FI67850B - FREQUENCY REFRIGERATION FOR IMMEDIATION (1,5-A) (1,4) DIAZEPINE-FOUNDATION - Google Patents

Description

ANNOUNCEMENT ISSUE

6 11 UTLÄGG NIN G SSKRIFT 678 5 0 c (45) "! 1" '' t: '' 6 1925 (51) Kv.lk. * / Lnt.CI.4 C 07 D 1 * 87 / Ob, 495 / 14 (21) Patent application - Patentansökning 800975 (22) Application date - Ansökningsdag 28.03.80 (F ·) (23) Starting date - Giltighetsdag 08.03.76 (41) Published public - Blivit offentlig 28.03.80

National Board of Patents and Registration Date of publication and publication. - 28.02 85

Patents and Registration * * Ansökan utlagd och utl.skrlften publicerad (32) (33) (31) Privilege claimed — Begärd priority 07.08.75 USA (US) 602691 171) F. Hoffmann-La Roche & Co. Aktiengesel1schaft, Basel, Switzerland-Switzerland (CH) (72) Armin Walser, West Caldwell, NJ, Rodney Ian Fryer, North Caldwell, NJ, USA (71+) Oy Koi ster Ab (54) Method imidazo / so, 5-aJD, 47diazepine for the preparation of compounds -Forfarande för framställning av imidazo / 1,5-a // 1,47diazepine-föreningar (62) Separated from application 760589 (patent 63405)

The invention relates to a process for the preparation of imidazoZ.1,5-> // 1,4-diazepine compounds of general formula xcx

OCX

R 6 wherein R 1 is hydrogen, lower alkyl or phenyl, is phenyl, halophenyl or pyridyl and is R 67850 x Ys'v x v ^ v

R4_AA · * —K or A

a) b) c) wherein X is hydrogen or chlorine and R 1 is hydrogen, halogen, nitro, cyano, lower alkyl, lower alkylamino, lower alkanoylamino, amino, hydroxy-lower alkyl or lower alkanoyl, and for the preparation of pharmaceutically acceptable salts of these compounds.

As used herein, the term "lower alkyl" refers to both straight and branched chain C 1 -C 4 hydrocarbon groups, preferably C 1 -C 4 hydrocarbon groups such as methyl, ethyl, propyl, isopropyl and butyl.

As used herein, "lower alkanoyl" or "acyl" means acyl groups of C 1 -C 4 - preferably C 1 -C 4 alkanoic acid, e.g. acetyl, propionyl, butyryl and the like, i. groups of the formula -COR2Q wherein R2Q is or hydrogen. As used herein, the term "lower alkanoyl" also means a protected ketone, such as an acetal or a ketal having 2 to 7 carbon atoms, e.g., an ethylenedioxy group. A ketal or aldehyde protecting group is used to prevent the conversion of an aldehyde or ketone in oxidation, reduction and condensation reactions.

The term "halogen" includes all four halogens, e.g. chlorine, bromine, fluorine and iodine.

Of the compounds prepared according to the present invention, preferred are the general formula 3 67850 v- ^ jr>

V

wherein R 1 'is hydrogen or lower alkyl, preferably methyl,' is hydrogen, nitro or halogen, most preferably chlorine, and more preferably is located in the fused benzene portion of the imidazobenzodiazepine at the 8-position, and R 9 'is phenyl, or halophenyl, preferably fluorine, preferably located in the 2-position of the phenyl ring.

Another preferred group of compounds are those compounds of formula wherein joissa is chlorophenyl or 8-chlorothieno / 1,2-f7, R1 is hydrogen or methyl and R8 is 2'-fluoro or 2'-chlorophenyl .

The term "pharmaceutically acceptable salt" includes both inorganic and organic pharmaceutically acceptable salts, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, acetic acid, succinic acid, tartaric acid, tartaric acid, tartaric acid, Such salts can be readily formed by methods known in the art, taking into account the prior art and the nature of the compound to be converted into a salt.

The process according to the invention is characterized in that the compound of the formula 4 67850 is decarboxylated.

D COOH

ΎΎ

N-v „XVIII

GTx

C = N X H

R 6 wherein R 1, R 8 and R 2 are as defined above, after which the resulting racemic compound of formula 1 'is optionally partitioned into its optical enantiomers, and / or the resulting compound of formula 1' is optionally converted to a pharmaceutically acceptable acid addition salt.

The decarboxylation is carried out using a catalyst or without a catalyst, either in a solvent or without a solvent. The decarboxylation is suitably carried out by heating, e.g. to a temperature in the range of about 100 to 350 ° C, preferably about 150 to 230 ° C. Suitable solvents for use in this reaction step include hydrocarbons such as mineral oil; chlorinated hydrocarbons, ethers, alcohols such as ethylene glycol, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide. Suitable catalysts are metals, such as copper powder, or metal salts, such as Cu + or Ag + salts.

The following reaction scheme illustrates methods for preparing starting materials of formula XVIII. In these reaction schemes, R is lower alkyl, and R 1, R 2, and R 2 are as defined in formula I '. It will be apparent to one skilled in the art that some of the substituents may be susceptible to change in the reactions below, but such susceptible groups may be modified before or after the reaction is performed. The reactions shown in the scheme can also be performed using the corresponding N-oxides, but any N-oxide present in the compounds of formula VI is removed in reactions VI to ^ VII.

