NO843376L - benzodiazepine - Google Patents

Description

The present invention relates to imidazobenzodiazepines

rivates with the general formula

in which R"*" means hydrogen, di-lower alkylamino-lower alkyl or lower alkyl, R<2>hydrogen, lower alkanoyl or lower alkyl, R^ hydrogen, lower alkanoyloxy or hydroxy, R 4 chlorine, bromine, fluorine or trifluorome-

tyl and R 5 hydrogen, fluorine or chlorine, with the proviso that a) R 3 cannot mean hydroxy if R 2 means lower

3 1

alkanoyl and b) R means hydrogen if R means di-

lower alkylamino-1aver alkyl,

and the pharmaceutically usable acid addition salts thereof.

The compounds of the above formula I have an anxiolytic effect

effect, without having the unfortunate side effects of CNS-

active compounds such as excessive sedation and ataxia.

The compounds of formula I are disclosed in US patent no.

4,280,957 published July 28, 1981 as part of a broad generic invention and claimed herein. Only later has it been found that the compound of formula I, a subgroup of the original compound, has a selective anxiolytic effect and does not have the unwanted side effects such as over-

driven sedation, ethanol potentiation and ataxia found in many of the anxiolytics currently sold. The term "lower alkanoyl" as used in this specification includes

ter acyl residue of a straight-chain or branched saturated

aliphatic carboxylic acid with 1-4 carbon atoms, such as e.g. formyl, acetyl, propionyl, etc. The term "lower alkanoyloxy" relates to a lower alkanoyl residue, which has a substituted oxygen function such as e.g. acetoxy, propionyloxy etc.

The term "lower alkyl" used in this description - alone or in combination - means straight-chain, branched cyclic hydrocarbon residues with 1-7 carbon atoms, preferably straight-chain or branched hydrocarbon residues with 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl etc.

The term "pharmaceutically usable salts" refers to salts with inorganic and organic, pharmaceutically usable acids, such as sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and p-toluenesulfonic acid. Such salts can be easily prepared by a person skilled in the art according to known methods and depending on the nature of the compound, which one wants to transfer in a salt.

A preferred class of compounds having the above for-1 2

mel I are those in which R means hydrogen, R hydrogen

4 5

or ethyl, R chlorine or fluorine and R hydrogen.

Particularly preferred compounds of formula I are, for example: 9-chloro-6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide,

6-(2-Chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide,

6-(2-Chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide,

6-(2-Chlorophenyl)-4-hydroxy-4H-imidazo[1,5-a][1,4-benzodiazepine-3-carboxamide and

N-acetyl-6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide.

The compounds of formula I and their pharmaceutically usable salts can be prepared according to the invention by

a) submits to a compound with the general formula

14 5

wherein R means lower alkyl and R , R , and R have

above meaning,

an aminolysis with an amino compound of formula

21 21

H 2 NR , where R means hydrogen or lower alkyl, or

b) submits to a compound with the general formula

14 5

wherein R , R and R have the above meaning,

an aminolysis with an amino compound of formula

21 21

F^NR , wherein R has the above meaning, or

c) reacts a compound with the general formula

wherein R"1", R^\ and R^ have the above meaning,

with a C₁-C₂ carboxylic acid anhydride, or

d) reacts with a compound of the general formula

1214

in which R' means C 1 -C 1 -alkyl and R , R , R and

5 14

R has the above meaning,

with an alkali metal hydroxide, or

e) reacts a compound with the general formula

in which R means hydrogen or lower alkyl and R, R' 4 5

R and R have the above meaning,

21 21 with an amino compound of formula P^NR , in which R has the above meaning, bg

f) reacts a compound with the general formula

in which R"*""*" , R^ , and R~* have the above meaning, with a C^-C^ carboxylic acid chloride or anhydride, or g) reacts a compound of the general formula

114 5

wherein R 1 , R , R and R have the above meaning,

with a C^-C^ carboxylic acid chloride or anhydride, and

h) if desired, transfers an obtained compound of formula I in a pharmaceutically usable salt.

The following general reaction schemes A-D illustrate the reactions useful for the preparation of the compounds of formula I. In this reaction core, R means low-11 21

are alkyl. R 1 , C 1 -C 4 alkyl , R and R hydrogen or lower alkyl. R<12>di-lower alkylaminomethyl, R31

lower alkanoyloxy or hydroxy, X halogen and Z benzyl-12 4 5

oxycarbonyl and R , R , R and R have the meaning given in formula I. The reaction according to scheme A can also be carried out with the corresponding N-oxides, but an N-oxide residue present in the compounds of formula VI is removed during the conversion VI-VII.

Steps

The compounds of formula III are prepared by nitrosation of compounds of formula II. Such a nitrosation can be effected by nitric acid formed in situ. Reagents which can be used are (1) alkali metal nitrites, e.g. sodium nitrite, in the presence of organic or inorganic acids, e.g. glacial acetic acid, and aqueous or non-aqueous solvents; (2) alkyl nitrites, for example methyl nitrite in the presence of an inert solvent, such as alcohol, a chlorinated hydrocarbon or e.g. dimethylformamide; and (3) a nitrosyl chloride gas solution in an inert solvent in the presence of an acid acceptor such as pyridine. Such a nitrosation reaction should be carried out at or below room temperature, i.e. in the range from -20° to 25°C.

Stage VIII — »IX

Compounds of formula IX can be prepared by reacting the compound of formula VIII with dimorpholinephosphine chloride. The reaction necessary for the production of compounds of formula IX from compounds of formula VIII with the phosphorylating agent is carried out by reacting a compound of formula VIII with a base strong enough to ionize the compound of formula VIII to form a corresponding anion. Suitable bases include alkali metal alkoxides such as potassium 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 from 0° to 100°C, and the reaction is preferably carried out in an aprotic polar inert solvent, i.e. a solvent which completely or at least partially solubilizes the surrounded salts of the compound of formula VIII. Preferred solvents are ethers, e.g. tetrahydrofuran or dioxane or tertiary amides, e.g. dimethylformamide.

Stage III or IX->IV

Compounds of formula III or IX can be condensed with the anion, which originates from a malonic acid ester of formula

forming a compound of formula IV. The anion is formed by deprotonation of the malonic acid ester with a suitable strong base such as alkali metal or alkaline earth metal alkoxides, hydrides or amides. The reaction of the compound of formula III or IX with the malonic ester anion is preferably carried out in a solvent such as a hydrocarbon, e.g. benzene, toluene or hexane, an ether, e.g. dioxane, tetrahydrofuran or diethyl ether, dimethylformamide, dimethylsulfoxide etc. at a temperature in the range from below room temperature to 150°C, preferably 0 to 100°C, and most preferably at room temperature.

Stage IV- »V

The compounds of formula V are obtained by decarboxylation of compounds of formula IV by reacting a compound of formula IV with an alkali metal hydroxide, such as sodium or potassium hydroxide in a suitable solvent, such as an alcohol, ether or dimethyl sulfoxide at a temperature in the range between room temperature and reflux temperature, preferably 60 to 100°C.

Stages XIV-^ V

According to an alternative method, a compound of formula V can also be prepared by reacting a compound of formula XIV with an acetic acid ester, e.g. a compound of the formula CH^COOR, in the presence of a base strong enough to remove the proton from the ester, forming the anion of the present acetic acid ester. A suitable example of such a base is lithium diisopropylamide.

Stage V-»VI

Compounds of formula VI are produced by nitrosation of compounds of formula V, this being reacted with nitrous oxide, which e.g. is prepared from an alkali metal nitrite, alkyl nitrite or nitrosyl chloride by reaction with an organic or inorganic acid. Suitable solvents for the nitrosation reaction are ethers, alcohols, water, acids, e.g. acetic acid, dimethylformamide, dimethylsulfoxide or chlorinated hydrocarbons. The reaction can be carried out at room temperature even if the temperature is not critical.

Stage VI- » VII

The compounds of formula VII are prepared by reducing compounds of formula VI with e.g. Raney nickel and hydrogen or zinc and acetic acid. This reduction gives mainly compounds of formula VII and at the same time small amounts of various possible isomers, i.e. compounds of formula

Stage VII->XII

Compounds of formula XII are then formed by reacting a compound of formula VII with an alkanoic acid orthoester with

formula

14

optionally in the presence of an acid catalyst, e.g. an organic tenant inorganic acid, e.g. p-toluenesulfonic acid, phosphoric acid, etc. at room temperature or higher, i.e. 25-150°C, during which the cyclization to compound XII proceeds spontaneously under these conditions. Technical equivalents of the above-mentioned orthoester are orthoamides, e.g. dimethyl acetal of N,N-dimethylformamide, N,N,N',N',N",N"-hexamethylenemethanetriamine, nitriles, e.g. acetonitrile, the ester imidate, e.g. CH3~C(=NH)-OC2H5.

Stage VII- »XI

Compounds of formula XI can be prepared by acylation of compounds of formula VII with a compound of formula

Solvents for a reaction step are methylene chloride, ether, chlorinated hydrocarbons, etc., preferably in combination with an acid acceptor, such as an organic or inorganic base, such as triethylamine, pyridine or an alkali metal carbonate. The reaction can be carried out above or below room temperature, but preferably at room temperature. Compounds with formula XI are isomers, i.e. they can have the following stereochemical structures:

Stages XI -^ XII

Compounds of formula XII can also be prepared by dehydrating compounds of formula XI or isomers thereof during simultaneous cyclization by heating. These reaction steps can be carried out with or without solvents, e.g. dimethylformamide, ethylene glycol, hexamethylphosphoric acid triamide, at a temperature in the range from 100-300°C, preferably 150-250°C, e.g. 200°C with or without catalyst and water binding agents.

Stages IX-^X

Compounds of formula X can be prepared by reacting a compound of formula IX with the anion derived from an acylaminomalonic acid ester of formula

The anion is produced by deprotonation of the acylaminomalonic ester with a suitable strong base, such as alkali metal or alkaline earth metal alkoxides, hydrides or amides. The reaction of a compound of formula IX with the acylaminomalonic acid ester anion is preferably carried out in a solvent such as a hydrocarbon, e.g. benzene, toluene or hexane, an ether, e.g. dioxane, tetrahydrofuran or diethyl ether, dimethylformamide, dimethylsulfoxide etc. at a temperature in the range from below room temperature to 150°C, preferably 0 to 100°C, preferably at room temperature.

Steps X-^ XI

Compounds of formula XI and isomers thereof are prepared by decarboxylation of compounds of formula X with an alkali metal alkoxide in a solvent, such as an ether, alcohol, dimethylsulfoxide, dimethylformamide, etc. above or below room temperature, preferably at room temperature. The compounds of formula X and XI do not need to be isolated, but can be transferred in situ in the compounds of formula XII.

Stage VII- »XIII

The compounds of formula XIII are prepared by reacting a compound of formula VII with an aldehyde of formula R^CHO. Suitable solvents for this reaction step are hydrocarbons, such as benzene, alcohols, ethers, chlorinated hydrocarbons, dimethylformamide, dimethylsulfoxide, etc. The reaction can be carried out with or without water-binding agents, e.g. molecular sieve, above or below room temperature, preferably between room temperature and the reflux temperature of the solvent.

A further method for the preparation of compounds of formula XIII, in which R"<*>" means di-lower alkylaminoethyl consists in the condensation of a compound of formula VII with a di-lower alkylamine, e.g. dimethylamine, along with acrolein.

Stage XIII- » XII

Compounds of formula XIII can be oxidized in situ with oxidizing agents, such as manganese dioxide, air, oxygen, etc., in connection with formula XII.

Another method of preparing compounds of formula XII consists first in reacting a compound of formula IX with a protected aminomalonic acid ester of formula

transferring the compound thus obtained, which corresponds to formula X in which R"^ however means benzyloxy, into a compound corresponding to formula XI, as indicated above for step X-^XI and finally treating the compound thus obtained with hydrogen bromide in glacial acetic acid to form a compound of formula VII.

The intermediates of formula X and XI do not need to be isolated. The thus obtained compound of formula VII is further transferred in connection with formula XII in the above-described reaction steps VII-XXIII and XIII->XII.

According to yet another method, compounds of formula XII, in which ^ means hydrogen, can be prepared by reacting a compound of formula III or IX or a compound corresponding to formulas III and IX, but which in the 2-position of another suitable cleavable g group, such as a di-lower alkoxy or ono group -OPO(Oalkyl) ^ , me(3 an iso-cyanate of the formula C=N-CH2-CO0Ri in the presence of a base basic enough to form the anion of the isocyanate acetate. The reaction takes place in an inert solvent such as dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide, tetrahydrofuran or any other suitable organic solvent. All that is required of the organic solvent in the above-mentioned step is that the starting materials are soluble in it and that the solvent does not interfere with the reaction The reaction temperature is between approximately -40°C and room temperature, preferably between 0°C and room temperature.

Bases strong enough to form the anion of the isocyanoacetate are alkali metal alkoxides such as potassium t-butoxide or sodium methoxide, alkali metal hydrides such as sodium hydride and alkali metal amides such as lithium amide or lithium diisopropylamide.

Stages XII-* >XV

Compounds of formula XV are prepared by hydrolysis of compounds of formula XII to the corresponding acids, preferably with alkali metal hydroxides, e.g. sodium or potassium hydroxide. The hydrlysis is conveniently carried out in an inert solvent. Suitable solvents are alcohols, e.g. methanol or ethanol, ethers, e.g. dioxane or tetrahydrofuran, dimethylformamide in combination with water. Preferably, this reaction step is carried out at a temperature between room temperature and the boiling point of the reaction mixture.

