WO1996023790A1

WO1996023790A1 - Acetylimidazobenzodiazepines

Info

Publication number: WO1996023790A1
Application number: PCT/CH1996/000021
Authority: WO
Inventors: René Borer; Max Gerecke; Ulrich Widmer
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 1995-02-02
Filing date: 1996-01-16
Publication date: 1996-08-08
Also published as: AU4382896A

Abstract

Substituted imidazo[1,2-1][1,4]benzodiazepines have the general formula (I), in which R1 is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkanoyloxy-lower alkyl, 2-pyridyl, phenyl, optionally substituted by lower alkoxy or lower dialkylamino; R2 is phenyl, optionally substituted by 2-halogen; R3 is -C(O)R5 or -C(OH)HR5; R4 is hydrogen, lower alkyl, lower hydroxyalkyl, carboxy, lower alkoxycarbonyl or phenyl, optionally substituted by lower alkoxy; R5 is hydrogen or lower alkyl. These compounds, as well as their pharmaceutically acceptable salts, may be used as anxiolytic, anti-convulsive, muscle relaxant and/or sedative-hypnotic active substances.

Description

Acetylimidazobenzodiazepines

The present invention relates to benzodiazepines. In particular, it relates to imidazo [1,2-a] [1,4] benzodiazepines of the general formula

wherein

R ^{1 is} hydrogen, lower alkyl, hydroxy lower alkyl, lower

Alkanoyloxy-lower alkyl, 2-pyridyl or phenyl, optionally substituted by lower alkoxy or di-lower alkylamino;

R ² phenyl, optionally substituted by 2-halogen;

R ³ -C (O) R ⁵ or -C (OH) HR ⁵ ;

R ^{4 is} hydrogen, lower alkyl, hydroxy lower alkyl, carboxy,

lower alkoxycarbonyl or phenyl, optionally substituted by lower alkoxy or di-lower alkylamino,

R ^{5 is} hydrogen or lower alkyl,

and pharmaceutically acceptable salts thereof.

These compounds and salts are new and have valuable pharmacodynamic properties. They are therefore suitable for therapeutic purposes, in particular for anxiolytic and / or anti convulsive and / or muscle relaxant and / or sedative-hypnotic purposes. A particular advantage of the new connections of the

general formula I is the good water solubility of its salts and a short duration of action for the above

Usage.

The present invention relates to the compounds of formula I and salts thereof as such and as therapeutic active substances, their preparation and their use for therapeutic purposes or for the preparation of corresponding medicaments and medicaments containing a compound of

Formula I or a salt thereof, and the preparation thereof

Drug.

The term "lower" denotes residues or compounds with at most 7, preferably at most 4, carbon atoms. The

The term "alkyl" denotes straight-chain or branched saturated

Hydrocarbon radicals, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl.

The term "halogen" includes fluorine, chlorine, bromine and iodine.

The term "alkanoyl" denotes residues such as acetyl, propionyl and the like.

The term "propargylamine derivative" preferably denotes the radical "lower alkyn-2-ylamine".

Particularly preferred compounds according to the invention are those in which R ^{1 is} methyl, hydrogen, hydroxymethyl or

CH ₂ OCOCH ₃ , R ² 2-F-phenyl, R ⁵ methyl and R ^{4 are} hydrogen, methyl or hydroxymethyl.

Examples of particularly preferred compounds are the following:

1- [6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone;

1- [6- (2-Fluoro-phenyl) -1-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone; 1- [6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone;

1- [2-Ethyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone and

1- [6- (2-Fluoro-phenyl) -1,2-dimethyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] -ethanone.

The following compounds are also preferred:

1- [6- (2-fluoro-phenyl) -2-hydroxymethyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone;

[8-acetyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-2-yl] methyl acetate;

8-acetyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine-1-methanol and

(RS) -1- [6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanol.

The compounds of the general formula I mentioned at the outset and their pharmaceutically acceptable acid addition salts can be prepared according to the invention by a) a compound of the general formula

wherein R ² and R ^{5 have} the meaning given above and Ra is hydrogen,

with an α-haloketone of the general formula

wherein

R ¹¹ lower alkyl, lower alkanoyloxy lower alkyl, 2-pyridyl or

Phenyl, optionally substituted by lower alkoxy or di-lower alkylamino and R ^{41 is} lower alkyl, carboxy, lower alkoxycarbonyl or phenyl, optionally substituted by lower alkoxy or di-lower alkylamino,

N-alkylated, and cyclized to the corresponding compounds of general formula I, or b) a compound of general formula II, in which R ² and R ^{5 have} the meaning given above and Ra is a propargylamine derivative, to the corresponding compounds of general formula I. cyclized c) a compound of the general formula

wherein R ² and R ^{5 have} the meaning given above,

cyclized with a propargylamine derivative in the presence of an alkali acetate and catalytic amounts of acid to give the corresponding compounds of the general formula I, or d) a compound of the general formula

wherein R ² and R ^{5 have} the meaning given above and R ^{6 is} lower alkyl,

in acidic medium to compounds of general formula I, wherein

R ¹ and R ^{4 are} hydrogen and R ² and R ^{5 have} the meaning given above, cyclized, or e) a compound of the general formula

wherein R ² , R ⁴ and R ^{5 have} the meaning given above, n is 1-4 and X is halogen,

with a basic reagent into compounds of the general formula I, wherein R ¹ Hydroxynieder alkyl, is reacted, f) a compound of general formula I, wherein R ¹ and R ² -R Hydroxynieder alkyl ⁴ have the meaning given above, to a compound of the general formula I in which R ^{1 is} lower alkanoyloxy-lower alkyl, or g) a compound of the general formula

in which R ² , R ⁵ and n have the meaning given above, cyclized in the acid medium to give a compound of the general formula I in which R ^{1 is} hydrogen and R ^{4 is} hydroxy-lower alkyl, or h) a compound of the general formula I, wherein R ¹ , R ² and R ^{3 have} the meaning given above and R ^{4 is} lower alkyloxycarbonyl, converted into a compound of the general formula I, in which R ^{4 represents} a carboxy group, or i) from a compound of the general formula

wherein R ¹ , R ² and R ^{4 have} the meaning given above and R ⁷ denotes a protected -COR ⁵ group,

the protective group is split off, or j) a compound of the general formula I, in which R ¹ , R ² and R ^{4 have} the abovementioned meaning and R ^{3 is} -C (OH) HR ⁵ , into a compound of the general formula I, in which R ³ denotes -C (O) R ⁵ , and k) converts a compound of the general formula I into a pharmaceutically acceptable acid addition salt.

According to process variant a), a compound of general formula II can be N-alkylated and cyclized to compounds of general formula I. The alkylation takes place according to methods known per se. A compound of the formula II is expediently dissolved in a solvent, for example in dioxane, N, N-dimethylformamide or toluene, with the corresponding

Alkylating agent added and in the presence of a basic

Reagenses implemented at 100-120 ° C. The response time can vary between 30 minutes and 24 hours. The following are particularly suitable as alkylating agents: chloroacetone, phenacyl bromide, 2-bromo-1- (4-methoxy-phenyl) propane, 4-dimethylamino-phenacyl bromide, 1-bromo-1- (methoxy-phenyl) propane-2- on, 2-bromo-1-pyridin-2-ylethanone, 4-hydroxyphenacylbromide, 1-chloro-2-butanone, 3-chloro-2-butanone, 2-chloroacetoacetic acid, ethyl ester and the like. According to process variant b) the cyclization takes place

Compound of the formula II with a propargylamine derivative,

preferably with lower alkyn-2-yl-amine. The group -C (O) R ⁵ is expediently protected. The cyclization takes place under reflux, for example in n-butanol. According to process variant c), a compound of the general formula II is cyclized by advantageously reacting a reactive amine, for example propargylamine hydrochloride and an acetate, for example sodium acetate, in the presence of p-toluenesulfonic acid with a compound of the formula III.

For example, n-butanol is suitable as the solvent. The reaction to the corresponding compounds of formula I takes place over a period of several hours in a temperature range around 120 ° C.

Process variant d) produces a compound of the general formula I in which R ¹ and R ^{4 are} hydrogen and R ² and R ⁵ are as defined above. It is convenient to start from a compound of general formula IV, which is cyclized under acidic conditions. Glacial acetic acid is particularly suitable for the cyclization. Advantageously, one compound of formula IV is dissolved in glacial acetic acid and several

Cooked at reflux at about 100 ° C for hours.