5,67850

A

NHCH3 - qtSc «(¾1 X"

H X-> vc = / \ VIII

«6 K

CH, * I 3 V ssCOOR 0 Π ^ OR ίί

H 11 / \ IX

R6 h

V v-COOR Re I

_ H H p ΛΛ ^ Νν yCOOR

R6 ^ - ^ C = N, H X

is R6

I H T

\ pnr / NN / C0CR

V ^ COOR ^ H _Jjf

Hc = N ^ H VI As C = N, H XI

1 \ h As' R R6 *

♦ \ jsCOOR R1'S ^ Nv / C00R

ösc = A VII \ l ^ = N / \ 1 K6 \ H Re *> R'lH y ^ C00R / ΘΓχ -

C = N H

V

6 67850

Phase II- »III

Compounds of formula III are obtained by nitrosation of compounds of formula II. Such nitrosation can be performed with nitric acid formed in situ. Suitable reagents for use include (1) alkali metal nitriles, i. sodium nitriles in the presence of an organic or inorganic acid, e.g. glacial acetic acid, and an aqueous or non-aqueous solvent; (2) alkyl nitriles, i.e. methyl nitriles, in the presence of an inert solvent such as an alcohol, a chlorinated hydrocarbon or e.g. dimethylformamide, and (3) a solution of nitrosyl chloride gas in an inert solvent in the presence of an acid scavenger such as pyridine. This nitrosation reaction should be carried out below room temperature, e.g. at a temperature in the range of -20 to + 25 ° C. The amino group or alkylamino group in the molecule can be protected during the nitrosation reaction, e.g. by acylation. Such a protecting group may be removed at any suitable later stage in the reaction sequence.

Phase VIII- »IX

Compounds of formula IX may be prepared by reacting compounds of formula VIII with dimorpholinophosphinic acid chloride. The reaction of compounds of formula VIII with phosphorylating agents to give compounds of formula IX is carried out by treating compounds of formula VIII with a strong base capable of ionizing the compound of formula VIII to the corresponding anion. Suitable bases include alkali metal alkoxides such as potassium tert-butoxide or sodium methoxide, alkali metal hydrides such as sodium hydride, and alkyllithium compounds such as n-butyllithium. The reaction temperature is in the range of 0 to 100 ° C, and the reaction is preferably carried out in an aprotic polar inert solvent, i. in one capable of dissolving all or at least part of the ambient salts of the compounds of formula VIII. Preferred solvents are ethers, e.g. tetrahydrofuran or dioxane, or tertiary amides, e.g. dimethylformamide.

It will be appreciated that the amino or substituted amino groups should be protected in this reaction step, whereby the protecting groups may be subsequently removed at any suitable stage, e.g. after formation of the compound of formula XII.

7

Phase III or IX- »IV 6 785 0

Compounds of formula III or formula IX may be condensed of formula

/ COOR

Θ

^ COOR

with the anion of the malonic acid ester of formula IV wherein R is lower alkyl to give a compound of formula IV. The anion is prepared by deprotonating the malonic acid ester with a suitable strong base such as an alkali metal or alkaline earth metal alkoxide, hydride or amide. The reaction of a capped compound of formula III or IX with a malonic acid ester anion is carried out in a solvent such as a hydrocarbon, e.g. benzene, toluene, hexane, ether, e.g. dioxane, tetrahydrofuran, diethyl ether, dimethylformamide or dimethylsulfoxide at 150 ° C at room temperature preferably 0 to 100 ° C, most preferably at room temperature.

Phase IV-— »V

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

Step V-> VI

Compounds of formula VI are prepared by nitrosating compounds of formula V in a reaction with nitric acid developed from e.g. alkali metal nitrite, alkyl nitrite or nitrosyl chloride in a reaction with an organic or inorganic acid. Suitable solvents for the nitrosation reaction include ethers, alcohols, water, acids, e.g. acetic acid, dimethylformamide, dimethylsulfoxide and chlorinated hydrocarbons. The reaction can be carried out at about room temperature.

Step VI-> VII

Compounds of formula VII are prepared by reduction of compounds of formula VI, e.g. with Raney nickel and hydrogen or zinc and acetic acid. This reduction yields mainly compounds of formula VII and, in addition, smaller amounts of several different isomers in side reactions, i. formulas 8 67850

COOR H W

? /) - NH 3 / -C00 R 17 -COOR ¥) -COOR

yc / - <y-c

VII A VII B VII C VII D

compounds. It should be noted that in the above reduction reaction, any sensitive reducing groups such as R 1, e.g., NO 2 in the 7-position or CN in the 7-position, may react. These groups can be reconnected by methods known in the art, as will be shown.

