FI67849B - IN THE FIELD OF THERAPEUTIC USE OF THERAPEUTIC I 3-STATIONARY SUBSTANCES IMIDATZO (1,5-A) (1,4) DIAZEPINE INFOERING SAMT MOTOR VARIABLE 3-CARBOXAMIDER SAOSOM MELLANPRODUKT ANVAENDBAR FOERENING - Google Patents

Description

ΓΒ1 m ^ ANNOUNCEMENT PUBLICATION, η »ISMI B 11 UTLÄGGNINGSSKRIFT 0 / o4y ° (45>!: '5 -' 5 (51) Kv.lk. * / Lnt.CI.4 C 07 D 487/04, 495/14 ENGLISH —FINLAND (21) Patent application - Patentansdkning 800974 (22) Filing date - Ansökningsdag 28.03.80 (F ») (23) Starting date —Giltighetsdag 08.03.76 (41) Published public - Bllvit offentllg 28.03 80

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

Patents and registries v; Ansökan utlagd ooh utl.skrlften publicerad 28.02.85 (32) (33) (31) Privilege claimed - Begird priority 07.08 75 USA (US) 602691 (71) F. Hoffmann-La Roche & Co. Aktiengesel1schaft, Grenzacherstrasse 124-184, Basel, Switzerland-Switzerland (CH) (72) Armin Walser, West Caldwell, NJ, Rodney Ian Fryer, North Caldwell, NJ, USA (US) (7 ^) Oy Kolster Ab (54) Therapeutically Intermediate compound for the preparation of useful 3-unsubstituted imidazo / 1,5-a7 / 1,47diazepine compounds and the corresponding 3 "carboxamides 3 “carboxamider sasom mellanprodukt användbar förening (62) Divided separated from application 760589 (patent 63405) -Avdelad frän ansökan 760589 (patent 63405)

The present invention relates to a compound of formula having the following formula as an intermediate in the preparation of therapeutically useful 3-unsubstituted iminazo [5,5-a] 1,4-diazepine compounds and the corresponding 3-carboxamides:

R1 / Nv / COOR

67849 GV ·· R6 wherein R is lower alkyl, R1 is hydrogen, lower alkyl, phenyl, di-lower alkylamino-lower alkyl, pyridyl or benzyl, R8 is phenyl, halophenyl or pyridyl, and

II COME

a) b) wherein R 4 is halogen, nitro or cyano, and acid addition salts of this compound.

The compounds according to the invention are, in the preparation of valuable intermediates, the corresponding compounds which are unsubstituted in the 3-position according to Finnish patent 63,234, as well as the corresponding 3-carboxamides according to Finnish patent 63,405, which patents show how valuable end products are prepared.

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

The imidazo [1,5-a] [λ, 47diazepine compounds of the invention are prepared by the following methods:

NH2 ^. COOR

67849 (a) of formula H //

\ / H

/ \ VII

The compound of R 6 or its N-oxide is reacted with an orthoester of an alkanoic acid of the formula R 1 ^ C (OR), wherein R 1 is hydrogen or lower alkyl and R is lower alkyl, or a technically equivalent compound to give a directly corresponding compound of formula I, and any amino or alkylamino groups present during the reaction are protected during the reaction, or b)

R 5L ^ C00R

'' XY

OF-\

(21 / \ XI11 --C = N '///// H

The compound of formula R6 or its N-oxide is oxidized to the corresponding compound of formula I, or

N, COOR

67849 c) the formula

B

R "c ° //

H I

_____- (

(from XI

h is a compound of formula R 6 wherein R "is hydrogen, lower alkyl, phenyl, pyridyl or benzyl, and R and R 8 and (Z 2 is as defined above, or its N-oxide is dehydrated simultaneously by cyclization to the corresponding compound of formula I , and if desired, the racemic compound of the above formula I or an analogue thereof as defined above is divided into its optical enantiomers, or converted into the desired acid addition salt.

The reaction scheme shown on the next page illustrates the reactions used to prepare the compounds of formula I. In these reaction schemes, R is lower alkyl, and R 1, R 2 and R 8 are as defined in Formula I, unless otherwise indicated. It will be apparent to those skilled in the art that some of the substituents may be susceptible to changes in the reactions below, but such susceptible groups may be modified before or after the reaction is performed. The reactions shown can also be carried out using the corresponding N-oxides, but any N-oxide present in the compounds of formula VI is removed in reaction VI -> VII.

67849 5 nhch3 ~ OX "» βΓχ "

V * -A'c = n H VAc / \ VIII

I * 6 * 6 I jHa n —- no

CjCJ / ^ h V ✓COOR 0 Π y ^^ COOR II ^

lA H v JL .X IX

K c-n. B

t ✓COOR R6 I

u ^ oc ^ n ^ coor

K ^ - ^ "C = N I H X

I | H H6 ♦

\ Dnr / N \ / COCR

^^ »COOR RjOC ^ \ y /

V-J \ c = n / ^ h VI y * s ^ n- ^ V "c = n, H XI

1V „* 6 i

“NX'COOR, N ^> NX / C00R

0ΓχΗ ”ΟΥ χΗ, -

Vv ^ - ^ XC = N Η νΠ 'Χ— \ V Η X' '«X ^ Nv / COOR / ΘΓχ * ,.

C = N h

V

6 67849

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 nitrites, i. sodium nitrites in the presence of an organic or inorganic acid, e.g. glacial acetic acid, and an aqueous or non-aqueous solvent; (2) alkyl nitrites, i.e. methyl nitrites, in the presence of an inert solvent such as an alcohol, a chlorinated hydrocarbon or e.g. dimethylformamide, and (3) a solution of 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 in the molecule or. the alkylamino group 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.

Step VIII-y 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 union. 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 67849

Phase III or IX-> IV

Compounds of formula III or formula IX may be condensed to 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 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, THF, diethyl ether, DMF, DMSO, etc., at temperatures below room temperature to 150 ° C, preferably 0 to 100 ° C, most preferably at room temperature.

