SE439165B - PROCEDURE FOR PREPARING IMIDAZO (1,5-A) (1,4) DIAZEPINES - Google Patents

Description

'i 8001619-9 wherein <: ¶: denotes the group 1 I! En \\ fç> ï fi: RAW B B 5 - Qi 3) b) or C) wherein X represents hydrogen or chlorine and R 4 represents hydrogen, halogen, nitro, cyano, lower alkyl, lower alkylamino, lower alkanoylamino. amino, hydroxy-lower alkyl much lower alkanoyl and R 1 represents hydrogen, lower alkyl or phenyl, R 3 represents hydrogen or lower alkyl and R 6 represents phenyl, halophenyl or pyridyl.

As used herein, the term "lower alkyl" includes or "alkyl" both straight-chain and branched C1-C7 hydrocarbon groups, preferably C1-C4 hydrocarbon groups such as methyl, ethyl, propyl, isopropyl, butyl and the like. The term "lower alkyl" includes also cyclic hydrocarbon groups such as cyclopropyl.

With the term "lower alkanoyl" as used herein means an acyl residue of a C1-C7f, preferably C1-C4-alkanoic acid, for example acetyl, propionyl, butyryl and the like, i.e., residues with the formula -COR 2 O, wherein R is C 1 -C 6 alkyl or hydrogen; As as used herein, the term "lower alkanoyl" also includes one protected ketone such as an acetal or ketal having 2 to 7 carbon atoms, for example an ethylenedioxy group. Ketal or aldehyde protecting group is used to prevent the transfer of the constituent ketone or the aldehyde in the oxidation, reduction and condensation reactions. 8001619-9 The term "halogen" is used to encompass all four the forms thereof, i.e. chlorine, bromine, fluorine and iodine.

Preferred compounds encompassed by the present invention finning are those with the general formula V ” hrs wherein X in groups b) and c) represents chlorine.

Particularly preferred compounds of formula I 'according to The invention is 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo- [1,5-a] [1,4] benzodiazepine and 8-chloro-6- (2-fluorophenyl) -1,4-di- methyl-4H-imidazole fi, 5- all fi, Q] benzodiazepine.

The term "pharmaceutically acceptable salts" is used for to include both inorganic and organic pharmaceutically acceptable only acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid acid, tartaric acid, methanesulfonic acid, para-toluenesulfonic acid and the like.

Such salts can very easily be formed by those skilled in the art with the state of the art and the nature of the association to be put in salt form in consideration.

Within the scope of the present invention, there are also compounds obtained by ring opening in compounds of formula I, wherein Qš fl is R4-phenyl. Such compounds have the formula * 8001619-9 ~ i 1 / where X- is the anion of an organic or inorganic acid, and R 1, R 2, R 3, R 4 and R 6 have the meaning given in formula I '.

It has been found that certain compounds of formula I ' in solution is opened to the corresponding compounds of formula ID.

Such open compounds are present in a pH-dependent equilibrium in solution with compounds of formula I2 i.e. their equivalent closed associations. Drying with the formula ID can be isolated as acid addition salts by treating their counter- corresponding closed-cell compounds with an aqueous mineral acid followed by evaporation of the solvent. When isolated these salts exhibit pharmacological activity comparable to it for their corresponding closed-ring parent associations.

The present invention relates to a process for producing position of compounds of the formula RXYN II N II (IN C = N H l “S wherein R 1, R 3, R 6 and (:}: have the meaning given in formula I '; 8001619-9 by decarboxylating a compound of the formula QYN coon N e rv d I 3 xvln sm / H ' n wherein R 1, R 3, R 6 and <: I: have the meanings given above if desired splits a racemic compound of formula I 'above into its optical enantiomers and, if desired transfer a compound of formula I 'above to a pharmaceutical ethically acceptable salt.

Compounds of formula I 'are formed by decarboxylation of the compounds of formula XVIII with or without catalyst and with or without solvent. This decarboxylation is conveniently carried out by using heat, e.g. at a temperature between approx 1000 ° C and 3500 ° C, preferably about 1500 ° C and 2300 ° C. Agents that can be used in this reaction step are hydrocarbons, for example mineral oil; chlorinated hydrocarbons, ethers, alcohols, e.g. ethylene glycol, dimethylformamide, dimethylsulfoxide, hexamethylphosphorus syratriamide. Useful catalysts are e.g. metals such as copper powder or metal salts such as Cu + or Ag + salts.

The general reaction schemes shown in the following sheets A is illustrative of several of the reactions that are useful for the preparation of starting compounds of formula XVIII. Unless unless otherwise indicated, in these reaction schemes R is lower alkyl and R1, R3, RÄ and R6 have the meaning given in formula I. The is obvious to those skilled in the art that some of the substituents can be attacked during the reactions listed below, but such reactions sensitive groups can be modified before or after a such reaction is performed. The reactions shown on sheet A can also performed with the corresponding N ~ oxides thereof [Ä = -C (R6) = N (- + O) 1], but any N-oxide residue present in compounds of formula VI will be removed during transmission VI ~ a VII. 8001619-9 COOR COOR ' 8001619-9 Steps II - III Compounds of formula III are prepared by nitrosation of compounds of formula II. Such nitrosation can be performed with "in situ formed" nitric acid. Reagents that can be used comprises (1) alkali metal nitrites, e.g. sodium nitrites, in presence of organic or inorganic acids, e.g. glacial acetic acid, and aqueous or non-aqueous solvents; (2) alkyl nitrites, for example methyl nitrites, in the presence of an inert solvent such as a alcohol, chlorinated hydrocarbons or e.g. dimethylformamide; and 3) a nitrosyl chloride gas solution in an inert solvent and in the presence of an acid acceptor such as pyridine. Such a nitrosation reaction should performed at about or below room temperature, i.e., in the range of -200 C to 250 ° C. An amino group or an alkylamino group present in the molecule can be protected during the nitrosation reaction, e.g. with using acylation. Such protecting groups can be removed at one suitably later stage of the reaction sequence.