Step VII- »XII

Compounds of formula XII are prepared by reacting compounds of formula VII with an alkanoic acid orthoester of formula r1 "c (or) 3, wherein R is lower alkyl and R1" is hydrogen lower alkyl, alkoxy-lower alkyl or halo-lower. alkyl, optionally in the presence of an acid catalyst, e.g. an organic or inorganic acid, e.g. p-toluic acid, phosphoric acid, etc., at or above room temperature, i.e. at 25-150 ° C, whereby cyclization to the compound of formula XII takes place immediately. As well as the above orthoester suitable for use are orthoamides, e.g. Ν, Ν-dimethylformamide dimethyl acetal, N, N, N ', N', N ", N" -hexylmethanetriamine, nitriles, e.g. acetonitrile; ester imidates, e.g. CH--C (= NH) -OC-H.-.

ό Z D

It should be noted that any amino or alkylamino groups must be protected during this reaction.

Step VII-> XI

Compounds of formula XI may be prepared by acylation of compounds of formula VII with compounds of formula R 1 COX or (R 1 CO) 2 O wherein X is halogen and R 1 is hydrogen, lower alkyl, phenyl, alkoxy-lower alkyl, substituted phenyl, pyridyl or aralkyl.

9,67850

Suitable solvents for the above step are e.g. methylene chloride, ethers, chlorinated hydrocarbons, etc., preferably in the presence of an acid scavenger such as an organic or inorganic base such as triethylamine, pyridine or alkali metal carbonate. The reaction may be carried out at room temperature, below and above it, but most preferably at room temperature. The compounds of formula XI are isomeric in nature, i. they may exist in the following stereochemical forms

NHCOR.J COOR

f V-COOR | )> - NHCOR, · "y- \ / ν ~ λ

XI A XI B

Step XI- »XII

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

Step IX- »X

Compounds of formula X may be prepared by the condensation reaction of a compound of formula IX and formula

COOR

® C-NHCOR ^

COOR

wherein R "is lower alkyl and R" 'is hydrogen, lower alkyl, phenyl, alkoxy-lower alkyl, substituted phenyl, pyridyl or aralkyl. The anion is formed by deprotonation of the acyl amino acid ester with a suitable strong base such as an alkali metal or alkali metal. The reaction of the compounds of formula IX with an acylaminomalonic acid ester is preferably carried out in a solvent such as a hydrocarbon, e.g. benzene, toluene, hexane, ether, e.g. dioxane, tetrahydrofuran, diethyl, diethylene. or in dimethyl sulfoxide, in the temperature range from below room temperature to 150 ° C, preferably at 0 to 100 ° C, most preferably at room temperature.

Phase X-XI

Compounds of formula XI and their isomers are prepared by decarboxylation of compounds of formula X with an alkali metal alkoxide in a solvent such as ethers, alcohols, dimethyl sulfoxide, dimethylformamide, etc., at, below or above room temperature, preferably at room temperature. The compounds of formulas X and XI do not need to be isolated but can be converted in situ to the compounds of formula XII.

Step VII- ^ XIII

Compounds of formula XIII are prepared by reacting compounds of formula VII with an aldehyde of formula R 1 CHO, wherein R 2 is as defined in formula I, wherein the amino or substituted amino groups present and preferably also the RCO groups should be protected. The protecting groups may be removed afterwards, e.g. after formation of the compound of formula XII. Suitable solvents for this reaction step include hydrocarbons such as benzene, alcohols, ethers, chlorinated hydrocarbons, dimethylformamide and dimethyl sulfoxide, and the reaction is carried out using a water-binding agent, e.g. molecular sieves, at room temperature, below or above, preferably at room temperature. -distillation to temperature.

Step XIII - ^ XII

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

As indicated above, the final product of formula XII wherein R 1 is amino can be converted in the Sandmeyer reaction to the corresponding compound wherein R 1 is nitro or cyano, as disclosed in this application.

Another process for preparing a compound of formula XII wherein R 1 is nitro or cyano comprises preparing compounds of formula VII. This can be prepared by reacting the corresponding compound of formula IX of formula 11,67850

COOR ^^

Θ0 --NHZ

"" CO 2 'with a protected aminomalonic acid ester wherein R is lower alkyl and Z is benzyloxycarbonyl, with a few thus obtained compounds of formula X wherein R 1 is benzyloxy and R 1 is nitro or cyano to the corresponding compound of formula XI above as described in Steps X-> XI, and treating the compound thus obtained with hydrogen bromide in glacial acetic acid to give a compound of formula VII wherein R 1 is nitro or cyano, without the need to isolate intermediates of formula X and XI. further to a compound of formula XII via reaction steps VII-> XIII and XIII * -> XII described above.

Phase XII- »XVIII

Compounds of formula XVIII are prepared by hydrolysing compounds of formula XII to the corresponding acids, preferably with an alkali metal hydroxide, e.g. NaOH or KOH. This hydrolysis is suitably carried out in an inert solvent. Suitable solvents are alcohols, e.g. methanol and ethanol, ethers, e.g. dioxane, tetrahydrofuran and dimethylformamide together with water. This reaction step is preferably carried out at temperatures between room temperature and the boiling point of the reaction mixture.

It is obvious that the acyloxy group present during this reaction step is hydrolyzed to the corresponding hydroxyalkyl group, which can again be converted back to the acyloxyalkyl group at a suitable step later. The R 1 group when denoting the -COOR 8 group is also hydrolyzed and decarboxylated to the corresponding compound wherein R 1 is hydrogen. The group -COOR 4 can again be attached by means of a formyl or hydroxymethyl group in a known manner. The haloalkyl group can react in this reaction step to give the corresponding hydroxyalkyl compound, which can also be converted back to the haloalkyl compound at a later stage in the usual manner. Compounds of formula XII in which R 1 is hydroxyalkyl should be protected during this halogenation step, e.g. by conversion to tetrahydropyranyl ether derivatives.

