JPS5833234B2 - Thienotriazolodiazepine - Google Patents

Description

[Detailed description of the invention] The present invention relates to diazepine derivatives.

More particularly, the present invention relates to chenotriazolodiazepine derivatives and methods for producing the same.

The chenotriazolodiazepine derivative provided by the present invention has the general formula [wherein R1 represents a halogen atom or a nitro group, R
2 is phenyl, 0=)lifluoromethylphenyl, 0-
Halophenyl, o-o'-dihalophenyl or 0-
Represents a nitrophenyl group or a pyridyl group, R3 is lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, lower alkoxy-lower alkyl, lower alkoxybenzyloxy- lower alkyl, morpholino-lower alkyl, lower alkylthio-lower alkyl, cyano-lower alkyl, halo-lower alkyl, lower alkanoyloxy-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or carbamoyl group] and chenotriazolodiazepine derivatives thereof It is an acid addition salt.

As used herein, the term "lower alkyl", by itself or in combination such as in hydroxy-lower alkyl, refers to a straight or branched hydrocarbon radical of 1 to 4 carbon atoms, such as methyl, ethyl , propyl, isopropyl, tert-butyl, etc.

The term "halogen" refers to bromine, chlorine, fluorine and iodine.

The term "lower alkoxy" refers to an alkyl group having a substituted oxygen functionality, such as methoxy, ethoxy, propoxy, and the like.

The term "lower alkanoyl" refers to acyl residues derived from linear or branched saturated aliphatic carboxylic acids of 1 to 4 carbon atoms, such as formyl, acetyl, zolopionyl, and the like.

The term "lower alkanoyloxy" refers to alkanoyl residues with substituted oxygen functionality, such as acetoxy, gropionyloxy, and the like.

A preferred group of chenotriazolodiazepine derivatives provided by the invention consists of those in which R1 represents a 710 gen atom, in particular a chlorine atom.

R2 preferably represents 0-halophenyl, o-o'-dihalophel or 2-pyridyl group.

R2 is. When representing a -halophenyl group, 0-fluorophenyl and 0-chlorophenyl groups are preferred.

When R2 represents a 0.theta.'-dihalophenyl group, the two halogen atoms are preferably identical and in particular fluorine atoms.

R3 preferably represents a lower alkyl, hydroxy-lower alkyl or amino-lower alkyl group, especially a methyl or hydroxymethyl group.

A preferred compound of formula (1) is 9-aminomethyl-2-chloro-4-(o-chlorophenyl)-6H-cheno[3.
2-f)-s-)riazolo[4.3-a)[1.4]diazepine.

According to the method of the invention, said chenotriazolodiazepine derivatives, i.e. compounds of formula I and acid addition salts thereof, have the following general formula: (a) in which R1, R2 and R3 are as defined above; or (b) cyclizes a compound of the general formula [wherein R1, R2 and R3 have the same meanings as above], or (C) a compound of the general formula [wherein R2 and R3 have the same meanings as above]. (synonymous with the above)], or (d) to produce a compound of formula (■) in which R3 represents a lower alkanoyl group, a compound of the formula (■) in which R3 represents an α-hydroxy lower alkyl group; In order to oxidize the compound of (I) or (e) to prepare a compound of formula (I) in which Ra represents a lower alkanoyloxy lower alkyl group, R3
A compound of formula (I) in which R represents a hydroxy lower alkyl group is esterified with a suitable alkanoylating agent, or (f) R3 is lower alkoxy-lower alkyl, lower alkoxybenzyloxy-lower alkyl, lower alkylthio-lower alkyl, amino -lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl or morpholino-lower alkyl to prepare compounds of formula (I) in which R3 represents a halo-lower alkyl group. ) or R3
The reactive ester of the corresponding compound of formula (I) in which represents a hydroxy-lower alkyl group can be substituted with a lower alkanol, a lower alkoxybenzyl alkyl group, a lower furkylmercaptan, ammonia, a lower alkylamine, a di-lower alkylamine or treatment with morpholine, or (g) reducing a compound of formula (1) in which R3 represents a lower alkoxycarbonyl group to prepare a compound of formula (I) in which R3 represents a hydroxymethyl group, and (h) It is produced by a method characterized in that the resulting compound of formula (I) is optionally converted into an acid addition salt.