Step VIII - + IX Compounds of formula IX can be prepared by reaction of compounds of formula VIII with dimorpholinophosphinic acid chloride.

The reaction of compounds of formula VIII with phosphorylation the agent for compounds of formula IX is carried out by treating compounds of formula VIII with a strong base which is sufficient to ionize the compound of formula VIII so that the corresponding anion is formed. Suitable bases include alkali metal alkoxides, such as potassium tert-butoxide or sodium methoxide, and alkali metal hydrides, such as sodium hydride, and alkyllithium compounds such as n-butyl- lithium. The reaction temperature ranges from 0 ° C to 1000 ° C and the reaction is preferably carried out in an aprotic polar inert solvent, i.e. one that completely or at least partially would solubilize the surrounding salts of the compounds by meln VIII. Preferred solvents are ethers, e.g. tetrahydro- furan or dioxane or tertiary amides, e.g. dimethylformamide.

It is apparent that each amino or substituted amino group must be present in protected form during this reaction step, and the protecting group can be removed afterwards at some appropriate stage, for example after the formation of the compound of formula XII.

Step III or IX - + IV Compounds of formula III or formula IX may be condensed with the anion generated by a malonic acid ester of the formula .3001619-9 8 COOR \ cooR where R is lower alkyl, so that compounds of formula IV are formed. The anion is generated by deprotonation of the malonic acid ester with a suitably strong base such as 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 hydrocarbons, e.g. benzene, toluene, hexane, ethers, e.g. dioxane, THF, diethyl ether, DMF, DMSO, etc., in a temperature range from below room temperature to 1500 C, preferably 00 C to 1000 C, very special room temperature.

Step IV -4 V Compounds of formula V are prepared by decarboxylation of compounds of formula IV by reacting the compound with formula IV with an alkali metal hydroxide such as NaOH or KOH in one suitable solvent such as alcohols, ethers or DMSO in one temperature range from room temperature to reflux temperature, preferably 60 ° C to 100 ° C.

Steps V -e-VI Compounds of formula VI are prepared by nitrosation of compounds of formula V by reacting them with nitric oxide. acidity generated from e.g. an alkali metal nitrite, alkyl nitrite or nitrosyl chloride, by reaction with organic or inorganic acid. Suitable solvents for the nitrosation reaction include ethers, alcohols, water, acids, e.g. acetic acid, DMF, DMSO and chlorinated hydrocarbons. The reaction can be carried out at about room temperature. luckily even if such temperature is not critical.

Step VI -> VII Compounds of formula VII are prepared by reduction of compounds of formula VI e.g. with Raney nickel and hydrogen or with zinc and acetic acid. This reduction results in predominantly status of compounds of formula VII with simultaneous by-products tion of small amounts of several possible isomers, i.e. associations with the formulas 80Û1619 ~ 9 9 UCOOR NH: H NH H uu, T NH: _ coon | °°° R | ç °° " N "" 'N N \\ / / N / / WA We wc WD It should be noted that the above reductive step reduces reaction-sensitive groups, if present, such as Ru, which for example N02 in 7-position or CN in 7-position. These groups can reinserted by methods known in the art and described here in.

Step VII - + XII Compounds of formula XII are then formed by the reaction of compounds of formula VII with an alkanoic acid orthoester of the formula RIc (oR) 3 where R is lower alkyl and R; is hydrogen, lower alkyl, alkoxy-lower alkyl or halogen-lower alkyl, possibly in the presence of an acid catalyst, e.g. an organic or inorganic acid, e.g. p-toluenesulfonic acid, phosphoric acid, etc., and at or above room temperature, ie. 250 ° C to 150 ° C, in which case the cyclization to compound XII occurs spontaneously. Technical equivalents to the above orthoester include orthoamides, e.g. di- the methyl acetal of N, N-dimethylformamide; N, N, N ', N', N ", N" -hexamethyl- methantriamine; nitriles, e.g. acetonitrile esterimidates, e.g.

CH 3 -C (= NH) -OC 2 H 5.

It is obvious that any amino or alkyl present amino group must be protected during this reaction.

Step VII -9 XI Compounds of formula XI may be formed by acylation of compounds of formula VII having a compound of formula R 1 COX or (R 1 CO) 2 O. where X is halogen and R 1 is hydrogen, lower alkyl, phenyl, alkoxy-lower alkyl, substituted phenyl, pyridyl or aralkyl.

Solvents for the above process step include methylene chloride, ethers, chlorinated hydrocarbons, etc., preferably in combination with an acid acceptor such as an organic or inorganic bass as e.g. triethylamine, pyridine or an alkali metal carbonate.

The reaction can be carried out at above or below room temperature 'Äsoms19-9 is preferably performed at room temperature. Compounds of formula XI is isomeric in nature, i.e. may exhibit either of the following stereochemical structures NHCQR 'COOR /. coon I / NHcoR, / * \ z __ = XI A XI B Step XI -% XII Compounds of formula XII may also be formed by dehydration compounding of compounds of formula XI or isomers thereof with simultaneous cyclization by heating. This reaction step can be performed with or without solvent, e.g. DMF, ethylene glycol, hexamethylphosphorus acid triamide, in a temperature range from 1000 ° C to 3000 ° C, approximately 1500 C to 250 ° C, eg 2000 C, with or without the presence of catalysts and water-binding agents.

Step IX -9 X Compounds of formula X can be formed by condensation the reaction of compound of formula IX with that of an acylamino- malonic acid ester generated the anion of the formula COOR and c-NHcoRf OOR where R is lower alkyl and R 1 'is hydrogen, lower alkyl, phenyl, alkoxy- lower alkyl, substituted phenyl, pyridyl or aralkyl, thereby forming a compound of formula X. The anion is generated by deprotonation of an acylaminomalonic acid ester with a suitable strong base such as alkali metal or alkaline earth metal alkoxides, hydrides or amides. The reaction of compounds of formula IX with acyl- the aminomalonic acid anion is preferably carried out in a solvent such as hydrocarbons, e.g. benzene, toluene, nexane, ethers, e.g. dioxane, THF, diethyl ether, DMF, DMSO, etc., in a temperature range from below room temperature to 150 ° C, preferably 0 ° C to 1000 ° C, at all ,, 8001619-9 Especially room temperature.

