DK167281B1 - CNS-active diazepine derivs. - e.g. imidazo(1,5-a)(1,4) benzo-, thieno- or pyrazolo-diazepines - Google Patents

Abstract

Diazepine derivs. of formula (I) and their pharmaceutically acceptable acid addn. salts (which in some cases have the ring opened by cutting of the 5-6 bond) are new: (A = -C(R6)=N-; R1 = H, alkyl (opt.substd. by OH, acyloxy, alkoxy, halo, amino, substd. amino or aryl), opt. substd. phenyl, pyridyl, COR10 or COOR; R10 = H or alkyl; R = alkyl; R2 = Cl, Br, I, Alkyl substd. by OH acyloxy, alkoxy, halo, amino, CN or substd. amino, CN, Acylamino, alkoxycarbonylamino, aralkoxycarbonylamino, COOR10 or COR10, or one of their derivs. (a) -C(R10)=N.R11 (R11 = H, alkyl, OH, alkoxyk amino opt. substd.=by aryl or by 1 or 2 alkyl); (b) CONR12R13 (R12 and R13 = H, alkyl (opt. OH substd.), alkenyl, aryl or (CH2)n.NR14R15; R14 and R15 = H, alkyl, (opt. OH substd.) or alkenyl or together form a heterocycle; n = 1-4; or R1i and R13 together complete a heterocycle); (c) CONR16.NR17R18; one of R16, R17 and R18 is H, alkyl or (CH2)nNR14R15; the others are H or alkyl; also R2 can be H or alkyl when R1 is alkyl substd. by OH, acyloxy, halo, amino or substd.amino; COR10 or COOR; R3 = H or alkyl; R6 = phenyl (opt. with 1 or 2 substits.) or pyridyl (opt. with 1 substit.); Z is a ring of formulae: where X = H, Cl, Br or I; T = H or alkyl; R4 = H, halo, NO2, CN, CF3, Alkyl, opt. substd. amino, hydroxyalkyl or alkanoyl; R5 = H or also, if Z is not (IV), alkanoyloxy or OH; also the analogues of (I) provided that when A is one of the gps.-then Z is not (IV), R5 is H, V is H or alkyl; all 'alkyl' are lower). (I) are muscle relaxants, sedatives and anticonvulsants; some are esp. useful for i.v. or i.m. administration because of the solubility of their salts in aq. solsn. Pref. doses are 1-40 mg.

Description

in DK 167281 B1

Patent No. 157,615 relates to an analogous method of preparing novel therapeutically active imidazo [1,5-a] [1,4] diazepine compounds of the general formula "Yy * 2 (zTN ~ ^ 'c-r3 (I 1a / Vh 10 in which A means -C = N 1, R 1, R 2 and R 3 each represent 1 * 6 hydrogen or lower alkyl, R 6 means phenyl, or halo-phenyl, and o

KX

wherein X is hydrogen or chloro and R 1 is halogen, lower alkyl, lower alkylamino, lower alkanoylamino, amino, hydroxy-lower alkyl, lower alkanoyl or the group wherein R 20 is hydrogen or C 1 -C 6 alkyl, or pharmaceutical 30 acceptable acid addition salts of these compounds, and the property of the main patent is that (a) dehydrogenates a compound of the general formula Y / 35-N-C R 2, R 3 and have the meaning given above to a corresponding compound of formula I, 5 or (b) converts a 2,3-lower alkylenedioxy substituent in the benzo group to R 4 in the sense of a lower alkanoyl substituent, or (c) converts a lower alkanoyl substituent present as R 4 substituent in an imidazobenzodiazepine to a hydroxy lower alkyl substituent, or (d) cyclizing a compound of the general formula

1 'N

Ύ) 4 · fY S * 2 R 4 - Η NH 2 20 / C “° R 6 * in which R 1 'is C 1 -C 6 alkyl, R 4' is chlorine or bromine, and R 6 'is o-halo phenyl or (e) subject to a compound of formula I wherein R4 is alkanoylamino, a mild hydrolysis to form a corresponding compound of formula I wherein R4 is amino, or (f) R4 in the sense converts a lower alkanoylamino substituent to R4 in the sense lower alkylamino or 30 (g) oxidizes a compound of the general formula w

NINE

35 γ / '\ / k3 (z | vii')

H

DK 167281 B1 3 i / rf in which A "means -c-N, and R1, R2, R3» R6 ° 9 Czl 5 L \ ^

R6 H

has the meaning given to formula VII for a corresponding compound of formula I, or (k) dissolves a racemic compound in its optical enantiomer and then, if desired (i), converts a compound of formula I into a pharmaceutically acceptable acid addition salt thereof.

The present invention relates to an analogous method, which is a further development of the method of Patent No. 157,615, for the preparation of therapeutically active imidazo [1,5-a] [1,4] diazepine compounds.

The process of the present invention is an analogous process for the preparation of therapeutically active, novel imidazo [1,5-a] [1,4] diazepine compounds of the general formula

25 A

in which A represents -C (R6) = N-, R1 represents hydrogen, lower alkyl or phenyl, R3 means hydrogen or lower alkyl, R6 means phenyl, halogenophenyl or pyridyl, and 3 ° (ΤΓ means the group -CX “Χχμχχ 35 a ) b) c) wherein R 4 represents hydrogen, halogen, cyano, nitro, lower alkyl, lower alkylamino, lower alkanoylamino, amino, hydroxy-lower alkyl or lower alkanoyl, and X represents hydrogen or chlorine, or pharmaceutical acceptable salts thereof, and this process is characterized by decarboxylating a compound of the formula 5 Rvrco ° (zT (XVIII) in which R 1, R 3, A and (Z J 1) have the above meanings and, if desired, dissolves a racemic compound of formula (I) in its optical enantiomer and, if desired, converts a compound of formula (I) into a pharmaceutically acceptable salt thereof.

In the present specification, the term "lower alkyl" or "alkyl" includes both straight and branched hydrocarbon groups having 1-7 carbon atoms, preferably hydrocarbon groups having 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl and butyl.