Stage XII or XV ^ »Ia

The compounds of formula Ia can be prepared by direct aminolysis of compounds of formula XII (with an amino for-21

bond with formula f^NR ) or by converting a compound of formula XV into the acid chloride XVI, for example by treatment with phosphorus pentachloride, and subsequently

statement with an amino compound of formula f^NR

Step XII-IIa is conveniently carried out in an inert solvent or without a solvent. Suitable solvents are hydrocarbons, e.g. hexane or toluene, ethers, e.g. tetrahydrofuran, alcohols, e.g. methanol or ethanol, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric acid triamide. It is preferred to carry out this reaction step at a temperature between approx. 50°C, especially between approx. 100 and 150°C at a pressure above atmospheric pressure.

Steps XV-^Ia via XVI are conveniently carried out in an inert solvent. Suitable solvents are hydrocarbons, e.g. hexane or toluene, ethers, e.g. tetrahydrofuran, chlorinated hydrocarbons, e.g. methylene chloride or chlorobenzene. Preferably, this reaction is carried out at a temperature between approx. -20°C and the boiling point of the reaction mixture, especially between approx. 0 and 50°C.

Stage Ia-^ >XVII

Compounds of formula XVII are prepared by converting the corresponding compounds Ia into their N-oxides. The conversion is achieved by reacting a compound of formula Ia with an organic peracid. A common organic peracid, such as peracetic acid, perpropionic acid, m-chloroperbenzoic acid, etc. can be used in carrying out this reaction step. The oxidation can take place at room temperature or

above or below room temperature.

Stage XVII- > Ib

Compounds of formula XVII can be used in the preparation of compounds of formula Ib by known methods, such as e.g. The Polonovski rearrangement using an acid anhydride to form the lower alkanoyloxy radical, which then on treatment with an alkali metal hydroxide such as sodium hydroxide can be transferred in the hydroxy group. An example of such a Polonovski rearrangement is described in US patent no. 3,296,249.

Stages Xlla-^ XVIII

The compounds of formula XVIII are obtained by reacting an N-oxide of formula Xlla with a C 1 -C 2 carbonic anhydride, preferably acetic anhydride, with or without an inert organic solvent, such as xylene or toluene at a reaction temperature between approx. 100°C and the boiling point of the solvent used, below which the reaction temperature is preferably at the boiling point of the solvent used. It should be noted that, if desired, this reaction can also be carried out without a solvent, i.e. with the anhydride alone.

Stage XVIII~ >Ib"

Compounds of formula Ib" can be prepared by reacting a compound of formula XVIII with ammonia or a lower alkylamine, for example a C₁-C₂-alkylamine, preferably methyl or ethylamine, in a C₁-C₂- alcohol, preferably methanol, or if desired provide the amine component itself.The reaction temperature is between approximately 0° and 100°C, below which around room temperature is preferred.

Step Ib"- frlc

Compounds of formula Ib" are reacted with a lower alkanoic acid chloride or anhydride with 1-4 carbon atoms in the presence of an acid acceptor such as pyridine. The obtained compound of formula Ic, in which R 2 is hydrogen, is allowed to react even further with the lower alkanoic acid chloride or anhydride, for example acetic acid chloride or anhydride, the hydrogen atom indicated as R 2 can be replaced by a lower alkanoyl group. The reaction is preferably carried out under normal conditions.

Step XIX^ »XX

A compound of formula XIX can be prepared using analogous conditions as described for the preparation of compounds of formula XII from the previously described compound of formula V. The diester of formula XIX can be reduced with sodium borohydride in a boiling alkanol, e.g. ethanol, to the compound of formula XX.

Stage XX~ »XI

The compound of formula XX can then be reacted with thionyl chloride, during which the hydroxy group is replaced by a chlorine atom.

Stage XXI- »XXII

The compound of formula XXI can then be reacted with a di-lower alkylamine, e.g. dimethylamine, at approx. 100°C below which a compound of formula XXII is obtained.

Stage XXII- »XIIb

The t-butyl ester substituent in a compound of formula XXII can be transferred into the corresponding methyl ester by reaction with methanolic sulfuric acid.

Step Xllb -$ Ed

The transfer of a compound of formula Xllb can be carried out as described above for step XII Ia, e.g. by reacting this compound with methanolic ammonia in the presence of ammonium chloride or an alkylamine in the presence of its hydrochloride salt.

The compounds of formula I act as anxiolytics. This activity can be influenced with the following experiments during which the preferred compounds according to the present invention are used. It should be pointed out that the compounds produced according to the invention are inactive or practically inactive in the rotating rod tests, which are relevant as a statement with regard to muscle relaxing effect, while in the antimetrazole test, which is relevant as a statement with regard to anxiolytic effect, they have a high Activity.

Rotating rod test

This experiment is a modification of the method described by N.W. Dunham and T.S. Miya in J.A. Ph.D. A. Say. Oath. 46, 208 (1957). CF-1 mice, which were selected due to his ability to stay 2 minutes on a rotating rod with a 30 mm cross-section and 16 revolutions per minute was used. Groups of 8 mice each are brought 30 minutes after administration of the test compound onto the rotating rod and observed for 2 minutes. Mice that cannot stay on the rotating rod for a full 2 minutes are qualified as affected by the test compound. The number of mice that could not stay on the rotating rod is given as a percentage of the total number of mice in each group at different doses. These percentage values are recorded against the dose on logarithmic paper and the EDj-q value is measured by the method of L.C. Miller and M.L. Tainter in Proe. Soc. Exp. Biol. With. 57, 26 (1944).

The purpose of the present experiments is to investigate chemical compounds with regard to their effect on muscle tone and/or muscular coordination, especially those for muscle relaxants, sedatives and stimulants.

Results:

Intravenous antimetrazole test

CF-1 male mice that are 45-54 days old and have not been fed for approx. 24 hours are used in this experiment. The test compound, dispersed 5% acacia oil, is given orally to 3 mice at a dosage corresponding to 1/10 of the lethal dose measured in the TSP experiment. One hour later, metrazol is given intravenously (70 mg/kg; convulsive dose 100 mg/kg) and the experimental animals are observed for 30 seconds, if protection against convulsions occurs. If the test compound is orally active, 3 trial deep doses are used. The dose at which 50% of the experimental animals do not have any kind of convulsion is called the ED^-q value.

Measurements carried out: The number of experimental animals protected against convulsions.

Calculations: If the test substance is active and 3 mice are used per dose, the approximate ED^^ value is calculated according to the method of Miller and Tainter (Proe. Soc. Exp. Biol. Med. 57:261 (1944)). If 6 or more mice per dose is used, the ED^^ value and the 95% significance range are calculated using a computer program based on the method of D.J. Finney (Probit Analysis, Cambridge University Press, Cambridge, England, 1971).

Activity of default connections

This experiment is suitable for the evaluation of anticonvulsants and is relevant as a statement with regard to the anxiolytic effect.

Results:

The imidazobenzodiazepine produced according to the present invention are valuable pharmaceuticals and are distinguished by a selective anxiolytic effect. These compounds can be given in the form of conventional pharmaceutical dosage forms. E.g. these compounds can be mixed with common organic or inorganic inert pharmaceutical carriers suitable for parenteral or enteral administration, such as e.g. water, gelatin, milk sugar, starch, magnesium stearate, talc, plant oils, rubber, polyalkylene glycols, petroleum jelly etc. They can also be given in usual pharmaceutical forms, e.g. in solid form, e.g. such as tablets, dragées, capsules, suppositories etc. or in liquid form, e.g. as solutions, suspensions or emulsions. In addition, the pharmaceutical mixtures containing compounds produced according to the invention can be subjected to usual pharmaceutical treatments such as sterilization and they can also contain usual pharmaceutical excipients such as preservatives, stabilizers, emulsifiers, salts for variation of osmotic pressure or buffers. The mixture may also contain other therapeutically valuable compounds.

A suitable pharmaceutical dosage unit may contain about 0.1 to 500 mg of an imidazobenzodiazepine product, with a dosage range from about 0.1 mg to 100 mg is preferred for oral administration, while a dosage range from approx. 0.1 to 50 mg is preferred for parenteral administration. However, for each individual the specific dosage should be determined depending on the individual needs and judgment of the person administering the mixture or supervising the administration. However, it must be emphasized here that the dosages mentioned above are only given as examples and in no way limit the scope of the present invention.

The term "dosage unit" used in this description refers to certain pharmaceutical units, which are suitable as unit doses for warm-blooded animals and, in addition to the necessary pharmaceutical diluents carrier or carrier substance, contain a precisely determined amount of active ingredient, which is necessary according to calculations to achieve the desired therapeutic effect.

The following examples illustrate the present invention without limiting it in any way. All temperatures are indicated in °C.

Example 1

6-(2-Chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester 9 g (0.08 mol) potassium t-butoxide is added to a solution of 19 g (0.07 mol) of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one in 350 ml of dimethylformamide cooled to 5°C. After 5 minutes of stirring under nitrogen, 18.1 g of diethylchlorophosphate are added, and the mixture is stirred for a further 10 minutes. 12.7 g (0.112 mol) of ethyl isocyanoacetate in 150 ml of dimethylformamide are then added, followed by 12.6 g of potassium t-butoxide. after stirring for 1 hour without cooling, the reaction mixture is acidified in glacial acetic acid and distributed between toluene and saturated sodium bicarbonate solution. The organic phase is dried and evaporated. Crystallization from ether gives 6-82-chlorophenyl)-4H-imidazo[1,5-a//1,4]-benzodiazepine-3-carboxylic acid ethyl ester, melting point 225-227°C. For analysis, it is recrystallized from methylene chloride/ethyl acetate, during which slightly yellowish crystals are obtained, m.p. 226-228°C.

Example 2

6-(2-fluorophenyl)-4H-imidazo/l,5-a//l,4/benzodiazepine-3-carboxylic acid ethyl ester

2.5 g (23 mol) of potassium t-butoxide are added to a solution of 5.08 g (820 mmol) of 5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one in 75 ml of tetrahydrofuran cooled to 0°C. After 5 minutes of stirring, 4.3 ml (30 mmol) of diethylchlorophosphate are added and stirring is continued under nitrogen for 15 minutes. A solution of 3.4 ml (32 mmol) of ethyl isocyanoacetate is then added, immediately followed by 3.5 g (32 mmol) of potassium t-butoxide. The mixture is stirred at room temperature for 2 hours, acidified with glacial acetic acid and distributed between water and methylene chloride. The organic phase is dried and evaporated, the residue is recrystallized from ether, whereby 6-(2-fluorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester is obtained. For analysis recrystallize

this from ether (m.p. 197-198°C).

Example 3

6-(2-bromophenyl)-4H-imidazo/l,5-a//l,4/benzodiazepine-3-carboxylic acid ethyl ester

4.5 g (40 mmol) of potassium t-butoxide are added to a solution of 11 g (35 mmol) of 5-(2-bromophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one in 300 ml of dimethylformamide cooled in ice water. Under nitrogen and stirring, 7.6 ml (9 g, 52 mmol) of diethyl chlorophosphate are added. After stirring for 5 minutes, 7.9 g (70 mmol) of ethyl isocyanoacetate and 7.8 g (70 mmol) of potassium t-butoxide are added. The mixture is stirred at room temperature for 2 hours, acidified with glacial acetic acid and distributed between toluene and water. The organic phase is washed with water, dried and evaporated. The residue is filtered with 10% ethyl acetate in methylene chloride over silica gel. The filtrate is evaporated and the residue is crystallized from ether, whereby 6-(2-bromophenyl)-4H-imidazo/1,5-a/- /1,4/benzodiazepine-3-carboxyethyl ester is obtained, m.p. 230-232°C. An analytical sample is recrystallized from methylene chloride/ethyl acetate, whereby colorless crystals with the same melting point are obtained.

The benzodiazepin-2-one used as starting material in example 3 can be prepared as follows (examples 4-8): Example 4

N-/ 2-/( 2- bromophenyl) hydroxymethyl/ phenyl/- N-( phenylmethyl)- 2-chloroacetamide

17.5 g (0.15 mol) of boron trichloride are dissolved in 100 ml of methylene chloride and added under ice-cooling to a solution of 27.45 g (0.15 mol) of N-(phenyl)benzyl amine in 400 ml of methylene chloride. After addition of 15.1 g (0.15 mol) of triethylamine, the reaction mixture was heated for 2 hours under reflux. While cooling with ice water, a solution of 27.75 g (0.15 mol) 2-bromobenzaldehyde and 19.7 g

(0.195 mol) of triethylamine in 400 ml of methylene chloride. After stirring for 18 hours at room temperature, the reaction mixture was washed with 10% aqueous sodium carbonate solution, dried and evaporated. The oily residue is dissolved in methylene chloride, and 32 g of chloroacetyl chloride are added to an ice-water-cooled solution. The reaction mixture is reacted with 10% aqueous sodium carbonate solution and the two-phase system is stirred vigorously for 30 minutes. The organic phase is dried and evaporated. Crystallization from ethyl acetate/ether gives a neighboring product, which is filtered off. The filtrate is evaporated and the residue is crystallized from ether, whereby N-/2-/(2-bromophenyl)hydroxymethyl/-phenyl/-N-(phenylmethyl)-2-chloroacetamide is obtained in three fractions. This material is oxidized without further cleaning. An analytical sample is obtained by recrystallization from methylene chloride/hexane and melts at 163-166°C. NMR (CDCl3) shows a mixture of two rotamers.