Process variant e) comprises the production of

Compounds of the general formula I, in which R ^{1 is} hydroxy-lower alkyl and R ² , R ⁴ and R ^{5 have} the meaning given above.

A compound of the general formula V is expediently treated with a basic reagent. The procedure is expediently as follows: A compound of the general formula V is optionally treated under an inert gas atmosphere for several hours with an alkali metal hydroxide solution, preferably with sodium hydroxide, or with an alkali metal bicarbonate,

preferably treated with sodium hydrogen carbonate and

then worked up according to known methods.

According to process variant 0, compounds of the formula I are obtained in which R ^{1 is} lower alkanoyloxy lower alkyl. It is expedient to start from a compound of formula I, which was prepared according to process variant e). Appropriately, one can proceed as follows: A compound of formula I, in which R ^{1 is} hydroxy-lower alkyl and R ² -R ^{4 have} the meanings given above, is added with the addition of

Pyridine reacted with acetic anhydride and worked up by generally known methods. Process variant g) comprises the preparation of compounds of the general formula I in which R ^{1 is} hydrogen and R ^{4 is} hydroxy-lower alkyl. Starting from a compound of formula VI, this is expediently treated with a strong acid, for example concentrated sulfuric acid, and several

Stirred for hours at room temperature. After working up, which is familiar to any person skilled in the art, the cyclized target products are obtained in good yield.

According to process variant h), compounds of the general formula I in which R ^{4 is} a carboxy group are formed, starting from compounds of the formula I in which R ¹ , R ² and R ^{3 have} the abovementioned meanings and R ^{4 is} lower alkyloxycarbonyl. This saponification takes place according to generally known

Methods by the connection with the ester group expediently with a water / ethanol solution in the presence of

Sodium hydroxide solution is treated under a protective gas atmosphere and saponified to form a compound with an acid group.

According to process variant i), compounds of the general formula I are formed by splitting off protective groups. Suitable protective groups and methods for their separation are everyone

Those skilled in the art are familiar, but of course only those protective groups can be used which can be split off by methods under whose conditions other structural elements in the

Compounds of formula VII are not affected. A corresponding carbonyl protective group is suitable

Dioxolane group, which can be split off by reaction in an acidic range, for example by reaction in hydrochloric acid.

Process variant j) comprises the transfer of a

Compound of formula I, wherein R ¹ , R ² and R ^{4 have} the meaning given above and R ^{3 is} -C (OH) HR ⁵ , in a compound of

Formula I, wherein R ^{3 is} -C (O) R ⁵ . Appropriately, one proceeds as follows: To a solution consisting of

Dimethyl sulfoxide, dichloromethane and trifluoroacetic anhydride are added in portions to a compound of the general formula VIII and then triethylamine is added dropwise. After one for everyone Working up, which is familiar to a person skilled in the art, gives the target compounds of the formula I.

According to process variant k), the compounds of formula I can be converted into pharmaceutically acceptable acid addition salts. Both salts with inorganic and salts with organic acids can be considered. Examples of such salts are the hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, maleates, succinates, methanesulfonates, p-toluenesulfonates and the like. These salts can be prepared by methods known per se.

The starting products of the above formulas II, III, IV, V, VI, VII and VIII can be prepared according to schemes 1, 2 or 3 below.

R ¹ -R ^{5 have} the meaning given above, R ⁶ means lower alkyl and R ⁷ means a protected -COR ⁵ group, Ra means hydrogen, n means 1-4 and X is halogen.

According to Scheme 1, compounds of the general

Formulas II, III, IV, V and VI are prepared, which can then be converted into compounds of the general formula I as described in process variants a) -e).

Starting from the known compound IX (described in US Pat. No. 3,627,754), compounds of the general formula III are obtained by expediently combining the compound IX with the

Lawesson's reagent treated. This is done in one

Solvents, for example in pyridine at about 100 ° C for several hours. The resulting thione of compound III can then be converted into a compound of

Implement Formula VI (described in J. Org. Chem. 46, 1575-1585 (1981).

A further reaction of the compound of formula III with a dialkoxyethylamine, e.g. with 2,2-dimethyloxyethylamine at room temperature leads to a corresponding compound of the general formula IV. To prepare a compound of the general formula II, a compound of the formula III is advantageously mixed with an aqueous ammonia solution, tetrahydrofuran being very suitable as solvent. Then one

Compound of general formula II in a compound of

Formula V are converted, which can expediently be accomplished with 1,3-dichloroacetone, dissolved in dioxane. Scheme 2 shows the preparation of special intermediates of the formulas VIIa and VIIb, these compounds containing a protective group or a protected carbonyl group on the phenyl ring. A compound of the formula XI can thus be prepared by expediently treating a compound of the formula X (described in DE-OS 2'163'522) with a solution consisting of a sodium hydride dispersion and N, N-dimethylformamide. Phosphoric acid diphenyl ester chloride and then ammonium carbonate are added, and after a number of hours using generally known methods to give a compound of the general

Formula XI implemented. If the compound obtained is dissolved in a solvent, e.g. Dioxane and mixed with 1,3-dichloroacetone and sodium hydrogen carbonate, a compound is obtained

general formula XII. The ring closure to the compound of formula VIII takes place by reaction with ammonium formate.

A compound of the general formula VIIIb is conveniently obtained by adding a compound of the formula X to propargylamine. One can proceed as follows: a sodium hydride dispersion, N, N-dimethylformamide and one

Compound of the general formula X is stirred with

Tetrahydrofuran added, cooled and treated with diphenyl ester of phosphoric acid. Then propargylamine is added dropwise and stirred for several hours. The cyclization to the compound of the formula IIIb is then advantageously carried out with an alcohol, for example with n-butanol.

Scheme 3 shows a possible course of the reaction

Preparation of compound VIII. The procedure is expediently as follows: A compound of the general formula XIV is dissolved in methanol saturated with hydrogen chloride and dissolved in

Introduction of hydrogen chloride heated to reflux. To

Working up produces a compound of general formula XV, which can be reduced to a compound of formula VIII. The reaction is conveniently carried out with lithium aluminum hydride in tetrahydrofuran at temperatures around -30 to -40 ° C. As mentioned at the beginning, the compounds of the formula I are new.

They have valuable pharmacodynamic properties. she have, as a common characteristic, a pronounced affinity for the central benzodiazepine receptors and, due to their agonistic action, have pronounced affinity for these receptors

anxiolytic, anticonvulsant, muscle relaxant and sedative hypnotic properties. They form very water-soluble

Acid addition salts and are therefore particularly suitable for the preparation of aqueous injection solutions.

The affinity of compounds of the general formula I for the central benzodiazepine receptors was determined in vitro according to the method described in Nature 224, 763-765 (1981) and J. Neurochemistry 37, 714-722 (1981)

described method found. According to this method, the inhibition of the binding of tritiated flumazenil to the specific benzodiazepine receptors in the rat cortex is determined by the respective test substances. It is referred to as the IC ₅₀

Concentration of the respective test substance, which is a 50 percent.

Inhibition of the specific binding of the tritiated flumazenil to the specific benzodiazepine receptors in the rat cortex.

The sedative / muscle relaxant properties of

Compounds of formula I according to the invention can

for example in the rotating rod test. Mice weighing 19-21 g are used for this test. You have free access to food and drinking water up to 1 hour before the start of the experiment. At least 30 minutes before the attempt, they will be in the

Test laboratory brought. In the rotating rod test, the animals are placed on a horizontally arranged, smooth metal rod of 3 cm

Diameter that rotates at 2 revolutions per minute. First, the animals are given 30 seconds to familiarize themselves with the test situation. Then those animals are selected that manage to stay on the stick for at least 1 minute. These animals are then the

Trial preparations administered intravenously in various doses. At various times, it is then determined whether the animals can stay on the stick for a minimum time (minimum time: 10 seconds, from 5 minutes after administration: 1 minute). The dose is determined at which 50% of the animals are able to stay on the stick (ED ₅₀ ). The following table shows the results which were obtained with representative representatives of the class of compounds defined by the general formula I in the experiments described above.

Here mean:

A 1- [6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone

B 1- [6- (2-Fluoro-phenyl) -1-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone

C 1- [6- (2-Fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone D 1- [6- (2-Fluoro-phenyl) -2-hydroxymethyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone

E [8-acetyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] - benzodiazepin-2-yl] methyl acetate F 8-acetyl-6- ( 2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine-1-methanol

G 1- [2-Ethyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone

H 1- [6- (2-Fluoro-phenyl) -1,2-dimethyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone

I (RS) -1- [6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanol

It can be seen from the table above that compounds A to I develop a sedative action which occurs very rapidly and lasts only for a relatively short time.

