NZ202714A - 5-diazacycloalkyl-imidazo(1,2-c)(1,3)benzodiazepine derivatives,a method for their preparation and pharmaceutical preparations - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £02714 202714 si Priority Date(s): ../.?.% !k( Complete Specification Filed: . £.

Class: Publication Date: .., ^ ^ r .C. Journal, To: Ikft if-'' v- * Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "IMIDAZOBENZODIAZEPINES" WE, CIBA-GEIGY AG, a Swiss Corporation of Klybeckstrasse 141, 4002 Basle, Switzerland, hereby declare the invention, for which we pray that a patent may be granted to us,and the method by which it is to be performed, to be particularly described in and by the following statement (Foflowed by page I A.) 2027 1 m- 4-13694/CGC 961/+ IMIDAZOBENZODIAZEPINES The invention concerns 5-diazacycloalkyl-imidazo[l,2-c][l,3]benzo-diazepines of formula I VA 4>\/ V\ _R (I) i ii i ii n J Xy\-5s 2 - x> n 2n wherein each of the symbols and R^ is hydrogen, lower alkyl, lower 5 alkanoyl, halogen, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, sulfamoyl, mono- or di-lower alkyl-(carbamoyl or sulfamoyl); is lower alkylene separating both nitrogen atoms by 2 or 3 carbon atoms; R^ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, aryl lower alkyl, lower alkoxycarbonyl, phenyl lower 10 alkoxycarbonyl or (hydroxy, lower alkanoyloxy, aryloxy or lower alkoxy) lower alkyl having at least two carbon atoms; R^ and R^ independently represent hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, trifluoromethyl, hydroxy, lower alkanoyloxy, sulfamoyl, mono- or di-lower alkylsulfamoyl; and R, and R represent b / hydrogen or lower alkyl; the N-oxides, lower alkyl quaternary derivatives, and salts, especially pharmaceutically acceptable salts thereof, process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application.

The term "lower" referred to above and hereinafter in connection with 20 organic radicals or compounds respectively defines^e.gT")such alkyl, alkenyl und alkynyl radicals with up to and including 7, preferably 3 2027 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 such 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-phenylpropyl, 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 preferably 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), halosulfonyl, phenyl lower alkoxycarbonyl and the like.

Lower alkanoyl is preferably acetyl or propionyl. Lower alkanoyloxy is preferably acetyloxy or propionyloxy. 202714 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 5 phenylmethoxycarbonyl or phenylethoxycarbonyl.

A lower alkylene group CnH2n i-s 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 piperazinyl or homopiperazinyl moiety.

A lower hydroxyalkyl group is preferably 2-hydroxy-(ethyl or propyl), 10 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), 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-20 (ethyl, propyl or butyl), said radicals being optionally substituted on the phenyl ring preferably by e.g. halogen, lower alkoxy or lower alkyl.

Lower alkyl quaternary salts of compounds of formula I are preferably, e.g. methyl, ethyl or propyl quaternary salts derived from 25 reactive esters of lower alkanols having preferably from 1 to 4 carbon atoms, e.g. methanol, ethanol or propanol. The anions of said quaternary salts are preferably those corresponding to pharma- 2027 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 5 of the depicted ring nitrogen atoms in formula I, said N-oxides, lower alkyl quaternary salts of the compounds of formula I are preferably derived from those wherein 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 10 and wherein only the nitrogen atom bearing said R^ 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 hydrohalic, e.g. 15 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, anthranilic, 4-hydroxybenzoic, 20 salicylic, 4-aminosalicylic, pamoic, nicotinic; methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogeno benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; or ascorbic acid.

Compounds of formula I with R^ and/or R^ being carboxy also form salts 25 with bases,-preferably with such bases which yield pharmaceutically acceptable salts, for example, ammonium salts, mono, di- or tri-lower alkyl amines, lower alkylene amines, morpholine, piperazine, piperidine, or lower alkyl derivatives of said cyclic bases, alkali or alkaline earth metal salts. 2027 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, 5 as test objects. Said compounds can be applied to them enterally or parenterally, advantageously orally, or subcutaneously, intravenously or intraperitoneally, for example, within gelatin capsules or in the form of starchy suspensions or aqueous solutions respectively.

The applied dosage may range between 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 15 onset of an electric foot shock. Each lever press postpones the shock for 30 seconds. Whenever the animal fails to press the lever once within said period, brief (0.5 sec.) shocks are delivered at 15 second intervals until the animal again presses the lever.

Under control conditions the animals press the lever at a moderately 20 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 25 with a marked increase in shocks taken by the animal. Both the avoidance responses and failures (shocks received) are recorded separately for evaluation.

Finally, said antihistaminic properties can be shown in vitro, e.g., according to Chasin et al., J. Neurochem. 22^, 1031 (1974). Vesicles from a cell free preparation of guinea pig cerebal cortex are 3 . 3 premcubated with H-adenine to form endogenous H-adenosine 2027 triphosphate. The vesicles are then incubated with 50 micromolar 3 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 5 inhibits the histamine activation of adenylate cyclase. The represents the concentration at which histamine activation is inhibited by 50%.

Accordingly, the compounds of the invention are useful neuroleptic and antihistaminic agents, for example, in the treatment or 10 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 of other valuable products, especially of pharmacologically active compositions.

