CH619953A5 - Process for the preparation of diazepine derivatives - Google Patents

Description

The present invention relates to a process for the preparation of pharmacologically active imidazo [1,5-a] [1,4] dia-zepin compounds of the general formula

10th

R-

H

vii wherein (Zjl one of the groups

XX

and

25th

30th

a)

b)

i ^ c c)

Ri represents hydrogen, halogen, cyano, trifluoromethyl, lower alkyl, amino, lower hydroxyalkyl or lower alkanoyl and A, R2, R3 and Re have the meaning given in claim 1, or pharmaceutically acceptable acid addition salts thereof.

11. The method according to claim 10, characterized in that one produces a compound of formula I, wherein

3S A the group -C = N

re

Ri is hydrogen or lower alkyl, R4 is hydrogen or halogen and Rö is phenyl or phenyl substituted by halogen or lower alkyl.

12. The method according to claim 11, characterized in that Ri is lower alkyl, Rî and R3 are hydrogen, R4 is halogen in the 8-position and R6 is 2-halophenyl.

13. The method according to claim 11, characterized in that R 1 and R 3 are lower alkyl, R 2 is hydrogen, R 4 is halogen in the 8-position and Re is 2-halophenyl.

14. The method according to claim 13, characterized in that R3 is methyl.

15. The method according to claim 12, characterized in that 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is prepared.

16. The method according to claim 14, characterized in that 8-chloro-6- (2-fluorophenyl) -1, 4-dimethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is prepared.

17. The method according to claim 4, characterized in that 2-chloro-13a- (2-fluorophenyl) -12,13a-dihydro-6-methyl-9H, IIH-imidazo [1,5-a] oxazolo [3, 2-d] [1,4] benzodiazepine.

Ri hydrogen, lower alkyl, phenyl, lower alkoxyalkyl, 40 substituted phenyl, pyridyl or aralkyl, R2 and R3 each hydrogen or lower alkyl, R4 hydrogen, halogen, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, lower hydroxyalkyl or lower alkanoyl , R6 is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl 45 or mono-substituted pyridyl and X is chlorine, bromine or iodine, analogs of the general formula

R.

H

IA

where AIV is one of the groupings

65

H !

• N.

V

a)

7

619 953

\

/

C = N

and

0

f)

and V is hydrogen or methyl and

0:

1"

Ri, R2, R3, R4, Rfi and X have the meaning given in formula I,

and pharmaceutically acceptable salts thereof.

As used in the present specification, the term "lower alkyl" means straight or branched chain hydrocarbon radicals having 1-7, preferably 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and the like.

The term "lower alkanoyl" or "acyl" as used herein means the acyl residue of an alkane carboxylic acid having 1-7, preferably 1-4 carbon atoms, e.g. acetyl, propionyl, butyryl and the like, i.e. Remains of the formula

R20-C-,

II

O

wherein R20 is hydrogen or alkyl of 1-6 carbon atoms. The term “lower alkanoyl” also includes a protected ketone, such as an acetal or a ketal having 2 to 7 carbon atoms, for example a group of the formula

25th

In the case of R3 as lower alkyl, optical isomerism results and such optical antipodes and racemates are encompassed by the present invention.

The term "aryl" denotes a substituted or unsubstituted monocyclic aromatic residue such as phenyl, chlorophenyl, tolyl and the like.

The term “lower alkoxy” means straight-chain or branched saturated hydrocarbonoxy groups having 1 to 7, preferably 1 to 4, carbon atoms, such as methoxy, ethoxy, propoxy and the like.

The term “substituted amino” is used herein to mean an —NH2 group which can be mono- or di-substituted by lower alkyl (for example methylamino or dimethylamino), or an acylamino group such as acetamino, which is additionally present on the nitrogen atom can be substituted by lower alkyl or aryl (such as methyl, phenyl or tolyl).

The term "aralkyl" means a hydrocarbon group which contains aromatic and aliphatic structural parts, i.e. a hydrocarbon group in which a hydrogen atom of a lower alkyl group is replaced by an aryl group (such as phenyl, tolyl and the like).

Preferred compounds are those in which R 1 is hydrogen or lower alkyl (preferably methyl), R 3 is hydrogen,

c the group R

30th

R4 is preferably in the 8-position of the imidazobenzodiazepine skeleton and hydrogen or halogen (preferably chlorine), A is the group

> c /

—C = N '

Rö

40

and Ró means phenyl or phenyl substituted by halogen or lower alkyl, preferably halophenyl, in particular fluorophenyl, the fluorine atom preferably being in the 2-position, for example compounds of the formula

45

where R20 has the meaning given above. The ketal or aldehyde protecting group is used to convert the ketone or aldehyde contained therein

(R2 ° —c_)

O

to be avoided in oxidation, reduction and condensation reactions.

The term "halogen" includes the four forms of chlorine, bromine, fluorine and iodine.

The phenyl radical denoted by Rô can be mono- or di-substituted, provided that the positions 2 and 3.2 and 5 or preferably 2 and 6 of the phenyl radical are occupied in the case of disubstitution. Suitable mono-substituents include halogen, preferably in the 2-position of the phenyl radical. Suitable di-substituents are 2,6- or 2,5-di-halogen. In the case of mono-substituted pyridyl, suitable substituents include halogen.

55

60

wherein R'i is as defined in formula IB 'below and R2 has the meaning given above.

As is clear from the foregoing, one includes

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especially preferred group in the context of the present invention compounds of the formula r60

wherein R ', hydrogen or lower alkyl (preferably methyl), R4 is hydrogen or halogen (preferably chlorine), which in a particularly preferred embodiment is in the 8-position of the imidazobenzodiazepine skeleton, Rôo phenyl or phenyl substituted by halogen or lower alkyl (preferably halophenyl, in particular fluorophenyl, where the fluorine atom is preferably in the 2-position of the phenyl radical) and R2 has the meaning given above.

Another preferred class of compounds within the scope of formula I are those in which R (, R2, R4, Rô and A have the meaning given in formula IB 'and R3 is lower alkyl (preferably methyl), for example compounds of the formula

Compounds of the formula IC and their pharmaceutically acceptable salts show optical isomerism. Such a compound has been separated into its optical enantiomers by a method similar to that which is generally explained in Advanced Organic Chemistry, L. Fieser and M. Fieser, 1961, pages 85-86, Reinholt Publishing Co. Both the optical isomers and the racemic form of the compound IC show pharmacological activity. In the case of the tartrates of compounds of the formula IC, the (+) isomer is considerably more active than the (-) isomer. The less active (-) isomer can, if desired, be converted to its active racemic form, for example by treatment with a non-aqueous base such as sodium tert-butoxide in the presence of an organic solvent in which the isomer is soluble.

The expression "pharmaceutically acceptable salts"

includes salts with inorganic and organic, pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. Such salts can be readily prepared by any person skilled in the art in view of the prior art and considering the nature of the compound to be salted.

The most preferred pharmaceutically acceptable acid addition salts of compounds of the formulas IC and ID are:

8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate;

8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine maleate

The imidazo [1,5-a] [1,4] diazepines of the formula I, their analogs of the formula IA and the pharmaceutically usable acid addition salts of these compounds can be prepared according to the invention according to the various process aspects which are defined in the claims. Compounds of the formula IA, in which AIV is the group

I.

Rô O

means obtained by converting corresponding compounds of formula I into their N-oxides. This conversion takes place by oxidation of a compound of formula I with an organic peracid. A common organic peracid such as peracetic acid, perpropionic acid, m-chloroperbenzoic acid and the like can be used to carry out this reaction. The oxidation can be carried out at room temperature or above or below it.

Compounds of the formula IA, in which AIV is the group

H

I /

"î \

R6 H

means obtained by reduction of corresponding compounds of the formula I to compounds of the formula

CH

where Ri, R2, R3, R4, Ró, X and (^ 3 ^

have the meaning given in formula I.

Any suitable reducing agent can be used to reduce the compounds of formula I to compounds of formula IA ", but preferably hydrogen in the presence of a platinum oxide catalyst or zinc in the presence of acetic acid.

8th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

9

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Temperature and pressure are not critical factors for the conversion of compounds of the formula I into corresponding compounds of the formula IA ". However, the compounds of the formula IA" are preferably prepared at about room temperature and atmospheric pressure. Compounds of the formula IA, in which A! V represents the group y

R6 0 V

means can be obtained by reacting a compound of formula I directly with ethylene oxide or propylene oxide in the presence of a Lewis acid.

The reaction of compounds of formula I with ethylene oxide or propylene oxide is preferably catalyzed by a Lewis acid, for example titanium tetrachloride, boron trifluoride, etc. The reaction parameters and the conditions for such a reaction are known per se, see for example US Pat. 3,868,362.

If in the compounds of formula I and their analogs there is a ketal group, for example in which Av, \ L

To have meaning.

III

, R.i, R-t, Rfi and X the above

20th

is present as a substituent in the 8-position in an imidazobenzodiazepine, such a ketal group can be converted into an 8-membered keto group by mild acid hydrolysis. The 8-ketone can then be converted to an 8-membered secondary or tertiary alcohol which is racemic in nature. The reaction conditions for this, i.e. for the above 2 stages, are described in U.S. Patent No. 3,846,410.

The compounds of Formula I above can be prepared by the following procedures.

In one of the new process aspects mentioned above for the preparation of compounds of the formula I, a compound of the formula is nitrosated

25th

30th

35

Such nitrosation can be carried out with nitrous acid formed in situ. Reagents that can be used for this include: 1. alkali metal nitrites such as sodium nitrite in the presence of organic or inorganic acids such as glacial acetic acid and aqueous or non-aqueous solvents; 2. alkyl nitrites, such as methyl nitrite, in the presence of an inert solvent, such as an alcohol, a chlorinated hydrocarbon or, for example, dimethylformamide; 3. a solution of gaseous nitrosyl chloride in an inert solvent and in the presence of an acid acceptor such as pyridine. Such a nitrosation reaction should occur at or below room temperature, i.e. in the range of approximately -20 ° to 25 °.

The nitrosoalkylamino group in the 2-position, for example

CH3

I.

-N-NO

represents a leaving group. Equivalent leaving groups which can be used as substituents in the 2-position 40 include groups such as alkoxy, e.g. B. OCH3, alkyl-thio, e.g. B.-SCH3, halogen, e.g. Chlorine, cyano, d. H. —CN, and phosphates, such as

45

-O-PO

NHCH.

O)

II

50 reactions to form alkoxy and alkylthio groups in the 2-position are well known; see, e.g., G.A. Archer and L.H. Sternbach, Journal of Organic Chemistry, 29, 231 (1964) and U.S. Patent No. 3,681,341.

Compounds of formula III can then be condensed with a 55 nitroalkane to give a new intermediate of the formula wherein Av represents the group —C = N ^

I.

Re

or the group —C

\ Re O

means and

(Sjj, R3, R4,

Rö and X have the meaning given above, and receives a compound of the formula

IV

R.

619953

10th

where Av, fg | R2, R3, R4, Rc and X are those given above where A,

To have meaning.

The condensation reaction takes place with a nitroalkane (R2-CH2-NO2), i.e. H. Nitromethane, nitroethane, etc., in the presence of a base which is strong enough to produce the nitroalkane ion. Suitable bases include alkali metal or alkaline earth metal alkoxides, e.g. Potassium tert-butoxide, amides, e.g. Lithium amide, or hydrides, e.g. Sodium hydride. The reaction is preferably carried out in an inert solvent such as dimethylformamide, dimethyl sulfoxide or ether, e.g. Tetrahydrofuran, at temperatures below or above room temperature, i.e. in a range from -50 ° to 150 °, preferably at about room temperature.

Compounds of formula IV can then be catalytically, e.g. over Raney nickel, hydrogenated or with other reducing agents, such as lithium aluminum hydride (only if A is not an N-oxide), and a compound of the formula is obtained

RH.

where A,

To have meaning.

Solvents suitable for hydrogenation with Raney nickel include alcohols, e.g. Ethanol, ether, e.g. Tetrahydrofuran, diethyl ether etc., hydrocarbons, e.g. B. toluene, and dimethylformamide. The reaction temperature can be above or below room temperature, i.e. -50 ° to 150 °, and the reaction can be carried out with or without pressure, i.e. at atmospheric pressure or above.