Example 5

N-/ 2-( 2- bromobenzoyl) phenyl/- N-( phenylmethyl)- 2- chloroacetamide

A mixture of 27.7 g (62 mmol) N-/2-/(2-bromophenyl)-hydroxymethyl/phenyl/-N-(phenylmethyl)-2-chloroacetamide, 140 g of manganese dioxide and 1.4 l of methylene chloride is stirred at room temperature for 5 hours. The manganese dioxide is filtered off over celite and the filtrate is evaporated. Crystallization of the residue from 2-propanol gives N-(2-(2-bromobenzoyl)phenyl)-N-(phenylmethyl)-2-chloroacetamide, m.p. 120-123°C.

Example 6

2- azido- N-/ 2-( 2- bromobenzoyl) phenyl/- N-( phenylmethyl) acetamide

A mixture of 16.7 g (37.5 mmol) N-(2-(2-bromobenzoyl)phenyl)-N-(phenylmethyl)-2-chloroacetamide, 3.45 g (53 mmol) sodium azide and 200 ml dimethylformamide is heated for 45 minutes at 65-76°C. It is then distributed between water and methylene chloride. The organic phase is dried and evaporated, and the residue is crystallized from ether/hexane. whereby 2-azido-N-/2-(2-bromobenzoyl)phenyl/-N-(phenylmethyl)acetamide is obtained, m.p. 93-95°C.

Example 7

5-( 2- bromophenyl)- 1, 3- dihydro- l-( phenylmethyl)- 2H- l, 4- benzodiazepine- 2- one

A mixture of 14.8 g (33 mmol) of 2-azido-N-(2-(bromobenzoyl)phenyl/-N-(phenylmethyl)acetamide, 200 ml of tetrahydrofuran, 350 ml of ethanol and 15 g of Raney nickel is hydrated at atmospheric pressure in within 1.5 hours. The catalyst is filtered off and the filtrate is heated for 30 minutes at reflux, after which 10 ml of glacial acetic acid is added. The solution is evaporated and the residue is distributed between methylene chloride and 10% aqueous sodium carbonate solution. The organic phase is dried and evaporated. Crystallization of the residues from 2-propanol gives 5-(2-2-bromophenyl)-1,3-dihydro-1-(phenylmethyl)-2H-1,4-benzodiazepine-2-one as •colorless product, m.p. 132-134°C. For the analysis, it is recrystallized from 2-propanol, m.p. 135-138°C.

Example 8

5-( 2- bromophenyl)- 1, 3- dihydro- 2H- 1, 4- benzodiazepine- 2- one

A solution of 6.6 g (16.3 mmol) of 5-(2-bromophenyl)-1,3-dihydro-1-(phenylmethyl)-2H-1,4-benzodiazepin-2-one in 125 ml conc. sulfuric acid is heated for 12 minutes on a steam bath. The cooled reaction mixture is poured onto ice and made alkaline with ammonia. The precipitate is extracted with methylene chloride/ethanol. The extracts are dried and filtered over silica gel, whereby 5% ethanol in methylene chloride is obtained by washing. The filtrate is evaporated and the residue is crystallized from methylene chloride/ethyl acetate/hexane, whereby 5-(2-bromophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one is obtained as colorless crystals, m.p. 220-222°C.

Example 9

6-/ 2-( trifluoromethyl) phenyl/- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxylic acid- ethyl ester

Reaction of 8 g (26.3 mmol) of 1,3-dihydro-5-(2-trifluoromethyl)phenyl-2H-1,4-benzodiazepine2-one with potassium t-butoxide and diethylchlorophosphate and subsequent treatment with the anion from ethyl isocyanate gives after crystallization from methylene chloride is 6-(2-(trifluoromethyl)phenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester. This is recrystallized from methylene chloride/ethanol to analytical grade and melts at 236-238°C.

Example 10

9- fluoro- 6-( 2- fluorophenyl)- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxylic acid ethyl ester

A solution of 0.82 g (3 mmol) of 8-fluoro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine 2-one in 20 ml of tetrahydrofuran is cooled to -10°C and is stirred under nitrogen, but 0.4 g (3.56 mmol) of potassium t-butoxide is added. After 5 minutes, 0.61 g (0.51 ml or 3.56 mol) of diethyl chlorophosphate is added and stirring is continued for 10 minutes. 0.4 ml of ethyl isocyanate is then added, followed by 0.4 g (3.56 mmol) of potassium t-butoxide. After removing the cooling, the mixture is stirred for 30 minutes, acidified with glacial acetic acid and distributed between methylene chloride and sodium bicarbonate solution. The organic phase is dried and evaporated. Crystallization from the residues of ether gives 9-fluoro-6-(2-fluorophenyl)-4H-imidazo/1,5-a//1,4/-benzodiazepine-3-carboxylic acid ethyl ester. This is recrystallized from ethyl acetate/hexane for analytical purposes and melts at 215-217°C.

The benzodiazepine-2-one used as starting material in example 10 can be prepared according to the indole method as follows (examples 11-15): Example 11

6- fluoro- 3-( 2- fluorophenyl)- 1H- indole- 2- carboxylic acid methyl ester

A solution of 30.4 g (0.44 mol) of sodium nitrite in 200 ml of water is added dropwise at -20 to -5°C to a mixture of 44.4 g (0.4 mol) of 3-fluoroaniline in 160 ml of conc. hydrochloric acid. After the addition is complete, this solution is stirred for 15 minutes at -5 to 0°C and then poured onto one of the following prepared mixtures: 90 g (0.4 mol) 2-acetyl-3-(2-fluoro-phenyl)propionic acid methyl ester is dissolved in 320 ml of methanol, and the resulting solution cooled to -50°C. A solution of 76

g (1.9 mol) of sodium hydroxide is added to 200 ml of water, while keeping the temperature below -5°C. After combining both reaction mixtures below 0°C, the new reaction mixture is stirred without cooling for 45 minutes. It is then diluted with water and extracted with methylene chloride. The extracts are dried and evaporated. The red oil is dissolved in methanol and the solution is saturated with hydrogen chloride gas. After 2 hours of heating at reflux, the solution is diluted with water and the precipitated crystals are removed. Recrystallization from ether/hexane gives 6-fluoro-3-(2-fluorophenyl)-1H-indole-2-carboxylic acid methyl ester. An analytical sample is cleaned by filtering with methylene chloride as solvent over silica gel. Crystallization from methylene chloride/hexane gives colorless crystals, m.p. 158-160°C.

Example 12

6- fluoro- 3-( 2- fluorophenyl)- 1H- indole- 2- carboxylic acid

A mixture of 50 g (0.174 mol) of 6-fluoro-3-(2-fluoro-phenyl)-1H-indole-2-carboxylic acid methyl ester, 39 g (0.7 mol) of potassium hydroxide, 150 ml of water and 1, 5 1 methanol is heated for 2 hours at reflux. The mixture is then acidified with glacial acetic acid and partially evaporated. The hot solution is diluted with water, whereby the product crystallizes. After cooling, the crystals are separated and sucked dry. Recrystallization from ether/hexane gives 6-fluoro-3-(2-fluorophenyl)-1H-indole-2-carboxylic acid as a colorless product, m.p. 215-218 C. An analytical sample is recrystallized from the same solvents and showed an unchanged m.p.

Example 13

6- fluoro- 3-( 2- fluorophenyl)- 1H-indole- 2- carboxamide

34.8 g (0.127 mol) of 6-fluoro-3-(2-fluorophenyl)-1H-indole-2-carboxylic acid is transferred into the corresponding acid chloride in which it is stirred with 37.1 g (0.178 mol) of phosphorus pentachloride in 3 1 of methylene chloride for 1 hour at room temperature. Ammonia is then introduced until the reaction mixture reacts basic. Water is then added and stirred for 1 hour. The organic phase is separated, dried and evaporated. Crystallization of the residues from ethyl acetate/hexane gives 6-fluoro-3-(2-fluorophenyl)-1H-indole-2-carboxamide, m.p. 191-193°C. For the analysis, it is recrystallized from the said,,e øæsmomgs,oddeøjvprved colorless crystals are obtained, m.p. 195-197°C.

Example 14

6- fluoro- 3-( 2- flurophenyl)- 1H- indole- 2- methanamine hydrochloride

A solution of 5 g (18.4 mmol) of 6-fluoro-3-(2-fluorophenyl)-1H-indole-2-carboxamide in 100 ml of tetrahydrofuran is added to a suspension of 5 g of lithium aluminum hydride in 150 ml of ether. This reaction mixture is heated under nitrogen for 6 hours at reflux and then stirred at room temperature overnight. The excess reagent is carefully removed by adding 25 ml of water. After dilution with ether, the inorganic material is filtered off and washed with methylene chloride. The filtrate is dried and evaporated. The residue is dissolved in ether and reacted with ethanolic hydrochloric acid. The precipitated crystals are separated and washed with ether, whereby 6-fluoro-3-(2-fluorophenyl)-1H-indole-2-methanamine hydrochloride is obtained as a colorless product. The analytical samples are recrystallized from ethanol/ether and ignited at 241-245°c (Spaltn.).

Example 15

8- fluoro- 5-( 2- fluorophenyl)- 1, 3- dihydro- 2H- 1, 4- benzodiazepine-2- one

A mixture of 8.4 g (28.5 mmol) 6-fluoro-3-(2-fluorophenyl)-1H-indole-2-methanamine hydrochloride, 84 ml acetic acid, 8.4 ml water and 8.4 g chromium trioxide stir in a cooling bath for 2 hours. It is then poured into ice water, made alkaline with ammonia and extracted with methylene chloride. The extracts are dried and, after adding 10 ml of acetic acid, they are allowed to stand over the weekend. The methylene chloride solution is washed with aqueous bicarbonate solution, dried and evaporated. The residue is chromatographed using methylene chloride/ethyl acetate 1:1 (V/V) as eluent on 100 g of silica gel. The fractions containing the final product are combined and the residue recrystallized from ethyl acetate/hexane, whereby 8-fluoro-5-(2-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine2-one is obtained as slightly yellowish crystals, m.p. 175-177°C. For the analysis, it is recrystallized from the same solvents, whereby colorless crystals are obtained, m.p. 177-179°C.

Example 16

6-( 2- Chlorophenyl)- 9- fluoro- 4H- imidazo/l, 5- a// l, 4/ benzodiazepine- 3- carboxylic acid ethyl ester

In the same way as described in example 9, this compound is obtained by reacting 5-(2-chlorophenyl)-8-fluoro-1,3-dihydro-2H-1,4-benzodiazepine-2-one with potassium t-butoxide and diethyl chlorophosphate and subsequent reaction with the anion of ethyl isocyanacetate. The ester is crystallized from ether and recrystallized from ethyl acetate for analytical purposes. The colorless crystals melt at 213-215°C.

The starting material for example 16 is prepared by indole oxidation as described below (examples 17-21): Example 17

3-(2-Chlorophenyl)-6-fluoro-1H-indo1-2-carboxylic acid ethyl ester

This compound is prepared as described in example 11, in which the diazonium salt of 3-fluoroaniline is coupled with the sodium salt of 2-acetyl-3-(2-chlorophenyl)propionic acid ethyl ester and then heated in ethanolic hydrochloric acid. 3-(2-Chlorophenyl)-6-fluoro-1H-indole-2-carboxylic acid ethyl ester is obtained and crystallized from ethanol/water. An analytical sample is recrystallized from hexane, whereby colorless crystals are obtained, m.p. 123-125°C.

Example 18

3-(2-Chlorophenyl)-6-fluoro-1H-indole-2-carboxylic acid

This compound is obtained by alkaline hydrolysis of the ethyl esters in the same way as described in example 12. They are crystallized from ether/hexane and recrystallized from the light solvents for analytical purposes, whereby 3-(2-chlorophenyl9-6-fluoro-lH -indole-2-carboxylic acid as slightly yellowish crystals, mp 198-200°C.

Example 19

3-(2-corphenyl)-6-fluoro-1H-indole-2-carboxamide

3-(2-chlorophenyl)-6-fluoro-1H-indole-2-carboxylic acid is transferred according to the phosphorus pentachloride/ammonia method as described in example 13 into 3-(2-chlorophenyl)-6-fluoro-1H-indole-2-carboxamide. This is crystallized from ethyl acetate/hexane and recrystallized for analytical purposes from the same solvents, whereby colorless crystals are obtained, m.p. 208-211°C.

Example 20

3-( 2- Chlorophenyl)- 6- fluoro- 1H- indole- 2- methanamine hydrochloride

A solution of 11 g (38 mmol) of 3-(2-chlorophenyl)-6-fluoro-1H-indole-2-carboxamide in 250 ml of tetrahydrofuran is added to a suspension of 6.5 g of lithium aluminum hydride in 500 ml of tetrahydrofuran. After heating at reflux for 1 hour, the excess reagent is carefully reacted by adding 40 ml of water. The inorganic material is filtered off and the filtrate is dried and evaporated. The residue is reacted with ethanolic hydrochloric acid and ether. The precipitated product is filtered off, whereby 3-(2-chlorophenyl)-6-fluoro-1H-indole-2-methanamine hydrochloride is obtained as crystals. Temp. 242-245°C. The analysis samples are recrystallized from ethanol/ether and melt at 252-255°C.

Example 21

5-( 2- chlorophenyl)- 8- fluoro- 1, 3- dihydro- 2H- 1, 4- benzodiazepine-2- one

This compound is prepared as in example 15, in which 3-(2-chlorophenyl)-6-fluoro-1H-indole-2-methanamine hydrochloride is oxidized with chromium trioxide. By filtration over silica gel using methylene chloride/ethyl acetate 1:1 (V/V) and crystallization from ethyl acetate/hexane, the product was purified and gave colorless crystals, m.p. 239-242°C.