12 67850

If a compound of formula I has a ketal group (e.g. an ethylenedioxy group is present in the imidazobenzodiazepine), it can be converted to the corresponding ketone by acid hydrolysis under mild conditions. The ketone can then be converted to a racemic secondary or tertiary alcohol. The reaction conditions in the above two reaction steps are disclosed in U.S. Patent 3,846,410.

The compounds of formulas 1 'and I'D and their pharmaceutically acceptable acid addition salts are useful muscle relaxants, sedatives and anticonvulsants, and many of them are particularly suitable for use as intravenous and intramuscular preparations because their acid addition salts are water soluble.

The compounds of this invention and their acid addition salts may be used in pharmaceutical dosage preparations containing from about 0.1 to about 40 mg, preferably from 1 to 40 mg, depending on the individual needs of the patient. The novel compounds of the formulas I ', I'A and I'D can be administered medicament internally, e.g. parenterally or enterally, in the usual pharmaceutical dosage forms. They may be incorporated, for example, into ordinary liquid or solid media such as gelatin, starch, magnesium stearate, talc, vegetable oils and the like, and may be formulated as tablets, elixirs, capsules, solutions, emulsions and the like in accordance with pharmaceutically acceptable 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 was heated to 230 ° C: The reaction mixture was partitioned between 1N hydrochloric acid and ether, the aqueous phase basified with ammonia and extracted with methylene chloride, the extracts dried and evaporated to dryness and the residue chromatographed on 60 g of silica gel using 20% (v / v) methylene chloride in ethyl acetate. The more non-polar 8-chloro-6- (2-fluorophenyl) -6H-imidazo [1,5-a], 4-benzodiazepine was crystallized from ethyl acetate to give colorless crystals, mp 195-196 ° C.

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

13 67850 The starting material was prepared as follows:

Solution of 200 g (0.695 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in 2 l of tetrahydrofuran and 250 ml of benzene , was saturated with methylamine in an ice bath under cooling. A solution of 190 g (1 mole) of titanium tetrachloride in 250 ml of benzene was added via addition funnel over 15 minutes. After the addition, the mixture was stirred and refluxed for 3 hours. Water (600 ml) was slowly added to the cooled reaction solution. The inorganic material was filtered off and washed well with tetrahydrofuran. The aqueous layer was separated and the organic phase was dried over sodium sulfate and evaporated to dryness. 7-Chloro-5- (2-fluorophenyl) -2-methylamino-3H-benzodiazepine obtained as a crystalline residue was collected, m.p. 204-206 ° C. An analytical sample was recrystallized from methylene chloride-ethanol, m.p. 204-206 ° C.

A) 8.63 g (0.125 mol) of sodium nitrite were added in three portions over 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 of glacial acetic acid. After stirring for 1 hour at room temperature, the reaction mixture was diluted with water and extracted with methylene chloride. The extracts were washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated to dryness, finally azeotropically with toluene to give 29 g of crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazine as a yellow oil.

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

This material was dissolved in 300 ml of dimethylformamide and added to a mixture of 150 ml of dimethyl maloate, 40.4 g of potassium tert-butoxide and 500 ml of dimethylformamide, which had been stirred at room temperature for 14 minutes. The reaction mixture was stirred overnight under nitrogen at room temperature, acidified by the addition of 50 ml of glacial acetic acid, diluted with water and aqueous sodium carbonate solution, dried over sodium sulphate and evaporated to dryness. Crystallization of the residue from ethanol gave 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine as colorless crystals, m.p. 170-172 ° C. For analysis, the product was recrystallized from methylene chloride / ethanol; the melting point did not change.

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 mol) of potassium hydroxide were heated to reflux under nitrogen for 5 hours. After part of the solvent was evaporated, the residue was gradually diluted with water, and the precipitated crystals were collected, washed with water and dried to leave 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (dimethoxycarbonylmethylene) -2H -1,4-benzodiazepine, m.p. 158-160 ° C.

For analysis, recrystallization from methylene chloride / hexane was performed, m.p. 161-162 ° C.

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- (methoxycarbonylmethylene) -2H-1 , 4-benzodiazepine in 250 ml of glacial acetic acid. The mixture was stirred at room temperature for 10 minutes and then diluted with 250 ml of water. The crystalline product was filtered, washed with water, methanol and ether and dried to leave 7-chloro-5- (2-fluorophenyl) -alpha-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester as yellow crystals, mp. 238-241 ° (dec.).