Phase IV-? V

Compounds of formula V are prepared by decarboxylin. Compounds of formula IV are reacted by reacting a compound of formula IV with an alkali metal hydroxide such as NaOH or CO 2 in a suitable solvent such as alcohols, ethers, or DMSO at a temperature ranging from room temperature to reflux, preferably 60-100 ° C. C.

Step V-> · VI

Compounds of formula VI are prepared by nitrosation of 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, DMF, DMSO and chlorinated hydrocarbons. The reaction can be carried out at about room temperature, although the temperature is by no means critical.

Step VI-f-VII

Compounds of formula VII are prepared by reduction of compounds of formula VI, e.g. with Raney nickel and hydrogen or 8 67849 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 NH NH, COOR NH, u \ juf 'Rco'

VIIA VII8 VIIC VII D

compounds. It should be noted that in the above reduction reaction, possible easily reducing groups such as R 1, e.g.

NO2 at the 7-position or CN at the 7-position are reduced. These groups can be reconnected by methods known in the art, as will be shown.

Step VII-> I

Compounds of formula I are prepared by reacting compounds of formula VII with an alkanoic acid orthoester of formula R 1 to C (OR) 3 wherein R is lower alkyl and R 1 is hydrogen or lower alkyl, optionally with an acid catalyst, e.g. or in the presence of an inorganic acid such as p-toluic acid or phosphoric acid, at or above room temperature, i.e. 25 to 150 ° C, whereby the cyclization to the compound of formula I takes place immediately. As well as the above orthoester, orthoamides are suitable for use, e.g., dimethylacetal of N, N-dimethylformamide, N, N, N1, N ', N ", N" -hexamethylmethanetriamine; nitriles, e.g. acetonitrile; ester imidates, e.g. CH 2 -C (= NH) -OC 2 H 2. .

It will be appreciated 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 "1COX or (R" 1CO) 209 67849, wherein X is halogen and R "1 is hydrogen, lower alkyl, phenyl, pyridyl or benzyl.

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 "-] COOR

\ -COOR V \ -NHCOR, "/ - \; - \

XI A XI B

Step XI-> I

Compounds of formula I 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, using a catalyst and a water-binding agent or without them.

Step IX - »X

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

COOR

® C-NHCOR 1

COOR

Between the anion of acylamino malonic acid according to 10 67849, wherein R is lower alkyl and R 'is hydrogen, lower alkyl, phenyl, pyridyl or benzyl. The anion is formed by deprotonating the acyl amino acid ester with a suitable strong base such as an alkali metal or alkaline earth metal alkoxide 11a, hydride or amide. The reaction of 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, ethers, e.g. dioxane, THF, diethyl ether, DMF, DMSO, etc., at a temperature in the range of room temperature. below 150 ° C, preferably at 0 to 100 ° C, most preferably at room temperature.

Step 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, DMSO, DMF, 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 I.

Step VII-y XII

Compounds of formula XII are prepared by reacting compounds of formula VII with an aldehyde of formula R 1 CHO having the same meaning as 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 I. Suitable solvents for this reaction step include hydrocarbons such as benzene, alcohols, ethers, chlorinated hydrocarbons, DMF, DMSO, etc., and the reaction is performed using a water-binding agent, e.g., molecular sieves, at, below, or above room temperature, preferably from room temperature to distillation temperature. .

Step XII-I

Formula XII. The compounds of formula I can be converted to the compounds of formula I by oxidation in situ with oxidizing agents such as manganese dioxide, air, acid, etc.

67849

Example 1

Methyl 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [η 5 -5,7] benzodiazepine-3-carboxylate

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 through a dropping 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 mixture. 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. The crystalline residue 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine 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 -benzodiazepine 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. At the end of the addition, the mixture was stirred at room temperature for one 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-benzodiazepine as a yellow oil.

This material was dissolved in 300 ml of dimethylformamide and added to a mixture of 150 ml of dimethylmalonate, 40.4 g of potassium tert-butoxide and 500 ml of dimethylformamide, which was stirred at room temperature for 10 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 1.3 g (0.059 mol) of potassium hydroxide were refluxed under nitrogen for 5 hours. After some 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.

8.8 g of sodium nitrite (0.125 mol) were 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 as crystals, m.p. 238-241 ° C (dec.).

7-Chloro-5- (2-fluoro-phenyl) -alpha-hydroxyimino-3H-1,4-benzo-13,67849-diazepine-2-acetic acid methyl ester (11.25 g, 0.03 mol) was hydrated to atmospheric under 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 to reflux for 10 minutes, evaporated to dryness and the residue partitioned between methylene chloride and aqueous sodium hydrogen carbonate solution. 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 [3,5-a] [1,47] benzodiazepine-3-carboxylate, mp. 162-164 ° C. The analytical sample was recrystallized from ethyl acetate / hexane.

Example 2

Methyl 8-chloro-6- (2-fluorophenyl) -4H-imidazo [3,4-b] benzodiazepine-3-carboxylate 7-chloro-5- (2-fluorophenyl-alpha-hydroxyimino-3H-1,4- Bent-zodiazepine-2-acetic acid methyl ester (11.25 g, 0.03 mol) was dissolved with heating in a mixture of 750 ml of tetrahydrofuran and 500 ml of methanol, Raney nickel (20 g) was added and the mixture was hydrogenated at atmospheric pressure 4 The catalyst was removed by filtration and the filtrate was evaporated to dryness, finally azeotropically with toluene, and 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 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 the title product which was recrystallized from methylene chloride / ether / hexane, m.p. 179-181 ° C.