Because of their agonistic action on the benzodiazepine receptors, the compounds of the formula I can be used as sedatives /

Hypnotics, anticonvulsants, muscle relaxants and anxiolytics can be used. They are suitable, for example, as quick but short-acting hypnotics for oral administration, but especially - in the form of aqueous solutions of their acid addition salts - as

injectable short hypnotics for premedication, sedation as well

Induction and maintenance of anesthesia; preferred applications are premedication before induction of anesthesia, basal sedation before diagnostic or surgical

Interventions with or without local anesthesia, long-term sedation on the intensive care unit, use as an induction agent in the

Inhalation anesthesia or as a sleep-inducing component of combination anesthesia (including total intravenous

Anesthesia) etc.

The compounds of formula I and pharmaceutically acceptable acid addition salts thereof can be used as medicines, for example in the form pharmaceutical preparations, find use. The pharmaceutical preparations can be taken orally, for example in the form of tablets,

Coated tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions or suspensions can be administered. However, administration can also be rectal, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

For the preparation of pharmaceutical preparations, the compounds of formula I and pharmaceutically acceptable

Acid addition salts thereof are processed with pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such a carrier for tablets, coated tablets, coated tablets and hard gelatin capsules. For

Soft gelatin capsules are suitable as carriers, for example

vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; Depending on the nature of the active ingredient, no carriers are required at all in the case of soft gelatin capsules. Carriers are suitable for the production of solutions and syrups

for example water, polyols, sucrose, invert sugar, glucose and the like. More water-soluble for aqueous injection solutions

Acid addition salts of compounds of the formula I, auxiliaries such as alcohols, polyols, glycerol, vegetable oils and the like can be used but are generally not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can also

Preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, aromatizing agents, salts for changing the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances.

As mentioned at the beginning, are medicinal products containing one

A compound of formula I or a pharmaceutically acceptable acid addition salt thereof and a therapeutically inert excipient. also the subject of the present invention, also a

Process for the preparation of such medicaments, which thereby characterized in that one or more compounds of formula I or pharmaceutically acceptable acid addition salts thereof and optionally one or more other therapeutically valuable substances together with one of the several therapeutically inert carriers are brought into a pharmaceutical dosage form.

As mentioned at the outset, the compounds of the formula I and pharmaceutically acceptable acid addition salts thereof can be used according to the invention for therapeutic purposes, in particular for anxiolytic and / or anticonvulsive and / or muscle relaxant and / or sedative-hypnotic purposes. The

Dosage can vary within wide limits and is of course to be adapted to the individual circumstances in each individual case. In general, intravenous administration is likely to result in a

Daily dose of about 1 mg to 1000 mg may be appropriate. Finally, the invention also relates, as mentioned at the outset, to the use of compounds of the formula I and of pharmaceutically acceptable acid addition salts thereof for the production of medicaments, in particular of

anxiolytic and / or anticonvulsive and / or

muscle relaxant and / or sedative-hypnotic drugs.

The following examples are intended to explain the present invention in greater detail, but in no way limit its scope.

example 1

1- [6- (2-Fluoro-phenyl) -2-methyl-4H-imidazori.2-a] [1,41benzodiazepin-8-yl] ethanone a) To a solution of 15.0 g (50.6 mmol) 7- Acetyl-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-2 (1H) -one (R.Ning & LHSternbach, US Pat. 3,627,754 (1971)) in 300 ml pyridine were 11 g (27.2 mmol)

Lawesson's reagent added. The mixture was heated at 100 ° C for 8 hours and then left at room temperature for 16 hours. The

Solution was concentrated in vacuo and the residue in

Chloroform and saturated aqueous sodium bicarbonate solution added. The aqueous phase was extracted twice more with chloroform. The chloroform extracts were made with Dried sodium sulfate and evaporated in vacuo. The

The residue was suspended in 500 ml of hot dioxane, and the suspension was concentrated to about 100 ml in vacuo. The crystals were filtered off while warm. 15.3 g (96%) of 7-acetyl-5- (2-fluorophenyl) -3H-1,4-benzodiazepine-2 (1H) -thione, mp. 213-215 ° C., which was used without further purification, were obtained the stage described below was used. b) To a solution of 15.0 g (48.1 mmol) of 7-acetyl-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-2 (1H) -thione in 750 ml of tetrahydrofuran were added 265 ml of aqueous ammonia solution (25% ) and that

Mixture stirred at room temperature. 5 ml of methanol were added 5 times at intervals of about 1 hour. After stirring at room temperature for 20 h, the mixture was concentrated in vacuo to about 50 ml and the crystals which had precipitated out were filtered off. These were dried in a vacuum. There were 11.5 g (81%) of 1- [2-amino-5- (2-fluoro-phenyl) -3H-1,4-benzodiazepin-7-yl] -ethanone as light yellow crystal powder of mp. 227-228 ° C. (Dec.) Obtained, which was used without further purification for the step described below. c) A solution of 2.95 g (10.0 mmol) of 1- [2-amino-5- (2-fluoro-phenyl) -3H-1,4-benzodiazepin-7-yl] ethanone and of 0.88 ml (11.0 mmol) Chloroacetone in 40 ml of dioxane was stirred at 100 ° C for 17 h. After cooling, the inorganic salts were filtered off, 60 ml of acetic acid were added to the filtrate, the mixture was stirred at 100 ° C. for 3 h and, after cooling, concentrated in vacuo. The residue was taken up in saturated aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The dichloromethane extracts were dried over sodium sulfate and in

Vacuum concentrated. The residue was dissolved in dichloromethane and chromatographed on 200 g of silica gel. With dichloromethane, which contained 0.5 to 2% ethanol, a small amount

By-product eluted. 0.62 g of crude 8-acetyl-6- (2-fluoro-phenyl) -4H-imidazo- [1,2-a] [1,4] benzodiazepine were eluted with dichloromethane, which contained 4 to 5% ethanol. This was dissolved in 15 ml of toluene / ethyl acetate 2: 1 and chromatographed on 30 g of aluminum oxide (current stage II). With toluene / ethyl acetate 2: 1 405 mg (12%) of 1- [6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] 1,4] benzodiazepin-8-yl] ethanone was eluted. After recrystallization from diethyl ether, pure 1- [6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone of mp. 183-184 ° C, which was converted into the hydrochloride of mp. 245 ° C (dec.).

Example 2

1- [6- (2-Fluoro-phenyl) -1-methyl-4H-imidazon.2-a] [1,4lbenzodiazepin-8-yl] -ethanone a) To a suspension of 3.12 g (10.0 mmol) 7- Acetyl-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-2 (1H) -thione (prepared according to Example la) in 80 ml of n-butanol were successively 1.2 g (12.8 mmol)

Propargylamine hydrochloride, 1.07 g (13.0 mmol) anhydrous

Sodium acetate, 10 mg p-toluenesulfonic acid and 0.5 ml water

added and the mixture heated to 120 ° C. for 5.5 h. The reaction mixture was evaporated in vacuo. The backlog was in

50 ml of acetic acid were added and the mixture was stirred at 100 ° C. for 2 h. To

After cooling, the solution was evaporated in vacuo. The residue was taken up in ethyl acetate and saturated aqueous sodium hydrogen carbonate solution; the aqueous phase was extracted twice more with ethyl acetate. The combined organic extracts were washed successively with aqueous sodium hydrogen carbonate solution and with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The oily residue was taken up in dichloromethane and chromatographed on 200 g of silica gel. With

Impurities were eluted from dichloromethane containing 2 to 3% ethanol. The desired product was eluted with dichloromethane, which contained 4 to 5% ethanol. The residue (1.46 g, 44%) was crystallized from toluene. This gave 1- [6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone, mp. 177-178 ° C., which was converted into the hydrochloride of mp. 241 ° C (dec.). Example 3

1- [6- (2-Fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazenin-8-yl] -ethanone a) To a suspension of 2.0 g (6.4 mmol) 7- Acetyl-5- (2-fluorophenyl) -3H-1,4-benzodiazepine-2 (1H) -thione (prepared according to Example la) in 50 ml of tetrahydrofuran were 2.1 ml (18.8 mmol)

2,2-Dimethoxyethylamine added and stirred for 4 h at room temperature. The solvent was removed in vacuo. The

The residue was dissolved in ethyl acetate and the solution was washed three times with saturated aqueous sodium chloride solution