According to embodiment (a) of the method, the compound of formula (I) is provided with a compound of formula (
(2) It can be produced by cyclizing the corresponding compound.

The cyclization of the compound of formula (II) is carried out according to methods known per se, for example by heating the compound of formula (I[).

The temperature at which the cyclization is carried out is not critical, however, it depends on the starting materials and conditions used.

Cyclization can be carried out at temperatures from about room temperature to 300°C.

Further, the cyclization can be carried out in the absence or preferably in the presence of an inert organic solvent. When the cyclization is carried out in the presence of an inert organic solvent, a suitable temperature range is about 60 to 180°C.
, preferably at the reflux temperature of the cyclization mixture.

On the other hand, if the reduction is carried out in the absence of a solvent, the preferred temperature range is about 200-260°C.

Suitable inert organic solvents are, for example, hydrocarbons such as toluene, xylene, halogenated hydrocarbons such as chlorobenzene, ethers such as tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, amides such as hexamethylphosphoric triamide, dimethylformamide. etc., dimethyl sulfoxide, and especially alkanols such as methanol, ethanol, -propatol, 2-propatol, 1-7"tanol, 2-7'tanol, cyclohexanol, etc.

The cyclization time varies from a few minutes to 48 hours, depending of course on the temperature used and the presence or absence of a solvent.

In the absence of solvent, the reaction preferably takes place within a few minutes.

In the presence of a solvent, the reaction time is preferably 1 to 24 hours.

The compound of formula (II) need not in all cases be used in isolated form.

This is because they often spontaneously cyclize under the conditions used for their preparation.

According to method 9 [b), the compound (I) has the formula (m)
It is produced by cyclizing the compound.

The cyclization of compounds of formula (III) is also carried out according to methods known per se.

For example, this cyclization can be carried out by warming the compound of formula (m) in an organic medium, often preferably in the presence of an acid to achieve satisfactory yields.

That is, the cyclization can be carried out in a relatively short period of time in a solution of an aliphatic carboxylic acid such as formic acid or acetic acid in an alkanol such as ethanol or n-propanol, or in an aliphatic carboxylic acid such as acetic acid, isobutyric acid or pivalic acid. time(
(about 5 minutes to 0.5 hours) by heating the compound of formula (m) under reflux to boiling.

The compound of formula (III) need not in all cases be used in isolated form.

This is because they often spontaneously cyclize under the conditions used for their preparation.

According to embodiment c) of the method, the compound of formula (I) is a corresponding compound in which the thiophene ring is unsubstituted, i.e. the above formula (
It can be produced by halogenating or nitrating the compound IV).

This halogenation can be carried out according to one of the halogenation methods customary in thiophene chemistry, for example using elemental chlorine, bromine or iodine.
This reaction is carried out using sulfuryl chloride or the like, and the reaction conditions mainly depend on the nature of the halogenating agent used.

Chlorination can be carried out, for example, using elemental chlorine in chloroform/pyridine or nitrobenzene, preferably at room temperature.

Bromination can be carried out, for example, using elemental bromine in chloroform at elevated temperatures, such as boiling temperature under reflux.

Iodination with elemental iodine is carried out, for example, in chloroform and in the presence of mercuric oxide at room temperature.

Chlorination with sulfuryl chloride can be carried out, for example, in chloroform or acetic acid at room temperature or at elevated temperatures, such as reflux temperature.

Nitration is carried out in the usual manner, for example using nitric acid or alkali nitrates in the presence of sulfuric acid.

Thus, for example, nitration can be carried out by dissolving the starting material in concentrated sulfuric acid and slowly treating this solution with a mixture of concentrated nitric acid and concentrated sulfuric acid.

Generally, nitration is advantageously carried out at low temperatures, such as temperatures from about -10°C to about +10°C.

According to embodiment [d) of the present process, a compound of formula (I) in which R3 represents a lower alkanoyl group is obtained by preparing a compound of formula (I) in which R3 represents an α-hydroxy lower alkyl group according to one of the oxidation methods customary in thiophene chemistry. It is produced by oxidizing the corresponding compound of I).