By the term "lower alkanoyl" as used in the present specification is meant an acyl moiety of an alkanoic acid having 1-7 carbon atoms, preferably 1-4 carbon atoms, e.g. acetyl, propionyl or butyryl, i.e. parts of the formula -COR 2 O, wherein R 20 represents C 1 -C 6 alkyl or hydrogen. The term "lower alkanoyl" as used in this specification encompasses a protected ketone such as an acetal or ketal having 2-7 carbon atoms, e.g. an ethylenedioxy group. The ketal-30 or aldehyde protecting group is used to prevent conversion of the ketone or aldehyde contained by oxidation, reduction and condensation reactions.

The term "halogen" is used to encompass all four forms thereof, ie. chlorine, bromine, fluorine and iodine.

The term "pharmaceutically acceptable salts" is used in DK 167281 B1 of the present description to include both inorganic and organic, pharmaceutically acceptable acids, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, citric, formic, maleic, acetic, succinic, tartaric, methanesulfonic and para-toluenesulfonic acids. Such salts can be formed relatively easily by any person skilled in the art when considering the prior art and the nature of the compound to be salted.

Thus, the compounds of formula I are formed by de-carboxylation of a compound of formula XVIII with or without catalyst and with or without solvent. This decarboxylation is conveniently carried out using heat, e.g. at a temperature between ca. 100 and approx. 350 ° C, preferably between ca. 150 and approx. Solvents which may be used in this reaction step are hydrocarbons such as mineral oils, chlorinated hydrocarbons, ethers, alcohols, for example ethylene glycol, dimethylformamide, dimethylsulfoxide and hexamethylphosphoric acid triamide. Useful catalysts are, for example, metals. such as copper powder or metal salts such as 20 Cu + or Ag + salts.

Preferred embodiments of the method of the invention are set forth in claims 2-9.

The general reactions shown in the following scheme illustrate a number of the reactions that can be used to prepare the starting compounds of formula XVIII. In these reaction schemes, unless otherwise indicated, R means lower alkyl, and A, R 1, R 3 and Z have the meaning given above. It will be apparent to one skilled in the art that some of the substituents may be attacked during the reactions below, but such vulnerable groups may be modified before or after such reaction is carried out. The reactions shown in the scheme can also be carried out with the corresponding 1-oxides thereof (A = -C (R6) = N (- * O) -), but any N-oxide moiety present in compounds of formula VI, will be removed during the conversion of VI -> will.

DK 167281 B1 6 o

Scheme nhch3. <xk öik ..

CH, * I 3 N-NO i *. 1

f / COOR O

H / T'COOR II S,: ø: 5 <: r-

t ✓COOR I

R RjOC-'Nv / COOR

20 (1 II f ^ cooR

Ir ha i h

25 Y ^ COOR R, OC ^ NV ^ COOR

ΟΓχ '. , GCX »" X "i

30 * \ * sCOOR y / S R1 \ ^ Nv / C00R

<* X ~ OCX »J

35 \ R H / \ \ l \ x Nvv'OOOR /

rvK / * R'XTCOOH

UO <ΧΠ, nfV xvm

h V / XH

DK 167281 B1 7

Stage II -> III

Compounds of formula III are prepared by nitrosating compounds of formula II. Such nitrosation can be carried out with "in situ" nitric acid. Reagents which may be used include (1) alkali metal nitrites, i. sodium nitrite, in the presence of organic or inorganic acids, i. glacial acetic acid and aqueous or non-aqueous solvents; (2) alkylnitrites, i. methyl nitrites, in the presence of an inert solvent such as an alcohol, a chlorinated hydrocarbon or e.g. dimethylformamide; and (3) a solution of a gaseous nitrosyl chloride in an inert solvent and in the presence of an acid acceptor such as pyridine. Such a nitrosation reaction should be carried out at about or below room temperature, i. in the range from -20 ° C to 25 ° C. An amino group or an alkylamino group present in the molecule can be protected during the nitrosation reaction, e.g. by means of acylation. Such a protecting group can be removed at a convenient later stage of the reaction sequence.

20

Step VIII -> IX

Compounds of formula IX can be prepared by reacting compounds of formula VIII with dimorpholino-phosphine chloride. The reaction of compounds of Formula VIII with the phosphorylating agent to form compounds of Formula IX is carried out by treating the compounds of Formula VIII with a strong base sufficiently strong to ionize the compound of Formula VIII to form the corresponding anion. Suitable bases include alkali metal alkoxides such as potassium tert. butyl oxide or sodium methoxide; and alkali metal hydrides, e.g. sodium hydride, and alkyl-lithium compounds such as n-butyllithium. The reaction temperature may range from 0 to 100 ° C, and the reaction is preferably carried out in an aprotic polar inert solvent, ie. a solvent which would solubilize the salts of compounds of formula VIII in total or at least partially. Preferred solvents are ethers, e.g. tetrahydrofuran or dioxane, or tertiary amides such as dimethylformamide.

It is to be understood that any amino group or substituted amino group should be present in protected form in this reaction step, since the protective moiety can be removed later at any convenient step, e.g. after the formation of the compound of formula XII.

10 Stage III or IX - »IV

Compounds of formula III or formula IX can be condensed with the anion formed from malonic acid esters of formula

> ^ C00R

15 θ C5H

'X ^ C00R

wherein R represents a lower alkyl group to form compounds of formula IV. The anion is produced by the deprotonation of malonic acid ester with a suitable strong base, e.g.

Alkali metal or alkaline earth metal alkoxides, hydrides or amides. The reaction of compounds of formula III or IX with the malonic acid ester anion is preferably carried out in a solvent such as a hydrocarbon, e.g. benzene, toluene or hexane, an ether, e.g. dioxane, tetrahydrofuran or diethyl ether, or in dimethyl formamide or DMSO, at a temperature in the range of from below room temperature to 150 ° C, preferably from 0 to 100 ° C, and most conveniently at room temperature.

Step IV -> V

Compounds of formula V are prepared by decarboxylating compounds of formula IV by reacting the compound of formula IV with an alkali metal hydroxide such as NaOH or KOH in a suitable solvent, e.g. an alcohol, an ether or DMSO, at a temperature ranging from room temperature to reflux temperature, preferably DK 167281 B1 9 from 60 to 100 ° C.