Preferred embodiments of this invention relate to compounds of formula I wherein each of and R^ is hydrogen, lower alkyl, cyano, carboxy, lower alkoxycarbonyl or carbamoyl; n represents the integer 2 to 4; R^ is hydrogen, lower alkyl, lower alkoxycarbonyl, or hydroxy lower alkyl of 2 to 4 carbon atoms; R^ represents hydrogen, lower 20 alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl; R,. represents hydrogen; and R^ and R^ represent hydrogen or lower alkyl; the N-oxides; lower alkyl quaternary salts; or salts, especially pharmaceutically acceptable salts thereof.

Highly preferred are compounds of formula I wherein each of R^ and 25 R2 is hydrogen, methyl, ethyl, cyano, carboxy, alkoxycarbonyl of 1 to 3 carbon atoms in the alkoxy portion or carbamoyl; n represents the integer 2 or 3; R^ is hydrogen, alkyl of 1 to 3 carbon atoms, alkoxycarbonyl of 1 to 3 carbon atoms in the alkoxy portion, hydroxyethyl or hydroxypropyl; R^ represents hydrogen, methyl, 30 methoxy, methylthio, chloro or trifluoromethyl; R,. represents hydrogen; R, and R. represent hydrogen or methyl; the N-oxides; methyl 0 / 2027 quaternary salts; and salts, especially pharmaceutically acceptable salts thereof.

Especially useful are compounds of formula II y\yCH2\_A._R.

Li.*1 (ii) R / ^ / \. 5/ "2 • n=» 4 V \ <'~K3 n 2n wherein R^ and R^ independently represent hydrogen or lower alkyl; R^ represents hydrogen, lower alkyl or hydroxy lower alkyl wherein the hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms; represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl; C H represents n zn ethylene or propylene; the N-oxides; and salts, especially pharmaceutically acceptable salts thereof.

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

Further preferred are compounds of formula II wherein R^ and R^ independently represent hydrogen or methyl; R^ represents hydrogen, 20 methyl, ethyl, propyl or 2-hydroxyethyl; R^ is hydrogen, methyl, fluoro, chloro or trifluoromethyl and C H 'is ethylene, and salts, especially pharmaceutically acceptable salts thereof. 2027 Indicative of the antipsychotic utility of the compounds of this invention, e.g., the compound of example 1, namely 5-(4-methyl-l-piperazinyl)-HH-imidazo[l,2-c] [1,3]benzodiazepine disrupts avoidance behavior, e.g. decreases avoidance responses in rats and 5 monkeys at an oral dose of 30 mg/kg or lower.

Illustrative of the antihistaminic activity, 5-(4-methyl-l- s piperazinyl)-llH-imidazo[l,2-c][l,3]benzodiazepine, the compound of example 1, inhibits histamine activation of adenylate cyclase, with an of about 1 x 10 %, Furthermore, 5-(4-methyl-l-piperazinyl)-llH-imidazo[l,2-c][1,3]— benzodiazepine, the compound of example 1, an illustrative example of this invention, is essentially free of extrapyramidal side effects, e.g. dyskinesias and dystonias in the monkey (dyskinetic movements and dystonic postures) and shows only minimal a-adrenergic 15 blocking activity in vitro.

The compounds of the invention are prepared according to methods known per se, advantageously by a) condensing a compound of formula 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 (III) 2027 14 HN, / V -R„ n 2n (IV) or an alkali metal derivative thereof wherein has meaning as defined for formula I; and, if desired, converting 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 10 by an optionally substituted hydrocarbon, particularly one of aliphatic 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 15 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 20 the compound IV, or with equivalent amounts of said metal derivatives prepared in situ therefrom, preferably when X in formula III is halogeno, lower alkylthio or thiocyanato, advantageously and depending on the nature of said X, at temperatures between about 0° and 150°, and preferably in an appropriate solvent e.g. a lower 25 alkanol such as amyl alcohol, dimethylformamide, hexamethylphosphor-amide or toluene. Said condensation of a compound of formula III with a compound of formula IV may also be carried out in the presence of an acid, e.g., a hydrohalic acid such as hydrochloric acid. 2 027 The novel llH-imidazo[l,2-c][l,3]benzodiazepine starting materials of formula III are prepared according to ring closure methods known per se. Advantageously by condensing compounds of formula V v6\ 7*7 R %\ / \ A A 1 - i_'j <v) E5 \h„ h wherein R^, R^, have meaning as previously defined for formula 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 10 compounds wherein X is sulfhydryl by conventional sulfurating agents, such as phorphorus pentasulfide.

These compounds of formula III can be further derivatized to compounds 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), e.g. aminoacetaldehyde dimethyl acetal, by known methods illu- strated in the examples herein.

A further process for the preparation of the compounds of general formula I consists in 2027 ii - b) cyclizing a compound of formula VI hn"—*-r, (VI) nnh—c-t/ \ R5 II c h; I II 2 • • • — • '-r, 3 z wherein Z is oxygen, sulfur, or NH, and the other symbols have the above-given meaning, under dehydrating, dehydrosulfurating or 5 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 toluene.

The starting materials of Formula VI ean be 15 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 20 chloride or toluene at temperatures between 0° and 150° advantageously between 10° and 50°. The ring opening reaction is preferably carried out at low temperature to minimize side reactions when R^ and R^ represent reactive functional groups.