Suitable oxidizing agents are carbodiimides such as dicyclohexylcarbodiimide in dimethylsulfoxide or pyridine/sulfur trioxide adducts in dimethylsulfoxide.

These oxidations are carried out in the presence of an organic base such as pyridine or triethylamine.

Silver oxide may also be used as an oxidizing agent. In this case it is preferably used in a water-miscible inert solvent, such as an alkanol or acetone.

But again, the oxidation reaction can be carried out in anhydrous toluene by using chromium trioxide or manganese dioxide in graphite.

All of the above oxidations (except when using chromium dioxide or manganese dioxide) are preferably carried out at room temperature or slightly above or below.

When carrying out the oxidation with chromium trioxide or manganese dioxide, it is advantageous to heat the oxidation mixture to reflux temperature.

According to the embodiment of the present process (%), compounds of formula (I) in which R3 represents a lower alkanoyloxy-lower alkyl group can be prepared according to methods known per se from the corresponding compounds of formula (I) in which R3 represents a hydroxy-lower alkyl group. It is produced by esterifying the compound with a suitable lower alkanoylating agent.

Esterification using an alkanoylating agent is carried out, for example, by reacting a hydroxy-substituted compound with an acid halide or anhydride in an inert organic solvent in the presence of an organic base such as pyridine or triethylamine.

Suitable solvents are hydrocarbons such as benzene or toluene,
Halogenated hydrocarbons such as carbon tetrachloride, chloroform or methylene chloride or an excess of an organic base.

This reaction is carried out at a temperature of about 0-80°C, preferably room temperature to about 60°C.

According to the embodiment of the method (f>), R3 is lower alkoxy-
Compounds of formula (I) representing a lower alkyl, lower alkoxybenzyloxy-lower alkyl, lower alkylthio-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl or morpholino-lower alkyl group are , the corresponding compounds of formula I in which R3 represents a halo lower alkyl group or R3
Treating the reactive ester of the corresponding compound of formula (L) in which represents a hydroxy-lower alkyl group with a lower alkanol, lower alkoxybenzyl alcohol, lower alkyl mercaptan, ammonia, lower alkylamine, cy-lower alkylamine or morpholine. Manufactured by.

For treatment with lower alkanols, lower alkoxybenzyl alcohols or lower alkyl mercaptans,
Methods known per se can be used for the production of ether or thioether functions.

The production of thioethers [compounds of formula (I) in which R3 represents a lower alkylthio lower alkyl group] can be carried out, for example, by converting the methanesulfonic acid ester of the corresponding compound of formula (I) in which R3 represents a hydroxy lower alkyl group to a lower alkyl mercaptan or the corresponding This can be done by treatment with mercaptide.

The reaction is carried out in the presence of a suitable solvent such as dimethylformamide, dioxane or tetrahydrofuran from room temperature to
It is carried out at 0°C, preferably 50°C.

In treatment with ammonia, lower alkyl amines, di-lower alkyl amines or morpholine, the reaction consists of the formation of aminoalkyl substituted compounds.

This step can be carried out according to a method known per se.

For example, methanesulfonic acid esters of compounds of formula I in which R3 represents a hydroxyalkyl group can be reacted with the corresponding amino compounds.

This reaction is carried out according to methods known per se, preferably in the presence of a suitable inert organic solvent such as dimethylformamide or an alcohol, such as methanol or ethanol, at a temperature of 0 to 100 DEG C., preferably 0 to 5 DEG C.

According to embodiment g) of the process, compounds of formula (I) in which R3 represents a hydroxymethyl group are prepared by reducing the corresponding compounds of formula (I) in which R3 represents a lower alkoxycarbonyl group. .

This reduction is carried out according to methods known per se, preferably by treatment with a complex hydride such as lithium aluminum hydride.

Compounds of formula (I) can be converted into acid addition salts by treatment with inorganic or organic acids.

In this case, pharmaceutically acceptable acid addition salts are preferred.

Examples of acids that form pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, tartaric acid, citric acid, maleic acid, ascorbic acid, phosphoric acid, acetic acid, Methanesulfonic acid, benzenesulfonic acid, p-)luenesulfonic acid, and the like.

The starting material of formula ([) can be prepared from the corresponding chenodiazepine derivative of the general formula, where R1 and R2 have the same meanings as above.