Step V -> VI

Compounds of formula VI are prepared by nitrosation of compounds of formula V by reacting the latter with nitric acid, e.g. is formed from an alkali metal nitrite, an alkyl nitrite or nitrosyl chloride, by reaction with organic or inorganic acid. Suitable solvents for the nitrosation reaction include ethers, 10 alcohols, water and acids, e.g. acetic acid, DMF, DMSO and chlorinated hydrocarbons. The reaction can be carried out approximately at room temperature, although such a temperature is not critical.

Step VI -4 VII

The compounds of formula VII are prepared by reducing compounds of formula VI, e.g. with Raney nickel and hydrogen or with zinc and acetic acid. This reduction results in a predominant formation of compounds of formula VII with simultaneous formation of small amounts of several possible isomers, i.e. compounds of the formulas <r00R NH2 NH NHj

II) NH * V— C00R? \ —COOR j1 Y — COOR

- y- \ / K / - </ - (

VIIA VIIB VIIC VII D

It should be noted that at the abovementioned reduction step, easily attackable groups will be reduced, if such groups are present, such as R a 7-position nitro group or a 7-position CN group. These groups can be replaced by methods known per se and as set forth herein.

35 DK 167281 B1 10

Step VII -> XII

Compounds of formula XII are then formed by reacting compounds of formula VII with an alkanoic acid orthoester of formula R1MC (OR) 3 wherein R is lower 5 alkyl and R1 "is hydrogen, lower alkyl, alkoxy lower alkyl or halogen lower alkyl, optionally in the presence of an acid catalyst, for example an organic or inorganic acid such as p-toluenesulfonic acid or phosphoric acid, and at room temperature or above, i.e. at from 25 to 150 ° C, in which case a cyclization to the compound of the formula XII occurs spontaneously.

Technical equivalents to the above-mentioned ortho-ester include ortho-amides, e.g. the dimethyl acetal of N, N-dimethylformamide, N, N, N ', N', N ", NM-hexamethylmethanetriamine, nitriles, e.g., acetonitrile, esterimidates, e.g., CH3-C (= NH ) OC2H5.

It is clear that any amino or alkylamino group present must be protected during this reaction.

Step VII -> XI

The compounds of formula XI can be prepared by acylating compounds of formula VII with a compound of formula R1U, COX or (R 1 'CCJ 2 O, where X represents a halogen atom and R 1 - is hydrogen, lower alkyl, phenyl, alkoxy-lower alkyl, substituted phenyl, pyridyl or aralkyl.

Solvents for use in this process step include methylene chloride, ethers and chlorinated hydrocarbons, preferably in combination with an acid acceptor such as an organic or inorganic base, e.g. triethylamine, pyridine or an alkali metal carbonate. The reaction may be carried out above or below room temperature, but preferably carried out at room temperature. Compounds of formula XI are isomers by nature, i.e. that they may exhibit one or the other of the following stereochemical structures: DK 167281 B1 11

NHCOR1 '' '^ OVER

* ί \ -COOR V \ -NHCOR1

/ -Λ M

5

XI A XI B

Step XI XII

Compounds of formula XII may also be prepared by dehydrating compounds of formula XI or 10 isomers thereof with subsequent cyclization upon heating. This reaction step can be carried out with or without solvent, e.g. dimethylformamide, ethylene glycol, hexamethylphosphoric triamide, and in a temperature range of 100 to 300 ° C, preferably at 150 to 250 ° C, e.g. at 200 ° C, with or without the presence of catalysts and water-binding agents.

Step IX -> X

Compounds of formula X can be prepared by condensation reaction between a compound of formula IX and the anion formed from the acylaminomalonic acid ester of formula

.COOR

θ C-NHCOR1

25 ^ COOR

in which R represents lower alkyl and R1 represents hydrogen, lower alkyl, phenyl, alkoxy-lower alkyl, substituted phenyl, pyridyl or aralkyl to form a compound of formula X. The anion is produced by deprotonating 30 acylaminomalonic acid esters with a suitable strong base, e.g. an alkali metal or alkaline earth metal alkoxide, hydride or amide. The reaction of compounds of formula IX with the acyl aminomalonic acid ester anion is preferably carried out in a solvent such as a hydrocarbon, e.g. benzene, toluene or hexane, an ether, e.g. dioxane, THF, diethyl ether, DMF, DMSO, at a temperature range below room temperature DK 167281 B1 12 to 150 ° C, preferably from 0 to 100 ° C, especially at room temperature.

Step X - + XI

Compounds of formula XI and isomers thereof are formed by carboxylating compounds of formula X with an alkali metal alkoxide in a solvent such as an ether, alcohol, DMSO or DMF, at or above room temperature, preferably at room temperature. Compounds of formulas 10 X and XI need not be isolated, but can be converted in situ to compounds of formula XII.

Step VII - * XIII

Compounds of formula XIII are formed by reacting compounds of formula VII with an aldehyde of formula R 1 CHO wherein R 1 is as defined in formula I, but any amino group or substituted amino group and preferably any RCO group should be present on protected form. The protective portion can be removed later, e.g. after the formation of the compound of formula VII. Solvents suitable for this reaction step are hydrocarbons such as benzene, alcohols, ethers, chlorinated hydrocarbons, DMF and DMSO, with or without the presence of water-binding agents, e.g. molecular sieves, at above or below 25 room temperature, preferably from room temperature to the reflux temperature of the solvent.

Step XIII -> XII

Compounds of formula XIII can be converted to the compounds of formula XII by oxidation in situ with oxidizing agents such as manganese dioxide, air and oxygen.

As indicated above, a final compound of formula XII in which R 4 represents amino may be converted to a corresponding compound wherein R 4 represents nitro or cyano via a Sandmeyer reaction as contemplated in this specification.