Example 3

Methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-b] N-benzodiazepine-3-carboxylate

Potassium tert-butoxide (26 g, 0.232 mol) was added to a mixture of 300 ml of dimethylformamide and 50 ml (0.44 mol) of dimethyl malonate. After the mixture was stirred under nitrogen for 14,678,4 minutes for 10 minutes, a solution of 66 g (0.209 moles) of 7-chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-1,4-benzodiazepine-4 was added over 10 minutes. oxide in 100 ml of dimethylformamide. The mixture was then slowly heated in a water bath and held at 65 ° C for 10 minutes. After cooling to room temperature, 40 ml of glacial acetic acid were added, followed by 1 liter of water over 30 minutes with occasional scraping. The precipitated crystals were collected, washed with water and dissolved in methylene chloride. The solution was dried over sodium sulfate and concentrated to a small volume. The product was crystallized by the addition of hexane to give 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine-4-oxide, m.p. 188-190 ° C. The analytical sample was recrystallized from methylene chloride / hexane, m.p. 194-195 ° C.

A) A mixture of 40.8 g (0.1 mol) of 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine-4-oxide, 250 ml of methanol, 250 ml of tetrahydrofuran and 1 tablespoon of Raney nickel were hydrogenated at atmospheric pressure for 5 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness. Crystallization of the residue from methylene chloride / 2-propanol gave 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine as colorless crystals, m.p. 160-163 ° C. It was recrystallized for analysis from 2-propanol, m.p. 165-166 ° C.

In some cases, another crystal transformation was obtained, the crystals of which melted at 138-140 ° C.

B) Phosphorus trichloride (4 ml) was added to a solution of 4 g (0.01 mol) of 7-chloro-1,3-dihydro-2- (2-dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine- 4-oxide in 100 ml of methylene chloride. After standing overnight at room temperature, the solution was washed with 10% aqueous sodium carbonate solution. The methylene chloride layer was dried and evaporated to dryness. Crystallization of the residue from 2-propanol and recrystallization from methylene chloride / 2-propanol gave 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine, m.p. 165-166 ° C.

A mixture of 115 g (0.3 mol) of 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine, 1.5 l of methanol and 14.4 g of (0.36 moles) of sodium hydroxide, was heated to reflux for 5 hours under nitrogen. The cooled reaction mixture was gradually diluted with 2.5 liters of water under ice-cooling.

is 67849

The precipitated crystals were collected, washed with water and dried in vacuo at 60 ° C to give 7-chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-2H-1,4-benzodiazepine as an off-white product. , sp. 167-170 ° C. An analytical sample was recrystallized from ether, m.p. 171-173 ° C.

Sodium nitrite (2.8 g, 0.04 mol) was added to a solution of 8 g (0.025 mol) of 7-chloro-1,3-dihydro-2-methoxycarbonylmethylene) -5-phenyl-2H-1,4- benzodiazepine in 100 ml of glacial acetic acid. The mixture was stirred under nitrogen for 10 minutes. The product started to crystallize after a few minutes. After diluting the mixture with 100 ml of water, the precipitated product was collected, washed with water, dried and recrystallized from tetrahydrofuran / methanol to give 7-chloro-alpha-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine. -2-acetic acid methyl ester as yellow crystals, m.p. 235-237 ° C (dec.).

7-Chloro-alpha-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-acetic acid ethyl ester (3.6 g, 0.01 mol) was dissolved with heating in a mixture of 200 ml of tetrahydrofuran and 100 ml of methanol. Raney nickel (1 teaspoon) was added and the mixture was hydrogenated at atmospheric pressure until hydrogen binding ceased (1 hour 10 minutes). The catalyst was removed by filtration and the filtrate was evaporated to dryness, finally azeotropically with toluene. The residue was dissolved in 20 ml of methanol. 3 ml of triethyl orthoacetate and 0.3 ml of ethanolic hydrochloric acid solution (5%) were added, and the solution was refluxed for 5 minutes. Evaporation to dryness and the residue obtained was partitioned between methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, dried and evaporated to dryness. Recrystallization from ether gave methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] 4-benzodiazepine-3-carboxylate, m.p. recrystallized from methylene chloride / ether / hexane is 254-256 ° C.

Example 4

Ethyl 8-cyano-6- (2-fluorophenyl) -1-methyl-4H-imidazo [J / 5-47] [] benzodiazepine-3-carboxylate To 100 ml of dry N, N-dimethylformamide was added under nitrogen protection 1.6 g (0.036 mol) of 54% sodium hydride, and 8.3 g (0.038 mol) of acetamidodiethyl malonate were added with stirring. After 30 minutes, 10 g (0.02 mol) of 7-cyano-5- (2-fluoro-16,67849 biphenyl) -2-bis- (morpholino) phosphinyloxy-3H-1,4-benzodiazepine were added and after 64 hours the reaction mixture was poured in 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 Frorisil 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 2 liters of ether. The ether fractions were recrystallized twice from a mixture of dichloromethane and ether to give (acetylamino) -7-cyano-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-2-yl / malonic acid diethyl ester as white prisms. , sp. 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-imidate-soβ, 5-αJβ, 4-benzodiazepine-3-carboxylate as off-white prisms, m.p. 272-274 ° C.

Example 5

Methyl 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo-Z 1,5,5,7,7-benzodazazine-3-carboxylate A solution of 3.75 g (0.01 moles) of 7-chloro-5- (2-fluorophenyl) -alpha-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester in 300 ml of tetrahydrofuran and 200 ml of methanol was hydrogenated at atmospheric pressure to 1 l. / 2 hours in the presence of Raney nickel (1 teaspoon). The catalyst was separated by filtration 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-Z (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 - [[benzoylamino) -methoxycarbonylmethylene] -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-17,67849 2H-1,4-benzodiazepine In 10 ml of hexamethyl-phosphoric acid triamide, 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. and chromatographed on 20 g of silica gel using a mixture of 10% (v / v) ethyl acetate in methylene chloride, crystallizing the combined pure fractions from ether / hexane to give methyl 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H- imidazo [1,5-b] benzodiazepine-3-carboxylate, mp 208-209 ° C.