Example 22

6- ( 2- chlorophenyl)- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxylic acid

A solution of 13.8 g (35 mmol) of 6-(2-chlorophenyl)-4H-imidazo-[1,5-a//1,4]benzodiazepine-3-carboxylic acid-(1,1-dimethyl)-ethyl ester in 50 ml of trifluoroacetic acid is stirred at room temperature for 16 hours. The reagent is evaporated, finally azeotroped with toluene. The residue is stirred with ethyl acetate and water, and the precipitated crystals are removed, whereby 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, m.p. . 257-259°C. The filtrate is extracted with dilute ammonia, and the extracts are acidified with acetic acid. The precipitate is separated, whereby a second fraction is obtained, which is recrystallized from methanol/ethyl acetate. The analysis sample is recrystallized from the same solvents and melts at 258-260°C.

Example 23

9- chloro- 6-( 2- chlorophenyl)- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine

- 3- carboxylic acid

A solution of 3.2 g (7.5 mmol) of 9-chloro-6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid (1,1- Dimethyl/ethyl ester in 30 ml trifluoroacetic acid is allowed to stand for 1.5 hours at room temperature. The reagent is evaporated under reduced pressure, finally azeotroped with toluene. The residue is dissolved in methylene chloride, washed with water, dried and evaporated. Crystallization from ethanol gives 9-chloro-6 -(2-Chlorophenyl)-4H-imidazo/1,5-a//l,4/benzodiazepine -3-carboxylic acid as a colorless product.For analytical purposes it is recrystallized from ethanol, mp 264-265°C.

Example 24

6- 82- chlorophenyl)- 9- fluoro- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxylic acid

A solution of 6.3 g (16.5 mmol) 6-(2-chlorophenyl)-9-fluoro-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester in 200 ml 6N hydrochloric acid is heated for 8 hours on a steam bath. After evaporation to dryness, the residue is stirred with 150 ml of water, 6 g of sodium acetate and 6 ml of acetic acid for 1 hour at room temperature. The precipitated crystals are filtered off, washed with water, sucked dry and recrystallized from methanol/ethyl acetate, whereby 6-(2-chlorophenyl)-9-fluoro-4H-imidazo/1,5-a//l,4/benzodiazepine- 3-carboxylic acid as a

colorless product, m.p. 270-272°C.

Example 25

9- fluoro- 6-( 2- fluorophenyl)- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxylic acid

A solution of 2.6 g (7 mmol) of 9-fluoro-6-(2-fluorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester in 100 ml of 6N hydrochloric acid heated for 8 hours in a steam bath. After evaporation to dryness, the residue is stirred with 50 ml of water, 2 g of sodium acetate and 2 ml of acetic acid. The precipitated acids are filtered off, washed with water and sucked dry. They are then recrystallized from methanol/ethyl acetate, whereby 9-fluoro-6-(2-fluorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid is obtained, m.p. 255-257°C, (Spltn.).

Example 26

6-(2-fluorophenyl)-4H-imidazo/l,5-a//l,4/benzodiazepine-3-carboxylic acid

A solution of 16.9 g (45 mmol) of 6-(2-fluorophenyl)-4H-imida-zo[1,5-a][1,4]benzodiazepine-3-carboxylic acid-(1,1-dimethyl)- ethyl ester in 60 ml of trifluoroacetic acid is allowed to stand at room temperature for 1.5 hours. The reagent is evaporated under reduced pressure, and the residue is dissolved in 250 ml of methylene chloride and reacted with 10% aqueous sodium acetate solution. After vigorous stirring for 30 minutes, the precipitated crystals are filtered off and sucked dry. After drying under reduced pressure overnight, the product is recrystallized from methanol/ethyl acetate, whereby 6-(2-fluorophenyl)-4H-imidazo-/l,5-a//l,4/benzodiazepine-3-carboxylic acid is obtained as colorless crystals, m.p. 241-243°C.

Example 27

6-(2-Chlorophenyl)-4H-imidazo/l,5-a//l,4/benzodiazepine-3-carboxamide

(A) A mixture of 5 g (13.7 mmol) of 6-(2-chlorophenyl)-4H-imidazo[1,5-a//1,4]benzodiazepine-3-carboxylic acid ethyl ester,5

g of ammonium chloride and 100 ml of methanol containing 20%

(V/V) ammonia is heated in a steel bomb for 18 hours at 100°C. The majority of the solvent is distilled off and the remainder is diluted with water. The crystals are filtered off, sucked dry and recrystallized from methylene chloride/ethanol, whereby 6-(2-chlorophenyl)-4H-imidazo/l,5-a//l,4/benzodiazepine- 3-carboxamide as colorless crystals, m.p. 310-314°C.

(B) The same compound is obtained, in which 6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid is reacted with phosphorus pentachloride and the unisolated acid chloride then with ammonia. Example 28 6-82-fluorophenyl)-4H-imidazo/l,5-a//l,4/benzodiazepine-3-carboxamide (A) A mixture of 1.5 g (4.3 mmol) 6-(2- fluorophenyl)-4H-imidazo/1,5-a//l,4/benzodiazepine-3-carboxylic acid ethyl ester, 1.5 g of ammonium chloride and 20 ml of methanolic ammonia (20%, V/V) are heated for 18 hours in a steel bomb at 100°C. The other preparations and crystals from methanol/ethanol/methylene chloride give 6-(2-fluorophenyl)-4H-imidazo/1,5-a/- /1,4/benzodiazepine-3-carboxamide as colorless crystals, m.p. >300°C. (B) The same compound was obtained by reacting 6-(2-fluorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid with phosphorus pentachloride and the unisolated acid chloride then with ammonia. Example 29 6-(2-bromophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide 3 g (7.3 mmol) 6-(2-bromophenyl)-4H-imidazo/ 1,5-a//l,4/- benzodiazepine-3-carboxylic acid ethyl ester is heated on a steam bath during 8 hours with 100 ml of 6N hydrochloric acid. After evaporation under reduced pressure, the residue is stirred with 150 ml of water, 2 ml of acetic acid and 1.5 g of sodium acetate for 1 hour at room temperature. The precipitated product is filtered off and sucked dry. Recrystallization from methanol/ethyl acetate gives a colorless acid, which melts at 265-268°C. This acid is transferred according to the phosphorus pentachloride/ammonia method described in example 31 into the amide and gives 6-(2-bromophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-corboxamide as crystals, which melts at 307-309°C (from methylene chloride/ethanol).

Example 30

6-/ 2-( trifluoromethyl) phenyl/- 4H- imidazo/ 1, 5- a// l, 4/ benzodiazepine- 3- carboxamide

6-/2-(trifluoromethyl)phenyl/-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester was, by heating as described in example 27, transferred into methanolic ammonia in contrast to ammonium chloride in 6-[2-(trifluoromethyl)-phenyl]-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide. This is recrystallized from methylene chloride/ethanol and gives colorless crystals, m.p. 295-296°.

Example 31

9- chloro- 6-( 2- chlorophenyl)- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine

- 3-corboxamide

A mixture of 2.3 g (6 mmol) of 9-chloro-6-(2-chlorophenyl)-4H--imidazo/1,5-a//l,4/benzodiazepine-3-carboxylic acid, 1.6 g ( 7.6 mmol) of phosphorus pentachloride and 75 ml of methylene chloride were stirred for 1.5 hours at room temperature. Ammonia was then added to the solution until it reacted alkaline. After the addition of water, the two-phase system was stirred for 1 hour. The product was extracted methylene chloride, the rest contains 10%

(V/V) ethanol. The extracts were dried and evaporated. Crystallization from methylene chloride/ethanol gave 9-chloro-6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-corboxamide as colorless crystals, m.p. 278-280°C.

Example 32

9-fluoro-6-(2-fluorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide (A) 2.4 g 9-fluoro-6-(2 -fluorophenyl)-4H-imidazo/l,5-a//l,4/- benzodiazepine-3-carboxylic acid was transferred into the amide, whereby one has proceeded according to the phosphorus pentachloride/ammonia method as described in example 31 and obtained the final product which is crystallized from methylene chloride/ethanol. For analytical purposes, this is recrystallized from the same solvents, whereby 9-fluoro-6-(2-fluorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-corboxamide is obtained as colorless crystals. 283-286°C. (B) This amide is obtained by reacting the corresponding ethyl esters with ammonia/ammonium chloride.

Example 33

6-( 2- chlorophenyl)- 9- fluoro- 4H- imidazo/ l>5- a// l, 4/ benzodazepine

- 3-carboxamide

3.3 g of 6-82-chlorophenyl)-9-fluoro-4H-imidazo/1,5-a//1,4/-benzodiazepine-3-carboxylic acid is transferred according to the phosphorus pentachloride/ammonia method as described in Example 31 into the amide , whereby after crystallization from methylene chloride/ethanol the final product is obtained, m.p. 295-297°C.

Example 34

6- 82- chlorophenyl)- N- methyl- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxamide

Reaction of 2 g (6 mmol) 6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid in 400 ml of methylene chloride with 1.7 g (8 mmol) of phosphorus pentachloride and subsequent reaction with methylamine gives the crude amide, which is filtered over silica gel, whereby 5% (V/V) ethanol in methylene chloride is used as solvent. Crystallization of the evaporated filtrates from ethyl acetate/hexane gives 6-(2-chlorophenyl)-N-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide as colorless crystals, m.p. 216-219°C.

Example 35

6-(2-Chlorophenyl)-ethyl-4H-imidazo/l,5-a//l,4/benzodiazepine-3

- carboxamide

2 g of 6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid are transferred as described in example 34 into the chloride and then reacted with ethylamine. The product is purified by chromatography on 50 g of silica gel using

methylene chloride/ethyl acetate 1:1 (V/V). The pure evaporated fractions are recrystallized from ethanol, whereby 6-(2-chlorophenyl)-N-ethyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide is obtained as colorless crystals, m.p. 211-212°c.

Example 36

6-(2-Chlorophenyl)-N-(1-methylethyl)-4H-imidazo/l,5-a//l,4/benzodiazepine-3-carboxamide

Reaction of 1.5 g (4.45 mmol) of 6-(2-chlorophenyl)-4H-imidazo-/1,5-a//1,4/benzodiazepine-3-carboxylic acid with 1.3 g (6, 25 mmol) phosphorus pentachloride in 150 ml methylene chloride and subsequent reaction with excess isopropylamine gives 6-(2-chlorophenyl)-N-(1-methylethyl)-4H-imidazo-/1,5-a//1,4/benzodiazepine -3-carboxamide. An analytical sample is cleaned by filtering with ethyl acetate/methylene chloride 1:1 (V/V) over silica gel and crystallized from ethyl acetate/ether, whereby colorless crystals are obtained, m.p. 218-221°C.

Example 37

9- chloro- 6-( 2- chlorophenyl)- N- ethyl- 4H- imidazo/l, 5- a// I, 4/- benzodiazepine- 3- carboxamide

9-chloro-6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid is transferred as described in example 31 into the acid chloride and reacted in situ with excess ethylamine. Crystallization from methylene chloride/ethanol gave 9-chloro-6-(2-chlorophenyl)-N-ethyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide as a colorless product, m.p. 198-200°C.

Example 38

( 2- amino- 4- chlorophenyl)( 2- chlorophenyl) methanone

52.8 ml (0.5 mol) of 3-chloroaniline is added in portions to 142.5 ml (1.125 mmol) of 2-chlorobenzoyl chloride heated at 120°C. The mixture is heated to 180-200°C and then reacted in portions with 87.2 g (0.64 mol) of zinc chloride.

After the addition is complete, the reaction mixture is heated for 1.5 hours at 200-205°C. After this time, hydrogen chloride evolution has ceased. After cooling to 120°c, 500 ml of 3N hydrochloric acid is added and the mixture is heated under reflux. The hydrochloric acid is then decanted, whereby this procedure is repeated two more times. The residue dissolved under heating in 500 ml of acetic acid. Add 300 ml conc. to this solution. hydrochloric acid, and the mixture is heated under reflux for 18 hours. The solvents are removed under reduced pressure and the residue is distributed between methylene chloride and water. The organic phase is washed with 3N sodium hydroxide solution, dried and evaporated. The residue is filtered with toluene through 300 g of silica gel. Crystallization of the final product containing fractions from ethanol gives (2-amino-4-chlorophenyl)(2-chlorophenyl)methanone as yellow crystals in two fractions. An analytical sample is recrystallized from ethanol, m.p. 104-106°C.

Example 39

2- chloromethyl- 4-( 2- chlorophenyl)- 6- fluoro- 1, 2- dihydroquinazoline- 3

- oxide

A mixture of 25 g (0.1 mol) (2-amino-5-fluorophenyl)-(2-chlorophenyl)methanone, 9 g of hydroxylamine sulfate, 120 ml of ethanol and a solution of 2-chloroacetaldehyde, which by heating for 10 minutes under reflux produces a mixture of 20 g of chloroacetaldehyde-dimethylacetal and 20 ml of 1.5N hydrochloric acid, stirred for 3 hours at room temperature. It is then distributed between water and methylene chloride. The organic phase is washed with saturated sodium bicarbonate solution, dried and evaporated. Crystallization of the residues from ether/hexane gives 2-chloromethyl-4-(2-chlorophenyl)-6-fluoro-1,2-dihydroquinazoline-3-oxide in two fractions. The analytical samples are recrystallized from ethyl acetate/ether/hexane, whereby yellow crystals are obtained, m.p. 138-141°C.

Example 40

7- chloro- 2- chloromethyl- 4-( 2- chlorophenyl)- 1, 2- dihydroquinazoline- 3-oxide

This compound is obtained in 78% yield by reacting (2-amino-4-chlorophenyl)-(2-chlorophenyl)methanone with hydroxylamine sulfate and 2-chloroacetaldehyde as described in example 41. This analytical sample is recrystallized from methylene chloride/ethanol, whereby yellowish crystals are obtained, m.p. 197-198°C. In this case, the 1,2-dihydroderivative is isolated for carrying out oxidation according to example 42 for analysis purposes.