Another method for preparing compounds of formula XII, in which R 4 means nitro or cyano, consists in preparing a corresponding compound of formula VII. The latter compound can be prepared by reacting a corresponding compound of Formula IX with a protected aminomalonic acid ester of Formula

^ COOR

θ ^

C-NH

^ COOR

wherein R is lower alkyl and Z is benzyloxycarbonyl, converting the compound of formula X wherein R1 represents benzyloxy and R4 is nitro or cyano thus obtained to a corresponding compound of formula XI as described above in compound with the step X - XI and subjecting the compound thus obtained to a treatment with hydrogen bromide in glacial acetic acid to give a compound of formula VII in which R 4 is designated nitro or cyano. The intermediates of formulas X and XI need not be isolated. The compound of formula VII obtained in this way is further converted to the compound of formula XII via the reaction steps VII - XIII and XIII - XII as described above.

Step XII - »XVIII

Compounds of formula XVIII are formed by hydrolysis of compounds of formula XII to the corresponding acids, preferably with alkali metal hydroxides such as NaOH or KOH. This hydrolysis is conveniently carried out in an inert solvent. Suitable solvents are alcohols, e.g. methanol and ethanol, ethers, e.g. dioxane and tetrahydrofuran, as well as 30 dimethyl formamide, in combination with water. It is preferred to carry out this reaction step at a temperature between room temperature and the boiling point of the reaction mixture.

Evidently, an acyloxyalkyl group present during this reaction step will be hydrolyzed to the corresponding hydroxyalkyl group which in turn can be converted back to the acyloxyalkyl group at a convenient later stage.

DK 167281 B1 14

An R1 group in the sense -COOR10 will also be hydrolyzed and decarboxylated to a corresponding compound in which R1 represents hydrogen. The -COOR10 moiety can be reintroduced from a formyl or hydroxymethyl group in known manner. A haloalkyl group present may be affected in this reaction step to provide a corresponding hydroxyalkyl compound which may also be converted back to the haloalkyl compound at a later stage in the usual manner. Any compound of formula XII wherein R 4 represents hydroxyalkyl should be protected during this reaction's reaction ionic step, e.g. in the form of the tetrahydropyranyl ether derivative thereof.

In the formula I, wherein a ketal group, e.g. an ethylene dioxo group, present in an imidazobenzodiazepine, such ketal groups can be converted to the corresponding ketone by subjecting the ketal group to mild acid hydrolysis. The ketone can then be converted to a secondary or tertiary alcohol having a racemic nature. The reaction conditions for these two steps are described in U.S. Patent No. 3,846,410.

Compounds of formulas I and their pharmaceutically acceptable acid addition salts are useful muscle relaxants, sedatives and anticonvulsants, and many are especially useful when used in intravenous and intramuscular preparations due to the solubility of the acid addition salts in aqueous solution.

The novel compounds of formula I and their acid addition salts can be incorporated into pharmaceutical dosage compositions containing from about 0.1 to approx. 40 mg, preferably 1-40 mg, the dose being regulated according to species and individual requirements. The novel compounds of formula I as well as their pharmaceutically acceptable salts may be administered internally, e.g. parenterally or internally, in conventional pharmaceutical dosage forms. For example, they can be incorporated into conventional liquid or solid carriers such as water, gelatin, starch, magnesium stearate, talc, vegetable oils or the like for the preparation of tablets, elixirs, capsules, solutions, emulsions and the like in accordance with acceptable pharmaceutical practice.

Example 1 A suspension of 1.5 g of 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 10 ml of mineral oil is heated to 230 ° C for 5 minutes. The reaction mixture is partitioned with 1N hydrochloric acid and ether. The aqueous phase is made alkaline with ammonia and extracted with methylene chloride. The extracts are dried and evaporated and the residue is chromatographed over 60 g of silica gel using 25% (by volume) of methylene chloride in ethyl acetate. The less polar 8-chloro-6- (2-fluorophenyl) -6H-imidazo [1,5-a] - [1,4] benzodiazepine is crystallized from ethyl acetate to give colorless crystals, m.p. 195-196 "C.

The more polar component is crystallized from ether to give 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5- a] [1,4] benzodiazepine, m.p. 150 to 151 ° C.

The starting material may be prepared as follows: A solution of 200 g (0.695 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in 2 liters of tea -trahydrofuran and 250 ml of benzene are saturated with methylamine while cooling in an ice bath. A solution of 190 g (1 mole) of titanium tetrachloride in 250 ml of benzene is added through a drop funnel 25 over 15 minutes. After the addition, the mixture is stirred and refluxed for 3 hours. 600 ml of water are slowly added to the cooled reaction mixture. The inorganic material is separated by filtration and washed thoroughly with tetrahydrofuran. The aqueous layer is separated and the organic phase is dried over sodium sulfate and evaporated. The crystalline residue of 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine is collected and has m.p. 204 to 206 ° C. An analytical sample is recrystallized from a mixture of methylene chloride and ethanol and has m.p. 204 to 206 ° C.

A) 8.63 g of sodium nitrite (0.125 mol) is added in three portions over a period of 15 minutes to a solution of 30.15 g (0.1 mol) of 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine in 150 ml glacial acetic acid. After stirring for 15 hours at room temperature, the reaction mixture is diluted with water and extracted with methylene chloride. The extracts are washed with saturated sodium bicarbonate solution, dried over sodium sulfate and finally azeotropically evaporated with toluene to give 29 g of crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosome-10-methylamino) -3H-1. 4-benzodiazepine in the form of a yellow oil.

B) 27.6 g of sodium nitrite (0.4 mole) are added in portions over 30 minutes to a solution of 90.45 g (0.3 mole) of 7-chloro-5- (2-fluorophenyl) -2- methylamino-3H-1,4-benzodiazepine in 400 ml glacial acetic acid. After complete addition, the mixture is stirred at room temperature for 1 hour and 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-nitrosomethyl-amino) -3H-1,4-benzodiazepine as a yellow oil.