Alternately, starting materials of formula VI, wherein R^ is lower 25 alkanoyl, lower alkoxycarbonyl or phenyl lower alkoxycarbonyl, are prepared by condensing a compound of formula V above with a compound 2027 12 of formula VII H> R. '3 (VII) C 'n 2n 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 R^ has the meaning given for formula VII, or advantageously e.g. the N-trimethylsilyl 10 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 15 other compounds of Formula I according to known methods. Thus, for example, those with R^ 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-20 phatic alcohols such as methanol, ethanol, methoxyethanol, phenoxy-ethanol, allyl alcohol, propargyl alcohol, e.g. such esterified by a strong inorganic or organic acid, 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 25 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 R^ is 202714 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 being lower alkenyl, lower alkynyl may be hydrogenated with catalytically activated hydrogen to obtain compounds wherein R^ is the corresponding lower alkyl. Conversely, resulting N-alkylated compounds can be converted into N-unsubstituted compounds, e.g. by catalytic hydrogenolysis of 10 N-benzyl compounds, or reaction of N-lower alkyl derivatives with lower alkyl haloformates, e.g. ethyl chloroformate, to yield N-acyl derivatives which, in turn, may be hydrolyzed to said unsubstituted compounds, those with = H, for example with aqueous bases, such as alkali metal hydroxides, e.g. aqueous sodium hydroxide 15 solution.

Compounds of formula I wherein R^ is hydroxy lower alkyl can also be prepared by first reacting corresponding compounds of Formula I, wherein R^ represents hydrogen, with reactive derivatives of corresponding glycols, glycolic acids or dicarboxylic acids, such as 15 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-20 mediates so obtained are either hydrolyzed or reduced with simple or complex light metal hydrides such as lithium aluminium hydride, alone or with diborane to compounds of formula I wherein R^ is hydroxyalkyl.

Compounds of formula I wherein R^ is lower alkyl, e.g. methyl can be prepared by reacting the corresponding compounds of formula I wherein ->7 2027 represents hydrogen with lower alkyl or phenyl lower alkyl halo-formates, such as ethyl chloroformate, to obtain compounds of formula I wherein R^ 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 R^ is lower alkanoyl can preferably be obtained from compounds of Formula I with R^ 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. These in turn can be reduced as above to the compounds of formula I wherein R^ is lower alkyl. Compounds of formula I wherein R^ is hydroxy lower alkyl may be acylated as above to the compounds wherein R^ is lower alkanoyloxy lower alkyl.

Compounds of Formula I with R^ and/or R^ being hydrogen, may be converted to the corresponding compounds with and/or R^ being halogen or acyl, e.g. by halogenation, preferably with chlorine in acetic acid or under Friedel-Crafts conditions by 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 amidized with ammonia, mono- or di-lower alkyl-r amines; the resulting primary carboxamides may in turn be dehydrated to the corresponding nitriles according to conventional methods. Compounds of the formula I in which R^ and/or R^ represents carboxy, can be prepared, for example, by hydrolysis of compounds wherein R^ and/or R^ represents cyano, lower alkoxycarbonyl or carbamoyl. 2 027 Tertiary amines in which 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 5 acid, advantageously at temperatures at or below room temperature with the latter, or up to 100° with hydrogen peroxide in the presence 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 converted 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 15 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 20 previously.

Compounds of formula I with R^ and/or R^ being carboxy can be converted 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 purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. 2027 14 In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

In 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-10 paration of diastereomeric salts thereof, e.g. by the fractional crystallization of the salts formed with d- or 1-tartaric acid.

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, 15 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, 20 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 25 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. 2027 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. 10 magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures and/or e) absorbents, colorants, flavors and sweeteners. Injectable compo-15 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 20 pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared 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. A unit dosage for a 25 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 some typical forms of application, but in no way do they represent the only embodiments thereof. Specific demonstrations are given in the 30 Examples. 2027 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 5 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 granulate 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 15 dragee 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 20 of active substance. c) 10.0 g of active substance and 1990 g of finely ground suppository foundation substance (for example cocoa butter) are thoroughly mixed and then melted. The melt is maintained homogeneous by stirring whilst 1000 2.0 g suppositories each containing 25 mg of active substance are being poured. d) To prepare a syrup having a content of active substance of 0.25%, there are dissolved in 3 litres of distilled water, 1.5 litres of glycerin, 42 g of p-hydroxybenzoic acid methyl ester, 18 g of p-hydroxybenzoic acid-n-propyl ester and, with slight warming, 2027 .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 5 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, 10 150.0 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 15 5 g of cough-sweet aroma or 30 g of grapefruit essence, both from Haarmann and Reimer, 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-20 tures are given in degrees Centigrade, and all parts wherever given are parts by weight. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 and 100 mm Hg.

Example 1: Amyl alcohol (5100 ml) and 918.35 g (9.17 moles) of N-methyl-25 piperazine are charged into a 12 liter 3—necked reaction flask fitted with a Dean-Stark adapter. The solution is stirred under nitrogen atmosphere and 989 ml of 10N ethanolic hydrogen chloride solution are 2027 added rapidly. The reaction mixture is heated to reflux and the distillate is collected in the Dean-Stark adapter. When the temperature of the reaction mixture reaches 131° the Dean-Stark adapter is removed and an additional 918.35 g (9.17 moles) of N-methylpiperazine 5 followed by 1045.0 g (4.56 moles) of 5-methylthio-llH-imidazo[1,2-c]-[l,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 10 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 15 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 20 Hg/40°) yields crude product, m.p. 113-120°. The crude product is dissolved in 8,000 ml of hot (60-70°) isopropanol. The solution 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 25 precipitate. The suspension is stirred overnight at ambient temperature to complete crystallization and the solid is collected by filtration. The product is washed with 3 x 500 ml of cold isopropanol and dried (0.5 mm/500). This is recrystallized from ethanol, the resulting product is washed first with ethanol and then 30 with ether and then dried to give 5-(4-methyl-l-piperazinyl)-llH-imidazo[1,2-c][l,3]benzodiazepine monomaleate, m.p. 204-205° (decomposition). 2 027 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/500) to 10 give 5-(4-methyl-l-piperazinyl)-llH-imidazo[l,2-c][l,3]benzodiazepine m.p c 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 for 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 adjusted to 1.0 with 6,000 ml of 12 N hydrochlorid acid. The stirring is continued overnight at 10° to complete the liberation of the free acid. The solid is collected, washed with 6 x 4,000 ml of water, air dried overnight and suspended 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 2 027 14 petroleum ether arid dried (5 mm Hg/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 5 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 10 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. 82-84°.