Steps X - XI Compounds of formula XI and isomers thereof are formed by decarboxylation of compounds of formula X with an alkali metal alkoxide in a solvent such as ethers, alcohols, DMSO, DMF, etc., at above or below room temperature, preferably at room temperature. Compounds of formula X and XI need not be isolated but can be transferred in situ to compounds of formula XII. §§Gg_VII -9 XIII Compounds of formula XIII are formed by reacting compounds compounds of formula VII with an aldehyde of formula RICHO, wherein R1 has the meaning given in formula I, but each amino- or substituted amino group and preferably each RCO group should be present in protected form. The protection group can be removed afterwards, for example, after the formation of the compound of formula XII. Suitable solutions means for this reaction step are hydrocarbons such as benzene, alcohol holes, ethers, chlorinated hydrocarbons, DMF, DMSO, etc., with or without presence of water-binding agents, e.g. molecular sieves, at above or below room temperature, preferably from room temperature to the reflux temperature of the solvent.

Step XIII - + XII Compounds of formula XIII may be converted into compounds of formula XIII formula XII by in situ oxidation with oxidizing agents such as gand dioxide, air, acid, etc.

As stated above, a final compound of formula XII, wherein Ru is amino, converted to a corresponding compound, wherein Rn is nitro or cyano via a Sandmeyer reaction as indicated herein description.

Another method for the preparation of compounds with formula XII, wherein Ru is nitro or cyano, consists in represents a corresponding compound of formula VII. The latter can be produced by turning over a corresponding company compound of formula IX with a protected aminomalonic acid ester of formula COOR 49 C - NHZ CDON where R is lower alkyl and Z is benzyloxycarbonyl, 8001619-9 transfers the compound of formula X thus obtained, wherein R 1 is benzyloxy and Ra are nitro or cyano, to a corresponding of formula XI as described above for steps X -e XI and subjecting the compound thus obtained to a treatment with hydrogen bromide in glacial acetic acid to give a compound of formula VII, wherein Ru is nitro or cyano. The intermediates of formulas X and XI does not need to be insulated. The compound thus obtained with The compound VII is further transferred to the compound of formula XII via the above-described reaction steps VII -e XIII and XIII -a XII.

Step XII -é XVIII Compounds of formula XVIII are formed by hydrolysis of compounds compounds of formula XII to the corresponding acids, preferably with alkali metal hydroxides, e.g. NaOH or KOH. This hydrolysis suitably in an inert solvent. Suitable solvents are alcohols, e.g. methanol, ethanol; ethers, e.g. dioxane, tetrahydro- furan; dimethylformamide, in combination with water. It is to perform this reaction step at a temperature between room temperature and boiling point of the reaction mixture.

It is obvious that during this reaction step a present acyloxyalkyl group will be hydrolyzed to the corresponding hydroxy alkyl group, which in turn can be converted back to acyloxy- the alkyl group at an appropriate later stage. An R1 group in the then -COORIO will also be hydrolyzed and decarboxylated a corresponding compound, wherein B1 is hydrogen. The COORIO group can re- introduced from a formyl or hydroxymethyl group in a known manner. A near- the haloalkyl group can be affected in this reaction step so that a corresponding hydroxyalkyl compound is obtained, which can also be recycled converted to the haloalkyl compound at a later stage on regular way. Any compound of formula XII wherein Ru is hydroxy alkyl, should be protected during this halogenation reaction step, e.g. in form of the tetrahydropyranyl ether derivative thereof.

In compounds of formula I, wherein a ketal group, e.g. one ethylenedioxy group, is present in an imidazobenzodiazepine, a such ketal group is converted to the corresponding ketone by exposes the ketal group to mild acid hydrolysis. The ketone can then transferred to a secondary or tertiary alcohol that is racemic by its nature. The reaction conditions for both of the above The steps are found in U.S. Pat. No. 3,846,410. 8001619-9 13 Compounds of formulas I ', and I'D and their pharmaceutically acceptable acid addition salts are useful as muscle relaxants, sedatives and anticonvulsants, and many are particularly useful when used in intravenous and intramuscular preparations please whether the solubility of the acid addition salts in aqueous solution.

As contemplated by the present invention, the novel the compounds of formula I and their acid addition salts are incorporated into pharmaceutical dosage formulations containing from about 0.1 to about h0 mg, preferably 1 - H0 mg with the dose adapted to stroke and individual needs. The new compounds of formulas I, IA and ID and their pharmaceutically acceptable salts may be administered internally, e.g. parenterally or enterally, in the usual pharmaceutical dosage forms. For example, they can be incorporated into conventional ones liquid or solid carriers such as water, gelatin, starch, magnesium stearate, talc, vegetable oils and the like into tablets, elixirs, capsules, solutions, emulsions and the like according to only pharmaceutical methods.

The following examples are illustrative but not limiting the invention. All temperatures are given in Celsius degrees.

Example 1 A suspension of 1.5 g of 8-chloro-6- (2-fluorophenyl) -1H-imidazo- [1,5-ayl, C] benzodiazepine-3-carboxylic acid in 10 ml of mineral oil heated to 230 ° for 5 minutes. The reaction mixture was partitioned between 1N hydrochloric acid and ether. The aqueous phase was made alkaline ammonia and extracted with methylene chloride. The extracts were dried and evaporated, and the residue was chromatographed on 60 g of silica gel using 25% (v / v) methylene chloride in ethyl acetate. The less polar component 8-chloro-6- (2-fluorophenyl) ~ The 55-imidazol-1,5-α7 [1,4] benzodiazepine was crystallized from ethyl acetate to colorless crystals with m.p. 195-196 °.