This material is dissolved in 300 ml of dimethylformamide and added to a mixture of 150 ml of dimethyl malonate, 40.4 g of potassium tert.butoxide and 500 ml of dimethyl formamide, which has been stirred at room temperature for 10 minutes. The reaction mixture is stirred under nitrogen overnight at room temperature, sieved by the addition of 50 ml of glacial acetic acid, diluted with water and aqueous sodium carbonate solution, dried over sodium sulfate and evaporated. Crystallization of the residue from ethanol gives 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5- (2-30 fluorophenyl) -2H-1,4-benzodiazepine as colorless crystals, m.p. 170 to 172 ° C. For analysis, the product is recrystallized from a mixture of methylene chloride and ethanol and the melting point is thus unchanged. A mixture of 20 g (0.05 mol) of 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine, 400 ml of methanol and 3.3 g (0.059 DK 167281 B1 17 mol) of potassium hydroxide are heated to reflux under nitrogen for 5 hours. After evaporation of the majority of the solvent, the residue is gradually diluted with water and the precipitated crystals are collected, washed with water and dried, leaving 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (dimethoxycarbonylmethylene) ) -2H-1,4-benzodiazepine, m.p.

158 to 160 ° C.

For analysis, the compound is recrystallized from a mixture of methylene chloride and hexane and m.p. is then 10 161 to 162 ° C.

8.8 g of sodium nitrite (0.125 mole) are added to a solution of 28 g (0.08 mole) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (methoxycarbonylmethylene) -2H- 1,4-benzodiazepine in 250 ml glacial acetic acid. The mixture is stirred at room temperature for 10 minutes and then diluted with 250 ml of water. The crystalline product is separated by filtration, washed with water, methanol and ether and dried to give 7-chloro-5- (2-fluorophenyl) -α-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid. acid methyl ester in the form of yellow crystals, m.p. 238 to 20 241 ° C with decomposition.

11.25 g (0.03 mole) of 7-chloro-5- (2-fluorophenyl) -α-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester are dissolved in a mixture of 750 ml of tetrahydrofuran and 500 ml methanol by heating. 20 g of Raney nickel are added, 25 and the mixture is hydrogenated at atmospheric pressure for 4 hours. The catalyst is removed by filtration and the filtrate is finally azeotropically evaporated with toluene. The residue is dissolved in 100 ml of methanol. After adding 10 ml of triethyl orthoformate and 5 ml of ethanolic hydrogen chloride (5%), the mixture is heated to reflux for 10 minutes. It is then evaporated and the residue partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The methylene chloride layer is separated, dried and evaporated and the residue is crystallized from ether to give methyl 8-chloro-6- (2-fluorophenyl) -4H-35-imidazo [1,5-a] [1,4] benzodiazepine-3 -carboxylate which is recrystallized from a mixture of methylene chloride, ether and hexane and has a sip. 179 to 181 ° C.

A mixture of 1.48 g (0.004 mol) of methyl 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxyl at 0.5 g (0.009 mol) of potassium hydroxide, 50 ml of methanol and 2 ml of water are heated to reflux for 3 hours under a nitro atmosphere. The methanol is partially evaporated and the residue is acidified with glacial acetic acid and diluted with water while the solution is still warm. The crystals are collected after cooling in a mixture of ice and water and dried in vacuo to give 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5a] [1,4] benzodiazepine-3 -carboxylic acid with m.p. 245 to 247 "C during decomposition.

Example 2

A solution of 0.5 g (0.00129 mol) of ethyl 8-cyano-6-15 (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 -carboxylate in 100 ml of ethanol and 10 ml of water is treated with 0.14 g (0.0026 mol) of potassium hydroxide. After refluxing for 30 minutes, the reaction mixture is evaporated and 10 ml of water is added. The mixture is acidified with acetic acid, filtered and extracted with 20 ml of dichloromethane which is separated, dried and evaporated. Ca. 0.2 g of the hydrolyzed product is obtained from the filtration and the same amount is obtained from the extraction. This material is added to 3 ml of dry hexamethylphosphoramide and kept at 200 to 205 ° C for 30 minutes under argon. 25 is cooled and 50 ml of ice water and 1 ml of ammonium hydroxide are added. The solution is filtered and the filtrates extracted with 25 ml of dichloromethane and evaporated to dryness. Water is added and the solution is filtered and the combined precipitates are dissolved in dichloromethane and developed on 2 silica gel-thick layer pads in a solution of ethyl acetate containing 15% methanol. The silica gel containing the product is scraped off (Rf value = 4-5), stirred with methanol and filtered. The material is crystallized from a mixture of isopropanol and ether to give 8-cyano-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in the form of grayish white prisms with m.p. 198 to 203 ° C.

DK 167281 B1 19

The starting material: can be prepared as follows:

A solution of 10 g (0.0358 mol) of 7-cyano-1,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepin-2-one in 150 ml of dry tetrahydrofuran under argon is treated with 2 4 g (0.0537 mol) of 54% sodium hydride and the reaction mixture is stirred and refluxed for 1 hour. The mixture is cooled to 0 ° C and 13.7 g (0.0537 mole) of phosphorus dimorpholine chloride is added. After 18 hours, the reaction mixture is filtered, concentrated to low volume and ether added. The precipitate 10 is filtered off and recrystallized from a mixture of dichloromethane and ether to give 7-cyano-5- (2-fluorophenyl) -2-bis- (morpholino) -phosphinyloxy-3H-1,4-benzodiazepine in the form of white rods with m.p. 194 to 197 ° C.

To 100 ml of dry Ν, Ν-dime thyl formamide under nitrogen is added 1.6 g (0.036 mole) of 54% sodium hydride and 8.3 g (0.038 mole) of acetamidodiethylmalonate added with stirring. After 30 minutes, 10 g (0.02 mole) of 7-cyano-5- (2-fluorophenyl) -2-bis (morpholino) -phosphinyloxy-3H-1,4-benzodiazepine is added and after 64 hours the reaction mixture is poured off. 20 mixture in ice-water containing 4 ml of acetic acid. The mixture is filtered and the solid dissolved in 100 ml of dichloromethane, washed with 50 ml of water, dried over anhydrous sodium sulfate and concentrated to a small volume. This solution is chromatographed over a column of florisil and eluted with 2 25 liters of dichloromethane discarded. It is then eluted with 1 liter of a mixture of dichloromethane and ether in a ratio of 10: 1 and then with 2 liters of ether. The ether fraction is twice recrystallized from a mixture of dichloromethane and ether to give (acetylamino) - [7-cyano-5- (2-fluoro-phenyl) -3H-1,4-benzodiazepin-2-yl] -malonic acid diethyl ester in form of white prisms with m.p. 138 to 140 ° C.