Example 41

2-chloromethyl-4-(2-chlorophenyl)quinazoline-3-oxide

A solution of 2-chloroacetaldehyde, which, through 5-minute heating at reflux of 200 g of 2-chloro-1,1-dimethoxyethane in 200 ml, obtains 1.5N hydrochloric acid, is added to a mixture of 231 g (1 mol) ( 2-aminophenyl)(2-chlorophenyl)methanone, 90 g hydroxylamine sulfate and 1.1 1 ethanol. After stirring for 2 hours at room temperature, the reaction mixture is diluted with water and the precipitated crystals are filtered off, washed with water and sucked dry, whereby crude 2-chloromethyl-4-(2-chlorophenyl)-1,2-dihydroquinazoline-3-oxide is obtained, which which follows is oxidized directly: A solution of the materials obtained is stirred in 1.4 1 methylene chloride for 2 hours with 600 g of manganese dioxide. The manganese dioxide is filtered off and the filtrate is evaporated and crystallized by adding ether, whereby 2-chloromethyl-4-(2-chlorophenyl)quinazoline-3-oxide is obtained as yellow crystals. For analytical purposes, recrystallize from methylene chloride/ether/hexane, m.p. 167-168°C.

Example 42

7- chloro- 2- chloromethyl- 4-( 2- chlorophenyl) quinazoline- 3- oxide

Oxidation of 24 g (70 mmol) of 7-chloro-2-chloromethyl-4-(2-chlorophenyl)-1,2-dihydroquinazoline-3-oxide in 300 ml of methylene chloride with 50 g of manganese dioxide gives 7-chloro-2-chloromethyl-4- (2-chlorophenyl)quinazoline-3-oxide, m.p. 159-162°C. The analytical sample is recrystallized from tetrahydrofuran/ethanol, whereby light yellow crystals are obtained, m.p. 161-162°<C>"

Example 43

5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene-acetic acid-ethyl tert-4-oxide

A solution of 193 ml of a 1.55 molar (0.3 mol) solution of butyllithium in hexane is added at -50°C to 200 ml of a 2 molar solution of diisopropylamine in tetrahydrofuran. Ethyl acetate is then added slowly, whereby the temperature is kept below -45°C. After addition, a further solution of 30.5 g (0.1 mol) of 2-chloromethyl-4-(2-chlorophenyl)quinazoline-3-oxide in 200 ml of tetrahydrofuran is added. After removal of cooling, the reaction mixture is stirred for 2 hours under nitrogen. It is then acidified by adding 30 ml of acetic acid and distributed between toluene and water. The organic phase is dried and evaporated. Crystallization of the residues from ether gives 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene acetic acid ethyl ester-4-oxide. For analytical purposes, a sample thereof is recrystallized from methylene chloride/ether, m.p. 172-174°C.

Example 44

5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene acetic acid-(1,1-dimethyl)ethyl tert-4-oxide

A solution of 406 ml of 1.6 molar (0.65 mol) n-butyllithium in hexane is added at -50°C to 400 ml (0.8 mol) of a 2 molar solution of diisopropylamine in tetrahydrofuran. After 10 minutes of stirring under nitrogen, 108 ml (0.8 mol) of t-butyl acetate are added, whereby the temperature is kept between -40 and -50°C. After the addition, the reaction mixture is stirred for 10 minutes, while cooling to -60°C. A solution of 57.7

g (0.2 mol) of 2-chloromethyl-4-(2-fluorophenyl)quinazoline-3-oxide in 750 ml of tetrahydrofuran is then added all at once. Cooling is stopped and the mixture is stirred for 2.5 hours. After acidification with glacial acetic acid, the reaction mixture is distributed between water and toluene. The organic phases are dried and evaporated. The product precipitated by dilution with hexane is separated and washed with a little ether, whereby 5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid-(1,1-dimethyl )ethyl ester-4-oxide, m.p. 184-186°C. For analytical purposes, recrystallize from ethanol, whereby colorless crystals are obtained, m.p. 186-188°C (Splitn.).

Example 45

5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene acetic acid-(1,1-dimethyl)ethyl tert-4-oxide

Reaction of 61 g (0.2 mol) of 2-chloromethyl-4-(2-chlorophenyl)-quinazoline-3-oxide with the anion of t-butyl acetate as described in Example 44 gives 5-(2-chlorophenyl)-1,3 -dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid-(1,1-dimethyl)ethyl ester-4-oxide, m.p. 229-231°C (Spltn.). The analysis samples are recrystallized from methylene chloride/ethanol.

Example 46

8- chloro- 5-(2- chlorophenyl)- 1, 3- dihydro- 2H- 1, 4- benzodiazepine- 2-ylideneacetic acid-( 1, 1- dimethyl) ethyl ester- 4- oxide

Reaction of 20 g (0.059 mol) of 7-chloro-2-chloromethyl-4-(2-chlorophenyl)quinazoline-3-oxide with the anion of t-butyl acetate as described in Example 44 gives 8-chloro-5-(2 -chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid-(1,1-dimethyl)ethyl ester-4-oxide, which is crystallized from ether. For analytical purposes, recrystallize from ether, m.p. 197-199°C.

Example 47

5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene-acetic acid-(1,1-dimethyl) ethyl ester

145 ml of phosphorus trichloride are added in three portions within 15 minutes to a solution of 145 g (0.376 mol) 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylideneacetic acid-(1, 1-dimethyl)ethyl ester-4-oxide in 1.5 l of methylene chloride cooled with ice water. After a further 15 minutes of stirring, the reaction mixture is evaporated under reduced pressure. The remainder is distributed between methylene chloride and 10% aqueous sodium carbonate solution. The organic phase is dried and evaporated, whereby 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid-(1,1-dimethyl)ethyl ester is obtained as a yellow oil. A 2 g sample is filtered over silica gel, whereby 10% (V/V) ethyl acetate in methylene chloride is used as solvent. Crystallization from methylene chloride/ethanol gives slightly yellowish crystals, m.p. 170-173°C.

Example 48

5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene acetic acid-(1,1-dimethyl)ethyl ester

126 ml of phosphorus trichloride are added in three portions over 15 minutes to a solution of 126.5 g (0.343 mol) 5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene acetic acid -(1,1-dimethyl)ethyl ester-4-oxide in 1.3 l of methylene chloride cooled with ice water. After a further 30 minutes of stirring, the solution was evaporated and the remaining oil was distributed between methylene chloride and 10% aqueous sodium carbonate solution. The organic phase is washed with carbonate solution, dried and evaporated. Crystallization of the residue from methanol gives 5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene acetic acid-(1,1-dimethyl)ethyl ester as crystals,

m.p. 154-157°C. The analytical sample is recrystallized from methanol, m.p. 155-157°C.

Example 49

8-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid-(1,1-dimethyl) ethyl ester

This compound is obtained by reacting, as described in example 47, 8-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2 ylideneacetic acid (1,1-dimethyl)ethyl ester- 4- oxide with phosphorus trichloride. Crystallization from ether and recrystallization for analytical purposes from methylene chloride/ethanol give colorless crystals, m.p. 158-160°C.

Example 50

5-( 2- chlorophenyl)- alpha-( hydroxyimino)- 3H- 1, 4- benzodiazepine-2- acetic acid-(l, l- dimethyl) ethyl ester

53 ml of phosphorus trichloride are added in two portions over 15 minutes to an ice-cooled solution of 53.4 g (0.138 mol) 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid-( 1,1-dimethyl)ethyl ester-4-oxide in 650 ml of methylene chloride. After a further 15 minutes of stirring, the solvent is evaporated under reduced pressure, and the residue is distributed between methylene chloride and 10% aqueous sodium carbonate solution. After preparation, the residue is reacted with 12.45 g (0.18 mol) of sodium nitrite in 350 ml of glacial acetic acid. Diluted with water, filtration and recrystallization from tetrahydrofuran/ethanol gives 5-(2-chlorophenyl)-alpha-(hydroxy-imino)-3H-1,4-benzodiazepine

-2-acetic acid-(1,1-dimethyl)ethyl ester as slightly yellowish crystals, m.p. 229-230°C. For analytical purposes, recrystallize from methylene chloride/ethanol, whereby the melting point remains unchanged. Example 51 5-(2-chlorophenyl)-alpha-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid ethyl ester 25 ml of phosphorus trichloride is added in three portions over 15 minutes to a solution of 25.2 g (0 .07 mol) 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid ethyl ester-4-oxide in 250 ml in ice-water cooled methylene chloride. After a further 15 minutes of stirring at room temperature, the reaction mixture is evaporated. The remainder is distributed between methylene chloride and 10% aqueous sodium carbonate solution. The organic phase is dried and evaporated and the residue is dissolved in 150 ml of glacial acetic acid and reacted with 6.8 g of sodium nitrite in two portions. The reaction mixture is stirred for 1 hour and then diluted with water. The precipitated product is filtered off, washed with water and sucked dry. Recrystallization from tetrahydrofuran/ethanol gives 5-(2-chlorophenyl)-alpha-(hydroxyimino)-3H-1,4-benzodiazepine 2-acetic acid ethyl ester as yellowish crystals, m.p. 245-248°C (Splitn.). Example 52 8-chloro-5-(2-chlorophenyl)-alpha-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid-(1,1-dimethyl)ethyl ester 4 g (58 mmol) of sodium nitrite is given a solution of 19 g (47 mmol) of 8-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2ylideneacetic acid-(1,1-dimethyl)ethyl ester in 150 ml of glacial acetic acid. After stirring for 30 minutes at room temperature, the reaction mixture is diluted and the precipitated crystals are filtered off, washed with water and sucked dry. Recrystallization from methylene chloride/ethanol gives 8-chloro-5-(2-chlorophenyl)-alpha-(hydroxyimino)-3H-1,4-benzod in azepine-2-acetic acid-(1,1-dimethyl)ethyl ester, m.p. 208-210°C.

Example 53

5-( 2- chlorophenyl)- alpha-( hydroxyimino)- 3H- 1, 4- benzodiazepine-2- acetic acid- ethyl ester- 4- oxide

A solution of 35.7 g (0.1 mol) of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid ethyl ester-4-oxide in 225 ml of glacial acetic acid is reacted with 9, 75 g (0.14 mol) sodium nitrite in two portions inert 10 minutes. After stirring for 1 hour at room temperature, the crystalline product is further precipitated and filtered off by dilution with water. It is washed with water and vacuumed dry. Recrystallization from tetrahydrofuran/ethanol gives 5-(2-chlorophenyl)-alpha-(hydroxy-oxyimino)-3H-1,4-benzodiazepine-2-acetic acid-ethyl ter-4-oxide as yellowish crystals, m.p. 262-264°C (Splitn.).

A second fraction can be isolated from the mother liquor.

Example 54

5- ( 2- fluorophenyl)- alpha-( hydroxyimino)- 3H- 1, 4- benzodiazepine

- 2-acetic acid-(1,1-dimethyl) ethyl ester solvated with 1 mol of ethanol

Reaction of 70.4 g (0.2 mol) 5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene acetic acid-(1,1-dimethyl)-ethyl ester with 19 .3 g (0.28 mol) of sodium nitrite in 425 ml of glacial acetic acid gives 5-(2-fluorophenyl)-alpha-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid-(1,1-dimethyl)ethyl ester which a product solvated with 1 mol of ethanol, m.p. 214-216°C (Splitn.). For analytical purposes, it is recrystallized from methylene chloride/ethanol.

Example 55

6-(2-Chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid-(1,1-dimethyl) ethyl ester

A mixture of 17 g (42.5 mmol)

5-(2-chlorophenyl)-alpha-(hydroxyimino)-3H-1,4-benzodiazepine-

2-acetic acid-(1,1-dimethyl)ethyl ester, 240 ml of tetrahydrofuran, 120 ml of methanol, 17 g of Raney nickel and 3 ml of methanolic ammonia (20%, V/V) are hydrated at atmospheric pressure for 2 hours. The catalyst is filtered off and filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in 100 ml of ethyl acetate. The solution is reacted with 6.8 ml (50 mmol) of dimethylformamide-dimethylacetal and heated for 5 minutes under reflux. After adding 100 ml of hexane, the product is crystallized by cooling. It is separated, whereby 6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid (1,1-dimethyl)ethyl ester is obtained as brownish crystals. The analytical samples are recrystallized from methylene chloride/ethyl acetate, whereby colorless crystals are obtained, m.p. 247-249°C.

Example 56

6-(2-Fluorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid-(1,1-dimethyl) ethyl ester

38.2 g (0.09 mol) 5-(2-fluorophenyl)-alpha-(hydroxy-imino)-3H-1,4-benzodiazepine-2-acetic acid-(1,1-dimethyl)ethyl ester, which is solvated with 1 mol of ethanol is hydrated as described in example 55 for 3 hours over Raney nickel. The crude hydration product is dissolved in 200 ml of ethyl acetate. After adding 19 ml of dimethylformamide-dimethyl acetal, the mixture is heated for 5 minutes at reflux. The product is crystallized by the addition of 500 ml of hexane and cooled, thereby obtaining 6-(2-fluoro-phenyl)4H-imidazo/1,5-a//1,4/benzodiazepine-2-acetic acid-(1,1-dimethyl )ethyl ester as crystals, m.p. 216-219°C. The analytical samples are recrystallized from ethyl acetate/hexane, m.p. 218-220°C.