7-Chloro-5- (2-fluoro-phenyl) -alpha-hydroxy-imino-3H-1,4-benzodiazepine-2-acetic acid methyl ester (11.25 g, 0.03 mol) was dissolved in the mixture with heating, containing 750 ml of tetrahydrofuran and 500 ml of methanol. Raney nickel (20 g) was added and the mixture was hydrogenated at atmospheric pressure for 4 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness, finally azeotropically with toluene. The residue was dissolved in 100 ml of methanol. After adding 10 ml of triethyl orthoformate and 5 ml of ethanolic hydrochloric acid solution (5%), the mixture was heated under reflux for 10 67850 minutes. It was then evaporated to dryness and the residue partitioned between methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The methylene chloride layer was separated, dried and evaporated to dryness, and the residue was crystallized from ether to give methyl 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] Bβ, 4-benzodiazepine-3-carboxylate, which was recrystallized from methylene chloride / ether / hexane, m.p. 179 - 181 C.

A mixture of 1.48 g (0.004 moles) of methyl 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] β, β-benzodiazepine-3-carboxylate, 0.5 g (0.009 moles) of potassium hydroxide, 50 ml of methanol and 2 ml of water were heated under reflux for 3 hours under nitrogen. A portion of the methanol was evaporated off and the residue was acidified with glacial acetic acid and diluted with water while the solution was still hot. After cooling in ice / water, the crystals were collected and dried in vacuo to give 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, m.p. 245-247 ° C (dec.).

Example 2

A solution of 0.5 g (0.00129 moles) of ethyl 8-cyano-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate 100 in 1 ml of ethanol and 10 ml of water, was treated with 0.14 g (0.0026 mol) of potassium hydroxide. After heating the reflux for 30 minutes, the reaction mixture was evaporated to dryness and 10 ml of water were added. This mixture was acidified with acetic acid, filtered and extracted with 20 ml of dichloromethane, which was separated, dried and evaporated to dryness. About 0.2 g of hydrolyzed product was obtained from the filtrate, and the same amount was obtained from the extract. This material was added to 3 mL of dry hexamethylphosphoric acid amide, and the mixture was kept at 200-205 ° C for 30 minutes under argon. The mixture was cooled and 50 ml of ice water and 1 ml of ammonium hydroxide were added. The solution was filtered and the filtrates were extracted with 25 ml of dichloromethane and evaporated to dryness. Water was added and the solution was filtered and the combined precipitates were dissolved in dichloromethane and eluted on a 2: 11 plate with a thick layer of silica gel using a solution of ethyl acetate in 15% methanol. The silica gel containing the product was scraped off (R ^ 4-5), mixed with methanol and filtered. This was crystallized from a mixture of 16,678,850 propanol and ether to give 8-cyano-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine as off-white prisms, mp. 198-203 ° C.

The starting material was prepared as follows:

A solution of 10 g (0.0358 moles) of 7-cyano-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepin-2-one in 150 ml of dry tetrahydrofuran under argon, treated with 2.4 g (0.0537 moles) of 54% sodium hydride and the reaction mixture was heated to reflux for 1 hour. The mixture was cooled to 0 ° C and 13.7 g (0.537 moles) of phosphorus dimorpholidine chloride was added. After 18 h, the reaction mixture was filtered, concentrated to a smaller volume, and ether was added. The precipitate was 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 as white rods, m.p. 194-197 ° C.

To 100 ml of dry N, N-dimethylformamide was added 1.6 g (0.036 mol) of 54% sodium hydride under nitrogen, and 8.3 g (0.038 mol) of acetamidodiethyl malonate was added with stirring. After 30 minutes, 10 g (0.02 moles) of 7-cyano-5- (2-fluorophenyl) -2-bis- (morpholino) phosphinyloxy-3H-1,4-benzodiazepine were added, and after 64 hours, the reaction mixture was poured into ice water containing 4 ml of acetic acid. This mixture was filtered and the solid was dissolved in 100 mL of dichloromethane, washed with 50 mL of water, dried over anhydrous sodium sulfate and concentrated to a smaller volume. This solution was chromatographed on a Florisil column and eluted with 2 liters of dichloromethane, which was discarded. It was then eluted with 1 liter of a mixture of dichloromethane and ether (10/1) and then with 2 liters of ether. The ether fraction was recrystallized twice from a mixture of dichloromethane and ether to give (acetylamino) -N-cyano-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-2-yl-malonic acid diethyl ester as white prisms, m.p. 138-140 ° C.

The column was eluted with 1.5 liters of a mixture of ethyl acetate and methanol (10/1). The eluate was concentrated and the residue was crystallized from ether. Recrystallization from a mixture of dichloromethane and ether gave ethyl 8-cyano-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate as off-white prisms. , sp.

272-274 ° C.

67850

Example 3

OF

8-Chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine

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

The starting material was prepared as follows:

A solution of 3.75 g (0.01 mol) of 7-chloro-5- (2-fluoro-phenyl) -alpha-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester in 300 ml: in tetrahydrofuran and 200 ml of methanol, hydrogenated at atmospheric pressure for 1 1/2 hours in the presence of Raney nickel (1 teaspoon). The catalyst was filtered off through Celite and the filtrate was evaporated to dryness in vacuo, finally azeotropically with toluene. The residue was dissolved in 20 ml of pyridine and the solution was treated with 4 ml of benzoyl chloride. After standing for 15 minutes at room temperature, the reaction mixture was partitioned between methylene chloride and 1N sodium hydroxide solution. The organic layer was dried and evaporated to dryness, finally azeotropically with toluene. Crystallization of the residue from ether gave 2- [N- (benzoylamino) -methoxycarbonylmethylene] -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine, m.p. 210-213 ° C. An analytical sample was recrystallized from ethyl acetate / hexane, m.p. 217-219 ° C, softening at 150-160 ° C.