Example 6

Methyl 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo-ZT, 5- [7ZTr47] benzodiazepine-3-carboxylate 7-chloro-5- (2-chlorophenyl) -2- [bis (morpholino) ) phosphinyloxy-3 H-1,4-benzodiazepine (5.3 g, 0.01 mol) was added to a mixture of 10 ml of dimethylmalonate, 20 ml of dimethylformamide and 2.2 g (0.02 mol) of potassium tert-one. butoxide stirred at room temperature for 5 minutes under nitrogen. The reaction mixture was then stirred and heated on a water bath for 15 minutes. After adding 1.5 ml of glacial acetic acid, the product was crystallized by gradual dilution with water. The precipitated crystals were collected, washed with water and dried in vacuo to give 7-chloro-5- (2-chlorophenyl) -2-dimethoxymalonylidene-1,3-dihydro-2H-1,4-benzodiazepine, which was recrystallized for analysis from ethyl acetate. mp. 205-207 ° C.

A mixture of 12.6 g (0.03 mol) of 7-chloro-5- (2-chlorophenyl) -2-dimethoxymalonylidene-1,3-dihydro-2H-1,4-benzodiazepine, 300 ml methanol and 2.1 g (0.0375 moles) of potassium hydroxide were heated under reflux under nitrogen for 41/2 hours, 200 ml of methanol were distilled off and the residue was diluted with water. The separated crystals were collected, washed with water and dried to give 7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2 - [(methoxycarbonyl) methylene] -1H-1,4-benzodiazepine, m.p. 154-158 ° C. It was recrystallized for analysis from methylene chloride / methanol, m.p.

158-159 ° C.

Sodium nitrite (2.2 g, 0.031 mol) was added portionwise over 5 minutes to a stirred solution of 7.2 g (0.02 mol) of 7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2- (Methoxy-18,67849 carbonyl) -methylene-7H-1,4-benzodiazepine in 75 ml of glacial acetic acid. After stirring for an additional 15 minutes, the mixture was diluted with 100 mL of water and the precipitated crystals were collected, washed with water, methanol and ether to give crude 7-chloro-5- (2-chlorophenyl) -alpha-hydroxyimino-3H- 1,4-Benzodiazepine-2-acetic acid methyl ester recrystallized from tetrahydrofuran / methanol to give pale yellow crystals, m.p. 223-225 ° C (dec.).

A solution of 3.9 g (0.01 mol) of 7-chloro-5- (2-chlorophenyl) -alpha-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester in 100 ml of tetrahydrofuran and 50 ml of methanol, hydrogenated in the presence of Raney nickel (2 teaspoons) for 1 1/2 hours at atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated to dryness, finally azeotropically with toluene. The residue was dissolved in 20 ml of ethanol. Triethyl orthoacetate (3 ml) and 0.2 ml of ethanolic hydrochloric acid solution (10%) were added and the mixture was heated under reflux for 15 minutes and then evaporated to dryness. The residue was partitioned between methylene chloride and saturated aqueous hydrogen carbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. Crystallization of the residue from methylene chloride / ether gave methyl 8-chloro-6- (2-chlorophenyl) -r1-methyl-4H-imidazo [5,5] aββ, 4-benzodiazepine-3-carboxylate, m.p.

225-227 C. The analytical sample was recrystallized from 2-propanol and ethyl acetate, m.p. 228-230 ° C.

Example 7

Methyl 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo-β / 5-α7β, 4-benzodiazepine-3-carboxylate 7-chloro-5- (2-chlorophenyl) -alpha-hydroxy- Imino-3H-1,4-benzodiazepine-2-acetic acid methyl ester (7.8 g, 0.02 mol) was dissolved with heating in a mixture of 200 ml of tetrahydrofuran and 100 ml of ethanol. The solution was hydrogenated in the presence of Raney nickel (2 teaspoons) at atmospheric pressure for 2 hours. The catalyst was filtered off through Celite * and the filtrate was evaporated to dryness in vacuo. Crystallization of the residue from ethanol gave 2-amino) -methoxycarbonylmethylene-7--chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine as orange crystals, m.p. 115-117 ° C (dec.). Recrystallization of this solvated product from ether / hexane gave yellow needles with m.p. was 145-150 ° C (dec.).

19 67849

Acetaldehyde (0.25 ml) was added to a solution of 0.5 g of 2- {((amino) -methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4- benzodiazepine in 25 ml of methylene chloride. To this was added a molecular sieve 5A, and the mixture was stirred at room temperature for 15 minutes. Activated manganese dioxide (1 g) was then added and stirring was continued for 30 minutes. The solid was separated by filtration through Celite and the filtrate was evaporated to dryness. Crystallization of the residue from ethyl acetate / hexane gave methyl 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo-1,5-benzo [b] 4-benzodiazepine-3-carboxylate, m.p. 228-230 ° C.

Example 8

Ethyl 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,47] benzodiazepine-3-carboxylate

A stirred suspension of 4 g (0.09 moles) of a 54% suspension of sodium hydride in 315 ml of dimethylformamide under argon was treated with 21 g (0.096 moles) of diethylacetamidomalonate, which was added in several portions. Stirring at room temperature was continued for 30 minutes and then 31.4 g (0.06 mol) of 7-chloro-5- (2-chlorophenyl) -2- [Jais (morpholino) phosphinyloxy] -3H-1,4-benzodiazepine were added in one portion. After stirring for a further 7 hours at room temperature, the dark mixture was poured onto a mixture of ice and acetic acid with stirring and diluted with water (ca. 2 L) to give a cream solid which was filtered, washed with water and air dried in a funnel to give acetylamino. [7-Chloro-5- (2-chloro-phenyl) -3H-1,4-benzodiazepin-2-yl] -malonic acid diethyl ester The dried product was stirred with a small amount of 2-propanol while heating in a water bath until dissolution had taken place. an off-white solid was obtained, and recrystallization of the sample from a 3-fold amount of ethanol gave off-white microneedles, m.p.