Example 57

6-( 2- Chlorophenyl)- 4H- imidazo/l, 5- a// l, 4/ benzodiazepine- 3- carboxylic acid- ethyl ester- 5- oxide

A mixture of 31 g (0.08 mol) 5-(2-chlorophenyl)-alpha-(hydroxyimino)-3H-1,4-benzodiazepine 2-acetic acid ethyl ester 4-oxide, 600 ml tetrahydrofuran, 300 ml of ethanol, 12 ml of methanol containing 20% (V/V) ammonia and 31 g of Raney nickel are hydrogenated at atmospheric pressure until hydrogen uptake ceases (2 hours). After filtration and evaporation, the residue is dissolved in 150 ml of ethyl acetate. 16 ml of dimethylformamide-dimethylacetal are added and the solution is heated for 5 minutes at reflux. The product is crystallized on cooling and filtered off and washed with ether, whereby 6-(2-chlorophenyl)-4H-imidazo[1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester 5-oxide is obtained as crystals, m.p. 245-248°C. For analytical purposes, recrystallize from methylene chloride/ethyl acetate whereby the melting point remains unchanged.

Example 58

6-(2-Chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid-(1,1-dimethyl) ethyl ester

A mixture of 12 g (0.03 mol) 5-(2-chlorophenyl)-alpha-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid-(1,1-dimethyl)-ethyl ester, 200 ml tetrahydrofuran, 100 ml of ethanol, 3 ml of methanolic ammonia (20%, V/V) and 23 g of Raney nickel are hydrated for 1.5 hours at atmospheric pressure. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The yellow residue is dissolved in 400 ml of methylene chloride and reacted with 5 ml (0.09 mol) of acetaldehyde. After stirring for 20 minutes at room temperature, 12 g of manganese dioxide is added and stirring is continued for 30 minutes. The manganese dioxide is filtered off and the filtrate is evaporated. Crystallization of the residues from ethyl acetate gives 6-(2-chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid-(1,1-dimethyl)ethyl ester, m.p. 250--253°C. The analysis samples are recrystallized from ethyl acetate, whereby the melting point remains unchanged.

Example 59

6-(2-Chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid-ethyl ester-5-ox yd 11 g 5-(2-Chlorophenyl)- alpha-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid ethyl ester-4-oxide is hydrated as described in example 58 and the crude hydration product is added and the solution is stirred for 20 minutes. After the following addition of 11 g of manganese dioxide, the mixture is stirred for a further 30 minutes. The manganese dioxide is filtered off over celite and the filtrate is evaporated. Crystallization of the residues from ethyl acetate gives 6-(2-chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester-5-oxide, m.p. 221-224°C. The analytical samples are recrystallized from methylene chloride/ethyl acetate, whereby colorless crystals are obtained, m.p. 224-226°C.

Example 60

6-(2-chlorophenyl)-l-ethyl-4H-imidazo/l,5-a//l,4/benzodiazepine

- 3- carboxylic acid-(1,1-dimethyl) ethyl ester

A mixture of 5 g (12.6 mmol) of 5-(2-chlorophenyl)-alpha-(hydroxy-oxyimino)-3 H-1,4-benzodiazepine-2-acetic acid-(1,1-dimethyl)-ethyl ester, 100 ml of tetrahydrofuran, 50 ml of ethanol, 2 ml of methanol containing 20% (V/V) ammonia and 5 g of Raney nickel are hydrogenated at atmospheric pressure until hydrogen absorption ceases (1-2 hours). After filtration and evaporation, the residue is dissolved in 200 ml of methylene chloride and after adding 2 ml of propionaldehyde, it is stirred for 20 minutes. The solution is then reacted with 5 g of manganese dioxide and stirred for a further 20 minutes. The manganese dioxide is filtered off over celite. The filtrate is evaporated and the residue is recrystallized from ether, whereby 6-(2-chlorophenyl)-1-ethyl-4H-imidazo/1,5-a//1,4/-benzodiazepine-3-carboxylic acid (1,1- dimethyl ) ethyl ester , which is crystallized from ethyl acetate/hexane for analytical purposes, m.p. 211-213°C.

Example 61

9- chloro- 6-( 2- chlorophenyl)- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine

- 3- carboxylic acid-(1,1-dimethyl) ethyl ester

A mixture of 15 g (35 mmol) of 8-chloro-5-(2-chlorophenyl)-alpha-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid-(1,1-dimethyl-9-ethyl) ter , 150 ml tetrahydrofuran, 75 ml methanol, 15 g Raney nickel and 5 ml methanolic ammonia (20%, V/V) are hydrated for 2.5 hours at atmospheric pressure, after which time the hydrogen absorption has ceased. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is dissolved in 200 ml of ethyl acetate and the solvent is reacted with 10 ml of dimethylformamide-dimethyl acetal. After 5 minutes of heating to reflux, the solvent is evaporated and the residue is recrystallized from ether, whereby 9-chloro-6-(2-chlorophenyl)-4H- imidazo/l,5-a//l,4/benzodiazepine-3-carboxylic acid-(1,1-dimethyl)ethyl ester, mp 232-234° C. The analytical sample is purified by chromatography on silica gel using methylene chloride/ethyl acetate 1: 1 (V/V) and crystallization from ethanol, mp 234-236°C.

Example 62

6-(2-Chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid

A solution of 10 g (24.5 mmol) 6-(2-chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid (1,1-dimethyl ) ethyl ester in 50 ml trifluoroacetic acid is allowed to stand overnight, whereby nitrogen is slowly blown through. The mixture is evaporated under reduced pressure, finally with toluene. The remainder is distributed between diluted ammonia and ethyl acetate. The ammonia concentrates are acidified with acetic acid and partially evaporated. The precipitated crystals are separated and washed with water, whereby 6-(2-chloro-phenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazep in-3-carboxylic acid is obtained as colorless crystals. Recrystallization from methanol/ethyl acetate gives a product which melts at 272-274°c.

Example 63

6-(2-Chlorophenyl)-1-methyl-4H-imidazo-/1,5-a//1,4/benzodiazepine-3-carboxamide

Reaction of 18.8 g (53 mmol) of 6-(2-chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid with 15.6 g (75 mmol) phosphorus pentachloride in 2 1 methylene chloride and subsequent reaction with excess ammonia gas leads to 6-(2-chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/- benzodiazepine n-3-carboxamide, which are recrystallized from methylene chloride/ethanol. The analytical sample is recrystallized from tetrahydrofuran/ethanol, m.p. 318-321°C.

Example 64

6-(2-Chlorophenyl)-N-ethyl-1-methyl-4H-imidazo/1,5-a//1,4/- benzodiazepine-3-carboxamide

Using the phosphorus pentachloride/ethylamine method as described in 63, 2.8 g (8 mmol) of 6-(2-chlorophenyl)-1-methyl-4H-imida2 o/l,5-a//l,4/-benzodiazepine- 3-carboxylic acid in the analogous ethylamide and crystallized from methylene chloride/ethyl acetate. The analysis sample is recrystallized from the same solvents, m.p. 240-242°C.

Example 65

6- 82- chlorophenyl)- l- ethyl- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine

- 3-carboxamide

Conversion of 1.85 g (5 mmol) of 6-(2-chlorophenyl)-l-ethyl-4H-imidazo/1,5-a//l,4/benzodiazepine-3-carboxylic acid, as by cleavage of the t-butyl ester group in the final product of Example 60 is obtained with trifluoroacetic acid, giving with 1.47 g (7 mmol) phorsphorpentachloride in 200 ml methylene chloride for 1 hour and subsequent reaction with ammonia 6-(2-chlorophenyl)-1-ethyl-4H-imidazo-/l ,5-α//l,4/benzodiazepine-3-carboxamide as colorless product, m.p. 288-290°C, which crystal-

is lysed from tetrahydrofuran/ethanol.

Example 66

6-(2-Chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide-5-oxide

A mixture of 1 g (2.5 mmol) 6-(2-chlorophenyl)-4H-imidazo-[1,5-a//1,4]benzodiazepine-3-carboxylic acid ethyl ester-5-oxide, 1 g ammonium chloride and 20 ml of methanol containing 20% (V/V) ammonia are heated for 18 hours at 95-100°C. The reaction mixture is diluted with water and the precipitated crystals are filtered off, sucked dry and recrystallized from methylene chloride/methanol, whereby 6-(2-chlorophenyl)-1-methyl-4H-imidazo/l,5-a//l,4/benzodiazepine is obtained -3-carboxamide-5-oxide as colorless product, m.p. 307-310°C (Splitn.).

Example 67

6( 2- Corphenyl)- 4H- imidazo/l, 5- a// l, 4/ benzodiazepine- 3- carboxamide- 5- oxide

(A) 1.55 g (9 mmol) m-chloroperbenzoic acid is added to a solution of 2 g (5.9 mmol) 6-(2-chlorophenyl)-4H-imidazo-/1,5-a/-

/1,4/benzodiazepine-3-carboxamide in 500 ml of methylene chloride. After standing at room temperature overnight, the solution is washed with saturated aqueous sodium bicarbonate solution, dried and evaporated. The crystalline residue is recrystallized from methylene chloride/methanol, whereby 6-(2-chlorophenyl)-4H-imidazo-/1,5-a//1,4/benzodiazepine-3-carboxamide-5-oxide is obtained as a colorless product, m.p. . 301-304°C (Spltn.).

(B) A mixture of 3 g (7.6 mmol) of 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester tert-5-oxide, 3 g of ammonium chloride and 75 ml of 20% methanolic ammonia are heated for 18 hours in a steel bomb at 100°C. The reaction mixture is diluted with water and the product is filtered off, sucked dry and recrystallized from methylene chloride/methanol, whereby 6-(2-chlorophenyl)-4H-imidazo/1,5-

α//l,4/benzodiazepine-3-carboxamide-5-oxide as crystals, which are identical to the product obtained in paragraph (A).

Example 68

N- acetyl- 6-( 2- chlorophenyl)- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxamide

3.36 g (10 mmol) of 6-(2-chlorophenyl)-4H-imidazo/1,5-a/-/1,4/- benzodiazepine-3-carboxamide is heated in 125 ml of acetic anhydride for 1.5 hours at reflux, while distilling off 50 ml of the reagent. The solvent is evaporated, finally azeotroped with silane and the residue crystallized from ethyl acetate, whereby N-acetyl-6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide is obtained, which is recrystallized from tetrahydrofuran/ethyl acetate/hexane to give colorless crystals, m.p. 178-180°C.

Example 69

N- acetyl- 6-( 2- chlorophenyl)- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxamide- 5- oxide

1.57 g (9 mmol) of m-chloroperbenzoic acid is given a solution of 2.3 g (6 mmol) of N-acetyl-6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/ - benzodiazepine-3-carboxamide in 125 ml methylene chloride. After leaving to stand at room temperature for 24 hours, the solution is washed with saturated sodium bicarbonate solution, dried and evaporated. Crystallization of the residue from methylene chloride/methanol gives N-acetyl-6-(2-chlorophenyl)-4H-imidazo/l,5-a//l,4/- benzodiazepine-3-carboxamide-5-oxide as a colorless product, m.p. 275-278°C (Splitn.).

Example 70

4- acetyloxy- N- acetyl- 6-( 2- chlorophenyl)- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxamide

A solution of 1.8 g (4.5 mmol) of N-acetyl-6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide-5-oxide in 150 ml of acetic anhydride are heated for 1.5 hours at reflux. The solution is evaporated and finally azeotroped with xylene. The residue is crystallized from ethyl acetate/ether, whereby 4-acetyloxy-N-acetyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a//1,4]benzodiazepine-3-carboxamide is obtained as crude product. This is cleaned by filtering it over silica gel with 10%

(V/V) ethyl acetate in methylene chloride. Evaporation and crystallization from ethyl acetate/hexane gives colorless crystals that melt at 170-173°C.

Example 71

N-acetyl- 4- acetyloxy- 6-( 2- chlorophenyl)- l- methyl- 4H- imidazo-/ l, 5- a// l, 4/ benzodiazepine- 3- carboxamide

A solution of 1 g (3 mmol) 6-(2-chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide-5-oxide in 75 ml of acetic anhydride is heated 1 hour in return. A portion of the solvent (25 ml) is removed with a Dean-Stark trap. After evaporation to dryness, the residue is chromatographed over 30 g of silica gel, whereby methylene chloride/ethyl acetate 1:1 (V/V) is used as eluent. The pure fractions of the product are combined and evaporated. Crystallization of the residue from ether gives N-acetyl-4-acetyloxy-6-(2-chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide as colorless crystals, m.p. 176-180°C. NMR (CDCl 2 ) shows a mixture of two rotamers in an approximately 1:1 ratio.

Example 72

6-( 2- Chlorophenyl)- 4- hydroxy- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxamide

8.5 ml (17 mmol) of 2N sodium hydroxide are added to a solution of 0.75 g (1.7 mmol) of 4-acetyloxy-N-acetyl-6-(2-chlorophenyl)-4H-imidazo/1,5-a //1,4/benzodiazepine-3-carboxamide in 25 ml of methanol. After stirring for 1.5 hours at room temperature under nitrogen, the solution is buffered with carbon dioxide and diluted with water. The precipitated crystals are filtered off, washed with water and sucked dry. Recrystallization from methylene chloride/methanol gives 6-(2-chlorophenyl)-4-hydroxy-4H-imidazo/1,5-a/- /1,4/benzodiaz epine-3-carboxamide as colorless crystals, m.p. 305-308°C (Splitn.).