Solvents suitable for use with a reducing agent such as lithium aluminum hydride include ethers, e.g. Tetrahydrofuran, dioxane, diethyl ether, and mixtures of ethers and hydrocarbons, e.g. Tetrahydrofuran and benzene. The reaction can take place in a temperature range from below room temperature to reflux temperature, i.e. preferably in a range from -50 to 60 °.

The compounds of the formula V can then be acylated with an acylating agent such as acid halides or acid anhydrides (ie compounds of the formula (RiC0) 20 in which Ri has the meaning given above), for example with acetanhydride or acetyl chloride, and a compound is obtained of the formula s Ri, R2, R3, R4, Re and X have the meaning given above and Y is hydrogen or —CORi.

When the compounds of the formula V are acylated to give the compounds of the formula VI, a mixture can be formed consisting of the predominant monoacylated product, i.e. 10. in which the NH2 group of V (position 2) in

NHCORi and the diacylated product, wherein both the NH2 group of V (2-position) and the nitrogen are acylated in the 1-position. The yield of diacylated product can be increased by subjecting the compounds to Formula V to more rigorous conditions, i.e. Excess of acylating agent and extended reaction time.

The acylation is preferably carried out in the presence of an aqueous or non-aqueous solvent, e.g. Water, methylene chloride, benzene, chloroform, etc., and preferably 20 using an acid acceptor such as organic or inorganic bases such as triethylamine, pyridine or alkali metal carbonates. The compounds of the formula VI can then become new compounds of the formula

R2, R3, R4, Rö and X the above

VII

where A, f 3

40 Ri, R2, R3, R4, Rö and X have the meaning given above, are cyclized.

The cyclization is carried out with a dehydrating agent, e.g. B. phosphorus pentoxide, polyphosphoric acid or other suitable acid catalysts, i.e. organic or

45 inorganic acids, e.g. concentrated sulfuric acid. A solvent is not required, but a solvent such as an aromatic hydrocarbon, e.g. Toluene or xylene can be used. The reaction takes place in a temperature interval between approximately 100 ° to 200 °.

50 The compounds of formula V can also at room temperature or above it, i.e. H. at 25 ° to 150 °, with acylating agents such as orthoesters, e.g. B. triethyl orthoacetic acid, orthoamides, e.g. B. N, N-dimethylformamide dimethylacetal, or a compound of the formula

55

CHs

N-CH3 CHs

CH-

-N CH3

VI

I.

N-CH3

CHs

65 optionally in the presence of an acid catalyst, for example an organic or inorganic acid, such as p-toluenesulfonic acid, phosphoric acid, etc., the cyclization to give compounds of the formula VII

11

619953

tan is done. Other useful acylating agents include esters, e.g. Methyl acetate, amidines, e.g. Acetamidine, nitriles, e.g. Acetonitrile and ester imidates, for example a compound of the formula

OC2H5 CH3-C = NH

According to the invention, the compounds of the formula VII become compounds of the formula

10th

where A,

Ri, R2, R3, R4, Rôund X have the meaning given above, dehydrated.

Preferred reagents for dehydrogenation include manganese dioxide and palladium on carbon, although potassium permanganate can also be used. Solvents that can be used include chlorinated hydrocarbons, aromatic hydrocarbons, dimethylformamide, etc. The dehydrogenation takes place at room temperature or above, i.e. H. in a range from about 25 ° to 200 °.

If desired, the above new process can proceed from the intermediates of formula IV or V to compounds of formula I without the need to isolate intermediates formed before proceeding to the next process step.

It should be noted that in the acylation of compounds of the formula V to the compounds of the formula VI, when R4 is amino, this amino group can also be acylated to an acylamino group. The acylamino group can be converted back to the amino group by subjecting the compounds of formula VII or I to mild hydrolysis.

It has also been found in the context of the present invention that compounds of the formulas IV, V, VI and VII can have both optical and geometric isomerism.

Another process for the preparation of the new intermediates of formula V, wherein R4 is not cyano, is the reduction of compounds of the formula

X

20th

25th

65

R3, R4, Ró and X have the meaning given above, with the exception that R4 is not cyano.

The reduction comprises the reaction of compounds of the formula X with a known reducing agent, such as Raney nickel in the presence of hydrogen or with other reducing agents, such as lithium aluminum hydride. Solvents suitable for hydrogenation with Raney nickel include alcohols, e.g. Ethanol, ether, e.g. Tetrahydrofuran, hydrocarbons, e.g. Toluene, and dimethylformamide. The reaction temperature can be above or below room temperature (i.e. -50 ° to 150 ° C) and the reaction can take place with or without pressure, i.e. in an atmosphere or above it.

Solvents which are suitable when using a reducing agent such as lithium aluminum hydride include ethers such as dioxane, diethyl ether and tetrahydrofuran. The reaction can take place between below room temperature and reflux temperature, i.e. preferably in the range of -50 ° C to 60 ° C.

A variation of the above process is mild acidic hydrolysis of the compounds of formula X to compounds of the formula

CONH

XI

35

where A,

R3, R4, Rö and X have the meaning given above. 40 The mild acidic hydrolysis is expediently carried out with a dilute mineral acid, for example with aqueous sulfuric acid in aqueous alcohol. The reaction temperature can vary between room temperature, i.e. about 25 ° C, and temperatures above it, i.e. about 6OC. The 45 compounds of formula XI can then be reduced to the new intermediates of formula V.

Compounds of formula IV above can also be prepared by using a compound of formula

60

'3 XII

where Av,

R3, R4, Rö and X have the meaning given above, with the exception that R4 does not mean amino or substituted amino,

with dimorpholinophosphinyl chloride to a compound of the formula

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12

XIII

where A,

R.3, R4, Rö and X have the meaning given above, and the iminophosphate is then replaced by the anion of a nitroalkane, giving the new intermediates of the formula IV.

The displacement reaction is carried out with a nitroalkane, i.e. H. Nitromethane, nitroethane, etc., in the presence of a base which is strong enough to form the nitroalkane anion. Suitable bases include the alkoxides, hydrides, amides or hydroxides of the alkali metals or alkaline earth metals. The reaction is preferably carried out in an inert solvent such as dimethylformamide, dimethyl sulfoxide or an ether at temperatures below or above room temperature, i.e. in the range of -50 ° C to 150 ° C.

Another process for the preparation of the intermediates of formula IV, wherein R2 is hydrogen and Av is an N-oxide, consists in the ring expansion of compounds of the formulas

20th

25th

35

VIII or

IX

wherein

Gt

R3, R4, Rö and X have the meaning given above, with the exception that R4 does not mean amino.

The ring extension involves the reaction of the compounds of formulas VIII or IX with nitromethane in the presence of a base which is strong enough to form the nitromethane anion. Suitable bases include the alkoxides of alkali metals and alkaline earth metals, e.g. Potassium tert-butoxide, amides, e.g. lithium amide, or hydrides, e.g. Sodium hydride. The reaction can preferably be carried out in an inert solvent such as anhydrous ether, e.g. Tetrahy-15 drofuran, dimethylformamide, dimethyl sulfoxide, etc., and at temperatures in the range of about -20 ° C to 25 ° C.

Compounds of formulas I and IA and their pharmaceutically acceptable acid addition salts are useful as muscle relaxants, sedatives and anticonvulsants, and many of them are particularly useful when used in intravenous and intramuscular preparations in view of the solubility of the acid addition salts in aqueous solutions . As provided in the present invention, the new compounds of formula I and their acid addition salts can be incorporated into pharmaceutical dosage forms containing about 0.1 to 40 mg, preferably 1 to 40 mg of active ingredient, the dose of the species and individual needs is to be adjusted. The new compounds of the formulas I and IA and their pharmaceutically acceptable salts can be administered internally, for example parenterally or enterally, in customary pharmaceutical dosage forms. For example, they can be incorporated into common liquid or solid carriers such as water, gelatin, starch, magnesium stearate, talc, vegetable oils and the like to provide tablets, elixirs, capsules, solutions, emulsions and the like according to recognized pharmaceutical methods.

Various articles and US patents have been cited in the foregoing description; this is intended to include the teaching of these references to complete the revelation.

The following examples are intended to illustrate the invention without, however, limiting it. All temperatures are given in degrees Celsius.

45

example 1

A solution of 200 g (0.695 M) 7-chloro-l, 3-dihydro-5- (d-fluorophenyl) -2H-l, 4-benzodiazepin-2-one in 21 tetrahydrofuran and 250 ml of benzene is cooled in one Ice-50 bath saturated with methylamine. A solution of 190 g (1 M) titanium tetrachloride in 250 ml benzene is added over 15 minutes through a drop channel. After the addition has ended, the reaction mixture is heated to reflux for 3 hours. Water (55 ml) (600 ml) is slowly added to the cooled reaction mixture. The inorganic material is removed by filtration and washed well with tetrahydrofuran. The aqueous phase is separated off and the organic phase is dried over sodium sulfate and evaporated. The crystalline residue consisting of 7-chloro-5- (2-fluorophen-60 nyl) -2-methylamino-3H-l, 4-benzodiazepine is collected; Melting point 204-206 °. An analytical sample is recrystallized from methylene chloride / ethanol and shows the melting point 204-206 °.

8.63 g (0.125 M) sodium nitrite is converted into 65 portions in three portions over 15 minutes to a solution of 30.15 g (0.1 M) 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1 , 4-benzodiazepinin 150 ml of glacial acetic acid. The reaction mixture is stirred for 1 hour at room temperature, then mixed with water.

13

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thin and extracted with methylene chloride. The extracts are washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated, finally evaporating azeotropically with toluene. 29 g of crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-l, 4-benzodiazepine are obtained as a yellow oil.

This material is dissolved in 100 ml of dimethylformamide and the solution is added to a mixture of 200 ml of dimethylformamide, 50 ml of nitromethane and 11.1 g (0.1 M) of potassium t-butoxide, which was stirred under nitrogen for 15 minutes, given. The reaction mixture is stirred for 1 hour at room temperature, then acidified by adding glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts are washed with water, dried over sodium sulfate and evaporated.

Crystallization of the residue from ether gives 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine with a melting point of 170-172 °.

An analytical sample is recrystallized from methylene chloride / ethanol and shows a melting point of 174-176 °.

A solution of 16.5 g (0.05 M) 7-chloro-l, 3-dihydro-

5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine in 500 ml of tetrahydrofuran and 250 ml of methanol is hydrogenated with 5 teaspoons of Raney nickel for 2 V2 hours at atmospheric pressure. Removal of the catalyst and evaporation gives crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine.

20 ml of acetic anhydride are added to a solution of 12 g of this product in 300 ml of methylene chloride. The solution is overlaid with 300 ml of 10% aqueous sodium carbonate solution, and the two-phase mixture is stirred for 30 minutes at room temperature. The organic phase is separated off, washed with sodium carbonate solution and dried over sodium sulfate. Evaporation gives crude 7-chloro-2,3-dihydro-5- (2-fluorophenyl) -2-propionylaminomethyl-1H-1,4-benzodiazepine. This product is heated in 50 g of polyphosphoric acid at 150-170 ° for 10 minutes. The reaction mixture is cooled, dissolved in water and made alkaline with concentrated ammonia and ice. The base is extracted with methylene chloride and the extracts are dried over sodium sulfate and evaporated. The residue is chromatographed on 300 g of silica gel, a 20% solution of methanol in methylene chloride being used as the mobile phase. The clear fractions are combined, evaporated and the residue is crystallized from ether, 8-chloro-3a, 4-dihydro-l-ethyl-6- (2-fluorophenyl) -3H-imidazo [l, 5-a] [l , 4] benzodiazepine with a melting point of 131-133 °.

A mixture of 3.4 g of 8-chloro-3a, 4-dihydro-l-ethyl

6- (2-fluorophenyl) -4H-imidazo [1,5] [1,4] benzodiazepine, 400 ml toluene and 30 g activated manganese dioxide is heated to reflux for 2 hours using a water separator. The manganese dioxide is separated off by filtration through Celite and the filtrate is evaporated. Crystallization of the residue from ether yields 8-chloro-l-ethyl-6- (2-fluorophenyl) -4H-imidazo [l, 5-a] [l, 4] benzodiazepine with a melting point of 140-143 °. For analysis purposes this product is recrystallized from ether and shows the melting point 143-145 °.