The more polar component was crystallized from ether to 8-Chloro-6- (2-fluorophenyl) -4H-imidazolyl, 5-a] [η, Q] benzodiazepine with amp. 1so - 1s1 °.

The starting material can be prepared as follows: 8001619-9 14 A solution of zoo g (0.695 mol) of chloro-β-anhydro-s- (z- -fluorophenyl) -2H-1,4-benzodiazepin-2-one in 2 l of tetrahydrofuran and 250 ml of benzene were saturated with methylamine while cooling on an ice bath.

A solution of 190 g (1 mol) of titanium tetrachloride in 250 ml of benzene was added. was passed through a dropping funnel over the course of 15 minutes. After well with tetrahydrofuran. The aqueous layer was separated and the organic the phase was dried over sodium sulfate and evaporated, The crystalline the residue of 7-chloro-5- (2-fluorophenyl) -2-methylamino-BH-1,4-benzodi- azepine was collected, m.p. 204 - 206 °. The analytical sample described was stalled from methylene chloride / ethanol, m.p. 204 - 2060.

A) Sodium nitrite, 8.63 g (0.125 mol), was added in three portions over a 15 minute period to a solution of 30.15 g (0.1 mol) 7-Chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine in 150 ml glacial acetic acid. After stirring for 1 hour at room temperature, dilute the reaction mixture with water and extracted with methylene chloride.

The extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated, finally azeotroped with toluene, to give 29 g of crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethyl- amino) -SH-1,4-benzodiazepine as a yellow oil.

B) Sodium nitrite (27.6 g, 0.4 mol) was added portionwise over a 30 minute period to a solution of 90.45 g (0.3 mol) of 7-chloro- -5- (2-fluorophenyl) -2-methylamino-BH-1,4-benzodiazepine in 400 ml of is- vinegar. After the addition was complete, the mixture was stirred at room temperature for 1 hour and diluted with 1 liter of water and extracted with methylene chloride. The extracts were washed twice with water and then after with 10% aqueous sodium carbonate solution. Solution dried and evaporated to give crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine in the form of a yellow oil.

This material was dissolved in 300 ml of dimethylformamide and added to a mixture of 150 ml of dimethyl malonate, 40.4 g of potassium t-butoxide and 500 ml of dimethylformamide, which was stirred at room temperature in minutes. The reaction mixture was stirred under nitrogen overnight at room temperature, acidified by adding 50 ml of glacial acetic acid, diluted with water and aqueous sodium carbonate solution, dried was added to sodium sulfate and evaporated. Crystallization of re ~ aoo1619 »9 0105 the residue from ethanol gave 7-chloro-1,5-dihydro-2- (dimethoximalonylidene) -5- - (2-fluorophenyl) -2H-1,0-benzodiazepine as colorless crystals with m.p. 170 - 1720. For analysis, the product was recrystallized from methylene chloride / ethanol, the melting point remaining unchanged.

A mixture of 20 g (0.05 mol) of 7-chloro-1,3-dihydro-2- (di- methoximalonylidene) -5- (2-fluorophenyl) -2H-1,1-benzodiazepine, H00 ml methanol and 3.3 g (0.059 mol) of potassium hydroxide were heated to reflux flow under nitrogen for 5 hours. After stripping the main part of the solvent, the residue was gradually diluted with water, and the the precipitated crystals were collected, washed with water and dried, to give 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (dimethoxy) carbonylmethylene) -2H-1,1-benzodiazepine with m.p. 158 - 160 °.

For analysis, it was recrystallized from methylene chloride / hexane. m.p. 161 - 162 °.

Sodium nitrite (8.8 g, 0.125 mol) was added to a solution of 28 g (0.08 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (methoxy- carbonylmethylene) -2H-1,1-benzodiazepine in 250 ml of glacial acetic acid. Among- The mixture was stirred at room temperature for 10 minutes and then diluted after with 250 ml of water. The crystalline product was filtered off; washed with water, methanol and ether and dried, received 7-chloro-5- (2-fluorophenyl) -mydroxyimino-BH-1,1-benzodiazepine -2-acetic acid methyl ester as yellow crystals, m.p. 258 - 2Nl ° (decomposition). 7-chloro-5- (2-fluorophenyl) β-hydroxyimino-α-1,0-benzodiazepine -2-acetic acid methyl ester (11, 25 g, 0.03 mol) was dissolved in a mixture of 750 ml of tetrahydrofuran and 500 ml of methanol by heating.

Raney nickel (20 g) was added, and the mixture was hydrogenated at atmospheric pressure for M hours. The catalyst was removed by filtration. and the filtrate was evaporated, finally azeotroped with toluene. The residue was dissolved in 100 ml of methanol. After adding 10 ml of tri- ethyl orthoformate and 5 ml of ethanolic hydrogen chloride (5%) were heated the mixture to reflux for 10 minutes. Then it was evaporated, and the residue was partitioned between methylene chloride and saturated aqueous containing sodium bicarbonate solution. The methylene chloride layer was separated, dried and evaporated, and the residue was crystallized from ether, to give methyl 8-chloro-6- (2-fluorophenyl) -UH-imidazo [1,5-a] [1, Q1 -benzodiazepine-5-carboxylate which was recrystallized from methylene chloride. rid / ether / hexane, m.p. 179 - l8l °.

* SÛÛ1619-9 I {e A mixture of 1.48 g (0.004 mol) of methyl 8-chloro-6- (2-fluoro- phenyl) -NH-imidazo [1,5-a7 [1,1-benzodiazepine-3-carboxylate, 0.5 g (0.009 mol) of potassium hydroxide, 50 ml of methanol and 2 ml of water was refluxed for 3 hours under a nitrogen atmosphere. The methanol was partially run, the residue was acidified with glacial acetic acid and diluted with water, while the solution was still warm. The crystals collected after cooling in ice / water and dried in vacuo received 8-chloro-6- (2-fluorophenyl) -UH-imidazole, 5-α7 [1,4] benzodiazepine-5 -carboxylic acid with m.p. 245 - 247 ° (dec.).