A solution of 1.15 g (2.5 mmol) of 2- [N- (benzoylamino) -methoxycarbonylmethylene] -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine In 10 ml of hexamethyl-phosphoric acid triamide, was heated to reflux for 10 minutes. The dark mixture was partitioned between water and ether / methylene chloride. The organic layer was washed with water, dried and evaporated to dryness. The residue was dissolved in methylene chloride and filtered through activated alumina using ethyl acetate. The filtrate was evaporated to dryness to 18,67850 and chromatographed on 20 g of silica gel using a mixture of 10% (v / v) ethyl acetate in methylene chloride. Crystallization of the combined pure fractions from ether / hexane gave methyl 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-d] benzodiazepine-3-carboxylate, m.p. 208-209 ° 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] benzodiazepine-3- carboxylate in 50 ml of boiling methanol, a solution of 755 mg (11.5 mmol) of potassium hydroxide in 10 ml of water was added, and the resulting mixture was heated for 2.5 hours. The solvent was removed in vacuo, 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 was 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 as an off-white solid. . An analytical sample was recrystallized from benzene, m.p. 267-269 ° C.

Example 4

A solution of 1.3 g of 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] / 1,47-benzodiazepine-3-carboxylic acid in 20 ml of ethylene glycol was heated under reflux for 1 hour. I drive. The reaction mixture was partitioned between water and methylene chloride / toluene. The organic phase was washed with saturated sodium hydrogen carbonate solution, dried and evaporated to dryness. Crystallization of the residue from ether / 2-propanol gave 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,47] benzodiazepine as brown crystals. An analytical sample was recrystallized from ethyl acetate / hexane, m.p. 189-190 ° C.

The starting material was prepared as follows: A 54% sodium oil dispersion of sodium hydride (11 g, 0.25 mol) was added portionwise to a stirred solution of 63.2 (0.2 mol) of 7-bromo-1,3-dihydro-5- (2- pyridyl) -2H-1,4-benzodiazepin-2-one in 1 liter of tetrahydrofuran under argon protection.

After heating the solution under reflux in a water bath for 1 hour, the solution was cooled to room temperature, and 76.2 g (0.3 mol) of dimorpholinophosphinic acid chloride was added portionwise. Stirring at room temperature was continued for 5 hours. The dark mixture was filtered through Celite. Concentration of the filtrate in vacuo and boiling a dark residue in ether with 19,67850 grams gave 7-bromo-2- [bis (morpholino) phosphinyloxy] -5- (2-pyridyl) -3H-1,4-benzodiazepine as brown crystals. The sample was recrystallized by dissolving in 2 mL of methylene chloride, filtering, diluting with 10 mL of ethyl acetate and cooling in an ice bath to give light brown plates, m.p. 180-182 ° C (dec.).

Dimethylacetamidomalonate (43 g, 0.2 mol) was added to a suspension of 10 g (0.2 mol) of a 50% mineral oil dispersion of sodium hydride in 500 ml of dry dimethylformamide. This mixture was stirred under argon for 1 hour at room temperature, and for 20 minutes in a water bath with heating. To the reaction mixture, which was cooled again to room temperature, was then added 7-bromo-2- [bis- (morpholino)] phosphinyloxy] -5- (2-pyridyl) -3H-1,4-benzodiazepine (53.4 g, 0, 1 mole). After stirring for 1 hour at room temperature, the mixture was again heated on a water bath for 2 hours. The cooled solution was partitioned between water and methylene chloride / ether. The organic phase was separated, washed with water, dried and evaporated to dryness. The residue was crystallized by adding seed crystals from ethyl acetate / ether to give ethyl 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazole / 5-§7 / β, 47-benzodiazepine-3-carboxylate as off-white as crystals, m.p. 240-243 ° C. The seed crystals were obtained by purification by chromatography on 30 times silica gel using a mixture of 5% (v / v) methanol in ethyl acetate. An analytical sample was recrystallized from ethyl acetate, m.p. 243-244 ° C.

A mixture of 2.15 g (5 mmol) of ethyl 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1.5%] ES, 47-benzodiazepine-3-carboxylate, 50 ml of methanol, 0-84 g (15 mmol) of potassium hydroxide and 2.5 ml of water were heated under reflux for 5 hours. Most of the methanol was evaporated and the residue was partitioned between water and ether. The aqueous phase was acidified with acetic acid and extracted with methylene chloride. The extracts were dried and evaporated to dryness. Crystallization of the residue from methylene chloride / ethyl acetate gave 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,47] benzodiazepine-3-carboxylic acid as colorless crystals which were crystallized. again for methanolic analysis; mp. 245-250 ° C (dec.) After pre-sintering.