Example 2

7 ml of acetic anhydride are added to a solution of 6.16 g of crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine in 200 ml of methylene chloride. The solution is covered with 200 ml of saturated sodium bicarbonate solution and the mixture is stirred for 20 minutes. The organic phase is separated off, washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated. Resinous 2-acetaminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine is obtained as a residue. This product is at 40 ° with 40 g of polyphosphoric acid for 10 minutes

warmed up. The cooled reaction mixture is dissolved in water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts are dried and evaporated. The residue is chromatographed on 120 g of silica gel, a 20% solution of methanol in methylene chloride being used as the mobile phase. The clear fractions are purified and evaporated to give resinous 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine. A mixture of this product with 500 ml of toluene and 30 g of manganese dioxide is heated to reflux for IV2 hours. The manganese dioxide is removed by filtering through Celite. The filtrate is evaporated and the residue is crystallized from ether, 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] -benzodiazepine melting at 152- Receives 154 °. An analytical sample is recrystallized from methylene chloride / hexane.

Example 3

152.5 g (0.5 M) of methylamine saturated 7-chloro-5- (2-chlorophenyl) -l, 3-dihydro-2H-l, 4-benzodiazepin-2-one are as in the first paragraph of Example 1 described with 133 g (0.7 M) of titanium tetrachloride in 21 tetrahydrofuran and 400 ml of benzene and provide 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-l, 4-benzodiazepine with a melting point of 216-219 ° . An analytical sample is recrystallized from methylene chloride / ethanol and shows the melting point 217-219 °.

10 g (0.145 M) sodium nitrite are added portionwise over 45 minutes to a solution of 22.4 g (0.07 M) 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-l, 4-benzodiazepinin 150 ml of glacial acetic acid. After the addition has ended, the reaction mixture is further stirred under nitrogen for 20 minutes. The product is precipitated by the addition of ice water, collected and dissolved in toluene. The solution is washed with saturated sodium bicarbonate solution, dried and evaporated under reduced pressure. The yellowish viscous oil obtained consists mainly of the desired nitroso-amidine according to the thin-layer chromatogram. This material is dissolved in 100 ml of dimethylformamide and added to a mixture of 30 ml of nitromethane, 100 ml of dimethylformamide and 10 g of potassium t-butoxide. The reaction mixture is slowly heated to 85 ° while stirring and passing a stream of nitrogen. After 5 minutes the reaction mixture is cooled and acidified by adding 10 ml of glacial acetic acid. The product is crystallized by the gradual addition of water with seeding (the seed crystals are obtained by chromatography on silica gel using a 10% solution of ethyl acetate in methylene chloride as the mobile phase). The precipitated crystals are collected, washed with water and recrystallized from methylene chloride / ethanol and yield 7-chloro-5- (2-chlorophenyl) -l, 3-dihydro-2-nitromethylene-2H-l, 4-ben-zodiazepine of melting point 182-185 °.

By hydrogenating 7 g of 7-chloro-5- (2-chlorophenyl) -l, 3-dihydro-2-nitromethylene-2H-l, 4-ben-zodiazepine in 300 ml of tetrahydrofuran and 150 ml of methanol in the presence of 5 teaspoons for 1 hour Raney nickel gives crude 2-aminomethyl-7-chloro-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine. This product is acety-lated in the usual way and provides oily 2-acetaminomethyl-7-chloro-5- (2-chlorophenyl) -2,3-dihydro-lH-l, 4-benzodiazepine, which in 15 g of polyphosphoric acid during Is heated to 140-150 ° for 10 minutes. The usual workup gives a yellow resin, which is chromatographed on 250 g of silica gel,

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a 20% solution of methanol in methylene chloride is used as the mobile phase.

The clear fractions provide resinous 8-chloro-6- (2-chlorophenyl) -3a, 4-dihydro-l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine. This product is oxidized with 10 g of manganese dioxide in 200 ml of toluene. After refluxing for 1 1/2 hours, the manganese dioxide is filtered off and the filtrate is evaporated. Crystallization of the residue from ether gives 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imi-dazo [1,5-a] [1,4] benzodiazepine with a melting point of 140-144 °. For analytical purposes, the product is recrystallized from methylene chloride / hexane and shows the melting point 142-144 °.

Example 4

A solution of 33 g (0.1 M) 7-chloro-2- (N-nitrosometh-yl-amino) -5-phenyl-3H-l, 4-benzodiazepine-4-oxide in 100 ml of dimethylformamide becomes a mixture of 50 ml of nitromethane, 12.5 g (0.11 M) of potassium t-butoxide and Ì00 ml of dimethylformamide. The reaction mixture is stirred for 1 hour while passing nitrogen through. After adding 10 ml of glacial acetic acid, the product is crystallized by gradually adding 250 ml of water. The precipitated yellow material is collected, washed with water, methanol and ether and gives 7-chloro-l, 3-dihydro-2-nitromethylene-5-phenyl-2H-l, 4-benzodiazepine-4-oxide with melting point 253 -255 ° (dec.). An analytical sample is recrystallized from methylene chloride and shows the same melting point.

5 teaspoons of Raney nickel become a solution of 16.5 g (0.05 M) of 7-chloro-l, 3-dihydro-2-nitromethylene-5-phenyl-2H-l, 4-benzodiazepine-4-oxide in 500 ml of tetrahydrofuran and 250 ml of methanol were added. The mixture is hydrogenated at atmospheric pressure for 5 hours. The catalyst is removed by filtration and the filtrate is evaporated. The residue is dissolved in 2-propanol and the solution is made strongly acidic with ethanolic hydrochloric acid. After evaporating part of the solvent, the dihydrochloride of the desired product crystallizes out. The orange crystals are collected and provide 2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-l, 4-benzodiazepine dihydrochloride with a melting point of 230-240 °.

10 ml of acetic anhydride are added to a solution of 10 g of this product in 50 ml of water and 50 ml of methanol. 100 ml of a 10% aqueous solution of sodium carbonate are added over 5 minutes with stirring. After the addition has ended, the mixture is stirred for a further 10 minutes, after which it is extracted with methylene chloride. The extracts are washed with sodium carbonate solution, dried over sodium sulfate and evaporated, finally evaporating azeotropically with toluene. This gives 2-acetaminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-l, 4-benzodiaze-pin as a yellow resin.

This product is heated in 50 g of polyphosphoric acid at 135-140 ° for 10 minutes. The initially orange color of the reaction mixture changes to a light yellow. The cooled reaction mixture is dissolved in water, made alkaline with concentrated ammonia and ice and extracted with methylene chloride. The extracts are dried and evaporated. The yellow resin is dissolved in 2-propanol and treated with ethanolic hydrochloric acid, the colorless dihydrochloride of the desired product crystallizing out. This product shows the melting point 240-245 °.

The dihydrochloride obtained above is partitioned between methylene chloride and aqueous ammonia. The organic phase is dried and evaporated. Crystallization of the residue from ether gives 8-chloro-3a, 4-dihydro-

l-methyl-6-phenyl-3H-imidazo [1,5-a] [1,4] benzodiazepine as a colorless product with a melting point of 116-118 °.

A mixture of 3.1 g (0.01 M) 8-chloro-3a, 4-dihydro-

1-methyl-6-phenyl-3H-imidazo [l, 5-a]] l, 4] benzodiazepine, 20 g activated manganese dioxide and 150 ml toluene are heated to reflux for 1 hour. The manganese dioxide is removed by filtration through Celite and washed well with methylene chloride. The filtrate is evaporated and the residue is crystallized from ether, 8-chloro-l-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine being colorless crystals of melting point 187-188 ° receives.

Example 5

A mixture of 11.2 g (0.1 M) potassium tert-butoxide, 50 ml nitroethane and 200 ml dimethylformamide is stirred for 15 minutes at room temperature. A solution of 29 g (0.088 M) of crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosome-thylamino) -3H-1,4-benzodiazepine in 100 ml of dimethylformamide is added with stirring and under a nitrogen atmosphere. whereupon the mixture is stirred for a further 6 hours under a nitrogen atmosphere. The reaction mixture is neutralized by adding glacial acetic acid and diluted with water. The product is extracted with ether. The extracts are washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. Crystallization from ether gives 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (1-nitroethylene) -2H-1,4-benzodiaze-pin as yellow crystals with a melting point of 136- 142 °.

5 teaspoons of Raney nickel become a solution of 17.3 g (0.05 M) 7-chloro-l, 3-dihydro-5- (2-fluorophenyl) -

2- (l-nitroethylene) -2H-l, 4-benzodiazepine in 750 ml of tetrahydrofuran. The mixture is hydrogenated for 4 hours at atmospheric pressure. The catalyst is separated by filtration through Celite and washed well with methanol. The filtrate is evaporated and provides crude 2- (l-aminoethyl) -7-chloro-2,3-dihydro-5- (2-fluorophenyl) -lH-l, 4-benzodiazepine as a reddish oil.

This product is dissolved in 300 ml of methylene chloride.

After adding 14 ml of acetic anhydride, 300 ml of saturated aqueous sodium bicarbonate solution are added and the two-phase mixture is stirred at room temperature for 1 hour. The methylene chloride phase is separated off, washed with bicarbonate solution, dried over sodium sulfate and evaporated. The residue is heated with 40 g of polyphosphoric acid at 160-170 ° for 10 minutes. The cold reaction mixture is diluted with water, made alkaline with ammonia and extracted with methylene chloride. The methylene chloride extracts are washed with water, dried and evaporated to give a brown residue which is chromatographed on 250 g of silica gel, using a 20% solution of methanol in methylene chloride as the mobile phase. The thin-layer chromatographically uniform fractions are collected and provide a resin which is subjected to the subsequent oxidation, Ird.

A mixture consisting of this material, 20 g activated manganese dioxide and 300 ml toluene is heated to reflux for 3 hours, a water separator being used to remove the water. The manganese dioxide is removed by filtration through Celite and washed well with methylene chloride. The filtrate is evaporated and the residue is chromatographed under pressure through 150 g of silica gel H, a 3% strength solution of ethanol in methylene chloride being used as the mobile phase. The first eluted major component is 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] bendzodiazepine.

This product was obtained by treating it with ethereal hydrochloric acid in ether in a crystalline dihydrochloride

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Melting point 247-250 ° (dec.) Transferred.

The more polar component is crystallized from methylene chloride / ether / hexane and gives 8-chloro-1,3-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine with a melting point 178-180 °.

Example 6

A mixture of 3.1 g (0.01 M) of 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 2.15 g (0.0125 M) m-chloroperbenzoic acid and 100 ml of methylene chloride are stirred for 48 hours at room temperature. The reaction mixture is then washed with a 10% aqueous sodium carbonate solution and water. The methylene chloride phase is dried over sodium sulfate and evaporated. The residue is chromatographed on 80 g of silica gel, a 10% strength solution of ethanol in methylene chloride being used as the mobile phase. The thin-layer chromatographic uniform fractions are combined and evaporated. Crystallization of the residue from methylene chloride / ether gives 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-5-oxide with a melting point of 260-261 ° .

Example 7

A warm solution of 6.5 g (0.02 M) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazof 1,5-a] [1,4] benzodiazepine in 30 ml Ethanol is combined with a warm solution of 2.6 g (0.022 M) of maleic acid in 20 ml of ethanol. The mixture is diluted with 150 ml of ether and heated on the steam bath for 3 minutes. After cooling, the precipitated crystals are collected, washed with ether, dried in vacuo and yield 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine -maleate from melting point 148-151 °.

Example 8

A mixture of 17.4 g (0.05 M) 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (1-nitromethylene) -2H-1,4-benzodia-zepin-4 -oxide, 500 ml of tetrahydrofuran, 200 ml of methanol and 5 teaspoons of Raney nickel is hydrogenated for 5 hours at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated, at the end being azeotropically evaporated with xylene. Crude 2-aminomethyl-7-chloro-5- (2-fluorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine is obtained as a residue.