Dried sodium sulfate and concentrated in vacuo. The residue (2.5 g) was crystallized from ethyl acetate / diethyl ether / diisopropyl ether. 2.0 g (81%) of 1- [2- (2,2-dimethoxyethylamino) -5- (2-fluoro-phenyl) -3H-1,4-benzodiazepin-7-yl] -ethanone were obtained

Mp 158-161 ° C, which was used without further purification as a starting product for the step described below. b) A solution in 70 of 1.9 g (4.95 mmol) of 1- [2- (2,2-dimethoxyethylamino) -5- (2-fluoro-phenyl) -3H-1,4-benzodiazepin-7-yl] ethanone ml of glacial acetic acid was heated to 100 ° C. for 16 h. After cooling it was

Solvent removed in vacuo. The backlog was in

saturated aqueous sodium bicarbonate solution

recorded and extracted 2 times with dichloromethane. The

Dichloromethane extracts were dried over sodium sulfate and chromatographed on 300 g of silica gel. By-products were eluted with dichloromethane containing 1% to 2% ethanol. With

Dichloromethane, which contained 4% to 5% ethanol, 1.54 g of the desired product was eluted. After recrystallization

Ethyl acetate / diisopropyl ether gave 0.8 g (51%) of 1- [6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] -ethanone from M.p. 188-189 ° C. After recrystallization from ethyl acetate again, the mp was 189-190 ° C. The hydrochloride was obtained in ethanol by adding ethanolic hydrochloric acid and diethyl ether, mp. 275 ° C (dec.). Example 4

1- [6- (2-Fluoro-phenyl) -2-hydroxymethyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone

A solution of 3.4 g (11.5 mmol) of 1- [2-amino-5- (2-fluoro-phenyl) -3H-1,4-benzodiazepin-7-yl] -ethanone (prepared according to Example 1b) and

1.66 g (12.4 mmol) 95% 1,3-dichloroacetone in 100 ml dioxane was mixed with 1.08 g (12.8 mmol) sodium hydrogen carbonate and heated to 98 ° C. for 23 h. The reaction mixture was filtered, the filtrate was mixed with 0.25 g of p-toluenesulfonic acid, heated to 98 ° C. for 2 h and concentrated in vacuo. The residue was taken up in water with

Sodium carbonate solution made weakly alkaline and extracted three times with the same volume of dichloromethane. The combined organic phases were dried over magnesium sulfate, concentrated in vacuo and chromatographed on 130 g of silica gel. With dichloromethane, which contained 2% methanol, 1- [2-chloromethyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] -ethanone eluted, which, after evaporation of the solvents, was obtained as a foam (3 g). This was dissolved in 50 ml of dioxane, 0.8 g of sodium hydrogen carbonate and 20 ml of water were added, and the mixture was stirred at 80 ° C. for 2 h. The mixture was concentrated in vacuo, and the

Chromatograph the residue on 100 g of silica gel. With dichloromethane, which contained 3% ethanol, 1- [6- (2-fluoro-phenyl) -2-hydroxymethyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] -ethanone eluted, which was recrystallized once from ethyl acetate and once from ethanol. 1.85 g (46%) of 1- [6- (2-fluoro-phenyl) -2-hydroxymethyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone of mp 191-193 ° C, which was converted into the hydrochloride of mp. 260-263 ° C (dec.).

Example 5 [8-acetyl-6- (2-fluoro-phenyl) -4H-imidazo [1, 2-a] [1,4] benzodiazepin-2-yl] methyl acetate

A solution of 0.50 g (1.43 mmol) of 1- [6- (2-fluoro-phenyl) -2-hydroxymethyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] -ethanone in 29.5 g of pyridine were mixed with 46 g of acetic anhydride. After 3 h another 2.3 g of acetic anhydride were added, and in

Evaporated vacuum. The residue was taken up in ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extracts were washed with water, dried over sodium sulfate and in vacuo

evaporated. The oily residue (0.6 g) was dissolved in chloroform and chromatographed on 30 g of silica gel. The desired substance was eluted with chloroform. 0.5 g of acetic acid [8-acetyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-2-yl] methyl ester was obtained as an oil. This was dissolved in ethyl acetate and a solution of hydrogen chloride in ethyl acetate was added. After addition of diethyl ether, 98 mg (16%) of acetic acid- [8-acetyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] - benzodiazepin-2-yl] crystallized methyl ester hydrochloride mp 156-158 ° C. Example 6

8-acetyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine-1-methanol a) To a suspension of 1.2 g (3.85 mmol) 7-acetyl- 5- (2-fluorophenyl) -3H-1,4-benzodiazepin-2 (1H) -thione (prepared according to Example la) in 80 ml of ethanol were 0.43 g (3.23 mmol) (2-hydroxymethyl-1,3-dioxolane 2-yl) methylamine (M.Gall & BV Kamdar, J. Org. Chem. 46, 1575-1585 (1981)) was added and the mixture was stirred at reflux temperature for 6 h. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate and chromatographed on 80 g of silica gel. With ethyl acetate, 0.2 g of starting material

(Thion) eluted together with smaller amounts of impurities. The desired product was eluted with ethyl acetate, which contained 3 to 8% ethanol. This was crystallized from ethyl acetate / diethyl ether. 1.15 g (73%) were obtained

1- [5- (2-Fluoro-phenyl) -2 - [(2-hydroxymethyl- [1,3] dioxolan-2-ylmethyl) aminol-3H-1,4-benzodiazepin-7-yl] ethanone of mp. 228-229 ° C, which was used without further purification as a starting product for the stage described below. b) 662 mg (1.6 mmol) 1- [5- (2-fluoro-phenyl) -2 - [(2-hydroxymethyl- [1,3] -dioxolan-2-ylmethyl) amino] -3H-1,4- benzodiazepin-7-yl] ethanone were added in portions in 2.1 ml of conc. Dissolved sulfuric acid, and this solution was stirred for 24 h at room temperature. The reaction mixture was poured into 250 ml of ice water. The pH was adjusted to about 10 by adding saturated aqueous sodium carbonate solution and the mixture was stirred at room temperature for 30 min. Then 50 ml of chloroform were added and the mixture was stirred for a further 30 min. The aqueous phase was separated and extracted again with 50 ml of chloroform. The combined organic extracts were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. This solution was chromatographed on 50 g of silica gel.

520 mg of an oil which crystallized from ethyl acetate and diethyl ether were eluted with chloroform, which contained 2 to 5% ethanol. 486 mg (87%) of 8-acetyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine-1-methanol of mp 130-135 ° C. were obtained . The hydrochloride was made more ethanolic by adding ethanol

Hydrochloric acid and diethyl ether obtained. It melts at 224 ° C (dec.).

Example 7

1- [6- (2-Fluoro-phenyl) -2-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] -ethanone A suspension of 519 mg (1.75 mmol) 1 - [2-Amino-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-7-yl] ethanone (prepared according to

Example lb) in 40 ml of dioxane was mixed with 438 mg (2.2 mmol) of phenacyl bromide and 210 mg (2.5 mmol) of sodium hydrogen carbonate and stirred at 100 ° C. for 16 h. Another 87 mg (0.45 mmol)

Phenacyl bromide and 210 mg (2.5 mmol) sodium hydrogen carbonate were added and the mixture was stirred at 100 ° C. for 5.5 h. After a further addition of 87 mg (0.45 mmol) phenacyl bromide and 105 mg (1.25 mmol)

Sodium bicarbonate was further stirred at 100 ° C for 30 h. The reaction mixture was concentrated in vacuo and the residue was taken up in 50 ml of dichloromethane and 20 ml of saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was separated and extracted twice more with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and with water, dried with sodium sulfate and evaporated in vacuo. The

The residue was dissolved in dichloromethane and on 100 g of silica gel chromatographed. Impurities were eluted with dichloromethane, which contained 0.5 to 2% ethanol. The desired substance was eluted with dichloromethane containing 2 to 3% ethanol (287 mg). After recrystallization twice from ethyl acetate / diethyl ether, 70 mg (10%) of 1- [6- (2-fluoro-phenyl) -2-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine-8 were obtained -yl] -ethanone dated

Mp 199-200 ° C, which was converted into the hydrochloride of mp. 241 ° C (dec.).