In the first step, a chenodiazepine derivative of the formula (■) is reacted with a sulfide such as phosphorus pentasulfide to produce a thione of the general formula [wherein R1 and R2 are as defined above].

Sulfide is preferably used in excess in this reaction.

The reaction is advantageously carried out in an inert organic solvent such as pyridine or xylene at about 40°C to the reflux temperature of the reaction mixture, preferably at the reflux temperature.

Pyridine is the preferred solvent for this reaction.

The thione of formula (VI) is then reacted with an organic acid hydrazide of general formula (wherein R3 has the same meaning as above) to form a compound of formula (II).

The reaction of the thione of formula (VI) with the acid hydrazide of formula (■) is carried out in an inert organic solvent, preferably an alcohol such as methanol, ethanol, 1- or 2-zolopanol, 1- or 2-butanol, etc. It is carried out at a temperature of -120 DEG C., preferably at the reflux temperature of the reaction mixture.

In a preferred method, the acid hydrazide is used in a 2 to 5 times excess over the theoretically required amount.

The reaction time depends on the reaction temperature and ranges from a few minutes to 48 hours, preferably from about 1 to 24 hours.

The crude product thus obtained is mainly of the desired formula (II
) and an already cyclized compound of formula (I).

These mixtures may be separated based on the differences in solubility of these compounds in organic solvents such as methylene chloride, chloroform, carbon tetrachloride, ethyl acetate, and the like.

After separation in the manner described above, the compound of formula (TI) is converted into a compound of formula (I
) can be converted into a compound.

According to an even simpler method, a mixture of compounds of formula (I) and formula (II) is prepared by heating in the manner described above.
) can be converted into a homogeneous compound.

The reaction of the thione of formula (VI) with the acid hydrazide of formula (■) is preferably carried out while passing an inert gas, preferably nitrogen, through the reaction mixture so that the hydrogen sulfide formed can be continuously removed. .

The acid hydrazide of formula (■) is a known compound or can be prepared according to analogous methods for known compounds, e.g.
Esters of COO-alkyl can be easily prepared by heating to reflux with hydrazine hydrate (eg in methanol).

Chenodiazepine derivatives of formula (V) are also known compounds or can be easily prepared by methods analogous to known compounds.

That is, they include α such as chloroacetyl chloride.
- can be prepared from 2-amino-3-aroyl-thionoene by reaction with a halocarboxylic acid halide, treatment of the resulting compound with ammonia and subsequent cyclization.

The starting material of formula (II) is a carboxylic acid of the general formula R3-C00H (wherein R3 is the same as above) from a compound of the general formula [wherein R1 and R2 are as defined above] or its They can also be produced by reaction with reactive derivatives.

Suitable reactive derivatives of the carboxylic acids are, for example, esters, anhydrides, halides, amides, iminoethers, amidines and orthoesters.

Particularly suitable are orthoesters.

Examples of such orthoesters are trimethyl orthoacetate, triethyl orthoacetate, triethyl orthoformate, triethyl orthofurohionate, triethyl orthobutyrate, and the like.

The reaction of the compound of formula (■) with a carboxylic acid or a reactive derivative thereof is preferably carried out in the presence of an inert organic solvent and an acid catalyst such as hydrohalic acid (e.g. hydrochloric acid), p-toluenesulfonic acid, etc. .

Suitable solvents are alkanols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethyl ether, etc., dimethyl sulfoxide, dimethyl formamide, etc.

Although temperature is not critical, the reaction is preferably carried out at elevated temperature, ie, from about 30°C to the reflux temperature of the reaction mixture, preferably at reflux temperature.

Furthermore, the starting material of formula (II) can be produced by reacting a compound of general formula [wherein R1 and R2 have the same meanings as above] with an acid hydrazide of formula (■).

This reaction is carried out in an inert organic solvent such as an alkanol (e.g. ethanol, propatool, butanol, etc.), dimethylformamide, ether (e.g. diglyme and methoxyethanol), etc. with a strong base such as an amine (e.g. triethylamine, methylpiperidine, etc.). tertiary amine) at elevated temperature, preferably at the reflux temperature of the reaction mixture.