This product is dissolved in 200 ml of ethanol and, after the addition of 14 ml of triethyl orthoacetate and 2.8 g of p-toluenesulfonic acid, the solution is heated to reflux for 2 hours. The solvent is removed under reduced pressure and the residue is partitioned between methylene chloride and a 10% aqueous sodium carbonate solution. The organic phase is dried and evaporated and yields oily 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -l-methyl-3H-imidazo- [l, 5-a] [l, 4] benzodiazepine. This crude product is dissolved in 500 ml of xylene. After addition of 50 g of activated manganese dioxide, the reaction mixture is heated to reflux for 1½ hours, the water being removed by a water separator. The inorganic material is removed by filtration and the filtrate is evaporated to give 10 g of a brown oil. A warm solution of 4.65 g (0.04 M) of maleic acid in 50 ml of ethanol is added to this residue. When the solution is complete, the product is crystallized out by adding ether. The crystals are collected, washed with ether and yield 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate with a melting point of 112-115 ° . By heating in vacuo to 90-100 ° this product is converted into a product with a higher melting point 148-151 °.

Example 9

A solution of 0.32 g (1 mmol) of 8-chloro-6- (2-fluoro-phenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in 5 ml ethanol treated with an excess of ethanolic hydrochloric acid. The salt is crystallized out by adding 2-propanol and ether. The colorless crystals are collected, washed with ether, dried and yield 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] -benzodiazepine dihydrochloride of melting point 290-2950.

Example 10

A solution of 0.325 g (1 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in 3 ml of ethanol is mixed with a Combined suspension of 0.4 g (1 mmol) of the dihydrochloride of this compound in 5 ml of ethanol. After filtering, the solution is treated with ether and heated for 5 minutes on the steam bath for crystallization. The crystals are collected, washed with ether, dried and yield 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine hydrochloride, melting point 295- 297 °.

Example 11

A solution of 23.6 g (0.10 moles) of l, 3-dihydro-5-phen-yl-2H-l, 4-benzodiazepin-2-one in 1 liter of tetrahydrofuran (containing about 20 moles of monomethylamine) is added in one Cooled ice bath. 14 ml (d = 1.73, 0.125 mol) of titanium tetrachloride in 200 ml of benzene are added to this mixture.

The reaction mixture is stirred for 2 days at room temperature. The titanium complex is destroyed by adding 20 ml of water. The precipitated inorganic salts are removed by filtration. The solvent is evaporated in vacuo and the residue is partitioned between methylene chloride and water. A colorless amorphous solid consisting of 2-methylamino-5-phenyl-3H-l, 4-benzodiazepine with a melting point of 227-229 ° is removed by filtration. After drying over sodium sulfate, evaporation and crystallization from ethyl acetate, a further sample of a colorless solid with a melting point of 226-228 ° is obtained from the methylene chloride mother liquors.

An analytical sample is recrystallized from dimethylformamide and provides colorless crystals with a melting point of 227-229 °.

100 ml of a saturated solution of nitrosyl chloride in acetic anhydride are added to a stirred solution, cooled to 10 °, of 10.0 g (0.04 M) of 2-methylamino-5-phenyl-3H-1,4-benzodiazepine in 100 ml of pyridine . The solution is stirred for 3.5 hours and during this time brought to ambient temperature. The solution is poured onto 300 ml of ice water and the aqueous solution is extracted five times with 150 ml of methylene chloride. The combined organic extracts are washed with water and brine and dried with calcium sulfate. After removing the solvent under reduced pressure, a black semi-solid residue is obtained. This residue is chromatographed on 500 g of silica gel (chloroform elution) and provides 2- (N-nitrosomethylamino) -5-phenyl-3H-l, 4-benzodiazepine with a melting point of 192-190 ° (dec.). This product is used in the following stage:

The conjugal base of nitromethane is obtained by treating 50 ml of nitromethane in 200 ml of dimethylformamide with 5.7 g (0.05 M) of potassium t-butoxide. The yellow suspension obtained is stirred and treated with 10.9 g of crude 2- (N-nitroso-methylamino) -5-phenyl-3H-1,4-benzodiazepine in 100 ml of dimethylformamide. The dark s

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Mixture is heated at 25 ° for 2 hours and at 85 ° for 1 hour and then cooled to 25 ° and poured onto 1 liter of water. After acidification with acetic acid, the aqueous solution is extracted four times with 250 ml of methylene chloride. The combined organic extracts are washed with water and brine, dried with calcium sulfate and evaporated in vacuo. The residue obtained is a dark oil, which is purified on 1 kg of silica gel (chloroform elution) and gives crude 1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine with a melting point of 131-142 ° . An analytical sample is prepared by recrystallization from ethanol and shows the melting point 141-142 °.

A mixture of 8.4 g (0.03 M) l, 3-dihydro-2-nitro-methylene-5-phenyl-2H-l, 4-benzodiazepine, 75 ml tetrahydrofuran, 75 ml methanol and 2 teaspoons Raney nickel are hydrogenated for 6 hours at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated to give crude 2-aminomethyl-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine.

This product is dissolved in 50 ml of methylene chloride and treated with 6 ml of acetic anhydride and 200 ml of saturated aqueous sodium bicarbonate solution with stirring for 15 minutes. The methylene chloride phase is separated off, washed with bicarbonate solution, dried and evaporated. The residue is heated to 130-150 ° for 15 minutes with 25 g of polyphosphoric acid. The cool reaction mixture is distributed between water and ether. The aqueous phase is made alkaline with ammonia and extracted with methylene chloride. The extracts are dried and evaporated. Chromatography of the residue on 70 g of silica gel, using a 20% solution of ethanol in methylene chloride as the eluent, gives 3a, 4-dihydro-l-methyl-6-phenyl-3H-imidazo [l, 5-a] [1,4] benzodiazepine as a light yellow resin.

This product is heated to reflux in 50 ml of toluene with 7 g of activated manganese dioxide for 1 2 hours. The inorganic material is filtered off and the filtrate is evaporated. The residue is purified by chromatography on 30 g of silica gel, a 10% solution of ethanol in methylene chloride being used as the mobile phase. The clear fractions are combined and evaporated. Crystallization of the residue from ether gives 1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine with a melting point of 180-182 °.

Example 12

To a stirred solution of 6 g (0.02 M) of 7-chloro-l, 3-dihydro-5- (2-fluorophenyl) -3-methyl-2H-l, 4-benzodiazepin-2-one in 100 ml of dry tetrahydrofuran are added 1.05 g (0.25 M) of a 57% sodium hydride dispersion in mineral oil. The reaction mixture is heated to reflux under argon for 1 hour. After cooling to room temperature, the reaction mixture is treated with 7.4 g (0.03 M) of dimorpholinophosphinic acid chloride and stirred for a further 2 hours under argon at room temperature. The reaction mixture is filtered, evaporated under reduced pressure and gives a gummy residue. By stirring this gum with 100 ml of anhydrous ether, white crystals are obtained, which are collected by filtration, washed with a little ether and air-dried. The 7-chloro-2-di- (morpholino) -phosphinyloxy-5- (2-fluorophenyl) -3-methyl-3H-1,4-benzodiazepine thus obtained has a melting point of 90-95 °.

A stirred solution of 2.4 g (0.04 M) of nitromethane in 50 ml of dry dimethylformamide is treated under argon at room temperature with 1 g (0.024 M) of a 57% sodium hydride dispersion in mineral oil. The reaction mixture is stirred for 1 hour at room temperature and then with 5.2 (0.01 M) 7-chloro-2-di- (morpholino) -phosphinoxy-5- (2-fluorophenyl) -3-methyl-3H -1,4-benzodiazepine were added, followed by stirring at room temperature and under argon for 24 hours. The dark mixture is poured onto a mixture of ice and glacial acetic acid and gives a yellow solid with stirring. Stirring continues until all ice has melted. The solid is filtered, washed with water, air-dried and yields 7-chloro-1,3-dihydro-6- (2-fluorophenyl) -3-methyl-2-nitromethylene-2H-1,4-benzodiazepine from melting point 215 ° (dec.). Recrystallization of a sample from methanol / methylene chloride (1: 1) gives yellow needles with a melting point of 219-221 ° (dec.).

A solution of 5.2 g (0.015 M) 7-chloro-l, 3-dihydro-

5- (2-fluorophenyl) -3-methyl-2-nitromethylene-2H-1,4-benzodiazepine in 450 ml of tetrahydrofuran / methanol (2: 1) is stirred for 3 hours using a Parr apparatus,

3 teaspoons of Raney nickel and an initial pressure of 18 psi are hydrogenated. The reaction mixture is filtered, evaporated under reduced pressure and provides crude 2-amino-methyl-7-chloro-2,3-dihydro-5- (2-fluorophenyI) -3-methyl-1H-1,4-benzodiazepine as a yellow oil .

The crude aminomethyl compound is mixed with 5 ml of triethyl orthoacetate and 0.5 g of p-toluenesulfonic acid monohydrate in 100 ml of ethanol. After refluxing for 2 hours, the solvent is evaporated under reduced pressure. The residue is cooled to room temperature, treated with a mixture of ice and concentrated ammonium hydroxide and extracted with methylene chloride. Evaporation of the dried extracts gives crude 8-chloro-3a, 4-dihydro-1,4-dimethyl-6- (2-fluorophenyl) -3H-imi-dazo [1,5-a] [1,4] benzodiazepine as rubber.

The crude dihydroimidazobenzodiazepine is mixed with 20 g activated manganese dioxide and 200 ml toluene and heated to reflux for 2 hours. The manganese dioxide is removed by filtration and washed with methylene chloride. Evaporation of the combined filtrates and washing liquids under reduced pressure gives a brown gum. Stirring this gum with ethanolic hydrochloric acid for a few minutes gives 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine dihydrochloride as White dust. The salt melts at 247-250 °.

Example 13

3 g of zinc dust become a solution of 2.8 g of 8-chlorine

6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in 74 ml methylene chloride and 75 ml glacial acetic acid. The reaction mixture is stirred for 2 hours at room temperature, whereupon the inorganic material is filtered off and washed with methylene chloride and water. The filtrate is diluted with 100 ml of methylene chloride and 200 ml of water and made alkaline with ammonia. The methylene chloride phase is separated off, dried and evaporated. Crystallization of the residue from ether / hexane gives 8-chloro-5,6-dihydro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine of melting point 200-203 °.

Example 14

A mixture of 100 g (0.8 M) chloroacetaldehyde dimethyl acetal and 100 ml 1.5N hydrochloric acid is refluxed for 15 minutes and then cooled, followed by a solution of 130 g (0.5 M) 2-amino -2'-fluoro-5-nitrobenzophe-non and 46 g (0.28 M) hydroxylamine sulfate and 1 liter of ethanol are added. The reaction mixture is stirred at room temperature for 2 hours and then heated to reflux for 1.5 hours. The reaction mixture is cooled and the product is obtained by filtration. By recrystallization of the s

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Residue from a mixture of chloroform and methanol gives pure 2-chloro-methyl-4- (2-fluorophenyl) -6-nitro-1,2-dihydroquinazoline-3-oxide as yellow prisms with a melting point of 220-224 °.

A solution of 142 g (0.423 M) of 2-chloromethyl-4- (2-fluorophenyl) -6-nitro-l, 2-dihydroquinazoline ~ 3-oxide in 2.3 l of dichloromethane is treated with 400 g of manganese dioxide and for 18 hours stirred, whereupon the solution is filtered. The manganese dioxide is washed with 600 ml of tetrahydrofuran and 600 ml of dichloromethane. The combined filtrates are concentrated to 400 ml and 1 liter of ether is added. Cooling and filtering gives 2-chloromethyl-4- (2-fluoropheny]) - 6-nitro-quinazoline-3-oxide. A sample is recrystallized from a mixture of dichloromethane and methanol and provides pure product as pale yellow prisms with a melting point of 127-130 °.