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 20 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° (decomposition) .

Ethanol (2,200 ml) and 5,156 g (8.81 moles) of ethyl 2-(2-nitro-25 phenyl)acetimidate hydrochloride are charged into a 22 liter flask. The suspension is stirred under nitrogen at room temperature and 1022.9 g (9.73 moles) of aminoacetaldehyde dimethylacetal are added all at once. The mixture is stirred for 1 hour and 1,693 ml 27 1 of 12N hydrochloric acid are added all at once 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 10N sodium hydroxide 5 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-nitro-benzyl)-imidazole, m.p. 155-157°. 50% Aqueous ethanol (5,672 ml) and 2,890 g (14.22 moles) of 2-(2-10 nitrobenzyl)-imidazole are charged into a 22 liter flask. The suspension 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. A vigorous exotherm reaction 15 results and a strong reflux occurrs that persists for 1.5 hours.

When the exotherm reaction subsides, a mixture of 290 ml of 12N HC1 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 10N sodium 20 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 25 yield 2-(2-aminobenzyl)-imidazole, m.p. 153-155°.

Dichloromethane (42,000 ml) and 5,120 g (50.65 moles) of triethylamine are charged into a 70 litre flask. The solution is stirred under nitrogen atmosphere and 4,370 g (25.23 moles) of 2-(2-aminobenzyl)-imidazole are added. The suspension is cooled to 0-5° and 3,421 g 30 (29.75 moles) of 85% thiophosgene in carbon tetrachloride are added over 3 hours, during which time the reaction temperature rises slowly 2027 to 15°. The suspension is then stirred at 10° for 4 hours and at ambient temperature overnight. The precipitated product is collected, washed with 2 x 3000 ml of dichloromethane and 5 x 4000 ml of water, and dried (5 mm Hg/60°) to give llH-imidazo[l,2-c][1,3]benzodiazepine-5 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. After stirring for 30 minutes there is complete solution and 2,063 g (9.58 moles) of llH-imidazo[1,2-c][1,3]benzo-10 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 15 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[l,2-c][l,3]benzodiazepine, m.p. 87-88°.

Similarly prepared from 4-chloro-2-nitrophenyl-acetonitrile is 20 8-chloro-llH-imidazo[l,2-c][l,3]benzodiazepine-5(6H)-thione, m.p. 200-201° and 8-chloro-5-methylthio-llH-imidazo[l,2-c][l,3]benzo-diazepine hydrochloride, m.p. 255-257°.

The following starting materials are similarly prepared from the correspondingly substituted 2-nitrophenylacetonitriles: 25 a) 8-methyl-5-methylthio-llH-imidazo[1,2-c][1,3]-benzodiazepine; b) 8-fluoro-5-methylthio-llH-imidazo[1,2-c][1,3]-benzodiazepine; c) 8-methoxy-5-methylthio-llH-imidazo[1,2-c][1,3]benzodiazepine. 2 027 Example 2: To a suspension of 2.46 g of l-[2-(2-imidazolylmethyl)-phenylcarbamoyl]-4-methylhomopiperazine in 19.4 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 5 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. 10 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 chromatography with 50 g of silica gel, using methylene chloride-methanol-15 conc. ammonium hydroxide (300:50:1) as eluent to give 5-(4-methyl-l-homopiperazinyl)-llH-imidazo[1,2-c][l,3]benzodiazepine as an oil.

This free base is dissolved in acetone and treated with maleic acid to give 5-(4-methyl-l-homopiperazinyl)-llH-imidazo[l,2-c][l,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 l-[2-(2-imidazolyl-methyl)phenylcarbamoyl]-4-methy1-piperaz ine.

The starting materials are prepared as follows: A solution of 32.4 g of phenyl chloroformate in 100 ml of aceto-25 nitrile is added dropwise under nitrogen while 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 addition is complete, the reaction mixture is heated under reflux for 12 hours, and allowed to cool to room temperature. Water (150 ml) is added, 30 the mixture is stirred at room temperature for 0.5 hour and cooled 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 202714 dried to give llH-imidazo[1,2-c][1,3]benzodiazepin-5(6H)-one, m.p. 255-257°.

Alternately, 0.75 g of 1,1'-carbonyldiimidazole is added at once to a suspension of 0.79 g of 2-(2-aminobenzyl)-imidazole in 38 ml of 5 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 10 cyclization, the following intermediates are obtained: a) 2,3-dimethy1-llK-imidazo[1,2-c][1,3]benzodiazepin-5-(6H)-one; b) 8-chloro-llH-imidazo[1,2-c][l,3]benzodiazepin-5(6H)-one; c) 8-methyl-llH-imidazo[l,2-c][l,3]benzodiazepin-5-(6H)-one; d) 8-methoxy-llH-imidazo[1,2-c][l,3]benzodiazepine-5-(6H)-one.