Example 2 A solution of 0.5 g (0.00129 mol) of ethyl 8-cyano-C (2-fluoro) phenyl) -1-methyl-1H-imidazole, 5-α, β, benzodiazepine-3-carboxylate in 100 ml of ethanol and 10 ml of water were treated with 0.1 g (0.0026 mol) potassium hydroxide. After refluxing for 30 minutes, evaporate the reaction mixture, and 10 ml of water were added. The whole sur- was made with acetic acid, filtered and extracted with 20 ml dichloromethane, which was separated, dried and evaporated. About 0.2 g of the hydrolyzed product was obtained from the filtration, and the same amount was obtained from the extraction. This material was added to 3 ml dry hexamethylphosphoramide and kept at 200 - 2050 for 50 minutes during argon. Cooled, and 50 ml of ice water and 1 ml of ammonium hydroxide were added. sat. The solution was filtered, and the filtrates were extracted with ml of dichloromethane and evaporated to dryness. Water was added, and the solution was filtered and the combined precipitates were dissolved in dichloromethane and was developed on two silica gel thick layer plates in a solution of ethyl acetate containing 15% methanol. The silica gel that The product contained was scraped off (Rf H - 5), stirred with methanol and was filtered. This was crystallized from a mixture of isopropanol and ether to give 8-cyano-6- (2-fluorophenyl) -1-methyl-1H-imi- dazoíï, 5-a7 [l, &] benzodiazepine as off-white prisms with m.p. 198 - 2 ° C.

The starting material can be prepared as follows: A solution of 10 g (0.0358 mol) of 7-cyano-2,3-dihydro-5- (2- -fluorophenyl) -1H-1,1-benzodiazepin-2-one in 150 ml of dry tetrahydro- furan under argon was treated with 2.0 μg (0.0537 mol) 54 2 μg sodium hydride, and the reaction mixture was stirred and refluxed. køkaaes for 1 hour. Then cooled to 0 °, and 13.7 g (0, o537 mol) phosphorus dimorpholidine chloride was added. After 18 hours, filter 8001619-1-9 17 the reaction mixture was concentrated to a small volume volume and ether were added. The precipitate was filtered and recrystallized. was obtained from a mixture of dichloromethane and ether to give 7-cyano-5- (2-fluorophenyl) -2-bis- (morpholino) phosphinyloxy-BH-1,1-benzo- diazepine as white rods with m.p. 194 - 1970.

To 100 ml of dry N, N-dimethylformamide under nitrogen was added 1.6 g (0.36 m 2) su: z-ig sodium naryaride, and 8.3 g (0.38 m 1) acetamidodiethyl malonate was added with stirring. After 30 minutes 10 g (0.02 mol) of 7-cyano-5- (2-fluorophenyl) -2-bis- (morphine) were added. folino) phosphinyloxy-BH-1, U-benzodiazepine, and after 64 hours was poured the reaction mixture in ice water containing U ml of acetic acid. This was filtered, and the solid was dissolved in 100 ml of dichloromethane which was washed with 50 ml of water, dried over anhydrous sodium sulfate and concentrated to a small volume. This solution matographed over a column of "Florisil" and eluted with 2 l discarded dichloromethane. It was then eluted with 1 l of one mixture of dichloromethane and ether (10 / l) and then with 2 l of ether.

The ether fraction was recrystallized twice from a mixture of dichloromethane and ether to give (acetylamino) -17-cyano-5- (2- -fluorophenyl) -} H-1,1-benzodiazepin-2-yllmalonic acid diethyl ester as vita prísmor med smp. 138 - 1ü0 °.

The column was eluted with 1.5 L of a mixture of ethyl acetate and methanol (10/1). The eluate was concentrated, and the residue was crystallized. was lysed from ether. Recrystallization from a mixture of dichloro- methane and ether gave ethyl 8-cyano-6- (2-fluorophenyl) -1-methyl-HH-imidate zoll, 5-a] [1,1-benzodiazepine-3-carboxylate as off-white prisms with m.p. 272 - 27u °.

Exemgel 3 A suspension of 1.5 g (3.1 U8 mmol) of 8-chloro-6- (2-fluorophenyl) - -1-phenyl-HH-imidazo [1,5-a] 1,1,4-benzodiazepine-3-carboxylic acid i ml of mineral oil was stirred vigorously at 190 ° for 1/2 hour. The the dark suspension was then slurried with hexane and extracted twice with 1N hydrochloric acid. The acidic water layer was then washed. after once with hexane and neutralized with 5 Z aqueous containing sodium carbonate. The precipitated product was collected and air dried. Concentration of the filtrate gave a further exchange of 8-chloro-6- (2-fluorophenyl) -1-phenyl-1H-imidazo11.5-a] 11, N7- -benzodiazepine as an off-white solid. An analytical test was obtained by column chromatography on silica gel eluting with ethyl acetate, m.p. Zül ~ 2ü3 °. 8001619-9 18 The starting material can be prepared as follows: A solution of 3.75 g (0.01 mol) of 7-chloro-5- (2-fluorophenyl) - Hydroxyamino-SH-1,4-benzodiazepine-2-acetic acid methyl ester in 300 ml of tetrahydrofuran and 200 ml of methanol were hydrogenated at atmospheric pressure. pre-press for 1 l / 2 hours in the presence of a teaspoon of Raney nickel. Kata- the lysator was separated by filtration over CELITE R, and the filtrate evaporated under reduced pressure, at the end azeotroped with toluene. The residue was dissolved in 20 ml of pyridine and treated with U ml of benzoyl chloride. After standing for 15 minutes at room temperature, distribute the reaction mixture between methylene chloride and 1N sodium hydroxide solution. The organic layer was dried and evaporated. at the end azeotropic with toluene. Crystallization of the residue from ether gave 2- [Tbenzoylamino) methoxycarbonylmethylene] -7-chloro-5- (2- -fluorophenyl) -1,3-dihydro-2H-1,1-benzodiazepine, m.p. 210 - 32 °.