15.6 g (0.673 M) of lithium amide are added to 500 ml of dimethyl sulfoxide and 75 ml (1.4 M) of nitromethane with stirring and nitrogen. After 30 minutes, the solution is cooled to 5 ° and 104 g (0.31 M) of 3-chloromethyl-4- (2-fluorophenyl) -6-nitroquinazoline-3-oxide are slowly added, the temperature being kept below 8 ° . The reaction mixture is left at room temperature for 68 hours and then poured onto a mixture of 2.51 ice water and 25 ml of acetic acid, and the solution is filtered. The gum obtained is dissolved in 1 liter of dichloromethane, washed with dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated. The residue is crystallized from ethyl acetate and provides 1,3-dihydro-5- (2-fluorophenyl) -7-nitro-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide. The filtrates are evaporated, dissolved in dichloromethane and filtered through Florisil. The Florisil is eluted with dichloromethane (600 ml), ether (600 ml) and ethyl acetate (2.11). The ether and ethyl acetate fractions are combined, concentrated and deliver another end product. A sample is recrystallized from a mixture of tetrahydrofuran and hexane and provides pure product in the form of yellow prisms with a melting point of 216-220 °.

A suspension of 25 g (0.0698 M) l, 3-dihydro-5- (2-fluorophenyl) -7-nitro-2-nitromethylene-2H-l, 4-benzodiazepine-4-oxide in 1.3 1 absolute ethanol is hydrogenated with 10 teaspoons of Raney nickel for 9 hours at room temperature and atmospheric pressure. The mixture is filtered through celite and the filtrate is evaporated to dryness. A sample of the oil obtained is crystallized from tetrahydrofuran and gives the intermediate 7-amino-2-aminomethyl-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine as yellow prisms with a melting point of 185 -192 ° (dec.).

The oil thus obtained is heated to reflux for 2 hours in a solution of 300 ml of absolute ethanol containing 4.5 ml (0.0257 M) of ethanolic hydrochloric acid and 50 g (0.309 M) of triethyl orthoacetate without further purification. The reaction mixture is then evaporated to dryness. The residue is dissolved in 150 ml of dichloromethane, washed with 100 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness.

The oil obtained as residue, which is crude 8-acetyllamino-3a, 4-dihydro-6- (2-fluorophenyl) -1-methyl-3H-imidazo [1,5-a] [1,4] benzodiazepine, is dissolved in 500 ml of benzene and treated with 100 g of activated manganese dioxide. The reaction mixture is heated to reflux with stirring for 9 hours using a water separator. A further 25 g of activated manganese dioxide are added, followed by heating to reflux for a further 4 hours. The manganese dioxide is removed by filtration and washed with 500 ml of tetrahydrofuran. The filtrates are combined and evaporated to dryness. The oil obtained as residue, which is 8-acetylamino-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, is dissolved in 75 ml of methanol and mixed with a Excess ethanolic hydrochloric acid added. After 10 minutes, 100 ml of water and after a further 20 minutes in which the 8-acetyl group is hydrolyzed, a mixture of ice and dilute ammonium hydroxide are added until the reaction mixture is basic. The reaction mixture is filtered and the precipitate and the filtrates are extracted separately with dichloromethane. The extracts are dried and evaporated. The extract from the filtrates is crystallized from isopropanol and provides 8-amino-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-isopropa-nol. The extracts from the precipitate are used on Florisil chromatographies, first using dichloromethane, then ether and ethyl acetate, containing 10% methanol as the eluent. Evaporation and crystallization from isopropanol give further end product. By recrystallizing the combined products from isopropanol, white rods with a melting point of 135-145 ° are obtained.

Example 15

A mixture of 17 g (0.05 M) of racemic 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine, which is available from Dihydrochloride was freed by partitioning between methylene chloride and aqueous ammonia, 18.8 g (0.05 M) of 0.0'-dibenzoyl-d-tartaric acid hydrate and 170 ml of ethanol is boiled until completely dissolved. The solution is left to stand overnight for crystallization. The crystals which have separated out are collected, washed with ethanol and ether and yield the 0.0'-dibenzoyl-d-tartrate with a melting point of 140-142 °. Recrystallization from ethanol / ether gives a product with a melting point of 141-142 °; [ajg5 = -43.39 ° (c = 1% in methanol).

A solution of 1.6 g (0.0106 m) of 1-tartaric acid in 11 ml of ethanol becomes a solution of 3.5 g of the base rotating to the left, which has been freed from the above 0.0'-dibenzoyl-d-tartrate , placed in 11 ml of ethanol. The crystals obtained are collected, washed with ethanol and ether and give (+) -8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-d-tartrate with a melting point of 178-180 °. Recrystallization from ethanol gives a product with a melting point of 183-185 °; [a] * = + 25.69 ° (c = 1.012% in methanol). The amorphous base, which was freed from this salt, shows an optical rotation of [ctß5 = -36.74 ° (c = 0.939% in methylene chloride).

Example 16

The mother liquor obtained after separating the crystalline salt with 0.0'-diben-zoyl-d-tartaric acid (as described in the previous example) is evaporated and converted back into the base by partitioning between aqueous ammonia and methylene chloride. The methylene chloride solution is dried over sodium sulfate and evaporated, and partly frees the base again.

A solution of 9.7 g (0.029 M) of this material in 15 ml of ethanol is treated with a solution of 4.4 g of d-tartaric acid in 14 ml of ethanol. The crystals that precipitate after many hours are collected and provide (-) - 8-chloro-l, 4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [l, 5-a] [l, 4] benzodia-zepin-d-tartrate with a melting point of 176-178 °. Recrystallization from ethanol gives a product with a melting point of 182-184 °;

[a] ^ s = -24.96 ° (0.9616% in methanol). The amorphous base freed from this salt shows an optical rotation of

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[a] £ f = + 37.6 ° (c = 1.0% in methylene chloride).

Example 17

A solution of 19.3 g (0.06 M) l, 3-dihydro-7- (2-methyl-l, 3-dioxolan-2-yl) -5-phenyl-2H-l, 4-benzodia-zepin -2-one in 300 ml of dry tetrahydrofuran is treated under an argon atmosphere with 3.1 g (0.075 M) of a 57% sodium hydride suspension in mineral oil. The reaction mixture is heated to reflux for 1 hour, cooled to room temperature and then mixed with 22.2 g (0.087 M) of dimorpholinophosphinic acid chloride. The reaction mixture is stirred at room temperature for 2 hours and then left to stand overnight. The sodium chloride is removed by filtration and the filtrate is freed from the solvent. Crystallization of the residue from ether gives crude 7- (2-methyl-l, 3-dioxolan-2-yl) -2- [bis (mor-pholino) phosphinyloxy] -5-phenyl-3H-l, 4-benzodiazepine .

A mixture of 100 ml of dry N, N-dimethylformamide and 6.8 g of nitromethane is treated with 2.8 g (0.066 M) of a 57% suspension of sodium hydride in mineral oil under a nitrogen atmosphere. The mixture is stirred at room temperature for 1 hour and then with a solution of 18 g (0.033 M) of crude 7- (2-methyl-l, 3-dioxolan-2-yl) -2- [bis (morpholino) phosphinyloxyl] -5-phenyl-3-Hl, 4-benzodiazepine in 50 ml of dry N, N-dimethylform amide. The reaction mixture is left to stand at room temperature for 15 hours, after which the dark viscous liquid is poured onto a mixture of ice and dilute acetic acid. The light yellow precipitate is removed by filtration and dissolved in dichloromethane. The solution is washed with dilute ammonium hydroxide and water, dried over sodium sulfate and evaporated. The original filtrate is extracted with dichloromethane and then washed, dried and evaporated as above. The two raw residues are combined and chromatographed on Florisil. Dichloromethane containing 10% ether is used as the eluent. The fractions are monitored by thin layer chromatography and several fractions containing the desired product are collected and evaporated. Crystallization and recrystallization from a mixture of dichloromethane and hexane gives pure 2,3-dihydro-7- (2-methyl-l, 3-dioxo-lan-2-yl) -2-nitromethylene-5-phenyl-IH- 1,4-benzodiazepine as pale yellow prisms with a melting point of 158-161 °.

5 g (0.0137 M) 2,3-dihydro-7- (l-methyl-l, 3-dioxolan-2-yl) -2-nitromethylene-5-phenyl-lH-l, 4-benzodiazepinin 250 ml absolute Ethanol is hydrogenated for 3.5 hours in the presence of 1 teaspoon of Raney nickel and provides crude 2-amino-methyl-2,3-dihydro-7- (l-methyl-l, 3-dioxolan-2-yl) -5 -phenyl-lH-l, 4-benzodiazepine. 0.7 g (0.0037 M) of p-toluenesulfonic acid and 6 g (0.037 M) of triethyl orthoacetate are added to a solution of 4 g (0.0119 M) of this compound in 75 ml of absolute ethanol. The reaction mixture is heated to reflux for 2 hours and then evaporated to dryness. The residue is dissolved in 50 ml dichloromethane. The solution is washed with 25 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate, evaporated and provides crude 3a, 4-dihydro-l-methyl-8- (l-methyl-l, 3-dioxolan-2-yl) -6-phenyl -3H-imi-dazo [1,5-a] [1,4] benzodiazepine in the form of an oil. A solution containing 3.8 g (0.0105 M) of this crude oil and 18 g activated manganese dioxide in 100 ml toluene is heated to reflux with stirring for 2 hours using a water separator. The reaction mixture is filtered and washed with a mixture of 250 ml dichloromethane and 250 ml tetrahydrofuran. The filtrates are evaporated and dissolved in a small amount of isopropanol and with

Treated 1.4 g (0.0121 M) maleic acid in ethanol. The precipitate obtained after adding ether is filtered and recrystallized from a mixture of methanol / ether and gives l-methyl-8- (2-methyl-l, 3-dioxolan-2-yl) -6-phenyl-4H-imidazo [ 1,5-a] [1,4] benzodiazepine-maleate-methanol (2/1) in the form of whitish prisms with a melting point of 179-182 °.

Example 18

A solution of 0.3 g (0.1000607 M) l-methyl-8- (2-methyl-l, 3-dioxolan-2-yl) -6-phenyl-4H-imidazo [l, 5-a] [ 1,4] benzodiazepine-maleate-methanol (2/1) in 10 ml (0.01 M) IN hydrochloric acid is left to stand for 18 hours. A small amount of activated carbon is added and the reaction mixture is filtered. The solution is made basic with ammonium hydroxide, extracted with 25 ml of dichloromethane, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is dissolved in isopropanol and treated with 0.35 g (0.10015 M) picric acid in 5 ml ethanol. The solution is evaporated and the residue obtained is crystallized from methanol. By recrystallization of the mixture of tetrahydrofuran and isopropanol, 8-acetyl-l-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodia-zepin dipicrate is obtained as yellow prisms with a melting point of 225-230 °.

Example 19

A solution of 1 g (0.00317 M) of 8-acetyl-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine dipicrate in 75 ml absolute ethanol is mixed with 0, Treated 78 g (0.0205 M) sodium borohydride. After 18 hours the solution is evaporated to dryness. The residue is acidified with dilute acetic acid, made basic with ammonium hydroxide and extracted with 75 ml of dichloromethane. The organic phases are combined, dried over anhydrous sodium sulfate and evaporated to dryness. The oil obtained as a residue is dissolved in isopropane and treated with 1.6 g (0.007 M) picric acid in 20 ml ethanol. The precipitated salt is filtered and recrystallized twice from methanol. 8- (l-Hydroxyethyl) -l-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine dipicrate is obtained as a yellow stick with a melting point of 223-225 °.

Example 20

The filtrates from the reaction according to Example 19 are concentrated and the crude residue obtained is filtered. By recrystallization twice from a mixture of tetrahydrofuran and methanol, pure 8- (l-hydroxyethyl) -l-methyl-6-phenyl-5,6-dihydro-4H-imidazo [l, 5-a] - [l , 4] -benzodiazepine dipicrate as yellow rods with a melting point of 143-145 °.

Example 21

A solution of 56.4 g (0.20 mol) l, 3-dihydro-7-ethyl-5- (2-fluorophenyl) -2H-l, 4-benzodiazepin-2-one in 2.01 tetrahydrofuran containing 4 mol Monomethylamine is cooled in an ice bath. 33.0 ml (0.30 mol) of titanium tetrachloride in 350 ml of benzene are added to the reaction gene. The reaction mixture is stirred for 3 days at room temperature.

The titanium tetrachloride is destroyed with 100 ml of water. The inorganic salts are removed by filtration. The filtrate is evaporated to dryness in vacuo. The residue is partitioned between methylene chloride and water. The methylene chloride phase is dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue from acetonitrile gives 7-ethyl-5- (2-fluorophenyl) -2-methylamino-3H-l, 4-benzodiaze-pin as light yellow prisms with a melting point of 172-174 °.

