3 represents hydrogen, lower alkyl or hydroxy lower alkyl wherein the hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms; R4 represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl; CnH2n represents ethylene or propylene; the N-oxides; and salts thereof.

5. Process according to claim 1, wherein there are prepared compounds of formula II shown in claim 4, wherein Rl and R2 independently represent hydrogen or methyl; R3 represents hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl or 3-hydroxypropyl; R4 is hydrogen, methyl, methoxy, fluoro,chloro or trifluormethyl; CnH2n represents ethylene or propylene; the N-oxides;and salts thereof.

6. Process according to claim 1, wherein there are prepared compounds of formula II shown in claim 4, wherein R1 and R2 independently represent hydrogen or methyl; R3 represents hydrogen, methyl, ethyl, propyl or 2-hydroxyethyl; R4 is hydrogen, methyl, fluoro, chloro or trifluoromethyl and CnH2n is ethylene, and salts thereof.

7. Process according to claim 1, wherein 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine or a salt thereof is prepared.

8. Process according to claim 1, wherein 5-[4-(2-hydroxyethyl)-piperazin-yl]-11H-imidazo[1,2-c][1,3]benzodiazepine or a salt thereof is prepared.

9. Process according to claim 1, wherein 5-(4-ethoxycarbonyl-1-pipera-zinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine or a salt thereof is prepared.

10. A compound of the general formula I shown in claim 1, in which formula all the symbols have the meanings given in claim 1, the N-oxides, lower alkyl quaternary derivatives, and salts thereof, whenever prepared or produced by the process of manufacture claimed in claim 1 or by any process which is an obvious chemical equivalent thereof.