153-155 ° C.

A sodium methylate solution was prepared by dissolving 0.8 g (0.04 g atom) of sodium metal in 50 ml of anhydrous ethanol and protecting with a drying tube. To the stirred solution was added acetylamino-T-chloro-5- (2-chlorophenyl) -3H-1,4-benzodiazepin-2-yl] haloic acid diethyl ester (10.1 g, 0.02 mol) in one portion and stirring was continued in dry conditions. in the atmosphere at room temperature for 5 hours. The resulting mixture was acidified with acetic acid and concentrated in vacuo. The residue was partitioned between dilute ammonium hydroxide and methylene chloride. After separation of the layers, the organic layer was dried over sodium sulfate and evaporated to dryness in vacuo to give a brown, amorphous solid. The solid was dissolved in 75 ml of dry ether and added to a warm solution of 4 g of maleic acid in 200 ml of ether. After decanting over a small amount of brown resin, the solution was concentrated to about 100 mL with a water bath. Upon cooling to room temperature with occasional scraping, crystals formed after about 30 minutes. Upon completion of crystallization, the orange crystals were filtered, washed with ether and dried in a funnel to give 2 - [, (acetylamino) ethoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine- maleate. Recrystallization of a small sample from ethyl acetate (5 ml / g) gave yellow microneedles, m.p. 139-142 ° C (dec.).

A solution of 3.2 g (0.0073 moles) of 2- [(acetylamino) -ethoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine in 15 ml in hexamethylphosphoramide, stirred under nitrogen and heated at 200-210 ° C for 10 minutes. After cooling to room temperature, the solution was poured into ice water and diluted by adding water until precipitation ceased. The brown solid was filtered, washed with water and air dried in a funnel. Upon stirring with ethyl acetate (2 ml / g), the solid dissolved and recrystallized immediately. The brown solid was filtered, washed with ethyl acetate / petroleum ether 1: 1 and air dried to give ethyl 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] / j, Benzodiazepine-3-carboxylate. Recrystallization of the sample from methylene chloride / ethyl acetate solution by removal of methylene chloride by boiling gave off-white needles, m.p. 214-215 ° C. Example 9

Ethyl 6- (2-fluorophenyl) -1-methyl-8-nitro-4H-imidazo-ZJ, 5-α7 / T, 4-benzodiazepine-3-carboxylate A stirred solution of 29.9 g (0.1 mol) 1,3-dihydro-5- (2-fluorophenyl) -7-nitro-2H-1,4-benzodiazepin-2-one in 500 mL of dry tetrahydrofuran, treated under argon with portionwise addition of 5.5 g (0.125 mol) 54 % mineral oil dispersion of sodium hydride, and stirring was continued for another hour. Dimorpholinophosphine chloride (38 g, 0.15 mol) was added in one portion to the dark solution and stirring under argon was continued for 8 hours. The resulting dark mixture was filtered using filter aid and concentrated in vacuo at 50 ° C to give 67849 dark resin. When the dark resin was stirred at room temperature in 75 ml of ethyl acetate, crystallization occurred and a paste formed. The mixture was cooled in an ice bath for 30 minutes, then filtered and the light brown solid was washed 3 times with 35 mL portions of ether / ethyl acetate (2: 1) and finally with ether. Air-drying in a funnel gave almost pure 5- (2-fluorophenyl) -2- [bis (morpholino) phosphinyloxy] -nitro-3H-1,4-benzodiazepine. Recrystallization from 15-fold ethyl acetate gave off-white needles, m.p. 169-172 ° C.

A stirred suspension of 0.85 g (0.018 mol) of a 54% sodium oil hydride mineral oil dispersion in 55 ml of dry dimethylformamide was treated by adding 3.5 g (0.016 mol) of diethylacetamidomalonate in several portions under argon. After stirring for 30 minutes, 5.2 g (0.01 mol) of 5- (2-fluorophenyl) -2- [bis (morpholino) phosphinyloxy] -7-nitro-3H-1,4-benzodiazepine were added in one portion and the mixture was stirred. protected under argon for a further 7 hours. The dark mixture was poured into a stirred mixture of ice and acetic acid and diluted with water to give a brownish yellow solid. The solid was washed with water and air dried in a funnel. In the plate chromatographic study of the obtained product (ethyl acetate), 3 yellow spots were found at 0.8, 0.5 and 0.25. Chromatography on silica gel using ethyl acetate as eluent gave ethyl 6- (2-fluorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] 1,7-4-iberodiazepine-3-carboxylate having an Rf value of 0. , 25, as a brownish yellow solid. Dissolving the sample in hot ethyl acetate (5 ml / g) and cooling in an ice bath gave yellow prisms, m.p. 231-233 ° C.

Example 10

Ethyl 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] Z-1,47-benzodiazepine-3-carboxylate 54% sodium hydride mineral oil dispersion (11 g, 0.25 mol) ) was added portionwise to a stirred solution of 63.2 g (0.2 moles) of 7-bromo-1,3-dihydro-5- (pyridyl) -2H-1,4-benzodiazepin-2-one in 1 liter of tetrahydrofuran under argon. . The solution was heated under reflux with a water bath for 1 hour, 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 of a dark residue in ether 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.) ♦

Diethyl acetamidomalonate (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 under a water bath. The reaction mixture was cooled to room temperature and 7-bromo-2- [bis- (morpholino) phosphinyloxy] -5- (2-pyridyl) -3H-1,4-benzodiazepine (53.4 g, 0.1 mol) was added. 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 an ethyl acetate / ether mixture to give ethyl 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate as off-white crystals. , sp. 240-243 ° C. The seed crystals were obtained by purification by K-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.