The analytical sample was recrystallized from ethyl acetate / hexane. m.p. 217 - 219 °, with softening at 150 - 1600.

A solution of 1.15 g (2.5 mmol) of 2- (1-benzoylamino) methoxy- carbonylmethylene] -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1,1H-benzo- diazepine in 10 ml of hexamethylphosphoric triamide was heated to reflux flow for 10 minutes. The dark mixture was partitioned between water and ether / methylene chloride. The organic layer was washed with water, dried and evaporated. The residue was dissolved in methylene chloride and filtered over activated alumina with ethyl acetate. acetate. The filtrate was evaporated and chromatographed over 20 g silica gel using 10% (v / v) ethyl acetate in methyl lenchloride. Crystallization of the combined pure fractions from ether / hexane gave methyl 8-chloro-6- (2-fluorophenyl) -1-phenyl-1H-imi- daz0 [1, §'ê7l1, Ä / benzodiazepine-3-carboxylate with m.p. 208 - 209 °.

To a solution of 2.66 g (5.77 mmol) of methyl 8-chloro-6- (2- -fluorophenyl) -1-phenyl-NH-imidazo [1,5-a], 4] benzodiazepine-3-carb- oxylate in 50 ml of refluxing methanol was added a solution of 755 mg (11.5 mmol) of potassium hydroxide in 10 ml of water, and the ere the mixture was heated for 2 l / 2 hours. The solvent is removed in a vacuum, after which the residue was dissolved in 50 ml of hot acetic acid and the solution was then poured into 100 ml of cold water. The product collected, washed with water and air dried to give 8-chloro-6- (2-fluorophenyl) -1-phenyl-RH-imidazole, 5-a] [1,4] benzodi- azepine-3-carboxylic acid as an off-white solid. An analytical samples were recrystallized from benzene, m.p. 267 - 2690.

POOB QUALITY s as 619-9 19 Example 4 A solution of 1.3 g of 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo- - [W, 5-a] 11β-benzodiazepine-3-carboxylic acid in 20 ml of ethylene glycol heated to reflux for 1 hour. The reaction mixture was partitioned between water and methylene chloride / toluene. The organic phase washes was saturated with saturated sodium bicarbonate solution, dried and evaporated.

Crystallization of the residue from ether / 2-propanol gave 8-bromo-1- -methyl-6- (2-pyridyl) -4H-imidazoline, 5-a] [η, Q] benzodiazepine as a brown yellow crystals. The analytical sample was recrystallized from ethyl acetate / hexane, m.p. 189 - 1900.

The starting material can be prepared as follows: A SM% dispersion of sodium hydride in mineral oil (11 g, 0.25 mol) was added portionwise to a stirred solution of 63.2 g (0.2 mol) 7-bromo-1,3-dihydro-5- (2-pyridyl) -2H-1,3-benzodiazepine-2- -one in 1 l of tetrahydrofuran under argon. After refluxing on in a steam bath for 1 hour, the solution was cooled to room temperature and was treated portionwise with 76.2 g (0.5 mol) of dimorpholinophosphinic acid chloride. Stirring was continued at room temperature for 5 hours. The dark the precipitate was filtered through CELITECÉ). Concentration of the filtrate in vacuum and boiling the dark residue with ether gave brownish yellow crystals of 7-bromo-2- [this (morpholino) phosphinyloxy-5- (2-pyridyl) - -BH-1,4-benzodiazepine. A sample was recrystallized by dissolving dilution of the same in 2 ml of methylene chloride, filtration, dilution with ml of ethyl acetate and cooling in an ice bath to give lgust brown-yellow plates with m.p. 180 - 1820 (decomposition).

Diethyl acetamidomalonate (H3 g, 0.2 mol) was added to a suspension pension of 10 g (0.2 mol) of a dispersion (50 μg) of sodium hydride in mineral oil in 500 ml of dry dimethylformamide. The mixture was stirred under argon for 1 hour at room temperature and for 20 minutes. with heating in a steam bath. 7-bromo-2 [tis (morpholino) phosphinyl- oxy-5- (2-pyridyl) -3H-1,1-benzodiazepine (55 μg, 0.1 mol) was added then to the reaction mixture, which was returned to room temperature. lucky. After stirring for 1 hour at room temperature, it was heated it again on steam bath for 2 hours. The cooled solution was distributed between water and methylene chloride / ether. The organic phase was separated, washed with water, dried and evaporated. The crystalline residue was inoculated by inoculation with ethyl acetate / ether to give ethyl -bromo-1-methyl-6- (2-pyridyl) -UH-imidazofl, 5-a] [1,1 / benzodiazepine-3- -carboxylate as off-white crystals with m.p. 2U0 - 2ü3 °. Inoculum crystal '8Û01619-9i clays were obtained by chromatographic purification over 30-fold the amount silica gel using 5% (v / v) methanol in ethyl acetate.

The analytical sample was recrystallized from ethyl acetate, m.p. zuz - 2uu °.

A mixture of 2.15 g (5 mmol) of ethyl 8-bromo-1-methyl-6- (2- -pyridyl) -UH-imidazo [1,5-a] [1,1-ulbenzodiazepine-5-carboxylate, 50 ml methanol, 0.8U g (15 mmol) of potassium hydroxide and 2.5 ml of water was refluxed for 5 hours. Most of the methanol was evaporated, and the residue was partitioned between water and ether. The aqueous phase is was made with acetic acid and extracted with methylene chloride. The extracts dried and evaporated. Crystallization of the residue from methylene chloride / ethyl acetate gave 8-bromo-1-methyl-6- (2-pyridyl) -UH-imidazo- [1,5-a] 1,1H / benzodiazepine-5-carboxylic acid as colorless crystals which was recrystallized from methanol for analysis, m.p. 2ü5 - 2500 (decomposition) with previous sintering.