An analytical sample is recrystallized from acetonitrile s

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and provides light yellow prisms with a melting point of 172-174 °.

8.6 g (0.125 M) sodium nitrite are added in three portions during a V2 hour to a solution of 29.5 g (0.1 M) 7-ethyl-5- (2-fluorophenyl) ~ -2-methylamino-3H- 1, 4-benzodia-zepin in 100 ml of glacial acetic acid. The reaction mixture is stirred for a further V2 hour at room temperature, then diluted with ice water and extracted with methylene chloride. The extracts are washed with water and aqueous bicarbonate solution, dried over sodium sulfate, evaporated and provide crude 7-ethyl-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-l, 4-benzodiazepine as a yellow oil.

This product is dissolved in 100 ml of dimethylformamide. The solution is added to a mixture of 100 ml of dimethylformamide, 35 ml of nitromethane and 9.9 g of potassium t-butoxide, which has been stirred for one hour at room temperature. When the addition is complete, the reaction mixture is stirred for 1 hour at room temperature and then for 30 minutes on the steam bath. The cooled solution is acidified with glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts are washed with water, dried and evaporated. The residue is dissolved in 50 ml of ethanol, whereupon the solution is crystallized overnight in the refrigerator with seeding. The yellow crystals are collected and recrystallized from ethanol, giving 1,3-dihydro-7-ethyl-5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine with a melting point of 138-140 °. The seed crystals are obtained by chromatography of the crude product on a 40-fold amount of silica gel using a 5% solution of ethyl acetate in methylene chloride as the mobile phase.

An analytical sample is crystallized from ether / hexane and shows the melting point 138-141 °.

2.6 g of l, 3-dihydro-7-ethyl-5- (2-fluorophenyl) -2-nitro-methylene-2H-l, 4-benzodiazepine in 30 ml of ethanol are hydrogenated with 1 teaspoon of Raney nickel for 4 hours. The catalyst is removed by filtration and the filtrate is evaporated. The residue is dissolved in ether and the amine is extracted with 10% aqueous acetic acid. The extracts are washed with ether and made alkaline with ammonia. The precipitated amine is extracted with methylene chloride. The extracts are dried, evaporated and provide crude 2-aminomethyl-2,3-dihydro-7-ethyl-5- (2-fluorophenyl) -1H-1,4-benzodiazepine. This product is dissolved in 50 ml of xylene. After the addition of 3 ml of triethyl orthoacetate, the solution is heated to reflux for 2 hours. The residue obtained after evaporation under reduced pressure is chromatographed on 50 g of silica gel, a 20% solution of methanol in methylene chloride being used as the mobile phase. The homogeneous fractions are combined and evaporated to give 3a, 4-dihydro-8-ethyl-6- (2-fluorophenyl) -l-methyl-3H-imidazo [1,5-a] [1,4] ben-zodiazepine. This material is dissolved in 50 ml of toluene. After adding 5 g of activated manganese dioxide, the solution is heated to reflux for 1 hour. The inorganic material is removed by filtration and the filtrate is evaporated. The residue is dissolved in ether and treated with ethanolic hydrochloric acid and acetone. The crystalline dihydrochloride (melting point 248-255 °) is collected and converted back into the base by partitioning between methylene chloride and aqueous ammonia. The methylene chloride phase is dried and evaporated. Crystallization of the residue from ether / hexane gives 8-ethyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazole-pin with a melting point of 152-154 ° .

Example 22

27.6 g (0.4 M) sodium nitrite is added in portions to a solution of 90.45 g over a period of 30 minutes

(0.3 M) 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-l, 4-benzodiazepine in 400 ml of glacial acetic acid. When the addition is complete, the reaction mixture is stirred at room temperature for 1 hour, diluted with 1 liter of water and extracted with methylene chloride. The extracts are washed twice with water and then with 10% aqueous sodium carbonate solution. The solution is dried and evaporated to give crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosome-thylamino) -3H-l, 4-benzodiazepine as a yellow oil.

Example 23

A solution of 0.8 g (0.0024 M) 8-acetamido-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in 10 ml Dry N, N-dimethylformamide is treated under nitrogen with 0.13 g (0.003 M) of a 55% sodium hydride dispersion in mineral oil, and after 30 minutes the reaction mixture is cooled in an ice bath. The stirred reaction mixture is mixed with 0.43 g (0.003 M) of methyl iodide, then left to stand at room temperature for 18 hours and then poured onto water. Filtration gives a crude product which is recrystallized from a mixture of ethyl acetate and ether. 6- (2-Fluorophenyl) -1-methyl-8- (N-methylacetamido) -4H-imi-dazo [1,5-a] [1,4] benzodiazepine are obtained as whitish prisms with a melting point of 217-223 °.

Example 24

A solution of 0.3 g (0.000828 M) 6- (2-fluorophenyl) -l-methyl-8- (N-methylacetamido) -4H-imidazo [1,5-a] [1,4] -benzodiazepine in 10 ml of methanol is treated with 3 ml of concentrated hydrochloric acid and heated to reflux for 1 hour. The solution is made basic with ammonium hydroxide and then distributed between 50 ml of dichloromethane and 50 ml of water. The organic phase is dried over anhydrous sodium sulfate and evaporated to dryness. The oil obtained as a residue is dissolved in 10 ml dichloromethane. The solution is filtered through Florisil, using ether, ethyl acetate and finally ethyl acetate containing 5% methanol as the eluent. This last mixture is evaporated and brought to crystallization from a mixture of ethyl acetate and ether. 6- (2-fluorophenyl) -1-methyl-8-methylamino-4H-imidazo [1,5-a] [1,4] benzodiazepine are obtained as whitish prisms with a melting point of 255-259 °.

Example 25

A mixture of 9.75 g (0.03 M) 8-chloro-6- (2-fluoro-phenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 200 ml Methylene chloride and 12 g (0.07 M) m-chloroperbenzoic acid are stirred for 1 2 hours. The solution is then extracted three times with 150 ml IN hydrochloric acid. The extracts are washed with ether, made alkaline with ammonia and extracted with methylene chloride. The methylene chloride extracts are dried and evaporated. The residue is crystallized from ethyl acetate and purified further by chromatography on 100 g of silica gel, a 5% solution of ethanol in methylene chloride being used as the mobile phase. The clear fractions are combined and evaporated. Crystallization of the residue from ethyl acetate / ether gives 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imi-dazo [1,5-a] [1,4] benzodiazepine-5-oxide as colorless Crystals with a melting point of 245-246 ° (dec.).

Example 26

A mixture of 9.75 g (0.03 M) of 8-chloro-6- (2-fluoro-phenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 18 g (0.105 M) m-chlorobenzoic acid and 200 ml methylene chloride are stirred overnight at room temperature. After dilution with 500 ml of ether, the reaction mixture

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extracted four times with 75 ml IN hydrochloric acid. The extracts are washed with ether, made alkaline with ammonia and extracted with methylene chloride. The extracts are dried and evaporated. Crystallization from ethyl acetate gives 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-5-oxide.

Example 27

A suspension of 17 g (0.05 M) 7-chloro-l, 3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-2H-l, 4-benzodiazepine-4-oxide in 200 ml of tetrahydrofuran and 100 ml of methanol is hydrogenated in the presence of 17 g of Raney nickel at an initial pressure of 155 psi for 24 hours. The catalyst is removed by filtration and the filtrate is evaporated. The residue is dissolved in 50 ml of 2-propanol and heated on the steam bath. The salt obtained after adding 17 g of warm maleic acid in 60 ml of ethanol is crystallized by cooling in an ice bath. This gives 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-l, 4-benzodiazepine dimaleate in the form of yellow crystals with a melting point of 196-198 °.

8.0 g (0.015 M) of 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -IH-l, 4-benzodiazepine dimaleate is partitioned between methylene chloride and aqueous ammonia. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated. The residue is dissolved in 50 ml of pyridine. After adding 10 ml of acetic hydride, the mixture is heated on the steam bath for 4 hours. After evaporation of the reaction mixture under reduced pressure, the residue is partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic phase is dried and evaporated. Crystallization of the residue from methylene chloride / ether with seeding gives 1-acetyl-2-acetylaminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine with melting point 213-215 °. The seed crystals are obtained by chromatography on silica gel (40 times the amount),

using a 10% solution of ethanol in methylene chloride as the eluent. An analytical sample is recrystallized from ethyl acetate / hexane and shows the melting point 215-217 °.

A mixture of 0.5 g of l-acetyl-2-acetylaminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -IH-l, 4-benzodia-zepin and 10 g of polyphosphoric acid is added for 10 minutes heated to 150-170 °. The cold reaction mixture is dissolved in ice water and the solution made alkaline with ammonia. The excreted base is extracted with methylene chloride. The extracts are washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 10 g of silica gel, using a 20% solution of methanol in methylene chloride as the eluent. The clear fractions are combined and evaporated. The residue is crystallized from ether and gives 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -l-methyl-3H-imidazo [1,5-a] [1,4] benzodiazepine with melting point 142 to 144 °.

Example 28

A solution of 2.9 g (0.00927 M) 2,3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-lH-l, 4-benzodiazepine-4-oxide in a mixture of 1 teaspoon Raney- Nickel, 90 ml of tetrahydrofuran and 45 ml of methanol are hydrogenated for 2.3 hours at atmospheric pressure and room temperature. The reaction mixture is filtered and the catalyst is washed with dichloromethane. The combined filtrates are evaporated and the oil obtained is dissolved in 50 ml dichloromethane. The dichloromethane solution is washed with 50 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. To

2.2 g (0.019 M) of maleic acid in 15 ml of ethanol are added to the solution, and the oil crystallizes out after the addition of ether. This gives 2-aminomethyl-2,3-dihydro-5- (2-fluorophenyl) -IH-l, 4-benzodiazepine dimaleate hemihydrate. By recrystallization from a mixture of methanol and ether, the product is obtained as a yellow stick with a melting point of 147 to 150 °.

A solution of 4.0 g (0.0149 M) of the base of 2-amino-methyl-2,3-dihydro-5- (2-fluorophenyl) -IH-l, 4-benzodia-zepin-dimaleate hemihydrate in 125 ml of absolute ethanol is treated with 4 g (0.0247 M) of triethyl orthoacetate and 0.5 g (0.00263 M) of p-toluenesulfonic acid. The reaction mixture is heated to reflux for 2 hours and then evaporated to dryness. The oil obtained as a residue is dissolved in 50 ml of dichloromethane. The solution is washed with 50 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate, evaporated and provides crude 3a, 4-dihydro-6- (2-fluorophenyl) -l-methyl-3H-imidazo [l, 5-a] [l, 4] -benzodiazepine in the form of an oil.

a) This crude product is dissolved in 100 ml of toluene and treated with 18 g of activated manganese dioxide. The reaction mixture is heated to reflux for 3.5 hours using a water separator. The reaction mixture is filtered through Celite and the precipitate is washed with 100 ml of tetrahydrofuran and then 100 ml of dichloromethane. The combined filtrates are evaporated and the residue is dissolved in 25 ml dichloromethane. This solution is chromatographed through a Florisil column, first using dichloromethane and then ether as the eluent. Elution with ethyl acetate and then with a 10% solution of methanol in ethyl acetate gives a crude product which is crystallized from ether and then from ethyl acetate and 6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a ] [1,4] benzodiazepine as white prisms with a melting point of 164-168 °.

b) A solution of 1.2 g (0.0041 M) 3a, 4-dihydro-5- (2-fluorophenyl) -1-methyl-3H-imidazo [1,5-a] [1,4] benzodiazepine in 50 ml of mesitylene and 0.5 g of 10% palladium-carbon are heated to reflux with stirring for 28 hours. The reaction mixture is filtered and evaporated to dryness. Crystallization of the residue from ethyl acetate gives 6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] ben-zodiazepine as white prisms with a melting point of 162-167 ° and a mixed melting point with authentic product from 162-168 °.