To a suspension of 0.76 g of llH-imidazo[1,2-c][l,3]benzodiazepin-5-(6H)-one in 9 ml of methylene chloride is added at once 0.41 g of N-methylhomopiperazine and the mixture is stirred at room temperature for 24 hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. Recrystallization of the 20 residue from methylene chloride-ether gives l-[2-(2-imidazolyl- methyl)-phenylcarbamoyl]-4-methylhomopiperazine, melting at 139-143°.

Similarly prepared from N-methylpiperazine is l-[2-(2-imidazolyl-methyl)-phenylcarbamoyl]-4-methylpiperazine, m.p. 172-174°.

The following compounds are prepared according to the above proce-25 dures: a) 1-[2-(4,5-dimethy1-2-imidazolylmethyl)-phenylcarbamoyl]-4-methyl-piperazine; and b) 1—[2—(2-imidazolylmethyl)-5-chlorophenylcarbamoyl]-4-methyl-piperazine. 2027 Example 3: A solution of 2.4 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 10 mixture is diluted with ether. The crude product crystallized, m.p. 183-186°, and is recrystallized to give the 5-(4-methyl-l-piperazinyl)~ HH-imidazo[l,2-c][l,3]benzodiazepine monomaleate of example 1. It melts at 204-205° (decomposition).

The starting material is prepared as follows: Sodium hydride (50% in mineral oil, 1.44 g,) is washed with dry ether and suspended in 100 ml of dry tetrahydrofuran; 6.45 g of HH-imidazo[l,2-c][l,3] benzodiazepine-5(6H)-thione is added in portions to the suspension of sodium hydride, with stirring and under nitrogen, over a period of 2 minutes. The mixture is stirred at 20 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 25 dissolved in methylene chloride, the solution is washed with water, dried over magnesium sulfate, decolorized with charcoal, and evaporated to a small volume. 5-Cyanomercapto-llH-imidazo[l,2-c]-[l,3]benzodiazepine, m.p. 111-113°, crystallized on dilution with ether. 2 027 Example 4: To a solution of 8.9 g of l-[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 5 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 10 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-l-piperazinyl)-llH-imidazo[l,2-c][1,3]-benzodiazepine, m.p. 137-139°.

The starting material is prepared as follows: A solution of 20 g 15 of 1-ethoxycarbonylpiperazine in 400 ml dry tetrahydrofuran is cooled to -65° and 61.5 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 20 of 15 minutes. The mixture is then allowed to warm up to room temperature overnight and evaporated to dryness. Ethyl ether is added, the solids are filtered off, 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 to -76° is added, while stirring and under nitrogen, a solution of 7 g of l-ethoxycarbonyl-4-trimethylsilylpiperazine in 35 ml of ethyl ether over a period of 20 minutes. The mixture is allowed to warm up to room temperature overnight. The suspension is 2027 filtered and the filtrate is evaporated to dryness. The residue is crystallized from methylene chloride-hexane to give 4-ethoxycarbonyl-1-piperazinyl-thiocarbonyl chloride, m.p. 107-111°.

To a suspension of 3.8 g of 2-(2-aminobenzyl)-imidazole in 38 ml of 5 tetrahydrofuran and 3.23 ml of triethylamine is added dropwise a solution of 5.5 g 4-ethoxycarbonyl-l-piperazinyl-thiocarbonyl 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 10 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 R, and R„ represent hydrogen, and C H„ represents 1,2-ethylen were l ^ n 2n obtained from equivalent amounts of the corresponding starting materials.

No. R„ R. 3 4 l CH2CH2OH H 2 CH2CH20H CI 3 CH3 CI 4 CH3 H ch3 h Salt m.p. 143-4° HC1 225° (decompo sition) 2HC1 226-8° (dec.) 2HC1 > 250° (dec.) HC1 217-220°.

Example 6: The mixture of 315 mg of l-[2-(2-imidazolylmethyl)phenyl-25 thiocarbamoyl]-4-methylpiperazine, 3.3 ml of dimethylformamide, 276 mg of potassium carbonate, 116 mg of cyanogen bromide and 50 mg of 8-crown-6 ether is stirred at room temperature under nitrogen for 3 hours. It is diluted with ethyl acetate, washed with saturated 2027 aqueous sodium chloride, dried and evaporated. The residue is dissolved in acetone, the solution treated with 116 mg of maleic acid and diluted with diethyl ether, to yield 5-(4-methyl-l-piperazinyl)-HH-imidazo[1,2-c][l,3]benzodiazepine monomaleate. The product is 5 identical with that of Example 1.

The starting material is prepared as follows: The mixture of 2.1 g of llH-imidazo[l,2-c][l,3]benzodiazepine-5(6H)~ thione, 23 ml of methylene chloride and 1.0 g of 1-methylpiperazine is stirred at room temperature for 15 hours. The crystalline product 10 formed is filtered off and washed with methylene chloride, to yield 1-[2-(2-imidazolylmethy1)-phenylthiocarbamoyl]-4-methylpiperazine.

Example 7: A mixture of 9.5 g of 5-methylthio-llH-imidazo[1,2-c][1,3]— benzodiazepine hydrochloride, 3.62 g of piperazine, and 350 ml of amyl alcohol is refluxed with stirring and under nitrogen for 15 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-20 imidazofl,2-c][1,3]benzodiazepine dihydrochloride.