The column is eluted with 1 1/2 liters of a mixture of ethyl acetate and methanol in a ratio of 10: 1. The eluent is concentrated and the residue is crystallized from ether. Recrystallization from a mixture of dichloromethane and ether gives ethyl 8-cyano-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5- DK 167281 B1 20 a] [1,4 ] benzodiazepine-3-carboxylate in the form of greyish white prisms with m.p. 272 to 274 ° C.

Example 3

A suspension of 1.5 g (3.48 mmol) of 8-chloro-6- (2-fluoro-5-phenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 -Carboxylic acid in 20 ml of mineral oil is stirred vigorously at 190 ° C for 1/2 hour. The dark suspension is then slurried with hexane and extracted twice with 1N hydrochloric acid. The acidic aqueous layer is then washed once with hexane and neutralized with 5% aqueous sodium carbonate solution. The precipitated product is collected and air dried. Concentrating the filtrate gives a further yield of 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine as a grayish white solid . An analytical sample is obtained by column chromatography on silica gel and eluting with ethyl acetate. Mp. 241 to 243 ° C.

The starting material can be prepared as follows:

A solution of 3.75 g (0.01 mole) of 7-chloro-5- (2-fluorophenyl) -α-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester in 300 ml of tetrahydrofuran and 200 ml methanol is hydrogenated at atmospheric pressure for 1 1/2 hours in the presence of 1 teaspoon of Raney nickel. The catalyst is separated by filtration over celite and the filtrate is evaporated under reduced pressure, finally azeotropically with toluene. The residue is dissolved in 20 ml of pyridine and treated with 4 ml of benzoyl chloride. After standing at room temperature for 15 minutes, the reaction mixture is partitioned with methylene chloride and 1N sodium hydroxide solution. The organic layer is finally dried and evaporated azeotropically with toluene. Crystallization of the residue from ether gives 2- [benzoylamino-methoxycarbonylmethylene] -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine, m.p. 210 to 213ec. An analytical sample is recrystallized from a mixture of ethyl acetate and hexane and m.p. 217 to 219 eC with softening at 150 to 160 ° C.

A solution of 1.15 g (2.5 mmol) of 2 - [(benzoylamino) -methoxy carbonylmethylene] -7-chloro-5- (2-fluorophenyl) -1,3-di-hydrochloride 2H-1,4-benzodiazepine in 10 ml of hexamethylphosphoric acid triamide is heated to reflux for 10 minutes. The dark mixture is partitioned between water and a mixture of ether and ethylene chloride. The organic layer is washed with water, dried 5 and evaporated. The residue is dissolved in methylene chloride and filtered over activated alumina with ethyl acetate. The filtrate is evaporated and chromatographed over 20 g of silica gel using 10% (volume per volume) of ethyl acetate in methylene chloride. Crystallization of the combined pure · 10 fractions from a mixture of ether and hexane gives methyl 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4 ] benzodiazepine-3-carboxylate, m.p. 208 to 209 ° C.

To a solution of 2.66 g (5.77 mmol) of methyl-8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazole 15 zepine-3-carboxylate in 50 ml of refluxing methanol is added a solution of 755 mg (11.5 mmol) of potassium hydroxide in 10 ml of water, and the resulting mixture is dissolved in 50 ml of hot acetic acid and then poured into 100 ml of cold water. The product is collected, washed with water and air dried to give 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 carboxylic acid in the form of a grayish white solid. An analytical sample is recrystallized from benzene and has m.p. 267 to 269 ° C.

Example 4 A solution of 1.3 g of 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 20 ml of ethylene glycol heated to reflux for 1 hour. The reaction mixture is partitioned between water and a mixture of methylene chloride and toluene. The organic phase is washed with saturated sodium bicarbonate solution, dried and evaporated. Crystallization of the residue from a mixture of ether and 2-propanol gives 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] - [1,4] benzodiazepine in the form of brown yellow crystals. An analytical sample is recrystallized from a mixture of ethyl acetate 35 and hexane and shows m.p. 189 to 190 ° C.

DK 167281 B1 22

The starting material can be prepared as follows: 54% sodium hydride in mineral oil dispersion (11 g or 0.25 mole) is added portionwise to a stirred solution of 63.2 g (0.2 mole) of 7-bromo-1,3-dihydro-hydroxide. 5- (2-Pyridyl) -2H-1,4-benzodiazepin-2-one in 1 liter of tetrahydrofuran under argon. After refluxing on a steam bath for 1 hour, the solution is cooled to room temperature and treated with 76.2 g (0.3 mole) of dimorpholinophosphine chloride portionwise. Stirring at room temperature is continued for 15 hours. The dark mixture is filtered through celite. Concentration of the filtrate in vacuo and boiling of the dark residue with ether give yellow-brown crystals of 7-bromo-2- [bis- (morpholino) -phosphinyloxy] -5- (2-pyridyl) -3H-1,4-benzodiazepine. A sample is recrystallized by dissolving in 2 ml of methylene chloride, filtering, diluting 15 with 10 ml of ethyl acetate and cooling in an ice bath to form light yellowish brown plates with m.p. 180 to 182 ° C with decomposition.

43 g (0.2 mole) of diethylacetamidomalonate are added to a suspension of 10 g (0.2 mole) of a dispersion (50%) of 20 sodium hydride in mineral oil in 500 ml of dry dimethyl formamide. This mixture is stirred under an argon atmosphere for 1 hour at room temperature and for 20 minutes under heating in a steam bath.

53.4 g (0.1 mole) of 7-bromo-2- [bis- (morpholino) -phosphinyloxy] -5- (2-pyridyl) -3H-1,4-benzodiazepine are then added to the reaction mixture which brought back to room temperature. After stirring for 1 hour at room temperature, it is heated again in a steam bath for 2 hours. The cooled solution is partitioned between water and a mixture of methylene chloride and ether. The organic phase is separated, washed with water, dried and evaporated. The residue is crystallized by grafting from a mixture of ethyl acetate and ether to give ethyl 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine - 3-carboxylate in the form of greyish white crystals with m.p.