Example 29

41.3 g of 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine dihydrochloride is distributed between methylene chloride and aqueous ammonia. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated. The free base is obtained in this way. This is dissolved in 50 ml of 2-propanol and the solution is treated with a solution of 12 g of maleic acid in 40 ml of 2-propanol. The solution is gradually diluted with 300 ml of ether. The separated crystals are collected, dried and yield 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine maleate, which according to Recrystallization from ethanol / ether melts at 130-132 °.

Example 30

A solution of 5 g (0.00153 M) 8-chloro-6- (2-fluoro-phenyl) -l-methyl-4H-imidazo [l, 5-a] [l, 4] benzodiazepine in 75 ml dry ethylene dichloride is cooled in an ice bath and treated with 5 g (0.0352 M) boron trifluoride etherate

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delt. After 10 minutes, a solution of 4 g (0.091 M) of ethylene oxide in 5 ml of ethylene dichloride is added with stirring. The reaction mixture is left to stand at room temperature for 1 hour and then made basic with a solution of potassium carbonate in water. The organic phase is separated off, dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 50 ml dichloromethane and filtered through 150 g Florisil. The Florisil is eluted with 750 ml dichloromethane and then with 750 ml ether.

The dichloromethane solution is evaporated and the residue is partitioned between 100 ml ether and 100 ml 0.5N hydrochloric acid. The acidic phase is separated off, made basic with ammonium hydroxide and extracted with 100 ml of dichloromethane. The dichloromethane phase is dried and evaporated. The oil obtained as a residue is dissolved in 15 ml of isopropanol and treated with 0.8 g (0.0068 M) maleic acid. The solution is warmed on the steam bath for 5 minutes, then cooled and mixed with ether. The precipitate obtained is filtered and recrystallized from a mixture of methanol / ether, whereby 2-chloro-13a- (2-fluorophenyl) -12,13a-dihydro-6-methyl-9H, IIH-imidazo [1,5 -a] -oxazolo [3,2-d] [1,4] -benzodiazepine maleate as white prisms with a melting point of 195-200 °. The ether eluate from the Florisil column is concentrated, filtered and crystallized from ether, the base being obtained as white prisms with a melting point of 178-180 °.

Example 31

A solution of 0.7 g (0.00203 M) (2-fluorophenyl) - [2- (5-hydroxymethyl-2-methyl-l-imidazolyl) -5-chlorophenyl] methanone in 40 ml dry dichloromethane is added in cooled in an ice bath and 0.22 ml (0.00227 M) of phosphorus tribromide was added with stirring. The reaction mixture is stirred at room temperature for 1 hour, then cooled in an ice bath and mixed with 2 ml (0.0328 M) ethanolamine. The solution is stirred at room temperature for 2 hours, heated to reflux for 1 hour and then poured onto 50 ml of water. The organic phase is separated off, dried over anhydrous sodium sulfate and concentrated to a small volume. The residue is developed on 4 silica gel plates with a solution of 5% methanol in ethyl acetate. The Rf 0.5 material is removed from the plate and treated with methanol. The solution is filtered and the filtrates are evaporated. The residue is crystallized from ether and provides 2-chloro-13a- (2-fluorophenyl) -12,13a-dihydro-6-methyl-9H, IIH-imidazo [1,5-a] -oxazolo- [3,2- d] [1,4] benzodiazepine. By recrystallization from a mixture of methanol and ether, pure product is obtained in the form of white prisms of melting point and mixed melting point with an authentic sample from 176 to 181 °.

Example 32

9.5 ml of nitromethane are dissolved in 100 ml of dimethylformamide under nitrogen and with stirring, and 5.2 g (0.045 mol) of potassium t-butoxide are added at 0-10 °. The reaction mixture is stirred for 1 hour at room temperature, then quenched on ice and slowly below 5.1 ° with 5.1 g (0.015 mol) of 6-chloro-2-dichloromethyl-1,2-dihydro-4-phenyl-quinazoline-3- oxide added. The reaction mixture is stirred at room temperature for 17 hours.

The reaction mixture is poured onto ice and dichloromethane and made slightly acidic with glacial acetic acid. The aqueous phase is back extracted three times with dichloromethane. The organic phases are combined, washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to an amber residue. Crystallization from boiling ethanol gives 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine-4-oxide as yellow prisms with a melting point of 245-248 ° (dec.). Adding an authentic sample did not result in melting point depression.

Example 33

A mixture of 64 mg (0.2 mmol) of 7-chloro-1, 3-dihydro-5- (2-fluorophenyl) -2H-1, 4-benzodiazepine-2-carboxamide and 15 mg (0.4 mmol) of lithium aluminum hydride in 3 ml of dry tetrahydrofuran is boiled for 15 minutes. The cold reaction mixture is mixed with saturated aqueous sodium sulfate solution. Thin-layer chromatographic analysis of the solution obtained shows the presence of starting material as the (faster running) main component and free base 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine as the smaller one Component. The solution is applied directly to a 20 X 20 cm2 preparative thin-layer plate (silica gel), after which the plate is developed with ethanol. The lower yellow band is removed and extracted twice with methanol / methylene chloride (2: 1). Evaporation of the filtered extract gives a clear, colorless oil. This is taken up in 1 ml of ethanol, treated with excess maleic acid (50 mg), scratched and stored in the refrigerator overnight. The yellow crystals are collected, washed with ether and air dried. This product was identified as 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -lH-l, 4-benzodiazepine dimaleate identified. The mixed melting point was 184-187 °.

Example 34

A mixture of 10 g (0.036 M) l, 3-dihydro-5-phenyl-2H-thieno [3,2-e] [1,4] diazepin-2-one in 50 ml benzene and 300 ml tetrahydrofuran is combined in one Ice bath stirred and saturated with methylamine gas. A solution of 9.48 g (0.05 M) titanium tetrachloride in 50 ml benzene is added dropwise to this mixture. After the addition has ended, the reaction mixture is stirred in an ice bath for 15 minutes. The ice bath is then removed and the reaction mixture is heated to reflux for half an hour. The reaction mixture is cooled and 100 g of ice are carefully added. The reaction mixture is filtered and the residue is washed with tetrahydrofuran. The filtrates are combined, dried and evaporated. The product is crystallized from methylene chloride and gives 2-methylamino-5-phenyl-3H-thieno [3,2-e] [1,4] diazepine with a melting point of 223-227 °. From the mother liquors, another product with a melting point of 222-225 ° is obtained. An analytical sample is recrystallized from methylene chloride and shows the melting point 222-229 °.

Nitrosylchloro is added to a solution of 7.8 g (0.03 M) of 2-methylamino-5-phenyl-3H-thieno [3,2-e] [1,4] diazepinin cooled in ice water in 100 ml of methylene chloride and 40 ml of pyridine -rid initiated. The reaction is monitored by thin layer chromatography, the nitrosyl chloride addition being stopped as soon as no starting material appears. The reaction mixture is then partitioned between methylene chloride and water. The methylene chloride solution is dried and evaporated. Crystallization of the residue from methylene chloride / hexane gives 2- (N-nitrosomethylamino) -5-phenyl-3H-thieno [3,2-e] [1,4] diazepine as yellow crystals with a melting point of 156-159 °. An analytical sample is crystallized from ether / hexane and shows a melting point of 158-160 °.

5.7 g (0.02 M) of 2- (N-nitrosomethylamino) -5-phenyl-3H-thieno [3,2-e] [1,4] diazepine are added to a mixture of 15 which is stirred at room temperature for 10 minutes ml nitro

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methane, 4.5 g of potassium t-butoxide and 60 ml of dimethylformamide. When the addition is complete, the reaction mixture is heated on the steam bath with nitrogen and stirring for 10 minutes. After acidification with 4 ml of glacial acetic acid, the reaction mixture is partitioned between methylene chloride / toluene and saturated sodium bicarbonate solution. The organic phase is washed with water, dried and evaporated. Crystallization of the residue from methanol with seeding gives 1,2-dihydro-2-nitromethylene-5-phenyl-3H-thieno [3,2-e] [1,4] diazepine as yellow crystals with a melting point of 160-163 °. The seed crystals were obtained by chromatographic purification on a 30-fold amount of silica gel, using a 10% solution of ethyl acetate in methylene chloride as the eluent. An analytical sample was recrystallized from methanol and showed the melting point 163-164 °.

A solution of 1.42 g (5 mmol) 1,2-dihydro-2-nitro-methylene-5-phenyl-3H-thieno [3,2-e] [1,4] diazepine in 200 ml ethanol is mixed with 2 Teaspoons of Raney nickel hydrogenated for 1 hour at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated. The residue is treated in 1.2 ml of 2-propanol with 1.2 g of maleic acid. By adding ether, the 2-aminomethyl-2,3-dihydro-5-phenyl-1H-thieno [3,2-e] [1,4] diaze-pin-dimaleate crystallized as yellow crystals with a melting point of 170-173 °. An analytical sample was recrystallized from methanol / 2-propanol and shows the melting point 187-189 °.

1 g (2 mmol) of 2-aminomethyl-2,3-dihydro-5-phenyl-1H-thieno [3,2-e] [1,4] diazepine dimaleate is distributed between methylene chloride and aqueous ammonia. The methylene chloride phase is dried and evaporated. The residue is refluxed with 1 ml of triethyl orthoacetate in 20 ml of xylene for 1 hour. The residue obtained after evaporation of the solvent under reduced pressure is crystallized from 2-propanol / ether and gives 1-methyl-3a, 4-dihydro-6-phenyl-4H-imidazo [1,5-a] thieno [2,3- f] [1,4] diazepine with melting point 150-152 °. This material is refluxed in 30 ml of toluene with 2 g of activated manganese dioxide for 2 hours. The manganese dioxide is filtered off and washed well with methylene chloride. The filtrate is evaporated and the residue is chromatographed on 7 g of silica gel, using a 3% solution of ethanol in methylene chloride as the eluent. The fractions containing the pure product are pooled and evaporated. Crystallization from methylene chloride / ether and recrystallization from ethyl acetate / hexane gives 1-methyl-6-phenyl-4H-imidazo [1,5-a] thieno [2,3-e] [1,4] diazepine with a melting point of 223- 225 °.

Example 35

A mixture of 7.7 g (0.0278 M) 7-chloro-1,3-dihydro-5-phenyl-2H-thieno [2,3-e] [1,4] diazepin-2-one, 50 ml Benzene and 250 ml of tetrahydrofuran are stirred in an ice bath and saturated with methylamine gas. 7.38 g (0.0389 M) of titanium tetrachloride in 50 ml of benzene are added to this mixture through a dropping funnel. After the addition has ended, the reaction mixture is stirred in an ice bath for 15 minutes. The ice bath is then removed and the reaction mixture is heated to reflux for 20 minutes. The reaction mixture is cooled and 100 g of ice are carefully added. The mixture is filtered and the residue is washed with tetrahydrofuran. The filtrates are combined, dried and evaporated. The residue is crystallized from methylene chloride / ether and gives 7-chloro-5-phenyl-2-methylamino-3H-thieno [2,3-e] [1,4] diazepine with a melting point of 246-249 °. An analytical sample is recrystallized from methylene chloride and shows the melting point 247-250 °.

In a solution of 5.8 g (0.02 M) 7-chloro-5-phenyl-2-

methylamino-3H-thieno [2,3-e] [1,4] diazepine in 100 ml methylene chloride and 50 ml pyridine nitrosyl chloride is introduced until the reaction has ended (according to the thin layer chromatogram). The reaction mixture is partitioned between water and toluene. The organic phase is dried and evaporated. Crystallization of the residue from ether / hexane gives 7-chloro-2- (N-nitrosome-thylamino) -5-phenyl-3H-thieno [2,3-e] [1,4] diazepine as yellow crystals with melting point 108 -110 °. For analysis purposes the product is recrystallized from ether / hexane and shows the melting point 111-113 °.