Compounds of formula (IX) can be easily prepared from the corresponding thienodiacehine derivatives of formula (V) by treatment with a lower alkylamine in the presence of a Lewis acid such as titanium tetrachloride.

Compounds of formula (■) are prepared** by preparing the corresponding N-nitroso compounds from the corresponding compounds of formula (IX) in a per se known reaction with nitrous acid.

Reaction of such an N-nitroso compound with hydrazine yields the desired compound of formula (■).

The compound of formula (■) can also be produced by treating the compound of formula (VI) with hydrazine.

The starting materials of formula (III) may be prepared according to the following reaction route which shows the preparation of compounds of formula (II[), ie R1 represents a halogen atom, R2 represents a phenyl group and R3 represents a methyl group.

Reaction Scheme 2-Amine-3-benzoyl-thiophene of formula (XI) is converted to a compound of formula (XI) by treatment with an orthoester of CH3-C(〇-lower alkyl)3.

This treatment is advantageously carried out in the presence of an inert organic solvent such as benzene, toluene and the like and an acid catalyst such as hydrochloric acid, sulfuric acid, acetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

This temperature is not critical, but typically the temperature being treated is about 50-16
It is carried out at a temperature of 0°C.

However, it may also be carried out at higher or lower temperatures.

Suitable solvents are hydrocarbons such as benzene, toluene, etc., or the orthoester used as a reaction component may be used in excess.

The compound of formula (XI) thus prepared is then reacted with hydrazine, preferably in the form of hydrazine hydrate, in an inert organic solvent.

Suitable solvents are alkanols such as methanol, ethanol, -zolopanol, 2-zolopanol, and the like.

The reaction is carried out at a temperature of about 0°C to the reflux temperature of the reaction mixture, preferably about 10°C to about 30°C.

This reaction can be accelerated by the addition of acid catalysts such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.

Subsequently, the crude product thus prepared is treated with α- such as chloroacetyl chloride, bromacetyl bromide, etc. in an inert organic solvent with ice cooling or at a temperature below the boiling point of the solvent.
c) React with loacetyl halide to obtain a compound of formula (■).

Suitable solvents are chloroform, methylene chloride, ether,
dimethylformamide, pyridine, acetic acid, monochloroacetic acid or a mixture of such solvents and water.

When using a neutral solvent, the reaction is preferably carried out using sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, pyridine triethylamine, imidazole, 2-
It is carried out in the presence of an acid acceptor such as methylimidazole.

The compound of formula (■) is then treated with ammonia or hexamethylenetetramine and the resulting compound of formula (III) is then cyclized to the corresponding compound of formula (I) without separation.

Therefore, the compound of formula (III) does not need to be separated prior to cyclization.

Thus, the cyclization to the compound of formula (I) can be carried out in the reaction mixture in which the compound of formula (m) was prepared, without its separation or without interrupting the reaction.

A compound of formula (■) can be added to alcoholic ammonia, e.g. ethanolic or methanolic ammonia, or dissolved in an inert organic solvent and treated with liquid ammonia or hexamethylenetetramine, to form a compound of formula ( The compound III) is obtained.

Suitable solvents for this treatment are methylene chloride, carbon tetrachloride, ethers such as tetrahydrofuran or dioxane, dimethyl sulfoxide, dimethyl formamide, alkanols such as methanol, ethanol, l-propanol, 2-propanol, -butanol, 2-butanol, etc. It is.

The resulting compound of formula (III), whether in crude or pure form, is cyclized by the method described above to form the compound of formula (I).
) can be a compound.

The formula (■
The chenotriazolodiazepine derivative of ) can be produced in the same manner as aspects ma) and (b) of the present invention.

Compounds of formula (I) and their pharmacologically acceptable acid addition salts are useful agents, such as antispasmodics, sedatives, muscle relaxants, tranquilizers.
) and especially as anxiolytics.

The anxiolytic properties of the compound of formula (I) were demonstrated in the conflict test (K
onfl ikt -Te5t ).

The test equipment was a feed pellet feeder (Futterpill).
Key-press Skinner box (E
1ntasten -5kinner box)
It is.

Train a hungry female rat to press a key on a food pellet feeder to obtain a food pellet during a 3-h pretest period (each key press is rewarded); Rats achieve a rate of 150-200 key presses per session.