240 to 243 ° C. Seed material is obtained by chromatographic purification 35 over the 30-fold amount of silica gel using 5% (volume per volume) of methanol in ethyl acetate. An analytical DK 167281 B1 23 sample is recrystallized from ethyl acetate and shows snips. 243 to 244 ° C.

A mixture of 2.15 g (5 mmol) of ethyl 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid 5 oxylate, 50 ml of methanol, 0.84 g (15 mmol) of potassium hydroxide and 2.5 ml of water are heated to reflux for 5 hours. Most of the methanol is evaporated and the residue is partitioned between water and ether. The aqueous phase is acidified with acetic acid and extracted with methylene chloride. The extracts are dried and evaporated. Crystallization of the residue from a mixture of methylene chloride and ethyl acetate gives 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in form of colorless crystals which are recrystallized from methanol for analysis to give m.p. 245 to 250 ° C under 15 decomposition with prior sintering.

Example 5

A mixture of 1.5 g of 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 10 ml of ethylene glycol is heated to reflux. for 1 hour.

The reaction mixture is then partitioned between a mixture of methylene chloride and toluene and saturated aqueous sodium bicarbonate solution. The organic phase is washed with water, dried and evaporated. The residue is dissolved in 10 ml of 2-propanol and treated with 0.6 g of maleic acid. The salt crystallizes by adding ether to the hot solution. It is collected, washed with 2-propanol and ether to give 6- (2-chloro-phenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine maleinate in the form of brownish yellow crystals which are recrystallized from 2-propanol for analysis and exhibit a melting point of 150 to 152 ° C. The free base released from this salt is crystallized from a mixture of ethyl acetate and hexane and has m.p. 170 to 173 ° C.

The starting material can be prepared as follows: 43 g (0.2 mole) of diethylacetamidomalonate is added to a suspension of 10 g (0.2 mole) of sodium hydride (50% in mineral oil) in 500 ml of dry dimethylformamide. The mixture is heated at 30 to 50 ° C for 30 minutes under argon. After the addition of 53 g (0.1 mole) of 5- (2-chlorophenyl) -2- [bis (morpholino) -phosphi-nyloxy] -7-nitro-3H-1,4-benzodiazepine, the reaction mixture is heated on a steam bath for 1 hour. hour. The cooled brown mixture 5 is partitioned between water and a mixture of methylene chloride and ether. The organic phase is washed with water, dried and evaporated. The residue is chromatographed over 1 kg of silica gel using ethyl acetate. The pure fractions are combined and evaporated. Crystallization of the residue from a mixture of 10 methylene chloride and ether gives ethyl 6- (2-chlorophenyl) -1-methyl 1-8 -nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3- carb oxylate in the form of light yellow crystals with m.p. 233 to 234 ° C.

An analytical sample is recrystallized from ethyl acetate to give m.p. 234 to 235 ° C.

A mixture of 4.25 g (0.01 mole) of ethyl 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine 3-carboxylate, 100 ml of methanol, 1.12 g (0.02 mole) of potassium hydroxide and 4 ml of water are heated to reflux under nitrogen for 3 hours. Most of the methanol is evaporated and the residue is partitioned between water and ether. The aqueous phase is washed with ether, acidified with acetic acid and extracted with methylene chloride. The extracts are dried and evaporated. Crystallization of the residue from a mixture of methylene chloride and ethyl acetate gives 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-25-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, m.p. .

272 to 274 ° C with decomposition. An analytical sample is recrystallized from a mixture of methanol and ethyl acetate and has m.p. 274 to 276 ° C during decomposition.

Example 6 A suspension of 1.2 g of 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 15 ml of hexamethylphosphoric triamide is heated to reflux in 3 minutes. The cooled solution is partitioned between a mixture of methylene chloride and ether and aqueous sodium bicarbonate solution. The organic phase is washed with bicarbonate solution, dried and evaporated. The residue is chromatographed over 30 g of silica gel using 3% (volume per volume) of ethanol in methylene chloride. Crystallization of the pure fractions from a mixture of ether, methylene chloride and ethyl acetate gives 1-methyl-8-nitro-6-phenyl-4H-imidazo-5 [1,5-a] [1,4] benzodiazepine, m.p. 168 to 170 ° C. The compound is converted to the maleate salt which crystallizes from ethyl acetate with 0.5 mole of solvent, m.p. 125 to 128 ° C with decomposition.

The starting material can be prepared as follows: 6 g (0.125 mole) of sodium hydride dispersion (50% in mineral oil) are added to a solution of 28.1 g (0.1 mole) of 1,3-dihydro-7-nitro-5-phenyl -2H-1,4-benzodiazepin-2-one in 300 ml of dry tetrahydrofuran. After stirring for 1 hour at room temperature, 30.2 g (0.12 mol) of dimorpholinophosphine chloride is added and stirring is continued for 4 hours. The product crystallizes by the addition of water and ether. The precipitate is collected and dissolved in methylene chloride. The solution is dried and evaporated and the residue is crystallized from ethyl acetate to give crude 7-nitro-2- [bis- (morpholino) -phosphine-phenoxy] -5-phenyl-3H-1,4-benzodiazepine, m.p. 208 to 209 ° C.

Part of this material is added to a mixture of 8.6 g (0.04 mole) of diethylacetaminomalonate, 2 g (0.04 mole) of sodium hydride suspension (50% in mineral oil) and 75 moles of dimethyl formamide heated to 40 ° C for 30 minutes.

After the addition, the reaction mixture is heated for 30 minutes on a steam bath and then partitioned between water and ether. The organic phase is washed with water, dried and evaporated. The residue is chromatographed over 250 g of silica gel using 30 ethyl acetate. The combined pure fractions are evaporated and the residue is crystallized from a mixture of methylene chloride and ether to give ethyl 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine -3-carboxylate in the form of greyish white crystals with m.p. 240 to 241 ° C. An analytical sample is recrystallized from ethyl acetate.

DK 167281 B1 26

A mixture of 1.95 g (5 mmol) of ethyl -1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, 50 ml of methanol, 0.56 g (0.01 mole) of potassium hydroxide and 2 ml of water are heated to reflux under nitrogen for 3 hours.