Example 11

Ethyl 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo-β, 5-α7Z, 4,7-benzodiazepine-3-carboxylate 1 To a stirred suspension of 7.8 g (0.174 mol) 54% mineral oil dispersion of sodium hydride in 480 ml of dimethylformamide, 3S g (0.18 mol) of diethylacetamidomalonate were added portionwise under argon. After the reaction was equilibrated (about 30 minutes), 48 g (0.096 mol) of 7-chloro-5- (2-fluorophenyl) -2- [bis (morpholino) phosphinyloxy] -3H-1,4-benzodiazepine was added in one portion. Stirring was continued at room temperature for 5 hours under argon. The dark mixture was poured with stirring into a mixture of ice and glacial acetic acid to give a light brown solid which was filtered, washed with water and partially air dried in a funnel. The wet solid was dissolved in methylene chloride. After separation of the aqueous layer, the solution was dried over sodium sulfate, filtered and evaporated to dryness in vacuo to give a brown foam. The foam was dissolved with stirring in isopropanol (4 mg / l) and the solution was kept at room temperature for 1 hour with occasional scraping to give off-white crystals. An equal volume of petroleum ether (30-60 ° C) was added and the mixture was kept at room temperature for another 30 minutes before filtration. Washing with petroleum ether and air drying in a funnel gave acetylamino-7-chloro-5- (2-fluorophenyl) -3H-1,3-benzodiazepin-2-yl-malonic acid diethyl ester, m.p. 150-180 ° C. By recrystallizing a sample taken from this ethanol (10 ml / g), the melting point rose to between 185 and 195 ° C, softening before that.

To a stirred solution of sodium methylate (prepared from 0.2 g, 0.01 g atom, sodium metal in 25 mL of anhydrous ethanol) was added 2.4 g (0.005 mol) of acetylamino - <{7-chloro-5- (2 (fluorophenyl) -3H-1,4-benzodiazepin-2-yl-malonic acid-diethyl ester under a drying tube and stirred for a further 5 hours at room temperature. The precipitated yellow solid was collected by filtration, washed successively with ethanol and ether, and air dried. The solid was partitioned between water and methylene chloride, acidified with acetic acid and re-extracted with methylene chloride. After washing with dilute ammonium hydroxide solution, the methylene chloride extract was dried over sodium sulfate and evaporated to dryness in vacuo to give a brown foam. A solution of 1 g (0.0024 moles) of base in 25 ml of ether was mixed with a solution of 0.56 g (0.0048 moles) of maleic acid in 25 ml of ether and kept at room temperature. Scratched from time to time to give orange crystals after some time. The crystals were collected by filtration, washed with ether and air-dried to give 2- [f (acetylamino) ethoxycarbonylmethylene] -7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine- maleate, m.p. about 150 ° C, recrystallization, after concentration to half volume, from 30 ml of ethyl acetate and addition of seed crystals gave orange prisms, m.p. 149-151 ° C.

Crude 2- (4- (acetylamino) ethoxycarbonylmethylene-7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine (6.3 g, 0.015 mol) prepared from the maleate by basification ammonia, extraction with methylene chloride and evaporation to dryness in vacuo, dissolved in 35 ml of hexamethylphosphoric acid amide and heated at 200-210 ° C with stirring for 5 minutes. The dark solution was cooled and poured into ice water to give a brown solid. The solid was filtered, washed with water and partially air dried in a funnel. The wet solid was dissolved in methylene chloride, dried over sodium sulfate and evaporated to dryness in vacuo to give ethyl 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [5, ba] [S, 47] benzodiazepine-3 carboxylate as a brown foam. Recrystallization of 1 g of a foam from a mixture of ethyl acetate and petroleum ether (30-60 ° C) (5 + 5 ml) gave the product as light brown prisms, melting at 176-179 ° C, slowly re-solidifying and re-melting at 195-198 ° C: in.

Example 12

Ethyl 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo-Z.1,5-a7Z, 1,47-benzodiazepine-3-carboxylate Diethylacetamidomalonate (43 g, 0.2 mol) was added to the suspension. containing 10 g (0.2 moles) 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. To this was added 53 g (0.1 mol) of 5- (2-chlorophenyl) -2-, Sis (morpholino) phosphinyloxy-7-nitro-3H-1,4-benzodiazepine, and the reaction mixture was heated on a water 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 to dryness. The residue was chromatographed on 1 kg of silica gel using ethyl acetate. The pure fractions were combined and evaporated to dryness. Crystallization of the residue from the methylene chloride / ether mixture gave ethyl 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo-q, 5-z-1,7,4-benzodiazepine-3-carboxylate as pale yellow crystals, m.p. 233-234 ° C. An analytical sample was recrystallized from ethyl acetate, m.p. 234-235 ° C.

Example 13

Ethyl 1-methyl-8-nitro-6-phenyl-4H-imidazo [2,5-a] Z / 1,47-benzodiazepine-3-carboxylate 6 g (0.125 mol) of a dispersion of sodium hydride (50% in mineral oil) were added to a solution in which was 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. The mixture was stirred for 1 hour at room temperature, 30.2 g (0.12 mol) of dimorpholinophosphinic acid chloride were 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. /. f '1 lene 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 mol) of diethylacetamidomalonate, 2 g (0.04 mol) of sodium hydride suspension (50% in mineral oil) and 75 ml of dimethylformamide heated to 40 ° C. at 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], 4,7-benzodiazepine-3-carboxylate as off-white crystals. mp. was 240-241 ° C. The analytical sample was recrystallized from ethyl acetate.