In the fourth child test, a pellet reward (P1llen bel ohnung) triggered by a key press was used.
) is combined with a short electric foot shock (Fuss 5hock).

Rats confused by this conflict state will initially still make about 5-10 key presses and then stop altogether due to anxiety.

In the fifth test, the rat presses the food pellet feeder key again if the foot shock is not applied, again achieving a rate of 150-200 key presses per hour.

In the sixth preliminary test, the selection of test animals is performed.

Half an hour before the start of this preliminary test, 10 Iv/kg chlorodiazepoquine is administered orally.

Each pellet reward is again combined with a foot shock.

Only rats that achieved 20-50 key presses in this preliminary test were left as test animals suitable for demonstrating potential anxiolysis.

In this study, as a rule, 8 rats are used per substance and per dose.

No untreated subject group is required.

This is because each animal also serves as its own object.

Distilled water (10rILl) and Tween 80 (Tween
The test substance, dissolved or suspended in a mixture of 80) (2 drops), is administered to the animal using an esophageal probe during the half hour rate of the 1 hour test.

The rate of key presses per hour is recorded during the test period in which a pellet reward is combined with a foot shock for each key press.

The dose that produces the first significant anxiolytic effect is determined by Wilcoxon test group C (paa
determined by directly comparing the number of key presses in the main test (foot shock, after treatment with test substance) with the number of key presses in the control test (foot shock, after treatment with saline). be done.

The results include the following items:

(1) Dose at which the first significant anxiolytic effect occurs (FSD - first significant dose); (2) Mean increase in shock with respect to dose; (3) Observation of the general behavior of the animals at various doses.

The above conflict test includes West German Patent Publication No. 222
2-acetyl-4-(o-chlorophenyl)-9-methyl-6Hthieno[3.2-f] known from No. 9845
-s-triazole[4.3-a)("1.4]diazepine (compound A) and the following 10 compounds of the present invention were used.

2-chloro-4-(o-chlorophenyl)-9-methyl-6H-cheno[3.2-f,1-s-)riazolo[4
・3-a)(1.4) diazepine (compound B), 2-bromo-4-(o-chlorophenyl)-9-methyl-6H-cheno[3.2-f)-s-)riazolo[4.
3-a) (1,4) diazepine (compound C), 2-iodo-4-(O-chlorophenyl)-9-methyl-6H-cheno[3,2-f)-s-)riazolo[4,
3-a) [1,4] diazepine (compound D), 2-chloro-9-methyl-4-(2-pyridyl)-6H
-Ceno [3.2-f) -s-) Riazolo [4.3-a
] [1.4] Diazepine (compound E), 9-aminomethyl-2-chloro-4-(o-chlorophenyl)-6H-
Cheno [3.2-f, 1-s-) Riazoro [4.3-a
) (1,4] diazepine (compound F), 2-chloro-4-(2,6-difluorophenyl)-9
-Methyl-6H-cheno[3,2-f]-8-triazolo[4,3-a][l,4]diazepine (compound G), 2-chloro-4-(o-fluorophenyl)9-methyl -6H-cheno[3.2-f)-s-triazolo[4.
3-a] (1,4) diazepine (compound H), 2-chloro-4-(0-chlorophenyl)-6H-cheno[3,2-f)-s-)riazolo[4,3-a)[ 1
・4] Diazepine-9-methanol (compound ■), 2-chloro-4-(o-chlorophenyl)-9-dimethylaminomethyl-6H-cheno[3.2-f)-s-triazo0C4-3-a ) (1-4) diazepine (compound J) and 2-chloro-4-(0-chlorophenyl)-9-methylaminomethyl-6H-cheno[3.2f)-s-)riazoloC43-a,l(1 -4) Diazepine (compound K)
.

The test results are summarized in the table below.

It is clear from the above table that all tested compounds of the invention exhibit anxiolytic action that is more pronounced and/or selective than previously known substances and with minimal (few) adverse side effects. It is.

The compounds of formula (I) and their pharmacologically acceptable acid addition salts are useful agents, such as antispasmodics, sedatives, muscle relaxants, tranquilizers, etc.
) and especially as anxiolytics.