Examples 8: To a solution of 0.2 g of 5-(4-carboethoxy-l-piperazinyl-llH-imidazo[l,2-c][l,3]benzodiazepine in 2 ml of dry tetrahydrofuran, 100 mg of lithium aluminium hydride are added at once and the mixture is refluxed under nitrogen for 48 hours. The mixture is cooled 25 to room temperature, stirred with 0.2 ml of 30% aqueous sodium hydroxide, and filtered. The filtrates are evaporated to dryness and the product is purified to give 5-(4-methyl-l-piperazinyl]-HH-imidazo[1,2-c][l,3]benzodiazepine, which is identical with the product of example 1. It melts at 123-124°. 2 027 Example 9: To a solution of 82 mg of 5-(4-methyl-l-piperazinyl)-llH-imidazo[l,2-c][l,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-oxido-1-piperazinyl-llH-imidazo[1,2-c][1,3]benzodiazepine hydrochloride.

Example 10: To a solution of 100 mg of 5-(4-benzyloxycarbonyl-l-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-imidazo[1,2-c][l,3]benzodiazepine hydrobromide precipitates„ The starting material is prepared similarly to starting material of 15 exmaple 4 by replacing 1-ethoxycarbonylpiperazine with the equivalent amount of 1-benzyloxycarbonylpiperazine.

Example 11: A mixture of 265 mg of 5-(4H-l-piperazinyl)-llH-imidazo-[1,2-c][l,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 mixture is 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[1,2-c][1,3]benzodiazepine.

Example 12: The following compounds of formula I (R,.-R^=H) are 25 prepared according to the methods illustrated by the previous examples and are obtained from equivalent amounts of the corresponding substituted starting materials. 2 027 No.

R1 R2 R3 R4 CnH2n 1 ch3 h CH3 h (CH2)2 2 CH3 CH3 ch3 h (cV2 3 h h CH3 8-cf3 (ch2)2 4 h h ch3 8-f (CH2)2 h h ch3 8-0ch3 (ch2)2 6 h h ch3 8-0h (ch2)2 7 h h ch3och2ch2 h (CH2)2 8 h h ch3c00ch2ch2 h (ch2)2 9 h h ch3 8-ch3 (ch2)2 Examples 13: Preparation of 10,000 tablets each containing 25 mg of the active ingredient: Formula: -(4-methyl-l-piperazinyl)-llH-imidazo[1,2-c][1,3]- benzodiazepine 250.00 g Lactose 957.00 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 of the starch are mixed in a suitable mixer. The 25 other half of the starch is suspended in 40 ml of water and the suspension added to the boiling solution of polyethylene glycol in 150 ml water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35°, broken on a screen with 1.2 mm openings and 30 compressed into tablets using concave punches with 6.4 mm diameter, uppers bisected. 202714 Example 14: Preparation of 10,000 capsules each containing 50 mg of the active ingredient: 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 machinec 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 l-[2-(4-methyl-2-imidazolylmethyl)-phenylcarbamoyl]-4-methylpiperazine, 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 chloride. The methylene chloride extracts are re-extracted with 2N aqueous 25 hydrochloric acid. The acidic extracts are basified with 2N aqueous sodium hydroxide and extracted three times with methylene chloride. The organic extracts are dried over magnesium sulfate, decolorized with charcoal and evaporated to dryness. The residue is chromato- Formula: -(4-methyl-l-piperazinyl)-llH-imidazo[1,2-c][1,3]- 500.0 g benzodiazepine monomaleate Lactose Talcum powder 1,400.0 g 100.0 g 2 027 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-5 l-piperazinyl)-llH-imidazo[l,2-c][l,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 10 ethyl 2-(2-nitrophenyl)-acetimidate hydrochloride in 224 ml of ethanol and the mixture is stirred at room temperature for one hour. The sodium chloride formed is filtered, 22.82 g of the ethylene ketal of 1-amino-2-propane is added to the filtrates and the mixture is stirred at room temperature overnight. The insoluble material is filtered off 15 and the filtrates are evaporated to dryness. The residue is dissolved in 470 ml of concentrated hydrochlorid acid and the solution is refluxed 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 20 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 23.44 g of 4-methyl-2-(2-nitrobenzyl)-imidazole, 2.34 g of 10% palladium on charcoal and 234 ml of ethanol is hydrogenated 25 at 42 psi (3 atmospheres) at room temperature for 4 hours. The catalyst is filtered and the filtrates are evaporated to dryness to give 4-methyl-2-(2-aminobenzyl)-imidadole showing signals in the NMR spectrum at & 2.09, 3.78, 6.08.

A mixture of 18.61 of 4-methyl-2-(2-aminobenzyl)-imidazole, 16.12 g 30 of 1,l'-carbonyldiimidazole and 375 ml of methylene chloride is stirred at room temperature overnight. The methylene chloride is * ''' . 2027 evaporated to a small volume, the mixture is cooled to 0° and the solids are filtered and washed with ether to give 2-methyl-llH-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-one, m.p. 234.5-236.5°.

A mixture of 16 g of 2-methyl-llH-imidazo[1,2-c][l,3]benzodiazepine-5-5 (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. 177-179°.

Example 16: To a solution of 5 g of 5-(4-methyl-l-piperazinyl)-llH-imidazo[l,2-c][l,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 15 Amberlite IRA-400 ion exchange resin using water as eluent. Evaporation of the eluent gives 5-(4-methyl-4-oxido-l-piperazinyl)-llH-imidazo[l,2-c][l,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 20 obtained in Example 9.