Example 8 1- [6- (2-Fluoro-phenyl) -2- (4-methoxy-phenyl) -1-methyl-4H-imidazo- [1,2-a] [1,41benzodiazepin-8-yl] - ethanone hydrochloride (1: 1)

A solution of 1.4 g (4.75 mmol) of 1- [2-amino-5- (2-fluoro-phenyl) -3H-1,4-benzodiazepin-7-yl] -ethanone (prepared according to Example 1b) in 10 ml of N. 1.6 g (6.65 mmol) of 2-bromo-1- (4-methoxyphenyl) propan-1-one and 0.8 g (9.5 mmol) of sodium hydrogen carbonate were added to N-dimethylformamide and the mixture was stirred at 100 ° C. for 1 h. Another 685 mg (2.8 mmol) of 2-bromo-1- (4-methoxy-phenyl) propan-1-one were added and the mixture was stirred at 100 ° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue was taken up in 30 ml of saturated aqueous sodium hydrogen carbonate solution. It was extracted twice with dichloromethane, dried with sodium sulfate and evaporated in vacuo. The residue was chromatographed on 80 g of silica gel with dichloromethane / acetone 9: 1, then 2: 1, whereby a brown oil was obtained. The crude product was again treated with 100 g of Alox (neutral, current stage I) with hexane /

Ethyl acetate, then chromatographed with ethyl acetate to give 150 mg (7%) of pure product. This was dissolved in about 3 ml of acetonitrile, acidified with ethereal hydrochloric acid and evaporated. After boiling up a suspension of the hydrochloride in 5 ml acetonitrile and drying in a vacuum

At 80 ° C., 47 mg (3%) of 1- [6- (2-fluoro-phenyl) -2- (4-methoxy-phenyl) -1-methyl-4H-imidazo [1,2-a] [1, 4] benzodiazepin-8-yl] -ethanone hydrochloride (1: 1) obtained as almost white crystals of mp. 248-250 ° C. Example 9

1- [2- (4-Dimethylamino-phenyl) -6- (2-fluoro-phenyl) -4H-imidazo [1, 2-a] - [1,4] benzodiazepin-8-yl] -ethanone fumarate (2nd :1)

A solution of 1.4 g (4.75 mmol) of 1- [2-amino-5- (2-fluoro-phenyl) -3H-1,4-benzodiazepin-7-yl] -ethanone (prepared according to Example Ib) in 3 ml of N 450 mg (1.85 mmol) of 4-dimethylaminophenacyl bromide and 155 mg (1.85 mmol) of sodium hydrogen carbonate were added to N-dimethylformamide and the mixture was stirred at 100 ° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with 10 ml of water, the crystals were filtered off with suction and dissolved in 10 ml of dichloromethane.

The solution was dried with sodium sulfate, filtered and evaporated to give 430 mg of crude product. The

The residue was chromatographed on 30 g of silica gel with dichloromethane / acetone 9: 1, then 4: 1, whereby 230 mg of a yellow foam was obtained. This was again on 40 g Alox (neutral, act.

Step I) with dichloromethane / diethyl ether 9: 1, then 4: 1 and finally 2: 1 chromatographed, 214 mg (10%) of yellow crystals being obtained. These were dissolved in about 10 ml of methanol and 57 mg (0.5 mmol) of fumaric acid were added. It was heated to reflux and methanol was added until everything was just dissolved. The mixture was allowed to cool slightly and the solution, which was still warm, was filtered. These were left in the fridge for a long time. The yellow crystals which precipitated out were filtered off with suction. After drying in vacuo at 80 ° C., 150 mg (6.5%) of 1- [2- (4-dimethylaminophenyl) -6- (2-fluorophenyl) -4H-imidazo [1,2-a] [1,2-a] [ 1,4] benzodiazepin-8-yl] ethanone fumarate

(2: 1) mp 238-242 ° C.

Example 10

1- [6- (2-Fluoro-phenyl) -1- (4-methoxy-phenyl) -2-methyl-4H-imidazo- [1,2-a] [1,4] benzodiazepin-8-yl] - ethanone hydrochloride (1: 1) A solution of 738 mg (2.5 mmol) of 1- [2-amino-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-7-yl] -ethanone (prepared according to

Example 1b) in 10 ml of N, N-dimethylformamide was mixed with 1.2 g (5.0 mmol) of 1-bromo-1- (4-methoxy-phenyl) -propan-2-one and 0.42 g (5.0 mmol) of sodium hydrogen carbonate and 80 min at 100 ° C touched. The reaction mixture was concentrated in vacuo and the residue was taken up in 20 ml of saturated aqueous sodium hydrogen carbonate solution. It was extracted twice with dichloromethane, dried with sodium sulfate, filtered and evaporated in vacuo. The crude product was on 80 g Alox (neutral, act

III) with hexane / ethyl acetate 1: 1, then chromatographed with ethyl acetate, 790 mg of a black oil being obtained. For further purification, chromatography was again carried out on 40 g of Alox (neutral, act. Stage I) with ethyl acetate, 513 mg (47%) of the free base being obtained. This was dissolved in about 5 ml of acetonitrile, acidified with ethereal hydrochloric acid, suction filtered and the filter residue was recrystallized from acetonitrile. It was suctioned off again and the crystals were dried in vacuo at 80 ° C. for 21 h. 51 mg (4%) of 1- [6- (2-fluoro-phenyl) -1- (4-methoxy-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] were obtained. -benzodiazepin-8-yl] -ethanone hydrochloride (1: 1) as almost white crystals of mp. 238-240 ° C.

Example 11

1- [6- (2-Fluoro-phenyl) -2-pyridin-2-yl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone hydrochloride (1: 1.2)

A solution of 590.6 mg (2.0 mmol) of 1- [2-amino-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-7-yl] -ethanone (prepared according to

Example 1b) in 5 ml of N, N-dimethylformamide was treated with 684 mg (3.7 mmol) of 2-bromo-1-pyridin-2-ylethanone and 311 mg (3.7 mmol)

Sodium bicarbonate was added and the mixture was stirred at 100 ° C. for 1 h. The

The reaction mixture was concentrated in vacuo and the residue was taken up in 15 ml of saturated aqueous sodium hydrogen carbonate solution. The precipitated crystals were filtered off with suction, dissolved in dichloromethane, dried with sodium sulfate, filtered and evaporated. The crude product was on 30 g of silica gel with hexane /

Chromatograph ethyl acetate 4: 1, whereby 222 mg of the free base were obtained. This was dissolved in about 5 ml of acetonitrile, acidified with ethereal hydrochloric acid and heated to reflux for 30 min. The mixture was allowed to cool and the product was isolated by suction. It was dried in vacuo at 70 ° C for 16 h. 121 mg (13%) were obtained.

1- [6- (2-Fluoro-phenyl) -2-pyridin-2-yl-4H-imidazo [1,2-a] [1,4] benzo diazepin-8-yl] -ethanone hydrochloride (1: 1.2) as almost white crystals of mp. 168-175 ° C (dec.).

Example 12

1- [6- (2-Fluoro-phenyl) -2- (4-methoxy-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone hydrochloride (1: 0.9 )

Example lb) in 5 ml of N, N-dimethylformamide was treated with 504 mg (2.2 mmol) of 4-methoxyphenacyl bromide and 185 mg (2.2 mmol)

Sodium bicarbonate added and stirred at 100 ° C for 30 min. Another 252 mg (1.1 mmol) of 4-methoxy-phenacyl bromide were added and the mixture was refluxed for 1 h. The reaction mixture was concentrated in vacuo and the residue was taken up in 15 ml of saturated aqueous sodium hydrogen carbonate solution and stirred for 30 min. The brown crystals were filtered off, dissolved in dichloromethane, dried with sodium sulfate, filtered and evaporated. The crude product was on 35 g of silica gel with dichloromethane / ethyl acetate 4: 1, then 1: 1 and finally with

Chromatographed ethyl acetate alone, giving 450 mg of the free base as an oil. The oil was crystallized by stirring in ethyl acetate for 4 h. The crystals were filtered off with suction, taken up in ethyl acetate and the hydrochloride was precipitated by adding ethereal hydrochloric acid. After filtration, the mixture was dried in vacuo at 80 ° C. for 16 h. 237 mg (26%) of 1- [6- (2-fluoro-phenyl) -2- (4-methoxy-phenyl) -4H-imidazo- [1,2-a] [1,4] benzodiazepine-8 were obtained -yl] -ethanone hydrochloride (1: 0.9) as almost white crystals of mp. 263-270 ° C (dec.).