Example 73

6-(2-Chlorophenyl)-4-hydroxyl-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide

A solution of 3.4 g (7.5 mmol) of N-acetyl-4-acetyloxy-6-(2-chlorophenyl)-1-methyl-4H-imidazo/1,5-a//1,4/benzodiazepine- 3-carboxamide in 40 ml of methanol is reacted with 37.5 ml of 2N sodium hydroxide solution. After 1 hour of stirring under nitrogen at room temperature, the solution is acidified with glacial acetic acid and diluted with water. The precipitated product is filtered off and recrystallized from methylene chloride/methanol, whereby 6-(2-chlorophenyl)-4-hydroxy-1-methyl-4H-imidazo/1,5-a//1,4/-benzodiazepine-3 is obtained -carboxamide as colorless crystals, m.p. 305-307°C.

Example 74

6-(2-chlorophenyl)-4H-imidazo/l,5-a//l,4/benzodiazepine-3-carboxylic acid-ethyl ester-5-oxide (A) A mixture of 40.2 g ( 0.019 mol) 6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester,

35.6 g (0.165 mol) of 80% chloroperbenzoic acid and 1 l of methylene chloride are stirred for 15 minutes, until the solid is dissolved and after 18 hours it is allowed to stand at room temperature. After washing with 10% aqueous sodium carbonate solution, the methylene chloride phase is dried and evaporated. Crystallization of the residue from 300 ml of saturated methyl acetate gives 6-(2-chlorophenyl)-4H-imidazo-/1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester-5-oxide, m.p. 242-245°C. (B) This compound is also obtained in 56% yield by reaction of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one-4-oxide with a base, followed by reaction with diethyl chlorophosphate and ethyl isocyanoacetate.

Example 75

4- acetyloxy- 6-( 2- chlorophenyl)- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3-c carboxylic acid ethyl ester

A mixture of 10 g (0.026 mol) 6-(2-chlorophenyl)-4H-imida-zo[l,5-a/l,4]benzodiazepine-3-carboxylic acid ethyl ester-5-oxide and 140 ml of acetic anhydride and heated with stirring for 1 hour at reflux. The solution is then evaporated to a small volume, diluted with ether and cooled on ice. Filtration and washing with ether gives 4-acetyloxy-6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester, m.p. 190-192°c. The analysis sample is recrystallized from ethyl acetate/hexane and melts at 192-195°C.

Example 76

6-( 2- Chlorophenyl)- 4- hydroxy- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxamide

A mixture of 9.5 g (0.022 mol) 4-acetyloxy-6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester and 95 ml of 20% 100 ml of methanolic ammonia is stirred in a closed container for 23 hours at room temperature. Filtration and washing with methanol gives 6-(2-chlorophenyl)-4-hydroxy-4H-imidazol/1,5-a//l,4/-benzodiazepine-3-carboxamide, m.p. 306-308°C.

Example 77

6-(2-chlorophenyl)-4-hydroxy-N-methyl-4H-imidazo/l,5-a//l,4/benzodiazepine-3-carboxamide

A mixture of 3 g (0.007 mol) 4-acetyloxy-6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester and 45 ml of 20% methylamine solution in ethanol stirred for 18 hours in a closed keep at room temperature. The product is filtered off and washed with ethanol and ether, whereby 6-(2-chlorophenyl)-4-hydroxy-N-methyl-4H-imidazo/1,5-a//1,4/- benzodiazepine-3-carboxamide is obtained, m.p. 258-260°C. Recrystallization for analytical purposes from tetrahydrofuran/ethanol yields colorless crystals, which melt at 260-262°C.

Example 78

6-( 2- Chlorophenyl)- N- ethyl- 4- hydroxy- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxamide (A) A mixture of 2 g of 4-acetyloxy-6- (2-Chlorophenyl)-N-ethyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide, 30 ml of methanol and 4 ml of 3N sodium hydroxide solution are stirred for 30 minutes at room temperature. The solution is then distributed between methylene chloride and aqueous sodium bicarbonate solution. The organic phase is dried and evaporated. Crystallization of the residue from methylene chloride/ethyl acetate gives 6-(2-chlorophenyl)-N-ethyl-4-hydroxy-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide as colorless crystals, m.p. 246-248°C.

(B) A mixture of 0.43 g of 4-acetyloxy-6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid ethyl ester and 10 ml of ethanol containing 20 % (V/V) ethylamine is stirred for 24 hours at room temperature. The solvent is evaporated, and the residue is recrystallized from ethylene chloride/ethyl acetate, whereby 6-(2-chlorophenyl)-N-ethyl-4-hydroxy-

4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide as colorless product, m.p. 246-248°C.

Example 79

4- acetyloxy- 6-( 2- chlorophenyl)- N- ethyl- 4H- imidazo/ l, 5- a// l, 4/

- benzodiazepine-3-carboxamide

A solution of 5.4 g of 6-(2-chlorophenyl)-N-ethyl-4H-imidazo-[1,5-a//1,4]benzodiazepine-3-carboxamide-5-oxide is heated in 70 ml of acetic anhydride in 18 hours at 100°C. The reagent is evaporated under reduced pressure and the residue is crystallized from ethyl acetate/ether/hexane and recrystallized from ethyl acetate/hexane, whereby 4-acetyloxy-6-(2-chlorophenyl)-N-ethyl-4H-imidazo/1,5-a/ /l,4/benzodiazepine-3-carboxamide as colorless crystals, m.p. 145-150°C.

Example 80

6-( 2- chlorophenyl)- N- ethyl- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine

- 3- carboxamide- 5- oxide

A mixture of 6.5 g (0.017 mol) 6-(2-chlorophenyl)-N-ethyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide, 4.75 g (0 .22 mol) 80% pure m-chloroperbenzoic acid and 250 ml methylene chloride are stirred until everything is dissolved. The solution is then allowed to stand for 18 hours at room temperature. After washing with a 10% aqueous sodium carbonate solution, the methylene chloride solution is dried and evaporated. The residue is chromatographed using a mixture of ethanol/methylene chloride 1:19 on silica gel. The fractions containing the product are combined and evaporated. Crystallization from ethanol gives 6-(2-chlorophenyl)-N-ethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide-5-oxide, m.p. 175-180°C.

Example 81

6-( 2- Chlorophenyl)- l-( 1, 1- dimethylethyl)- 4H- imidazo/ l, 5- a// l, 4/ benzodiazepine- 3- carboxylic acid-( l, l- dimethyl) ethyl ester

A mixture of 7.95 g (0.02 mol) 5-(2-chlorophenyl)-alpha-(hydroxyimino)-3H-1,4-benzodiazepine 2-acetic acid-(1,1-dimethyl)ethyl ester, 8 g Raney nickel, 150 ml of tetrahydrofuran, 75 ml of ethanol and 2 ml of 20% methanolic ammonia were hydrated at atmospheric pressure for 2.5 hours. The catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in 200 ml of toluene, reacted with 5.16 g (0.06 mol) of pivalaldehyde and stirred for 1 hour. After adding 8 g of manganese dioxide, the mixture is stirred for half an hour. It is then filtered off and the filtrate is evaporated. Crystallization from ether/hexane gives 6-(2-chlorophenyl)-1-(1,1-dimethylethyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid (1,1-dimethyl )-ethyl ester, m.p. 194-19°C. Recrystallization for analytical purposes from ethyl acetate/hexane gives a product which melts at 195-197°C.

Example 82

6-(2-chlorophenyl)-l-(1,1-dimethylethyl)-4H-imidazo/l,5-a//l,4/benzodiazepine-3- carboxylic acid

A solution of 1.1 g (2.5 mmol) of 6-(2-chlorophenyl)-1-(1,1-dimethylethyl)-4H-imidazo[1,5-a[1,4]benzodiazepine- 3-carboxylic acid-(1,1-dimethyl)ethyl ester in 10 ml of trifluoroacetic acid is allowed to stand for 2 hours and then evaporated. The oil is azeotropically distilled with toluene and then crystallized from saturated ethyl acetate. Recrystallization from methanol/ethyl acetate gives 6-(2-chlorophenyl)-1-(1,1-dimethylethyl)-4H-imidazo/1,5-a//1,4/ benzodiazepine-3-carboxylic acid.

Example 83

6-(2-chlorophenyl)-!-(!,1- dimethylethyl)- 4H- imidazo/l, 5- a// l, 4/ benzodiazepine- 3- carboxamide

A solution of 0.56 g (1.4 mmol) of 6-(2-chloro-phenyl)-1-(1,1-dimethylethyl)-4H-imidazo[1,5-a][1,4]benzodiazepine- 3-carboxylic acid in 75 ml methylene chloride is reacted with 0.38 g (1.8 mmol) phosphorus pentachloride and stirred for 1 hour. Ammonia is introduced into the solution until it reacts basic. After adding 25 ml of water and 10 ml of ethanol and stirring for 1 hour, the methylene chloride phase is separated, dried and evaporated. Recrystallization from methylene chloride/ethanol gives 6-(2-chlorophenyl)-1-(1,1-dimethylethyl)-4H-imidazo-/1,5-a//1,4/benzodiazepine-3-carboxamide, m.p. 275-278°C.

Example 84

6-(2-Chlorophenyl)-1-propyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid-(1,1-dimethyl) ethyl ester

A mixture of 7.95 g (0.02 mol) 5-(2-chlorophenyl)-alpha-(hydroxyimino)-3H-1,4-benzodiazepine 2-acetic acid-(1,1-dimethyl) ethyl ester, 8 g Raney nickel, 150 ml of tetrahydrofuran, 75 ml of ethanol and 2 ml of 20% ammonia in methanol are hydrated for 2.5 hours at room temperature. The catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in 200 ml methylene chloride, reacted with 4.32 g (0.06 mol) butyraldehyde, stirred for 1 hour in an open vessel and then evaporated. The residue is chromatographed on silica gel, whereby a 1^-mixture of ethyl acetate/methylene chloride is used as eluent. The fractions containing the desired product are combined and evaporated. Crystallization from ether gives 6-(2-chlorophenyl)-1-propyl-4H-imidazo-[1,5-a//1,4]benzodiazepine-3-carboxylic acid-(1,1-dimethyl)ethyl ester, m.p. . 176-179°C. For analytical purposes, recrystallize from ether, whereby a product is obtained which melts at 178-180°C.

Example 85

6-(2-chlorophenyl)-l-propyl-4H-imidazo/l,5-a//l,4/benzodiazepine-3- carboxylic acid

A solution of 1.9 g (4.3 mmol) of 6-(2-chlorophenyl)-1-propyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid-(1,1 -dimethyl)ethyl ester in 20 ml of trifluoroacetic acid is allowed to stand for 2 hours at room temperature and is then evaporated and azeotropically distilled with toluene. Crystallization from methanol/ethyl acetate and recrystallization from the same solvents gives 6-(2-chlorophenyl)-1-propyl-4H-imidazo/1,5-a/- /1,4/benzodiazepine-3-carboxylic acid, m.p. . 271-273°C.

Example 86

6-(2-Chlorophenyl)-1-propyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide

A solution of 1.1 g (2.8 mmol) of 6-(2-chlorophenyl)-1-propyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid in 125 ml of methylene chloride is reacted with 0.78 g (3.7 mmol) phosphorus pentachloride and stirred for 1 hour. Ammonia is introduced into the solution until it reacts alkaline. After adding 50 ml of water and 25 ml of ethanol, the solution is stirred for 1 hour. The methylene chloride phase is separated, dried and evaporated. Recrystallization from methylene chloride gives 6-(2-chlorophenyl)-1-propyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide, m.p. 290-292°C.

Example 87

5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one 4-oxide

(A) 50 ml of a 1N sodium hydroxide solution is added to a solution of 5 g of 2-chloromethyl-4-(2-chlorophenyl)quinazoline-3-oxide in

250 ml of tetrahydrofuran. After stirring for 3 hours at room temperature, the mixture is acidified by adding glacial acetic acid and

is evaporated to a small volume. This is then distributed between methylene chloride, containing 10% ethanol and aqueous sodium bicarbonate solution. The organic phase is dried and evaporated and the residue is recrystallized from methylene chloride/ethanol, whereby 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one-4-oxide is obtained as colorless crystals, m.p. 231-232°C.

(B) This compound is obtained in 88% yield when oxidizing 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one

with m-chloroperbenzoic acid in methylene chloride.

Example 88

5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene-propanedicarboxylic acid- dimethyl ester

A solution of 27 g (0.1 mol) of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one in 400 ml of tetrahydrofuran is cooled with ice water. After adding 13 g (0.115 mol) of potassium t-butoxide, the mixture is stirred for 5 minutes under nitrogen. Then 18 ml (0.125 mol) of diethyl chlorophosphate are added and stirring is continued for a further 10 minutes. After adding 26.4 g (0.2 mol) of dimethyl malonate and 22.4 g (0.2 mol) of potassium t-butoxide, the mixture is stirred without cooling for 2 hours and then reacted with 20 ml of acidified acetic acid and distributed between toluene and sodium bicarbonate solution. The organic phase is separated, dried and evaporated. Crystallization of the residue from ether gives yellowish crystals, m.p. 133-138°C. For analysis purposes, the product is cleaned by filtering it over silica gel, using 5%

(V/V) ethyl acetate in methylene chloride as eluent. Crystallization from ether gives pure material consisting of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene-propanedicarboxylic acid dimethyl ester, m.p. 135-138°C.

Example 89

5- ( 2- Chlorophenyl 9- alpha-( hydroxyimino)- 3H- 1, 4- benzodiazepine-2- ed in xyr em ethyl ester

A mixture of 9 g (23.4 mmol) 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene propanedicarboxylic acid dimethyl ester, 6.6 g (0.117 mol) potassium hydroxide and 300 ml of methanol are heated under nitrogen for 3 hours at reflux. The majority of the solvent is removed under reduced pressure, and the remainder is distributed between water and methylene chloride. The organic phase is separated, dried and evaporated, whereby oily 5-(2-chlorophenyl9-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid methyl ester is obtained. This material is dissolved in 50 ml of glacial acetic acid, and the solution is reacted with 1.96 g (28 mmol) of sodium nitrite. After stirring for 1 hour at room temperature, the mixture is diluted with water and the precipitated product is filtered off, washed with water and sucked dry. Recrystallization from methylene chloride/ethanol gives 5-(2-chlorophenyl) -alpha-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid methyl ester as yellow crystals, mp 246-248°C.