Example 17: A mixture of 8.67 g of 5-methylthio-llH-imidazo[l,2-c]-[l,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 25 and the solution is washed successively with 10% aqueous potassium carbonate and brine, dried over magnesium sulfate, decolorized with charcoal and evaporated. The residue is chromatographed with 300 g of silica gel using methylene chloride-methanol-ammonium hydroxide (150:50:1) as eluent to give 5-(4H-l-piperazinyl)-llH-imidazo[l,2-c]-30 [l,3]benzodiazepine as an oil. The oil is treated with 2.74 g of maleic acid in acetone to give 5-(4H-l-piperazinyl)-llH-imidazo[l,2-c]-

Claims (25)

2 027 - 36 - [l,3]benzodiazepine bis-maleate, m.p. 171.5-173.5°. Example 18: A mixture of 0.2 g of 5-(4-ethoxycarbonyl-l-piperazinyl)-HH-imidazo[l,2-c][l ,3 ] —benzodiazepine, 10 ml of tetrahydrofuran and 50 mg of lithium aluminium hydride is refluxed overnight with 5 stirring. The mixture is cooled to 0°, and the excess of the lithium aluminium hydride is destroyed with ethyl acetate, and the mixture is 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 1. Example 19: A mixture of 0.1 g of 5-(4H-l-piperazinyl)-llH-imidazo [1,2-c][l,3]benzodiazepine, 0.058 g of methyl iodide, 0.16 g of potassium carbonate and 1 ml of dimethylformamide is stirred at room temperature overnighte 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[l,2-c][l,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 25 Compound of example Dose mg/kg P.O. n Number of Avoidance Failures (difference from vehicle) 30 min 90 min 210 min 1 10 6 +31 +13 +14 1 30 6 +44 +49 +40 5/2 30 3 +22 +19 + 8 5/3 10 3 +10 +14 +15 n = number of rats. A decrease in the avoidance response is indicative of neuroleptic activity and is characterized by an increase in the number of avoidance 30 failures. - 37 - 202714 WHAT'f/WE CUA'IM IS:- Claima

1. A compound of the general formula I R6\/7 R4 >\ / \ A ^ »-R (I) i " A 11 n1 X/\ /* 2;R * N_,\ ! X <"• n 2n wherein R^ and R^ independently represent hydrogen, lower alkyl, 5 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; R^ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, aryl lower alkyl, lower alkoxycarbonyl, 10 phenyl lower alkoxycarbonyl or (hydroxy, lower alkanoyloxy, aryloxy or lower alkoxy) lower alkyl having at least two carbon atoms; R^ and R,. independently represent hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, trifluoromethyl, hydroxy, lower alkanoyloxy, sulfamoyl, mono- or di-lower alkylsulfamoyl; and R and R_ o 7 15 independently represent hydrogen or lower alkyl; the N-oxides and lower alkyl quaternary derivatives thereof.

2. A compound of the formula I shown in claim 1, wherein R^ and R^ independently represent hydrogen, lower alkyl, cyano, carboxy, lower alkoxycarbonyl or carbamoyl; n represents the integer 2 or 3; is hydrogen, lower alkyl, lower alkoxycarbonyl, or hydroxy lower alkyl of 2 to 4 carbon atoms; represents hydrogen, lower 20 alkyl, lower alkoxy, lower alkylthio, halogen or trif luoromethyl ;R,_ represents hydrogen; and R, and R, independently represent hydrogen o / or lower alkyl; the N-oxides or lower alkyl quaternary derivatives thereof. ^ ^ r ' Ti.• 11 20ju^ s °'V C O ^ .• '• V 202714 - 38 -

3. A compound of the formula I shown in claim 1, wherein and R^ independently represent hydrogen, methyl, ethyl, cyano, carboxy, alkoxycarbonyl of 1 to 3 carbon atoms in the alkoxy portion or carbamoyl; n represents the integer 2 or 3; is hydrogen, alkyl of 5 1 to 3 carbon atoms, alkoxycarbonyl of 1 to 3 carbon atoms in the alkoxy portion, hydroxyethyl or hydroxypropyl; represents hydrogen, methyl, methoxy, methylthio, chloro or trifluoromethyl; R,_ represents hydrogen; R, and R independently represent hydrogen or methyl; the D / N-oxides or methyl quaternary derivatives thereof. 10

4. A compound of the formula II wherein R^ and R2 independently represent hydrogen or lower alkyl; R^ represents hydrogen, lower alkyl or hydroxy lower alkyl wherein the hydroxy group is separated from the nitrogen atom by at least 15 2 carbon atoms; R^ represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl; C represents n 2 n ethylene or propylene; and the N-oxides thereof.

5. A compound of the formula II shown in claim 4, wherein R^ and R^ independently represent hydrogen or methyl; R^ represents hydrogen, 20 methyl, ethyl, propyl, 2-hydroxyethyl or 3-hydroxypropyl; R^ is hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyl; C represents ethylene or propylene; and the N-oxides thereof.

6. A compound of the formula II shown in claim 4, wherein R^ and R^ independently represent hydrogen or methyl; R^ represents hydrogen, 25 methyl, ethyl, propyl or 2-hydroxyethyl; R^ is hydrogen, methyl, ^ 20271A - 39 - fluoro, chloro or trifluoromethyl and C H- is ethylene. n 2n

7. 5-(4-Methyl-l-piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine.