Example 13

1- [2-Ethyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone hydrochloride (1: 1)

To a suspension of 1.69 g (5.7 mmol) of 1- [2-amino-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-7-yl] -ethanone (prepared according to

Example lb) in 10 ml of toluene was added dropwise to 1.95 ml (1.15 mmol) of N-ethyl-diisopropylamine and 1.22 g (1.15 mmol) of 1-chloro-2-butanone added. The mixture was heated to 110-120 ° C over 18 h. The

The reaction mixture was concentrated in vacuo, the residue was taken up in 20 ml of water and extracted three times with dichloromethane. It was evaporated and the crude product on 200 g Alox (neutral, act. Stage III) with dichloromethane / diethyl ether 9: 1 and 4: 1, then on 75 g Alox (neutral, act. Stage III) with hexane / ethyl acetate 9 : 1, 4: 1 and finally 1: 1 chromatographed, whereby 1.1 g of not quite pure product were obtained. This crude product was dissolved in acetonitrile and acidified with ethereal hydrochloric acid. It was evaporated and the residue was dissolved in water. The

The water phase was extracted three times with dichloromethane and then made dropwise basic with 5M aqueous sodium hydroxide solution. It was extracted again with dichloromethane, with

Dried sodium sulfate, filtered and evaporated. The free base was dissolved in acetonitrile and acidified with ethereal hydrochloric acid.

It was evaporated, recrystallized from acetonitrile, suction filtered and the product was dried at 60 ° C. in vacuo for 16 h. 236 mg (11%) of 1- [2-ethyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone hydrochloride were obtained ( 1: 1) as almost white crystals of mp 139-145 ° C (dec.).

Example 14

1- [6- (2-Fluoro-phenyl) -1,2-dimethyl-4H-imidazori.2-a] [1, 4] benzodiazepin-8-yl] -ethanone hydrochloride (1: 1)

To a suspension of 1.80 g (6.1 mmol) of 1- [2-amino-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-7-yl] -ethanone (prepared according to

Example lb) in 10 ml of toluene, 2.08 ml (12.2 mmol) of N-ethyl-diisopropylamine and 1.84 ml (18.3 mmol) of 3-chloro-2-butanone were added dropwise under argon. The mixture was heated to 120 ° C. for 20 hours. The mixture was allowed to cool, 2.08 ml (12.2 mmol) of N-ethyl-diisopropylamine and 1.84 ml (18.3 mmol) of 3-chloro-2-butanone were added dropwise and the mixture was heated for a further 5 h. The mixture was allowed to cool again and 1.04 ml (6.1 mmol) of N-ethyl-diisopropylamine and 0.92 ml (9.1 mmol) of 3-chloro-2-butanone were added dropwise. The mixture was heated again to 120 ° C. for 5 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in 150 ml of water and extracted three times with ethyl acetate. It was evaporated and the crude product on 280 g of Alox (neutral, act. stage II) chromatographed with ethyl acetate / hexane 9: 1 and 1: 1, 499 mg (24%) of the free base being obtained. This was dissolved in acetonitrile and ethereal

Acidified hydrochloric acid. It was evaporated and the residue was dissolved in water. The water phase was extracted three times with dichloromethane and then dropwise with 5M aqueous

Sodium hydroxide solution made basic. It was extracted again with dichloromethane, dried with sodium sulfate, filtered and evaporated. The free base was dissolved in acetonitrile and with ethereal

Acidified hydrochloric acid. It was evaporated from acetonitrile /

Recrystallized diethyl ether, suction filtered and the product dried in vacuo at 80 ° C for 16 h. 310 mg (13%) of 1- [6- (2-fluorophenyl) -1,2-dimethyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone hydrochloride ( 1: 1) as almost white crystals of mp 155-160 ° C (dec.). Example 15

8-Acetyl-6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1.4] benzodiazepine-1-carboxylic acid, ethyl ester

A suspension of 2.95 g (10.0 mmol) of 1- [2-amino-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-7-yl] -ethanone (prepared according to

Example lb) in 30 ml of N, N-dimethylformamide was added dropwise under argon with 1.8 ml (10.5 mmol) of N-ethyl-diisopropylamine and 1.5 ml (11.0 mmol) of ethyl 2-chloro-acetoacetate. The mixture was heated to 100 ° C. for 24 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in water and extracted three times with dichloromethane. It was evaporated and that

Crude product (1.8 g) dissolved in methanol and heated to reflux with the addition of activated carbon for 30 min. It was filtered, evaporated and the crude product was chromatographed on 260 g Alox (neutral, act. Stage III) with hexane / ethyl acetate 4: 1, then 1: 1, 1.33 g of not quite pure product being obtained as a light brown oil . The

Crude product was dissolved in 20 ml of hexane and left in the refrigerator. It was suctioned off and at 60 ° C for 20 h in vacuo

dried. 850 mg (21%) of 8-acetyl-6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepine-1-carboxylic acid ethyl ester were obtained as white Crystals of mp 135-138 ° C (dec.). Example 16

8-acetyl-6- (2-fluoro-phenyl) -2-methyl-4H-imidazori.2-a] [1, 4] benzodiazepine-1-carboxylic acid

721 mg (1.78 mmol) of 8-acetyl-6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepine-1-carboxylic acid ethyl ester were obtained in

10.5 ml of water / ethanol 3: 4 in the presence of 0.44 ml of 5M sodium hydroxide solution were heated under reflux for 30 min under argon. It was concentrated and acidified with 5M hydrochloric acid. The light brown crystals were filtered off and dried at 80 ° C in a vacuum for 18 h. 258 mg (38%) of 8-acetyl-6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepine-1-carboxylic acid of mp 208 were obtained -212 ° C (dec.).

Example 17

(RS) -1- [6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanol hydrochloride (1: 1.5 H Cl)

186 mg (0.56 mmol (1- [6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl]) -ethanone (obtained according to the example 1) were dissolved in 5 ml of ethanol under argon and cooled to -5 ° C. to 0 ° C. 211 mg (5.6 mmol) of sodium borohydride were added in portions to the solution and the mixture was stirred for 1 hour The water phase was hydrolyzed with

Extracted dichloromethane and dried the combined organic phases with sodium sulfate, filtered and evaporated. The residue was chromatographed on 10 g of silica gel with dichloromethane / acetone 9: 1, then 2: 1 and then with dichloromethane / methanol 19: 1. The solvents were removed in vacuo to give 166 mg (89%) (RS) -1- [6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanol were obtained. The free base was dissolved in acetonitrile and acidified with ethereal hydrochloric acid, evaporated and the

Crude product recrystallized from acetonitrile. 132 mg (61%) (RS) -1- [6- (2-fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl were obtained. -ethanol (1: 1.5 H Cl) of mp 163-170 ° C (dec.). Example 18

1 - (2-Methvl-6-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl) - ethanone hydrochloride (1: 1 HCl) a) To 120 mg (2.75 mmol ) 55 percent Sodium hydride dispersion in oil (washed with n-hexane) in 5 ml of N, N-dimethylformamide were 806 mg (2.5 mmol) of 7- (2-methyl- [1,3] dioxolane) under argon at approx. 5-6 ° C -2-yl) -5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one (prepared according to Ger. Offen. 2'163'522 (1972)) added dropwise in 7.5 ml of N, N-dimethylformamide, a crystal slurry formed. It was diluted with 10 ml of absolute tetrahydrofuran and at 30 ° C. for 30 minutes

continued stirring. It was cooled to -20 ° C. and 0.61 ml (2.75 mmol) of phosphoric acid diphenyl ester chloride was added dropwise. The cooling bath was removed and allowed to warm to 0 ° C, forming a cloudy yellow solution. After 30 min, 2.4 g (25 mmol) of ammonium carbonate were added and the mixture was allowed to warm to room temperature. The reaction was complete after 18 hours. It was

evaporated and the residue taken up in 20 ml of water. The water phase was decanted off and the residue was dissolved in dichloromethane, dried with sodium sulfate, filtered and

evaporated to give 1.8 g of a light brown oil.