3.2 g (0.01 M) 7-chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-thieno [2,3-e] [1,4] diazepine are added to a mixture of 10 ml nitromethane , 35 ml of dimethylformamide and 2.26 g (0.02 M) of potassium t-butoxide, which was stirred under nitrogen at room temperature for 10 minutes. After heating on the steam bath for 10 minutes, the reaction mixture is acidified by adding 2 ml of glacial acetic acid and then partitioned between water and toluene. The toluene phase is washed with water, dried and evaporated. The residue is crystallized from ethyl acetate / hexane and gives crude 7-chloro-2,3-dihydro-2-nitromethylene-5-phenyl-lH-thieno [2,3-e] [1,4] diazepine. This product is purified by chromatography on 40 g of silica gel, using a 10% solution of ethyl acetate in methylene chloride as the eluent. The pure product is obtained in the form of yellow crystals with a melting point of 154-156 °.

a) A solution of 320 mg (1 mmol) of 7-chloro-2,3-dihydro-2-nitromethylene-5-phenyl-lH-thieno [2,3-d] [1,4] diazepinin 20 ml of ethanol is added during Hydrogenated for 5 hours in the presence of Raney nickel at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated. The residue is chromatographed on 7 g of silica gel, a mixture of methylene chloride, methanol and triethylamine in a ratio of 13: 6: 1 being used as the eluent. The pure fractions containing the desired product are cleaned and evaporated. The residue is treated with maleic acid in 2-propanol. Crystallization of the dimaleate from 2-propanol / ether and recrystallization from ethyl acetate / ethanol gives 2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-lH-thieno [2,3-e] [1,4 ] diazepine di-maleate as yellow crystals with a melting point of 176-177 °.

b) A solution of 320 mg (1 mmol) of 7-chloro-2,3-di-hydro-2-nitromethylene-5-phenyl-lH-thieno [2,3-e] [1,4] diazepine in 3 ml Tetrahydrofuran is added to a suspension of 0.8 g of lithium aluminum hydride in 20 ml of tetrahydrofuran. After refluxing for 5 minutes, the reaction mixture is cooled and hydrolyzed by adding 5 ml of water. The inorganic material is removed by filtration and the filtrate is evaporated. The residue is chromatographed as described above and the pure product is converted into the maleate and yields 2-amino-methyl-7-chloro-2,3-dihydro-5-pîi3r-3'-1H-thieno [2,3- e] [1,4] di-azepine dimaleate with a melting point of 176-178 °.

0.52 g (1 mmol) of 2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-lH-thieno [2,3-e] [1,4] diazepine dimaleate is added between methylene chloride and aqueous ammonia distributed. The methylene chloride solution is dried and evaporated. The residue is heated to reflux for 1 hour with 0.5 ml of triethyl orthoacetate in 10 ml of xylene. The crude product obtained after evaporation under reduced pressure is dissolved in 25 ml of toluene. After adding 2.5 g of activated manganese dioxide, the solution is heated to reflux for 1½ hours. The manganese dioxide is filtered off and the filtrate is evaporated. The residue is chromatographed on 6 g of silica gel, a 49Hge solution of ethanol in s

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Hexane gives 8-chloro-l-methyl-6-phenyl-4H-imi-dazo [1,5-a] thieno [3,2-f] [1,4] diazepine with a melting point of 168 to 170 °.

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Claims (10)

619 953 PATENT CLAIMS 1. Process for the preparation of imidazo [1,5-a] [1,4] -diazepine compounds of the general formula R. 2. Process for the preparation of imidazo [1,5-a] [1,4] -diazepine compounds of the general formula 10th H IA where (gli one of the groups - p 15 in which (§C one of the groups and and a) b) a) b} 'XK 25th 30th TT c) A the group -C = N, Ri hydrogen, lower alkyl, ROE Phenyl, lower alkoxyalkyl, substituted phenyl, pyridyl or aralkyl, R2 and R3 each hydrogen or lower alkyl, R4 hydrogen, halogen, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, lower hydroxyalkyl or lower alkanoyl, Rô phenyl, monosubstituted phenyl, in positions 2, 3; 2, 5 or 2, 6 di-substituted phenyl, pyridyl or mono-substituted pyridyl and X are chlorine, bromine or iodine, and of pharmaceutically acceptable acid addition salts of these compounds, characterized in that a compound of the general formula / 35 A 'the group-C - N I 4r Re O C) , Ri hydrogen, lower alkyl, Phenyl, lower alkoxyalkyl, substituted phenyl, pyridyl 40 or aralkyl, R2 and R3 each hydrogen or lower alkyl, R4 hydrogen, halogen, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, lower hydroxyalkyl or lower alkanoyl, Ré phenyl, monosubstituted phenyl , in positions 1, 2, 3; 2, 5 or 2, 6 di-substituted phenyl, 45 pyridyl or mono-substituted pyridyl and X are chlorine, bromine or iodine, and of pharmaceutically acceptable acid addition salts of these compounds, characterized in that a compound of the general formula vii in which © c where A is —C — N ^ and, Ri, R2, R3, R4 and Rô A, Ri, R2, R3, R4 and Rö have the meaning given in formula I, are dehydrated and, if desired, convert a compound obtained into a pharmaceutically acceptable acid addition salt. 65 Re have the meaning given in formula IA ', dehydrated, the compound obtained converted into its N-oxide and 3. Process for the preparation of imidazo [1,5-a] [1,4] -diazepine compounds of the general formula which have the meaning given in formula IA, dehydrated, reducing the compound obtained and, if desired, converting a compound obtained into a pharmaceutically acceptable acid addition salt . s 4. Process for the preparation of imidazo [1,5-a] [1,4] -diazepine compounds of the general formula IA II 10th in one of the groups ■ ~ CX "ûC and a) b) c) H A "the group -C-N", Ri hydrogen, lower alkyl, l \ Rô H Phenyl, lower alkoxyalkyl, substituted phenyl, pyridyl or aralkyl, R2 and R3 each hydrogen or lower alkyl, R4 hydrogen, halogen, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, lower hydroxyalkyl or lower alkanoyl, Rô phenyl, mono-substituted Phenyl, in positions 2, 3; 2, 5 or 2, 6 di-substituted phenyl, pyridyl or mono-substituted pyridyl and X are chlorine, bromine or iodine, and of pharmaceutically acceptable acid addition salts of these compounds, characterized in that a compound of the general formula R. where one of the groups IA II * 20th 25th and a) b) 35 c) A '"the group C-t C ° 'V means Ri is hydrogen, lower alkyl, phenyl, lower alkoxyalkyl, substituted phenyl, pyridyl or aralkyl, R2 and R3 are each hydrogen or lower alkyl, R4 is hydrogen, 45 halogen, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, lower hydroxyalkyl or lower alkanoyl, Rô phenyl, mono-substituted phenyl, in positions 2, 3; 2,5 or 2, 6 di-substituted phenyl, pyridyl or mono-substituted pyridyl, X is chlorine, bromine or iodine and V is hydrogen or methyl, and of pharmaceutically usable acid addition salts of these compounds, characterized in that a compound of the general formula Uk / \ 60 vii vu 65 / where A-C = N and Ri, R2, R3, R-t and Re whereA means _c = N and ^ Sjp, Ri, R2, R3, R4 and Re re I. re 619953 3rd 619953 if desired, a compound obtained is converted into a pharmaceutically acceptable acid addition salt. 4th have the meaning given in formula IA, are dehydrated, the compound obtained is reacted with ethylene oxide or propylene oxide in the presence of a Lewis acid and, if desired, a compound obtained is converted into a pharmaceutically acceptable acid addition salt. 5 619 953 where A is the group _c = re Ri is hydrogen, lower alkyl, phenyl, lower alkoxyalkyl, substituted phenyl, pyridyl or aralkyl, R2 and R3 are each hydrogen or lower alkyl, substituted phenyl, pyridyl or aralkyl, R2 and R3 each hydrogen or lower alkyl, R7 amino and Rö phenyl, monosubstituted phenyl, in positions 2, 3; 2, 5 or 2, 6 are di-substituted phenyl, pyridyl or mono-substituted pyridyl s, and of pharmaceutically acceptable acid addition salts of these compounds, characterized in that a compound of the general formula ■, 1V ,. R23 I. Ri the group R20 - C -, OH Re phenyl, mono-substituted phenyl, in positions 2, 3; 2, 5 or 2, 6 disubstituted phenyl, pyridyl or monosubstituted pyridyl, R20 is hydrogen or alkyl having 1-6 carbon atoms and R23 is lower alkyl, and of pharmaceutically acceptable acid addition salts of these compounds, characterized in that a compound of the general formula VII IV Vìi wherein Ry1 is acylamino and A, Ri, R2, R3 and Rô have the meaning given in formula IIV, dehydrated, subjecting the compound obtained to mild hydrolysis and, if desired, converting a compound obtained into a pharmaceutically acceptable acid addition salt. 5. Process for the preparation of imidazo [1,5-a] [1,4] -diazepine compounds of the general formula / R4 vii H 10th "Yt 2 <cx 20th where A is the group -C = N Re Ri represents hydrogen, lower alkyl, phenyl, lower alkoxyalkyl, substituted phenyl, pyridyl or aralkyl, R2 and R3 each represent hydrogen or lower alkyl, R'4 the group O II R20 —C- R6 phenyl, mono-substituted phenyl, in positions 2, 3; 2, 5 or 2, 6 di-substituted phenyl, pyridyl or monosubstituted pyridyl and R20 is hydrogen or alkyl with 1-6 carbon atoms, and of pharmaceutically usable acid addition salts of these compounds, characterized in that a compound of the general formula in which A is the group —C = N ' I. re Ri is hydrogen, lower alkyl, phenyl, lower alkoxyalkyl, substituted phenyl, pyridyl or aralkyl, Rzund R3 each hydrogen or lower alkyl, R. the group H I. R: o -C-, ! 25 OH Rö phenyl, mono-substituted phenyl, in positions 2,3; 2, 5 or 2, 6 disubstituted phenyl, pyridyl or monosubstituted pyridyl and R20 is hydrogen or alkyl having 1-6 30 carbon atoms, and of pharmaceutically acceptable acid addition salts of these compounds, characterized in that a compound of the general formula VII " 45 O where R4 is the group R20 - C - means and A, Ri, R2, R3, R6 and R20 have the meaning given in formula I, dehydrated, the group 50 O where R4 is the group R20-C and R21 and R22 R21 R22 alone or together represent an acetal or ketal group having 2-7 carbon atoms and A, Ri, R2, R3, Rs and R20 have the meaning given in formula I ', dehydrated, the residue R "hydrolyzed and, if desired, a compound obtained in a pharmaceutical applicable acid addition salt transferred. 6 noyl, Rô phenyl, mono-substituted phenyl, in positions 2, 3; 2, 5 or 2, 6 di-substituted phenyl, pyridyl or mono-substituted pyridyl and X are chlorine, bromine or iodine, and of pharmaceutically acceptable acid addition salts of these compounds, characterized in that a racemate of a compound of the general formula wherein A, Ri, R2, R3, R4 and Rô have the meaning given in formula I, dehydrated, the racemic compound of the formula I obtained is separated into its optical enantiomers and, if desired, a compound obtained is converted into a pharmaceutically acceptable acid addition salt. 6. Process for the preparation of imidazo [1,5-a] [1,4] -diazepine compounds of the general formula R20-C ss reduced and, if desired, a compound obtained is converted into a pharmaceutically acceptable acid addition salt. 7. Process for the preparation of imidazo [1,5-a] [1,4] -diazepine compounds of the general formula 60 8. Process for the preparation of imidazo [1,5-a] [1,4] -diazepine compounds of the general formula 45 R and a) b) c) 60 / where A is the group -C = N, re Ri is hydrogen, lower alkyl, phenyl, lower alkoxyalkyl, A the group -C = N ' I. re Ri hydrogen, lower alkyl, phenyl, lower alkoxyalkyl, «5 substituted phenyl, pyridyl or aralkyl, R2 hydrogen or lower alkyl, R3 lower alkyl, R4 hydrogen, halogen cyano, trifluoromethyl, lower alkyl, substituted amino, amino, lower hydroxyalkyl or lower Alka 619953 9. Process for the preparation of the optical enantiomers of imidazo [1,5-a] [1,4] diazepine compounds of the general formula 30th 35 O where R4 is the group R20 - C -, R20 is hydrogen or alkyl having 1-6 carbon atoms and A, Ri, R2, R3 and Rô have the meaning given in formula F, dehydrated, the group 40 in 'OC one of the groups O R20 - c - reacted with lower alkyl lithium and, if desired, converted a compound obtained into a pharmaceutically acceptable acid addition salt. 10. The method according to claim 1, characterized in that a compound of formula I, wherein the group @k the group