Example 5 A mixture of 1.5 g of 6- (2-chlorophenyl) -1-methyl-8-nitro-HH- -imidazo [1,5-a] [1,1] H] benzodiazepine-3-carboxylic acid and 10 ml of ethylene glycol was heated to reflux for 1 hour. The reaction mixture was then partitioned between methylene chloride / toluene and saturated aqueous containing sodium bicarbonate solution. The organic phase was washed with water, dried and evaporated. The residue was dissolved in 10 ml of 2-pro- panol and treated with 0.6 g of maleic acid. The salt crystallized when adding ether to the hot solution. It was collected, was washed with 2-propanol and ether to give 6- (2-chlorophenyl) -1- The starting material can be prepared as follows: Diethyl acetamidomalonate (H3 g, 0.2 mol) was added to one suspension of 10 g (0.2 mol) of sodium hydride (50% in mineral oil) in 500 ml of dry dimethylformamide. The mixture was heated to 500 ° C for 30 minutes under argon. After adding 53 g (0.1 mol) of 5- (2- -chlorophenyl) -2- [bis (morpholino) phosphinyloxy-7-nitro-BH-1,1H-benzo- diazepine, the reaction mixture was heated on a steam bath for 1 hour.

The cooled brown mixture was partitioned between water and methylene chloride / ether. The organic phase was washed with water, dried and evaporated. The residue was chromatographed on 1 kg of silica gel using ethyl acetate. The pure fractions were combined and evaporated. Crystallization of the residue from methylene chloride 8001619-9 21 ether gave ethyl 6- (2-chlorophenyl) -1-methyl-8-nitro-1H-imidazo [1,5-a] - [1, H / benzodiazepine-3-carboxylate as light yellow crystals, m.p. 233 - 23U °. The analytical sample was recrystallized from ethyl acetate. m.p. 25A - 255 °.

A mixture of 0.5 g (0.01 mol) of ethyl 6- (2-chlorophenyl) -1- -Methyl-8-nitro-1H-imidazole, 5-α / 1,47benzodiazepine-3-carboxylate, 100 ml of methanol, 1.12 g (0.02 mol) of potassium hydroxide and H ml of water heated to reflux under nitrogen for 3 hours. Most of it the methanol was evaporated, and the residue was partitioned between water and ether. The aqueous phase was washed with ether, acidified with acetic acid and extracted with methylene chloride. The extracts were dried and fumes. Crystallization of the residue from methylene chloride acetate gave 6- (2-chlorophenyl) -1-methyl-8-nitro-HH-imidazo [1,5-a] [η, U] - -benzodiazepine-3-carboxylic acid, m.p. 272 - 27U ° (dec.).

The analytical sample was recrystallized from methanol / ethyl acetate. m.p. 27H - 276 ° (dec.).

Example 6 A suspension of 1.2 g of 1-methyl-8-nitro-6-phenyl-NH-imidazo -11,5-α, 1, Ulbenzodiazepine-3-carboxylic acid in 15 ml of hexamethylphosphoric acid acid triamide was heated to reflux for 3 minutes. The cooled solution The mixture was partitioned between methylene chloride / ether and aqueous sodium bicarbonate solution. The organic phase was washed with bicarbonate. bonat solution, dried and evaporated. The residue is chromatographed was diluted over 30 g of silica gel using 3 Z (v / v) ethanol in methylene chloride. Crystallization of the pure fractions from ether / 1-Methylene chloride ethyl acetate gave 1-methyl-8-nitro-6-phenyl-4H-imidazo- - / 1,5-a // 1, U / benzodiazepine with m.p. 168-170 °. This was converted to the maleate salt, which crystallized from ethyl acetate of 0.5 mol of the solvent, m.p. 125 - 1280 (decomposition).

The starting material can be prepared as follows: G g (0.125 mol) of sodium hydride dispersion (50 l in mineral oil) was added to a solution of 28.1 g (0.1 mol) of 1,5-dihydro-7- -nitro-5-phenyl-2H-1,1-benzodiazepin-2-one in 300 ml of dry tetrahydro- furan. After stirring for 1 hour at room temperature was added , 2 g (0.2 mol) of dimorpholinophosphinic acid chloride, and continued stir for N hours. The product was crystallized by the addition of water and ether. The precipitate was collected and dissolved in methylene chloride. The solution was dried and evaporated and the residue was crystallized. was eluted from ethyl acetate to give crude 7-nitro-2- [this (morpho- lino) phosphinyloxy] -5-phenyl-BH-1,1-benzodiazepine, m.p. 208 - 2090 8001619-9 22 A portion of this material was added to a mixture of 8.6 g (0.0ü mol) diethyl acetaminomalonate, 2 g (0.0ü mol) sodium hydride suspension (50% in mineral oil) and 75 ml of dimethylformamide, which heated at HO ° for 30 minutes. After the addition was heated the reaction mixture for 30 minutes on a steam bath, after which it is distributed between water and ether. The organic phase was washed with water, dried and evaporated. the residue was chromatographed over 250 g of silica gel using ethyl acetate. The merged clean the fractions were evaporated and the residue was crystallized from methylene chloride / ether to give ethyl 1-methyl-8-nitro-6-phenyl- -HH-imidazo [η 5 -α] [1,1-b] benzodiazepine-3-carboxylate as off-white crystals with m.p. ZHO - 24l °. The analytical sample is recrystallized. serades from ethyl acetate.

A mixture of 1.95 g (5 mmol) of ethyl-1-methyl-8-nitro-6- -phenyl-HH-imidazo [1,5-a] (1,1-benzodiazepine-3-carboxylate, 50 ml methanol, 0.56 g (0.0l mol) of potassium hydroxide and 2 ml of water was refluxed under nitrogen for 3 hours. After partial evaporation of the solvent, the residue was acidified with 2 ml of ice- vinegar and partitioned between methylene chloride containing 10 L (v / v) ethanol and water. The organic phase was dried and evaporated. Crystallization of the residue from ethyl acetate / methanol gave 1-methyl-8-nitro-6-phenyl-1H-imidazole, 5-allyl, benzodiazepine-3- -carboxylic acid as straw-colored crystals, which were recrystallized from the same solvent for analysis, m.p. 240 - 243 ° (dec.