After partial evaporation of the solvent, the residue is acidified with 2 ml of glacial acetic acid and partitioned between methylene chloride containing 10% (volume per volume) of ethanol and water. The organic phase is dried and evaporated. Crystallization of the residue from a mixture of ethyl acetate and methanol yields 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in the form of straw colored crystals recrystallized from the same solvents for analysis. Mp. 240 to 243 ° C with decomposition.

EXAMPLE 7 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazori-5-a, Q, 41benzodiazepine and 8-chloro-6- (2-fluorophenyl) -1-methyl-6H-imidazo - n.5-alri.41 benzodiazepine

A solution of 185 mg of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 5 ml of ethylene glycol is heated to reflux in 1 hour under a nitrogen atmosphere. The cooled reaction mixture is partitioned between a mixture of ether and toluene and saturated sodium bicarbonate solution. The organic phase is separated, dried and evaporated. The residue is chromatographed over 7 g of silica gel using 3% (volume per volume) of ethanol in methylene chloride to give both the less polar 8-chloro-6- (2-fluorophenyl) -1-methyl-6H-imidazo [1 , 5- a] [1,4] benzodiazepine, m.p. 177 to 179 ° C as 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine 30, m.p. 151-153 "C.

The starting material may be prepared as follows: 11.25 g (0.03 mole) of 7-chloro-5- (2-fluorophenyl) -α-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester is hydrogenated at atmospheric pressure. Raney nickel in a mixture of 750 ml of tetrahydrofuran and 500 ml of methanol. The nickel is separated by filtration and the filtrate is evaporated. The residue DK 167281 B1 27 is dissolved in 100 ml of methanol and 11 ml of triethyl orthoacetate and 5 ml of ethanolic hydrogen chloride (5%) are added. The mixture is heated to reflux for 10 minutes and evaporated and the residue partitioned between methylene chloride and aqueous sodium bicarbonate solution. The methylene chloride solution is dried and evaporated and the residue is chromatographed over 300 g of silica gel using a mixture of methylene chloride and ethyl acetate in a 1: 3 ratio. The pure fractions are combined and evaporated and crystallized from 10 ether to give methyl 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine 3-carboxylate, m.p. 162 to 164 ° C. An analytical sample is recrystallized from a mixture of ethyl acetate and hexane.

A mixture of 7.7 g (0.02 mol) of methyl 8-chloro-6- (2-15 fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine 3-Carboxylate, 2.24 g (0.04 mole) of potassium hydroxide, 200 ml of methanol and 6 ml of water are heated to reflux for 3 1/2 hours. The solvent is partially evaporated and the residue is acidified with glacial acetic acid and diluted with water while warm.

The precipitated crystals are collected after cooling in a mixture of ice and water and dried to give 8-chloro-6- (2-fluoro-phenyl) -1-methyl-4H-imidazo [1,5-a] [1 , 4] benzodiazepine-3-carb-oxylic acid. For analysis, the compound is recrystallized from a mixture of methylene chloride, methanol and ethyl acetate, and then has m.p. 271 to 274 ° C with decomposition.

Example 8

Analogously to Examples 1-7, the following compounds may be prepared: 30-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, m.p. 180-182 °; 8-Ethyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, m.p. 152-154 °; 8-amino-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine isopropanolate, m.p. 135-145 °; 8-acetyl-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiaze-pin dipicrate, m.p. 225-230 °; 5 rac. 8- (1-hydroxyethyl) -1-methyl-6-phenyl-4H-imidazo [1,5- a] [1,4] benzodiazepine dipicrate, m.p. 223-225 °; 8-acetamido-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] -10 [1,4] benzodiazepine, m.p. 326-331 ° (decomposition); 6- (2-fluorophenyl) -1-methyl-8-methylamino-4H-imidazo [1,5- a] [1,4] benzodiazepine, m.p. 255-259 °; 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] thieno [3,2-f] - [1,4] diazepine, m.p. 168-170 ° and 1-methyl-6-phenyl-4H-imidazo [1,5-a] thieno [2,3-f] [1,4] diazepine, m.p. 223-225 °.

20

Claims (9)

An analogy method, which is a further development of the method of patent No. 157,615 for the preparation of therapeutically active imidazo [1,5-a] [1,4] diazepine compounds of general formula 'YT'. qYc- in which A represents -C (R6) = N-, R1 represents hydrogen, lower alkyl or phenyl, R3 means hydrogen or lower alkyl, R6 means phenyl, halogenophenyl or pyridyl, and the group represents 20 κ4-ζϊ a) b) c) wherein R 4 represents hydrogen, halogen, cyano, nitro, lower alkyl, lower alkylamino, lower alkanoylamino, amino, hydroxy-lower alkyl or lower alkanoyl, and X represents hydrogen or chlorine, or pharmaceutically acceptable salts thereof characterized by decarboxylating a compound of formula 35 in which R1, R3, A and (Z j1 have the above meanings and dissolving, if desired, a racemic compound with the formula (I) in its optical enantiomer and, if desired, converts one compound of formula (I) to a pharmaceutically acceptable salt thereof. Process according to claim 1, characterized in that compounds of formula (I) are prepared, wherein X in the groups b) and c) is chlorine. Process according to claim 1 or 2, characterized in that a compound of formula (I) is prepared wherein R 1 is hydrogen or lower alkyl, O R4 means hydrogen, nitro or halogen, R6 means phenyl or halophenyl and R3 means hydrogen. A process according to any one of claims 1-3, characterized in that R 4 is 8-halogen and R 6 is 2-halogen phenyl. Process according to claim 4, characterized in that R 4 is 8-chloro and R 6 is 2-chloro or 2-fluorophenyl. Process according to any one of claims 1-5, characterized in that R1 represents methyl. Process according to any one of claims 1, 2, 4, 5 or 6, characterized in that R 3 is methyl. DK 167281 Bl Process according to claim 1, characterized in that 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is prepared. Process according to claim 1, characterized in that 8-chloro-6- (2-fluorophenyl) -1,4-dimethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is prepared. 10