67850 20

Example 5

A mixture of 1.5 g of (6-2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [2,7] [] benzodiazepine-3-carboxylic acid and 10 ml of ethylene glycol was heated under reflux for 1 hour. The reaction mixture was then partitioned between methylene chloride / toluene and saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with water, dried and evaporated to dryness. The residue was dissolved in 10 ml of 2-propanol and 0.6 g of maleic acid was added. The salt crystallized upon addition of ether to the warm solution. The salt was collected, washed with 2-propanol and ether to give 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5] a7β, 4H-benzodiazepine maleate as brown crystals which were recrystallized from analysis. for 2-propanol, m.p. 150-152 ° C. The free base liberated from this salt was crystallized from ethyl acetate / hexane, m.p. 170-173 ° C.

The starting material was prepared as follows:

Diethyl acetamidomalonate (43 g, 0.2 mol) was added to a suspension of 10 g (0.2 mol) of sodium hydride (50% in mineral oil) in 500 ml of dry dimethylformamide. The mixture was heated at 50 ° C for 30 minutes under argon. After adding 53 g (0.1 mol) of 5- (2-chlorophenyl) -2- [bis (morpholino) phosphinyloxy] -7-nitro-3H-1,4-benzodiazepine, the reaction mixture was heated on a water bath for one hour. The cooled brown mixture was partitioned between water and methylene chloride / ether, the organic phase was washed with water, dried and evaporated to dryness, the residue was chromatographed on 1 kg of silica gel using ethyl acetate and the pure fractions were combined and evaporated to dryness. Ethyl 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,47 "benzodiazepine-3-carboxylate was obtained as pale yellow crystals, m.p.

233-234 ° C. An analytical sample was recrystallized from ethyl acetate, m.p. 234-235 ° C.

A mixture of 4.25 g (0.01 mol) 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 mol) of potassium hydroxide and 4 ml of water were heated under reflux under nitrogen for 3 hours. Most of the methanol was evaporated off and the residue was partitioned between 21,67850 water and ether. The aqueous phase was washed with ether, acidified with acetic acid and extracted with methylene chloride. The extracts were dried and evaporated to dryness. Crystallization of the residue from methylene chloride / ethyl acetate gave 6- (2-chlorophenyl) methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, m.p. 272-274 ° C. An analytical sample was recrystallized from methanol / ethyl acetate, m.p. 274-276 ° C (dec.).

Example 6

A suspension of 1.2 g of 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,1,5-a] [1,47] benzodiazepine-3-carboxylic acid in 15 ml of hexamethylphosphoric acid triamide was heated under reflux for 3 minutes. The cooled solution was partitioned between methylene chloride / ether and aqueous sodium bicarbonate. The organic phase was washed with bicarbonate solution, dried and evaporated to dryness. The residue was chromatographed on 30 g of silica gel using a mixture of ethanol (3% v / v) and methylene chloride. Crystallization of the pure fractions from ether / methylene chloride / ethyl acetate gave 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] [4,7,4] iododiazepine, m.p. was 168-170 ° C. It was converted to the maleate salt which, when crystallized from ethyl acetate, contained 0.5 moles of solvent, m.p. 125-128 ° C (dec.).

The starting material was prepared as follows: 6 g (0.125 mol) of a dispersion of sodium hydride (50% in mineral oil) was added to a solution of 28.1 g (0.1 mol) 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 dimorpholinophosphinic acid chloride was added and stirring was continued for 4 hours. The product was crystallized by adding water and ether. The precipitate was collected and dissolved in methylene chloride. The solution was dried and evaporated to dryness and the residue was crystallized from ethyl acetate to give crude 7-nitro-2- [bis- (morpholino) phosphinyloxy] -5-phenyl-3H-1,4-benzodiazepine, m.p. 208-209 ° C. A portion of this material was added to a mixture of 8.6 g (0.04 moles) of diethylacetamidomalonate, 2 g (0.04 moles) of sodium hydride suspension (50% in mineral oil) and 75 ml of dimethylformamide heated to 40 ° C. At C for 30 minutes. After the addition, the reaction mixture was heated on a water bath for 30 minutes and then partitioned between water and ether. The organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed on 250 g of silica gel using ethyl acetate. The combined pure fractions were evaporated to dryness and the residue was crystallized from methylene chloride / ether to give ethyl 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] 4,4-benzodiazepine-3-carboxylate as off-white crystals, with m.p. was 240-241 ° C. The analytical sample was recrystallized from ethyl acetate.

A mixture of 1.95 g (5 mmol) of ethyl 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] β, 7-benzodiazepine-3-carboxylate, 50 ml of methanol, 0.56 g (0.01 mol) of potassium hydroxide and 2 ml of water were heated under reflux under nitrogen for 3 hours. After part of the solvent was removed, the residue was acidified with 2 ml of glacial acetic acid and partitioned between methylene chloride containing 10% (v / v) ethanol and water-soluble portions. The organic phase was dried and evaporated to dryness. Crystallization of the residue from ethyl acetate / methanol gave 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] N, 47'-benzodiazepine-3-carboxylic acid as oily crystals which were recrystallized from the same solvents for analysis. , sp. 240-243 ° C (dec.).

Example 7 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] β, 47'-benzodiazepine and 8-chloro-6- (2-fluorophenyl) -1-methyl-6H- imidazo-1,5-α / β, 4 / benzodiazepine

A solution of 185 mg of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] 1,7,4-benzodiazepine-3-carboxylic acid in 5 ml of ethylene glycol was heated under 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 on 7 g of silica gel using 3% (v / v) ethanol in methylene chloride to give both less polar 8-chloro-6- (2-fluorophenyl) -1-methyl-6H-imidazo [1,5-] t7ZT, l7benzodiazepine, m.p.