8. 5-(4-Methyl-l-homo-piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine. 5

9. 5-(4-Ethoxycarbonyl-l-piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine.

10. 5-[4-(2-Hydroxyethyl)-l-piperazinyl)-llH-imidazo[l,2-c][1,3]benzodiazepine.

11. 8-Chloro-5-[4-(2-hydroxyethyl)-1-piperazinyl]-llH-imidazo-[1,2-c][l,3]benzodiazepine.

12. 8-Chloro-5-(4-methyl-l-piperazinyl)-llH-imidazo[1,2-c][1,3]— benzodiazepine.

13. 2-Methyl-5-(4-methyl-l-piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine . 15

14. 5-(4H-l-piperazinyl)-llH-imidazo[l,2-c][1,3]benzodiazepine.

15. A salt of a compound having a salt forming group, as claimed in any one of claims 1 to 12.

16. A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in any one of claims 1 to 12. 20

17. A salt of a compound having a salt forming group, as claimed in either of claims 13 and 14. " 202714 - 40 -

18. A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in either of claims 13 and 14.

19. A pharmaceutical preparation comprising a compound claimed in any one of claims 1 to 12 and 16 in admixture or conjunction with 5 a pharmaceutically suitable carrier.

20. A pharmaceutical preparation comprising a compound claimed in any one of claims 13, 14 and 18 in admixture or conjunction with a pharmaceutically suitable carrier.

21. A process for the manufacture of a compound of formula I 10 claimed in claim 1, of the N-oxides, lower alkyl quaternary derivatives, and salts thereof, which consists in a) condensing a compound of formula III wherein X is a group able to be removed with hydrogen or an alkali 15 metal and the remaining symbols have meanings as defined for formula I; with a compound of formula IV (III) (IV) or an alkali metal derivative thereof wherein and n have meanings as defined for formula I; or 20 b) cyclizing a compound of formula VI 20 NOV ft - 41 - 202714 R, > \/ ° -R, HN—•-R„ -c-n( ii v -R„ n 2n (vi) wherein Z is oxygen, sulfur, or NH, and the other symbols have the meanings as defined for formula I, under dehydrating, dehydrosulfu-rating or deamination conditions, and/or 5 1) if a compound of the formula I is required in which R^ is lower alkyl, introducing such a radical into a compound of the formula I in which R^ is hydrogen or an alkali metal atom, and/or 2) if a compound is required in which R^ is lower alkyl, reducing a compound having a lower alkenyl or lower alkynyl group instead of 10 a lower alkyl group, and/or 3) if a compound is required in which R^ is hydroxy-lower alkyl, reacting a compound in which R^ is hydrogen or an alkali metal atom with a corresponding oxirane or with a reactive ester of a mono-esterified lower alkanediol, and/or, 15 4) if a compound is required in which R^ is hydroxy-lower alkyl, reacting a compound in which R^ is hydrogen with a reactive derivative of a corresponding glycol, glycolic acid or a dicarboxylic acid and hydrolyzing or reducing the compound so obtained to a compound in which R^ is hydroxy-lower alkyl, and/or, 20 5) if a compound is required in which R^ is lower alkoxycarbonyl, converting a compound in which R^ is lower alkyl into a lower alkoxycarbonyl group, and/or, r/V [N 6) if a compound is required in which R^ is an acyl radical named above, acylating a compound in which R^ is hydrogen, and/or 202714 - 42 - 7) if a compound is required in which represents hydrogen, hydrolyzing a compound in which R^ is an acyl radical, and/or, 8) if a compound is required in which R^ represents methyl, reducing a compound in which R^ is lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl to obtain a compound in which R^ is methyl, and/or, 9) if a compound is required in which R^ and/or R2 is/are halogen, halogenating a compound in which R^ and/or R^ is/are hydrogen, and/or, 10) if a compound is required in which R^ and/or R^ is/are carboxy, lower alkoxycarbonyl or a carbamoyl residue named above, reacting a compound in which R^ and/or R^ is/are hydrogen, with a trihaloacetyl halide and treating the compound obtained with an alkali metal lower alkoxide, alkali metal hydroxide or alkali metal amide, and/or, 11) if a compound is required in which R^ and/or R^ is/are sulfamoyl, mono- or di-lower alkylsulfamoyl, reacting a compound in which R^ and/ or R2 is/are hydrogen with a halosulfonic acid and treating the compound obtained with ammonia, a mono- or di-lower alkylamino, and/or, 12) if a compound is required in which R^ and/or R^ is/are cyano, dehydrating a compound in which R^ and/or R^ is/are carbamoyl, and/or, 13) if a compound is required in which R^ and/or R^ is/are carboxy, hydrolyzing a compound in which R^ and/or R^ is/are cyano, lower alkoxycarbonyl or carbamoyl, and/or, 14) if an N-oxide is required, oxidizing a compound in which is different from hydrogen, and/or, 15) if a lower alkyl quaternary derivative is required, reacting a compound in which represents hydrogen or alkali metal with a reactive esterified lower alkanol, and/or, 202714 - 43 - 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 5 a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if required, resolving a recemate obtained into the optical antipodes.

22. The process for the preparation of a compound as defined in claim 1 described in any one of examples 1 to 12. 10

23. The process for the preparation of a compound as defined in claim 1 described in any one of examples 15 to 19.

24. The compounds prepared according to claim 22.

25. The compounds prepared according to either of c 3^23.