Example 14

Methyl 1-benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate Phenylacetaldehyde (2.4 g, 0, 02 moles) was added to a solution of 3.8 g (0.01 moles) of 2- (damino) methoxycarbonylmethylene-7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine. methylene chloride. To the mixture was added 10 g of molecular sieve 5A, stirred at room temperature for 15 minutes and treated with 10 g of activated manganese dioxide for another 15 minutes at room temperature. The inorganic material was separated by filtration through Celite. The filtrate was evaporated to dryness and the residue was crystallized from ether / hexane to give methyl 1-benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [S, 47ber] azodiazepine-3- carboxylate as colorless crystals having a m.p. was 155-158 ^ 0. An analytical sample was recrystallized from ethyl acetate / hexane, m.p. 160-162 ° C.

Example 1_5

Methyl 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo-Zd, 5-α-thieno [3,2-f] [1,4] diazepine-3-carboxylate A solution of 50 g (0.161 mol) ) 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2K-thieno ([2,3-e] [1,4] diazepin-2-one in 900 ml of dry tetrahydrofuran and 300 ml of dry benzene, was cooled in an ice bath and purged with methylamine gas until solution 011 was saturated, then a solution of 40 g (0.209 moles) of titanium tetrachloride in 100 ml of benzene was added dropwise with stirring, and the mixture was kept at room temperature for 4 hours, after which a few grams of ice were added. The reaction mixture was filtered, the precipitate was washed several times with hot tetrahydrofuran, and the combined filtrates were evaporated to dryness, the residue was partitioned between 250 ml of dichloromethane and 200 ml of water and filtered, and the dichloromethane solution was separated, dried and evaporated to dryness. and the precipitate was recrystallized from tetrahydro from a mixture of rofuran and ethanol to give 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-thieno [2,3-d] [1,4] diazepine. A sample of this was recrystallized for analysis from a mixture of tetrahydrofuran and hexane to give pale yellow prisms, m.p. 259-262 ° C.

A mixture of 40 g (0.123 mol) of 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-thieno [2,3-e] 7,7-diazepine, 700 ml of dichloromethane and 350 ml of pyridine , cooled in an ice bath and charged with nitrosyl chloride with stirring for 20 minutes. After 1 hour, the gas was continued for a further 5 minutes and then 600 ml of water were added slowly. The dichloromethane layer was separated, washed with 200 ml of water, dried over anhydrous sodium sulphate and evaporated to dryness, the oil dissolved in dichloromethane and filtered through Florisil using 400 g. This was eluted with dichloromethane and then ether. Crystallization of the dichloromethane fraction from a mixture of ether and petroleum ether gave 7-chloro-5- (2-chlorophenyl) -2- (N-nitrosomethylamino) -3H-thieno- (2,3-e7, 4'-diazepine) and more product was obtained from the ether fraction. A sample of the product was recrystallized for analysis from a mixture of ether and petroleum ether to give yellow prisms, mp 104-107 ° C.

A mixture of 3.4 g (0.03 mol) of potassium tert-butoxide, 7 ml of dimethyl malonate and 20 ml of dimethylformamide was stirred for 5 minutes under nitrogen. 3.55 g (0.01 mol) of 7-chloro-5- (2-chlorophenyl) -2-nitrosomethylamino) -3H-thieno [2,3-d] Z, 47-diazepine were added and the mixture was stirred and heated on a water bath. For 5 minutes, the mixture was acidified by the addition of 3 ml of acetic acid and crystallized by the slow addition of water. The precipitate was collected, washed with water and methanol and dissolved in methylene chloride. The solution was dried and evaporated to dryness and the residue was crystallized from ethanol to give 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2-dimethoxymalonylidene-2H-thieno / 2,3-e7 / T, 47diazep. iin as pink crystals which were recrystallized from ethanol for analysis, m.p. 158-160 ° C.

27 67849

A mixture of 2.15 g (5 mmol) of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2-dimethoxymalonylidene-2H-thieno [2,3-e] -1,4,4] -diazepine, 50 ml of methanol and 0.7 g (1.25 mmol) of potassium hydroxide were heated under reflux for 3 hours under nitrogen. A portion of the solvent was evaporated and the residue was partitioned between methylene chloride and saturated sodium carbonate solution. The organic phase was dried and evaporated to dryness. The obtained 7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2- (methoxycarbonylmethylene) -2H-thieno [2,3-e] -1H-diazepine was dissolved in 20 ml of glacial acetic acid. Sodium nitrite (0.5 g) was added and the mixture was stirred for 15 minutes at room temperature, diluted with water and extracted with methylene chloride. The extracts were washed with water and sodium hydrogen carbonate solution, dried and evaporated to dryness. Crystallization of the residue from methylene chloride / ether and recrystallization from tetrahydrofuran / methanol gave 7-chloro-5- (2-chlorophenyl) -alpha-hydroxyimino-3H-thieno [2,3-d] diazepine-2 -acetic acid methyl ester as yellow crystals, m.p. 242-245 ° C (dec.).

7-Chloro-5- (2-chloro-phenyl) -alpha-hydroxy-imino-3H-thieno-2- [1,7,7-diazepine-2-acetic acid methyl ester (0.4 g, 1 mmol) was dissolved with heating in 30 mL: tetrahydrofuran and 20 ml of ethanol. To this was added Raney nickel (1/2 teaspoon) and the mixture was hydrogenated for 45 minutes at atmospheric pressure. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in 10 ml of methanol, and 0.4 ml of triethyl orthoacetate and 3 drops of ethanolic hydrochloric acid solution were added to the solution.

After refluxing for 10 minutes, the solvent was evaporated and the residue was partitioned between methylene chloride and sodium hydrogen carbonate solution. The organic layer was dried and evaporated to dryness. Chromatography of the residue on 10 g of silica gel, eluting with methylene chloride / ethyl acetate 3: 5 (v / v) and crystallizing the residue after removal of the eluent from ethanol, gave methyl 8-chloro-6- (2-chlorophenyl) -1-methyl -4H-imidazo [J, 5-a] / J, 47-thieno [3,2-f] [J] -diazepine-3-carboxylate, m.p. 211-212 ° C.