177-179 ° C, that 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo-β, 5-a7H, 7,7-benzodiazepine, m.p. 151-153 ° C.

23,67850 The starting material was prepared as follows: 7-Chloro-5- (2-fluoro-phenyl) -alpha-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester (11.25 g, 0.03 mol) ) was hydrogenated at atmospheric pressure using Raney nickel in a mixture of 750 ml of tetrahydrofuran and 500 ml of methanol. The nickel was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in 100 ml of methanol, and 11 ml of triethylorthoacetate and 5 ml of ethanolic hydrochloric acid solution (5%) were added to the solution. The mixture was heated by refluxing for 10 minutes, evaporated to dryness and the residue partitioned between methylene chloride and aqueous sodium hydrogen carbonate. The methylene chloride solution was dried and evaporated to dryness and the residue was chromatographed on 300 g of silica gel eluting with methylene chloride / ethyl acetate 1: 3 (v / v). The pure fractions were combined, evaporated to dryness and crystallized from ether to give methyl 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, mp.

162-164 ° C. The analytical sample was recrystallized from ethyl acetate / hexane.

A mixture of 7.7 g (0.02 mol) of methyl 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-b] 7β-benzodiazepine-3-carboxylate , 2.24 g (0.04 mol) of potassium hydroxide, 200 ml of methanol and 6 ml of water were heated under reflux for 3 1/2 hours. The solvent was partially evaporated off and the residue was acidified with glacial acetic acid and diluted with hot water. Cooled with ice / water and the precipitated crystals were collected and dried to give 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid. . For analysis, a portion was recrystallized from methylene chloride / methanol / ethyl acetate, m.p. 271-274 ° C (dec.).

In an analogous manner to Examples 1-7, 1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,47] benzodiazepine was prepared, m.p. 180-182 ° C 18 -ethyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] / 1,47 ° benzodiazepine, m.p. 152-154 ° C; 8-Amino-6- (2-fluorophenyl) -1-methyl-4H-imidazole7 , 5-α, β, 4J-benzodiazepine isopropanolate, m.p. 135-145 ° C; 8-acetyl-1-methyl-6-phenyl-4H-imidazo [1,5-a] Bβ, 4-benzodiazepine dipicrate, m.p. 225-230 ° C; 67850 24 ras. 8- (1-hydroxyethyl) -1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,47] benzodiazepine dipicrate, m.p. 223-225 ° C; 8-acetamido-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-d] 7-benz, 4-benzodiazepine, m.p. 326-331 ° C (dec.); 6- (2-fluorophenyl) -1-methyl-8-methylamino-4H-imidazo-η 5 -α, 7,4,7-benzodiazepine, m.p. 255-259 ° C; 8-chloro-1-methyl-6-phenyl-4H-imidazo [2-a] thieno [3,2-b] [4,4] diazepine, m.p. 168-170 ° C; and 1-methyl-6-phenyl-4H-iraidazo [1,5-a] thieno [2,3-f] [4,7,4] diazepine, m.p. 223-225 ° C.

Claims (5)

25 67850 A process for the preparation of imidazo [4,7] diazepine compounds of the general formula R 1 TT vy GfX C = NSH R 6 wherein hydrogen, lower alkyl or phenyl, R 9 is phenyl, halophenyl or pyridyl and •• <X. 'e * - a) b) c) wherein X is hydrogen or chlorine and R 4 is hydrogen, halogen, nitro, cyano, lower alkyl, lower alkylamino, lower alkanoylamino, amino, hydroxy-lower alkyl or lower alkanoyl, and for the preparation of pharmaceutically acceptable salts of these compounds, characterized in that a compound of the formula .cooh ΛΤ sx xviii * 6 26 67850 wherein t Rg and (zji have the same meaning as above, followed by a racemic compound of the formula I'nluJcainen) is decarboxylated. if desired, being divided into its optical enantiomers, and / or the resulting compound of formula 1 'is, if desired, converted into a pharmaceutically acceptable acid addition salt. A process according to claim 1 for the preparation of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,4] benzodiazepine. A process according to claim 1 for the preparation of 8-chloro-6- (2-fluorophenyl) -1,4-dimethyl-4H-imidazo [1,5-a] 1,4-benzodiazepine. 27 Patentkrav 6 7 8 5 0 1. A compound for the preparation of imidazo / l, S-aJβ, 4_7-diazepine-derivatives with the formula A - XC = N E6 color is hydrogen, alkyl, or phenyl, Rg is phenyl, halophenyl or pyridyl, and groups - <x . χχ .. "O. a) b) c) color X is a derivative or chlorine and R 1 is a derivative, halogen, nitro, cyan, alkyl, carbon-alkyl-amino, alkanoyl-amino, amino, hydroxyl -alkyl or alkyl alkanoyl, and a pharmaceutically acceptable salt of the present invention, derived from the decarboxylated form of a compound of formula R1 COOH N_Ϊ H XVIII ΟζΧ R6