This was chromatographed on 40 g of silica gel with dichloromethane / acetone 4: 1, then 2: 1 and finally with dichloromethane / methanol 19: 1. The solvents were removed in vacuo, giving 440 mg (55%) of 7- (2-methyl- [1,3] dioxolan-2-yl) -5-phenyl-3H-1,4-benzodiazepin-2-ylamine as a yellow Foam was obtained. This

Material is pure enough to be used in the next stage. After crystallization from ethyl acetate / diethyl ether, the product melts at 188-191 ° C. b) 440 mg (1.37 mmol) of the material obtained under a) were taken up in 15 ml of dioxane and after addition of 182 mg (1.44 mmol)

1,3-dichloroacetone and 120 mg (1.44 mmol) sodium bicarbonate heated to 100 ° C for 16 h. It was evaporated and the residue was chromatographed on 25 g of silica gel with dichloromethane / acetone 9: 1, then 4: 1, 250 mg (46%) of not quite pure 2-chloromethyl-8- (2-methyl- [1,3] dioxolan-2-yl) -6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine were obtained. c) To a solution of 100 mg (0.25 mmol) of 2-chloromethyl-8- (2-methyl- [1,3] dioxolan-2-yl) -6-phenyl-4H-imidazo [1,2-a] [ 1,4] benzodiazepine in 5 ml of methanol, 160 mg (2.54 mmol) of ammonium formate and 100 mg of 10% Pd / C were added and the mixture was heated under reflux for 20 min. The mixture was allowed to cool and the catalyst was removed by filtration. It was evaporated in vacuo and the residue was chromatographed with dichloromethane / acetone 9: 1, 4: 1, 2: 1 and finally with dichloromethane / methanol 19: 1. 40 mg (44%) of 2-methyl-8- (2-methyl- [1,3] dioxolan-2-yl) -6-phenyl-4H-imidazo [1,2-a] [1,4] were obtained. benzodiazepine as an oil. d) 185 mg (0.51 mmol) of 2-methyl-8- (2-methyl- [1,3] dioxolan-2-yl) -6-phenyl-4H-imidazo [1,2-a] [1,4] -benzodiazepine were in 10 ml

Dissolved tetrahydrofuran and added 1.54 ml of 1M hydrochloric acid. The mixture was stirred at room temperature for 41 h and refluxed for a further 3 h to complete the reaction. The mixture was allowed to cool and poured onto 20 ml of saturated sodium bicarbonate solution. It was extracted three times with ethyl acetate, which combined

organic phases dried over sodium sulfate, filtered and evaporated. The raw material was chromatographed on 50 g Alox (neutral) with 4: 1 hexane / ethyl acetate, then 1: 1. The oil thus obtained was converted into the hydrochloride by ethereal hydrochloric acid. 161 mg (90%) of 1- (2-methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl) ethanone hydrochloride (1: 1 HCl) were obtained as almost white crystals of mp. 249-252 ° C Example 19

[6- (2-Fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] methanone hydrochloride (1: 1) a) To a solution of 3.4 g (12.2 mmol) 5- (2-fluoro-phenyl) -2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-7-carbonitrile (G.Saucy, FASmith and LHSternbach, US Pat. 3 '329'701 (1967)) in 250 ml of pyridine

5.2 g (12.6 mmol) Lawesson reagent added. The mixture was heated to 100 ° C for 16 h. The reaction mixture was poured into 1 liter of saturated aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic extracts were with saturated aqueous sodium hydrogen carbonate solution and washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized in 100 ml of methanol. 3.3 g (92%) of 5- (2-fluoro-phenyl) -2-thioxo-2,3-dihydro-1H-1,4-benzodiazepine-7-carbonitrile of mp 194-196 ° C. were obtained. These were dissolved in 150 ml of tetrahydrofuran, 3.7 ml (33.2 mmol) of 2,2-dimethoxyethylamine were added, and the mixture was stirred at room temperature for 16 h. The mixture was in

Evaporated in vacuo and the residue crystallized from methanol. 3.85 g (94%) of 2- (2,2-dimethoxyethylamino) -5- (2-fluorophenyl) -3H-1,4-benzodiazepine-7-carbonitrile, mp. 194-196 ° C., were obtained. b) A solution of 3.3 g (9.0 mmol) of 2- (2,2-dimethoxyethylamino) - 5- (2-fluoro-phenyl) -3H-1,4-benzodiazepine-7-carbonitrile in 100 ml

Acetic acid was stirred at 110 ° C for 60 h. The mixture was evaporated in vacuo, the residue was taken up in saturated aqueous sodium hydrogen carbonate solution and twice with

Extracted ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in dichloromethane and chromatographed on 300 g of silica gel. Impurities were eluted with dichloromethane, which contained 1.5 to 2% ethanol. The desired product was eluted with dichloromethane containing 4% ethanol. After the solvents had been evaporated off, the substance was crystallized from ethyl acetate. 1.85 g (68%) of [6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine] -8-carbonitrile of mp 206-208 ° C. were obtained. c) 1.4 g (4.65 mmol) of [6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine] -8-carbonitrile in 300 ml of methanol saturated with hydrogen chloride dissolved and heated to reflux temperature for 2.5 h while introducing hydrogen chloride. The solution was concentrated in vacuo. The residue was dissolved in 50 ml of water

added, made alkaline with saturated sodium bicarbonate solution and stirred at room temperature for 15 min. The

Mixture was extracted twice with dichloromethane. The

Dichloromethane extracts were dried with sodium sulfate and chromatographed on 100 g of silica gel. With dichloromethane, which contained 2% methanol, 1.4 g (90%) [6- (2-fluoro-phenyl) -2-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine] -8 -carboxylic acid methyl ester eluted. This was obtained as a solid foam after evaporation of the solvents, and in this form for the following

described level used. d) Under argon, a solution of 335 mg (1.0 mmol) [6- (2-fluoro-phenyl) - to a solution of 190 mg (4.85 mmol) lithium aluminum hydride in 20 ml tetrahydrofuran cooled to -40 ° C. 2-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine] -8-carboxylic acid methyl ester in 5 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -30 to -35 ° C for 1 h, then cooled to -40 ° C and 1.5 ml of water was added dropwise. The mixture was then stirred at room temperature for 30 min and the

Filtered suspension. The filtrate was concentrated in vacuo, the residue was taken up in dichloromethane and washed twice with saturated aqueous sodium chloride solution. The

Dichloromethane solution was dried with sodium sulfate and evaporated in vacuo. The oily residue was taken up in dichloromethane and chromatographed on 30 g of silica gel. With

Dichloromethane, which contained 5 to 6% ethanol, the desired product was eluted. After evaporation of the solvents, 216 mg (70%) of [6- (2-fluoro-phenyl) -2-phenyl-4H-imidazo- [1,2-a] [1,4] benzodiazepine] -8-methanol were obtained as Foam. e) To 0.27 ml (3.84 mmol) of dimethyl sulfoxide and 5 ml of dichloromethane, a solution of 0.4 ml (2.9 mmol) of trifluoroacetic anhydride in 1 ml of dichloromethane was added dropwise at -55 ° C. to -50 ° C. under argon within 10 min. a white precipitate formed. 0.59 g (1.92 mmol) of [6- (2-fluorophenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine] -8-methanol were then added in portions and the mixture was stirred for a further 30 min, during which a yellow solution formed. 0.80 ml (5.76 mmol) of triethylamine were then added dropwise to this solution. The mixture was allowed to warm to room temperature, the organic phase was washed once with 15 ml of saturated sodium bicarbonate solution, dried with sodium sulfate, filtered and the solvent was removed in vacuo. The raw material was over 35 g of silica gel

Dichloromethane / methanol 98: 2 chromatographed. After evaporation, 0.26 g (44%) of light beige product was obtained, which in 5 ml

Diethyl ether was stirred. It was filtered again. The crystals were taken up in 3 ml of ethyl acetate and with acidified hydrochloric acid. The crystals which separated out were filtered off with suction and boiled in 5 ml of ethyl acetate for 30 min. 215 mg (33%) of [6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] methanone hydrochloride (1: 1) were obtained as light beige Crystals of mp 232-237 ° C (dec.).