28 67849

Example 16

A mixture of 375 mg of (2 - [(amino) methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine, 20 ml of toluene and 0.5 ml of benzaldehyde, heated by back-distillation for 10 minutes using molecular sieves 5 A. 1 g of activated manganese dioxide was added to the mixture, and heating by refluxing was continued for a further 10 minutes, the mixture was filtered through Celite and the filtrate was evaporated. / hexane to give methyl 8-chloro-6- (2-chlorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate as off-white crystals, mp 272- 275 ° C.

Example 17

Methyl 8-chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -4H-imidazo [1,5-a] benzodiazepine-3-carboxylate

A mixture of 8.5 g (0.02 mol) of 2-amino) methoxycarbonylmethylene-7-7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine ethanolate, 200 ml toluene, 4 ml of pyridine-2-carboxaldehyde and 15 g of molecular sieves 4A were heated to reflux for 10 minutes. 20 g of activated manganese dioxide were then added and heating and stirring were continued for a further 10 minutes. The mixture was filtered through Celite, and the filtrate was evaporated. Crystallization of the residue from ethyl acetate / ether gave off-white crystals, m.p. 282-285 ° C. An analytical sample was obtained by recrystallization from methylene chloride / ethyl acetate, m.p. 283-285 ° C.

Example 18

Methyl 8-chloro-6- (2-chlorophenyl) -1-propyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate

A mixture of 4.5 g (0.0107 mol) of 2- (amino) methoxycarbonylmethylene, 7-7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine ethanolate , 100 ml of methylene chloride, 2 ml of butyl aldehyde and 5 g of molecular sieves 5A were stirred at room temperature for 15 minutes. 10 g of activated manganese dioxide were then added and stirring was continued for a further 15 minutes. The mixture was filtered through Celite and the filtrate was evaporated. Crystallization of the residue from ether gave the final product, m.p. 196-198 ° C. An analytical sample was obtained by crystallization from ethyl acetate / tetrahydrofuran / hexane, m.p. 197-198 ° C.

Example 19 29 67849

Methyl 8-chloro-6- (2-chlorophenyl) -1-isopropyl-4H-imidazo [1,5-b] benzodiazepine-3-carboxylate Following the procedure of Example 18, but using isobutylaldehyde instead of butylaldehyde, the final product was obtained. ether. For analysis, it was recrystallized from ethyl acetate / tetrahydrofuran / hexane, m.p. 234-235 ° C.

Example 20

Methyl 8-chloro-6- (2-chlorophenyl) -1- (2-dimethylaminoethyl) -4H-imidazo [1,5-a] 1,4,7-benzodiazepine-3-carboxylate

To a solution of 4.5 g (0.0107 moles) of 2 - [(amino) methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine. ethanolate in 100 ml of methylene chloride, 5 ml of dimethylamine and 2 ml of acrolein were added. After stirring for 10 minutes at room temperature, 12 g of activated manganese dioxide were added and stirring was continued for 15 minutes. The MnCl 2 was removed by filtration through Celite and the filtrate was evaporated. Crystallization of the residue from ethanol / ether gave the final product which was recrystallized from ethyl acetate / methanol / hexane for analysis, m.p. 203-204 ° C.

Example 21

Methyl 8-chloro-6-phenyl-4H-imidazo [1,5-a] [N, N] benzodiazepine-3-carboxylate 2 teaspoons of Raney nickel were added to a solution of 10 g (0.028 moles) of 7-chloro. -O-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-acetic acid methyl ester in a mixture of methanol (200 ml) and tetrahydrofuran (200 ml). The mixture was hydrogenated under normal pressure for 5 hours. The catalyst was removed by filtration through Celite and the filtrate was evaporated to dryness. The residue was dissolved in 100 ml of methanol, and 10 ml of triethyl orthoformate and 5 ml of ethanolic hydrogen chloride solution were added to the solution. The mixture was refluxed for 10 minutes, the solvent was evaporated under reduced pressure, and the residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase was dried and evaporated. Crystallization of the residue from ether gave the final product, which was recrystallized from methylene chloride / ether, melting at 235-236 ° C.

Example 22

Methyl 8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] β, 4,7-benzodiazepine-3-carboxylate

A mixture of 9 g of 2-βamino) methoxycarbonylmethylene-7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine ethanolate, 100 ml of toluene and 20 ml of triethyl orthoformate was heated to reflux. 15 minutes. The solvent was evaporated under reduced pressure, and the crystalline residue was taken up in ether and recrystallized from ethyl acetate / methanol to give the final product, m.p. 206-208 ° C.

Claims (6)

31 67849 A compound of the formula ^ COOR TY ___ N -1f 'k /' IV z X χ \ Β for use in the preparation of therapeutically useful 3-unsubstituted imidazo [1,5-a] / 1,47diazepine compounds and the corresponding 3-carboxamides. Wherein R is lower alkyl, is hydrogen, lower alkyl, phenyl, di-lower alkylamino-lower alkyl, pyridyl or benzyl, R 9 is phenyl, halophenyl or pyridyl, and (3t is a group Cl .S. ΓΥ YY r4 — or a) b) containing halogen, nitro or cyano, and acid addition salts of this compound. A compound according to claim 1 which is 3-carbalkoxy-8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] O [47] enzodiazepine. A compound according to claim 1 which is 3-carbalkoxy-8-chloro-6- (2-fluorophenyl) -1,4-dimethyl-4H-imidazo [1,5-a] E, 1,47cents diazepine . 32 67849 A compound according to claim 1 which is 3-carbalkoxy-8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [1,2-d] [λ, 4-7diazepine. A compound according to claim 1 which is 3-carbalkoxy-8-chloro-6- (2-chlorophenyl) -4H-imidazol-1,5-a7 / 1,47-benzodiazepine. A compound according to claim 1 which is 3-carbalkoxy-8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] 1,4,4-benzodiazepine. 67849 33