Example 90

6- ( 2- Chlorophenyl)- l - / ( 2- dimethylamino) et yl / - 4H- imidazo- / l, 5- a / / l, 4 / benzodiazepine- 3- carboxylic acid - methyl ester

A mixture of 8 g of 5-(2-chlorophenyl)-alpha-(hydroxyimino)-3H-1,4-benzodiazepine 2-acetic acid methyl ester, 200 ml of tetrahydrofuran, 80 ml of methanol, 14 g of Raney nickel and 2 ml of 20% 100 ml of methanolic ammonia (V/V) is hydrated at atmospheric pressure for 2 hours. The catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of methylene chloride and heated with 20 ml of a 20% (V/V) solution of dimethylamine in tetrahydrofuran and 4 ml of acrolein. After 20 minutes of stirring at room temperature, 14 g of activated manganese dioxide are added and stirring is continued for 30 minutes. The manganese dioxide is filtered off over celite and the filtrate is evaporated. Crystallization of the residue

from ethyl acetate/ether gives 6-(2-chlorophenyl)-1-/(2-dimethyl-

amino)-ethyl/-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid methyl ester which is recrystallized from methanol/ethyl acetate/ether, whereby colorless crystals are obtained, m.p. 170-172°C.

Example 91

6-( 2- Chlorophenyl)- 1-/ 2-( dimethylamino) ethyl/- 4H- imidazo-/ l, 5-a// l, 4/ benzodiazepine- 3- carboxamide

A mixture of 3 g of 6-(2-chlorophenyl)-1-(dimethylamino)-ethyl/-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid methyl ester, 3 g ammonium chloride and 75 ml of methanol containing 20% (V/V) ammonia are heated for 18 hours in a steel bomb at 100°C. The solvent is partially evaporated, and the residue is distributed between methylene chloride and aqueous ammonia. The organic phase is dried and evaporated. The residue is crystallized from methanol/ethyl acetate, whereby 6-(2-chlorophenyl)-1-(dimethylamino)ethyl/-4H-imidazo/1,5-a//1,4/-benzodiazepine-3-carboxamide is obtained . The analysis sample is recrystallized from the same solvents, whereby slightly yellowish crystals are obtained, m.p. 257-260°C.

Example 92

6-( 2- Chlorophenyl9- 1-( Hydroxymethyl)- 4H- imidazo/l, 5- a// l, 4/benzodiazepine- 3- carboxylic acid-(l, l- dimethyl) ethyl ester

A mixture of 1.9 g of 6-(2-chlorophenyl)-4H-imidazo-/1,5-a//1,4/benzodiazepine-1,3-dicarboxylic acid-1-ethyl-3-(1,1- dimethyl)ethyl ester, 100 ml of ethanol and 1 g of sodium borohydride are heated for 15 minutes at reflux. The solvent is partially evaporated and the remainder distributed between water and methylene chloride. The organic phase is dried and evaporated. Crystallization of the residue from methylene chloride/ethyl acetate gives 6-(2-chlorophenyl)-1-(hydroxymethyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid-(1,1-dimethyl) ethyl ester. For analytical purposes, recrystallize from methanol/ethyl acetate, whereby colorless crystals are obtained, m.p. 253-254°c

(Spaltn . ) .

Example 93

1-(Chloromethyl)- 6-(2- Chlorophenyl)- 4H- imidazo/l, 5- a// l, 4/- enzo-diazepine- 3- carboxylic acid-(l, l- dimethyl) ethyl ester

6 g 6-(2-chlorophenyl)-1-(hydroxymethyl)-4H-imidazo-/1,5-a/-

/1,4/b enzodiazepine-3-carboxylic acid (1,1-dimethyl)ethyl ester is added to 30 ml of thionyl chloride. After stirring for 1 hour at room temperature, the reagent is evaporated and the residue is distributed between methylene chloride and 10% aqueous sodium carbonate solution containing ice. The organic phase is dried and evaporated. The residue is crystallized from methylene chloride/ether, whereby l-(chloromethyl)-6-(2-chlorophenyl)-4H-imidazo/l,5-a//l,4/- benzodiazepine-3-carboxylic acid (1,1- dimethyl)ethyl ester, m.p. 190-194°C (Splitn.). The analytical sample is purified by chromatographing next on the 30-fold amount of silica gel using 10% (V/V) ethyl acetate in methylene chloride as eluent and then crystallized from ethyl acetate/hexane, whereby colorless crystals are obtained, m.p. 194-195°C, (Spltn.).

Example 94

6-(2-Chlorophenyl)-l-(dimethylamino)methyl/-4H-imidazo-/l,5-a/l,4/benzodiazepine-3-carboxylic acid-(1,1-dimethyl)-ethyl ester

A mixture of 3 g of 1-(chloromethyl)-6-(2-chlorophenyl)-4H-imida-zo/1,5-a//1,4/benzodiazepine-3-carboxylic acid-(1,1-dimethyl)- ethyl ester and 40 ml of tetrahydrofuran containing 20% (V/V) dimethylamine are heated in a steel bomb for 3 hours at 100°C. The solvent is evaporated and the residue is distributed between methylene chloride and 10% aqueous sodium carbonate solution. The organic phase is dried and evaporated. Crystallization of the residue from ethyl acetate/ether gives 6-(2-chlorophenyl)-1-(dimethylamino)methyl/-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid-(1, 1-dimethyl)ethyl ester, m.p. 192-195°C. The analysis sample is recrystallized from ethyl acetate/hexane, whereby

colorless crystals are obtained, m.p. 198-200°C.

Example 95

6-(2-Chlorophenyl)-!-/(dimethylamino) methyl/- 4H- imidazo-/ l, 5- a/ / l, 4/ benzodiazepine- 3- carboxylic acid- methyl ester

A mixture of 2 g of 6-(2-chlorophenyl)-1-(dimethylamino)methyl-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxylic acid-(1,1-dimethyl)ethyl ester , 40 ml methanol and 5 ml conc. sulfuric acid is allowed to stand for 24 hours at room temperature. The mixture is distributed between methylene chloride and ammonia diluted with ice. The methylene chloride phase is separated, dried and evaporated. The residue is filtered with 5% ethanol in methylene chloride over silica gel. Evaporation and crystallization from ethyl acetate/ether gives 6-(2-chlorophenyl)-1-(dimethylamino)methyl/-4H-imidazo/1,5-a// 1,4/benzodiazepine-3-carboxylic acid methyl ester in two factions. The analytical sample is recrystallized from ether and melts at 184-185°C. A deeper molten modification which melts at 166-169°C is also considered.

Example 96

6-(2-Chlorophenyl)-l-/(dimethylamino)methyl/- 4H- imidazo-/l, 5- a/ / l , 4/ benzodiazepine- 3- carboxamide

A mixture of 2.5 g of 6-(2-chlorophenyl)-1-(dimethylamino)methyl/ -4H-imidazo/l,5-a//l,4/benzodiazepine-3-carboxylic acid methyl ester, 2.5 g of ammonium chloride and 40 ml of methanol containing 20% (V/V) ammonia are heated in a steel bomb for 18 hours at 100°C. The solvent is partially evaporated and the remainder distributed between methylene chloride and water. The organic phase is dried and evaporated. The residue is chromatographed on 50 g of silica gel using 5% (V/V) ethanol in methylene chloride as eluent. Crystallization from ethyl acetate/ether gives 6-(2-chlorophenyl)-1-(dimethylamino)methyl/- 4H-imidazo/1,5a//1,4/benzodiazepine-3-carboxamide as colorless crystals, m.p. 228-230°C.

Example 97

6-( 2- Chlorophenyl)- 4H- imidazo/l, 5- a// l, 4/ benzodiazepine- l, 3-dicarboxylic acid- l- ethyl- 3-( 1, 1- dimethyl) ethyl ester

A mixture of 4 g (10 mmol) 5-(2-chlorophenyl)-alpha-(hydroxy-cyimino)-3H-1,4-benzodiazepine-2-acetic acid-(1,1-dimethyl)-ethyl ester, 50 ml of tetrahydrofuran , 20 ml of ethanol, 1 ml of methanol containing 20% (V/V) ammonia and 5 g of Raney nickel are hydrogenated at atmospheric pressure until hydrogen absorption has ceased (2 hours). The catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of methylene chloride, reacted with 2.5 g of ethyl glyoxalate and stirred in an open, kept for 18 hours at room temperature. The mixture is filtered over silica gel using 5% (V/V) ethyl acetate in methylene chloride as eluent. The filtrate is evaporated and the residue is crystallized from ether, whereby 6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-1,3-dicarboxylic acid-1-ethyl-3- (1,1-Dimethyl)ethyl ester. The analytical sample is recrystallized from ethyl acetate/hexane, whereby colorless crystals are obtained, m.p. 185-187°C.

Example A

Micronized 6-(2-chlorophenyl)-4-hydroxy-4H-imidazo-/1,5-a//1,4/benzodiazepine-3-carboxamide can use the following composition as an active ingredient for the production of medicines:

a) Tablets (direct pressing)

b) Tablets (direct pressing) c) Capsules: d) Capsules:

Example B

Micronized 6-(2-chlorophenyl)-4H-imidazo/1,5-a/-/1,4/benzodiazepine-3-carboxamide can be used as active ingredient for the preparation of medicines with the following composition:

a) Tablets (direct pressing)

b) Tablets (direct pressing) c) Capsules: d) Capsules:

Example C

Micronized 9-chloro-6-(2-chlorophenyl)-4H-imidazo-/1,5-a/- /1,4/benzodiazepine-3-carboxamide can be used as an active substance for the production of medicines with the following composition:

a) Tablets (direct pressing)

b) Tablets (direct pressing) c) Capsules: d) Capsules:

Claims (10)

1. Procedure for the preparation of imidazobenzodiazepine derivatives with the general formula where R"*" means hydrogen, di-lower alkylamino-lower alkyl or lower alkyl, R <2> hydrogen, lower alkanoyl or lower alkyl, R <3> hydrogen, lower alkanoyl-4 oxy or hydroxy, R chlorine, bromine, fluorine or trifluoromethyl and R^ hydrogen, fluorine or chlorine, with the 3 2 proviso that a) R cannot mean hydroxy if R 3 means lower alkanoyl and b) R means hydrogen if R"*" means di-lower alkylamino-lower alkyl, and pharmaceutically usable salts thereof, characterized by atmana) reacts with a compound of the general formula 14 5 in which R means lower alkyl and R , R and R have the above meaning, 21 21 with an amino compound of the formula r^NR , in which R.means hydrogen or lower alkyl or b) reacts with a compound of the general formula 14 5 in which R , R and R have the above meaning, 21 21 with an amino compound of formula F^NR, in which R has the above meaning, or c) reacts a compound with the general formula wherein R"*", R^, R^ and R^ have the above meaning, with a C 1 -C 3 -carboxylic acid anhydride, or d) reacts a compound of the general formula 1214 in which R' means C,-C .-alkyl and R , R , R and 5 14 R has the above meaning, with an alkali metal hydroxide, or) reacts a compound of the general formula in which R means hydrogen or lower alkyl and R, R', 4 5 R and R have the above meaning, 21 21 with an amino compound of formula r^NR , in which R has the above meaning, or f) reacts a compound with the general formula in which R"*""*", R^"*", R^ and R~* have the above meaning, with a C^ -C^ -carboxylic acid chloride or anhydride, org) reacts a compound with the general formula 114 5 wherein R', R , R and R have the above meaning, with a C^ -C^ -carboxylic acid chloride or anhydride, and h) if desired, transfers the obtained compound of formula I in a pharmaceutically usable salt. 2. Process according to claim 1, in the preparation of compounds of formula I in which R means hydrogen, characterized in that correspondingly substituted starting materials are used. 3. Method according to claim 1 or 2, when manufacturing 2 of compounds of formula I in which R means hydrogen or ethyl, characterized by using correspondingly substituted starting materials. 4. Method according to one of claims 1 to 3 by making 4 position of compounds of formula I in which R means chlorine or fluorine, characterized by using correspondingly substituted starting materials. 5. Method according to one of claims 1 to 4 for the preparation of compounds of formula I in which R 1 means hydrogen, characterized in that correspondingly substituted starting materials are used. 6. Method according to claim 1 for the production of 9-chloro- -6-(2-Chlorophenyl)-4H-imidazo[1,5-a//1,4]-benzodiazepine-3-carboxamide, characterized by using correspondingly substituted starting materials. 7. Process according to claim 1 for the production of 6-(2-chlorophenyl)-4H-imidazo/1,5-a//1,4/benzodiazepine-3-carboxamide, characterized in that correspondingly substituted starting materials are used. 8. Method according to claim 1 in the preparation of 6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a//1,4]-benzodiazepine-3-carboxamide, characterized in that correspondingly substituted starting materials. 9. Method according to claim 1 for the production of 6-(2- -chlorophenyl)-4-hydroxy-4H-imidazo/1,5-a/-/1,4/benzodiazepine-3-carboxamide, characterized by using correspondingly substituted starting materials. 10. Process according to claim 1 in the preparation of N-acetyl-6-(2-chlorophenyl)-4H-imidazo/1,5-a/-/1,4/benzodiazepine-3-carboxamide, characterized in that correspondingly substituted starting materials.