Example 7 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazole, 5-a] azepine and 8-chloro-6- (2-fluorophenyl) -1-methyl-63-imidazoline, 5-a7 [1,4] - bensodiazegin - A solution of 185 mg of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H- imidazo [1,5-a] [1,1] benzodiazepine-3-carboxylic acid in Sm1 ethylene- glycol was heated to reflux for 1 hour under a nitrogen atmosphere.

The cooled reaction mixture was partitioned between ether / toluene and saturated sodium bicarbonate solution. The organic phase was separated dried and evaporated. The residue was chromatographed over 7 g silica gel using 3% (v / v) ethanol in methylene chloride to give both the less polar 8-chloro-6- (2-fluoro- phenyl) -1-methyl-6H-imidazo [1,5-a] 11, Q] benzodiazepine, m.p. 177 - 1790 and 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo- -11.5-α] [β, 4] benzodiazepine, m.p. 151 - 1530 ' 8001619-9 23 The starting material can be prepared as follows: 7-Chloro-5- (2-fluorophenyl) -ck-hydroxyimino-3H-1,4-benzo- diazepine-2-acetic acid methyl ester (11.25 g, 0.03 mol) was hydrogenated at atmospheric pressure with Rany nickel in a mixture of 750 ml of tetrahydro- furan and 500 ml of methanol. The nickel was filtered off and the filtrate was filtered. fumes. The residue was dissolved in 100 ml of methanol and 11 ml of triethyl orthoacetate and 5 ml of ethanolic hydrogen chloride (5%) were added. Among the mixture was heated to reflux for 10 minutes, after which it was evaporated and the residue partitioned between methylene chloride and aqueous containing sodium bicarbonate solution. The methylene chloride solution was dried and evaporated, and the residue was chromatographed over 300 g of silica gel using methylene chloride / ethyl acetate 1: 3 (v / v).

The pure fractions were combined and evaporated, and crystallized. sation from ether gave methyl 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidate. zo / W, 5-a] [1,4] benzodiazepine-3-carboxylate, m.p. 162 - 164 °. The the analytical sample was recrystallized from ethyl acetate / hexane.

A mixture of 7.7 g (0.02 mol) of methyl 8-chloro-6 '(2-fluorine) phenyl) -1-methyl-4H-imidazo [1,5-a] Al, 4] benzodiazepine-3-carboxylate, 2.24 g (0.04 mol) of potassium hydroxide, 200 ml of methanol and 6 ml of water heated to reflux for 3 1/2 hours. The solvent is evaporated was partially diluted, and the residue was acidified with glacial acetic acid and diluted with water while still warm. The precipitated crystals collected after cooling in ice / water and dried to give 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazoline, 5-a] [1,4] benzodiazepine pin-3-carboxylic acid. For analysis, it was recrystallized from methylene chloride / methanol / ethyl acetate, m.p. 271 - 2740 (decompositionh Exemgel 8 In an analogous manner as described in any of Examples 1-7 the following compounds are prepared: 1-methyl-6-phenyl-4H-imidazoli, 5-aryl, ¶] benzodiazepine, melting point 1so-1s2 °; 8-ethyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo [η 5 -α] [α, β] benzo- diazepine, melting point 152-154 °; ε-amino-6- (2-fluorophenylyl-1-methyl-4n-1-methylazo / H, s-aj / 3,4] benzodiazepine isopropanolate, melting point 135-145 °; so flfi sw-s » 24 α-facetyl-1β-methyl-s-phenyl-: z fl-imidazo [1,8-a] [1,4] - benzodiazepine dipicrate, melting point 225-2300; rac. 8- (1-hydroxyethyl) -1-methyl-6-phenyl-4H-imidazo- [,, 5-q] [ï, 4] benzodiazepine dipicrate, melting point 223-225 °; 8-acetamido-6- (2-fluorophenyl) -1-methyl-4H-imidazo- [W, 5-a]! Ï, 4] benzodiazepine, melting point 326-3s1 ° (sönaeraelninqn 6- (2-fluorophenyl) -1-methyl-8-methylamino-4H-imidazo- [Ü, 5-q7 [ï, 4] benzodiazepine, melting point 2s5-259 °; 8-Chloro-1-methyl-6-phenyl-4H-imidazole, 5-a] thieno [§, 2 - 2] - [ï, 4] diazepine, melting point 1ss-17 ° and 1-methyl-e-phenyl-: zn-imiaazophi, s-qtienofz, s-f] [1,4] - diazepine, melting point 223-22 °.

Claims (4)

8001619-9 25 PATENT REQUIREMENTS A process for the preparation of imidazo [1,5-a // 1,4] -diazepine compounds of the general formula V 'NR O. H wherein <:}: represents the group X (I S b) or Q) wherein X represents hydrogen or chlorine and R 4 represents hydrogen, halogen, nitro, cyano, lower alkyl, lower alkylamino, lower alkanoylamino, amino, hydroxy-lower alkyl or lower alkanoyl and R1 represents hydrogen, lower alkyl or phenyl, R 3 represents hydrogen or lower alkyl and R 6 represents phenyl, halophenyl or pyridyl, and pharmaceutically acceptable salts of these compounds, characterized in that they decarboxylate a compound of the general formula R xvIII c fl v / f * 1 R 8ÛQL6¿19 “9 i 26 wherein (: II, R1, R3 and RE have the meaning given above, and that, if desired, a racemic compound of formula I 'above is divided into its optical enantiomers and, if desired, transferring a compound of formula I 'above to a pharmaceutically acceptable salt. 2. A process according to claim 1, characterized in that compounds of formula I 'are prepared, wherein X in groups b) and c) represents chlorine. 3. A 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. 4. A process according to claim 1, characterized in that 8-chloro-6- (2-fluorophenyl) -1,4-dimethyl-4H-imidazo / 1,5-a // 1,4 / benzodiazepines.