Example 20

1- (1-Methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl) ethanone hydrochloride (1: 1.65 H Cl) a) To 154mg (3.5 mmol) 55 percent Sodium hydride dispersion in oil (washed with n-hexane) in 7 ml of N, N-dimethylformamide were 1.03 g (3.2 mmol) of 7- (2-methyl- [1,3] dioxolane) under argon at approx. 5-7 ° C -2-yl) -5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one (prepared according to Ger. Offen. 2'163'522 (1972)) added dropwise in 9 ml of N, N-dimethylformamide, a crystal slurry formed. It was diluted with 14 ml of absolute tetrahydrofuran and at 30 ° C. for 30 minutes

continued stirring. It was cooled to -2 ° C. and 0.78 ml (3.5 mmol) of phosphoric acid diphenyl ester chloride was then added dropwise. The cooling bath was removed and allowed to warm to 0 ° C, forming a cloudy yellow solution. After 30 min, 0.41 ml (6.4 mmol) of propargylamine were added dropwise and the mixture was stirred for 30 min. The mixture was allowed to warm to room temperature and stirred for 17 h. The solvent was removed in vacuo and the residue was taken up in 25 ml of water. The water was decanted off, the residue was dissolved in dichloromethane, dried with sodium sulfate, filtered and evaporated. The crude product was on 60 g of silica gel with dichloromethane / acetone 9: 1, then on Alox (neutral) with dichloromethane / diethyl ether 9: 1

chromatographed. 0.63 g (55%) of 7- (2-methyl- [1,3] dioxolan-2-yl) -5-phenyl-3H-1,4-benzodiazepin-2-prop-2-ynylamine were obtained as yellowish Foam. b) A solution of 0.83 g (2.31 mmol) of 7- (2-methyl- [1,3] dioxolan-2-yl) -5-phenyl-3H-1,4-benzodiazepin-2-prop-2-ynyl- amine in 20 ml of n-butanol was heated to reflux for 1 h. The solvent was in

Vacuum removed and the crude product on 60 g of silica gel

Dichloromethane / methanol 98: 2, then 97: 3 chromatographed, 685 mg (82%) 1-methyl-8- (2-methyl- [1,3] dioxolan-2-yl) -6-phenyl-4H- imidazo [1,2-a] [1,4] benzodiazepine were obtained as DC. pure foam. c) A solution of 540 mg (1.5 mmol) of 1-methyl-8- (2-methyl- [1,3] dioxolan-2-yl) -6-phenyl-4H-imidazo [1,2-a] [1 , 4] benzodiazepine in 25 ml of tetrahydrofuran was mixed with 4.5 ml of 1M hydrochloric acid and under

Argon heated to reflux for 3 h. The mixture was allowed to cool and poured onto 50 ml of saturated sodium bicarbonate solution. It was extracted four times with ethyl acetate, dried over sodium sulfate, filtered and evaporated to give 0.43 yellow oil. The crude product was chromatographed on 50 g of silica gel with dichloromethane / methanol 98: 2. It was evaporated. 1- (1-Methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl) ethanone was obtained. This material was dissolved in 4 ml of acetonitrile and with ethereal

Hydrochloric acid converted into the hydrochloride. It was evaporated and the salt was refluxed in ethyl acetate for 30 min. The mixture was cooled in an ice bath, suction filtered and dried in vacuo at 70 ° C. for 22 hours. 0.4 g (76%) of 1- (1-methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl) ethanone hydrochloride (1: 1.65 HCl) of Mp 247-250 ° C (dec.). Example 21

1- [6- (2-Fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl) ethanone

A solution of 3.2 g (8.7 mmol) of 1- [2-chloromethyl-6- (2-fluorophenyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] -ethanone (prepared According to Example 4) in 180 ml of acetic acid, 200 mg of 5% Pd / C was added and the mixture was hydrogenated at normal pressure for 8 h, filtered and evaporated, the residue was dissolved in ethyl acetate and washed twice with saturated aqueous sodium hydrogen carbonate solution Phases were extracted again with ethyl acetate and the combined organic phases over

Dried sodium sulfate, filtered and evaporated. The crude product was chromatographed on 300 g of silica gel. With dichloromethane, which contained 1.5%, then 2.5% ethanol, 310 mg of educt were recovered. The product was obtained in pure form with dichloromethane, which contained 3%, then 3.5% ethanol. To Recrystallization from ethyl acetate / diethyl ether and drying in vacuo gave 2.1 g (72%) of 1- [6- (2-fluorophenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl) -ethanone, mp. 182.5-183.5 ° C.

Claims

claims

1. Imidazo [1,2-a] [1,4] benzodiazepines of the general formula

wherein

R ^{1 is} hydrogen, lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl, 2-pyridyl, phenyl, optionally substituted by lower alkoxy or lower dialkylamino;

R ² phenyl, optionally substituted by 2-halogen;

R ³ -C (O) R ⁵ or -C (OH) HR ⁵ ;

R ^{4 is} hydrogen, lower alkyl, hydroxy lower alkyl, carboxy,

lower alkoxycarbonyl or phenyl, optionally substituted by lower alkoxy,

R ^{5 is} hydrogen or lower alkyl,

and pharmaceutically acceptable salts thereof.

2. Compounds according to claim 1, wherein R ^{1 is} hydrogen, methyl,

Hydroxymethyl or -CH ₂ OCOCH ₃ , R ² 2-F-phenyl, R ⁵ methyl and R ^{4 are} hydrogen, methyl or hydroxymethyl.

3. 1- [6- (2-Fluoro-phenyl) -2-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone. 4. 1- [6- (2-fluoro-phenyl) -1-methyl-4H-imidazo [1,2-a] [1,

4] benzodiazepin-8-yl] ethanone.

5. 1- [6- (2-Fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone.

6. 1- [2-Ethyl-6- (2-fluoro-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone.

7. 1- [6- (2-Fluoro-phenyl) -1,2-dimethyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone.

8. 1- [6- (2-fluoro-phenyl) -2-hydroxymethyl-4H-imidazo [1,2-a] [1,4] benzodiazepin-8-yl] ethanone;

9. Medicament, in particular anxiolytic and / or anticonvulsant and / or muscle relaxant and / or sedative-hypnotic agent, comprising a compound according to any one of claims 1-8 and a therapeutically inert carrier.

10. Process for the preparation of compounds according to one of the

Claims 1-8, characterized in that a) a compound of the general formula

wherein R ² and R ^{5 have} the meaning given in claim 1 and Ra is hydrogen,

with an α-haloketone of the general formula

wherein

R ¹¹ lower alkyl, lower alkanoyloxy lower alkyl, 2-pyridyl or

N-alkylated, and to the corresponding compounds of

general formula I cyclized, or b) a compound of general formula II, wherein R ² and R ^{5 have} the meaning given in claim 1 and Ra is a propargylamine derivative, to the corresponding compounds of general formula I cyclized c) a compound of general formula

wherein R ² and R ^{5 have} the meaning given in claim 1, with a propargylamine derivative in the presence of an alkali acetate and catalytic amounts of acid to give the corresponding

Cyclized compounds of general formula I, or d) a compound of general formula

wherein R ² and R ^{5 have} the meaning given in claim 1 and R ^{6 is} lower alkyl,

in acidic medium to compounds of general formula I, wherein

R ¹ and R ^{4 are} hydrogen and R ² and R ^{5 have} the meaning given in Claim 1, cyclize, or e) a compound of the general formula

wherein R ² , R ⁴ and R ^{5 have} the meaning given in claim 1, n is 1-4 and X is halogen,

with a basic reagent into compounds of the general formula I, wherein R ¹ Hydroxynieder alkyl, is reacted, f) a compound of general formula I, wherein R ¹ and R ² -R Hydroxynieder alkyl ⁴ referred to in claim 1

Have meaning, to a compound of the general formula I, in which R ^{1 is} lower alkanoyloxy-lower alkyl, or g) a compound of the general formula

wherein R ² , R ⁵ and n have the meaning given in claim 1,

cyclized in the acidic medium to a compound of the general formula I, in which R ^{1 is} hydrogen and R ^{4 is} hydroxy-lower alkyl, or h) a compound of the general formula I in which R ¹ , R ² and R ³ are as stated in claim 1 Have meaning and R ^{4 is} lower alkyloxycarbonyl, in a compound of general

Converts formula I, wherein R ^{4 represents} a carboxy group, or i) from a compound of the general formula

wherein R ¹ , R ² and R ^{4 have} the meaning given in claim 1 and R ^{7 is} a protected -COR ⁵ group,

the protective group is split off, or j) a compound of the general formula I, in which R ¹ , R ² and R ^{4 have} the meaning given in claim 1 and R ^{3 is} -C (OH) HR ⁵ , into a compound of the general formula I, wherein R ³ denotes -C (O) R ⁵ , and k) converts a compound of the general formula I into a pharmaceutically acceptable acid addition salt.

11. Compounds according to one of claims 1-8, if by the method according to claim 10 or an equivalent thereto

Process manufactured.

12. Compounds according to any one of claims 1-8

Use as therapeutic agents, in particular as anxiolytic and / or anticonvulsive and / or muscle relaxant and / or sedative-hypnotic agents.

13. Use of compounds according to any one of claims 1-8 for anxiolytic and / or anticonvulsive and / or muscle relaxant and / or sedative-hypnotic purposes or for the preparation of corresponding medicaments.

14. The invention as described above.

15. Method for the treatment of patients with therapeutic agents, in particular with anxiolytic and / or anticonvulsive and / or muscle relaxant and / or sedative-hypnotic agents, which treatment with an effective dose of a compound according to any one of claims 1-8 together with a therapeutically inert carrier includes.