Compounds of formula (I) and their pharmacologically acceptable acid addition salts can be prepared into pharmacological preparations (e.g. tablets, dragees, herbal medicines, capsules, solutions, suspensions) according to generally known methods. , emulsions, etc.).

Usually pharmacologically inert carrier materials such as lactose,
Starch, magnesium stearate, water, vegetable oil,
Apart from polyalkylene glycols etc., these preparations may contain preservatives, stabilizers, wetting agents, emulsifiers, salts for changing the osmotic pressure, buffers or other therapeutically useful substances. Good too.

The pharmacological preparation can be sterilized, if necessary, or subjected to other operations common to the pharmaceutical industry.

The invention therefore includes within its scope pharmacological preparations containing a compound of formula (I) or a pharmacologically acceptable acid addition salt thereof together with a compatible pharmacological carrier material. You should understand.

A suitable pharmacological dosage unit may contain about 1 to 50 m9 of a compound provided by the invention.

Suitable daily doses for oral administration to mammals range from about 0.1 to about 30 kg/kg, and suitable daily doses for parenteral administration to mammals range from about 0.1 to about 30 kg/kg. 0.1
~corresponds to approximately 10■/kg.

However, these dosages are merely exemplary and the particular dosage should be adjusted in each case according to individual requirements.

The following examples further illustrate the invention.

Example 1 2-(2-acetylhydroxide/)-7-chloro-5-(o-chlorfe=#)- in an oil bath (250° C.) until gas evolution is no longer observed.
3H-cheno(2.3-e)-1-4-diazepine 2
．． 51 was heated under reduced pressure (water pump vacuum) for 5-7 minutes.

Thoroughly crush the obtained product in a mortar and add 40 ml of ethyl acetate.
It was boiled several times with the entire amount of oTILl.

After removal of the solvent, the resulting crude product was recrystallized from ethanol containing activated carbon to obtain 2-chloro-4-(o
-chlorophenyl)-9-methyl-6H-cheno(3.
2-f)-s-Triazolo[4.3-a)(1.4]diazepine was obtained in cream-colored crystalline form with a melting point of 205-206°C.

The starting material was prepared as follows: 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-cheno[2,3] in 100 ml of anhydrous pyridine, bubbling dry nitrogen through the solution. -e)-
3.11 (o, oi mol) of 1,4-diazepin-2-one were heated under reflux for 30 minutes with 2.451 mol of phosphorous pentasulfide.

Next, a column with a length of 35 cIrL (φ
3.5 cut) was used to separate the solution obtained above.

Separation was performed by thin layer chromatography (eluent: benzene/ethanol 9:2).

Elution was stopped when a substantially slow-flowing impurity appeared.

When the solvent was removed under vacuum, 7-chloro-5-(o-
Chlorphenyl)-1,3-dihydro-2H-cheno [
2.3-e)-1.4-Diazepine-2-thione immediately crystallized out in a yellow form with a melting point of 223-225°C.

This thione was used in the next step without further purification.

7-Chlor-5-(o-chlorophenyl)-1-3-dihydro-2H-cheno[2,3-e)-1,4-diazepine-2-thione 3.3r (0.01 mol) in acetic acid Heat to reflux with 2.51 hydrazide and 150 U7 n-butanol under nitrogen atmosphere for 30 minutes.

The solvent was removed under vacuum and the residue was dissolved in 200r of ethyl acetate.
/Ll and shaken three times with 200TLl of water each.

The precipitated starting material was filtered under vacuum and combined with the ethyl acetate phase.

After concentrating this solution to 50 rfLl, the residue was crystallized.

The product was then filtered under vacuum and recrystallized from ethyl acetate containing activated carbon.

As a result, 2-(2-acetylhydrazino)-7-chloro-5(O-chlorophenyl)-3H-cheno[2.3e
]-1,4-diazepine was obtained in the form of orange crystals with a melting point of 211-213°C.

Example 2 0.21 of 7-chloroto 3-dihydro-5-(o-nitrophenyl)-2H-cheno[2,3-e]1,4-diazepin-2-one in 60 d of n-butanol It was heated to reflux with 0.2y of acetic acid hydrazide under nitrogen atmosphere for 5 hours.

After evaporation of the solvent, the product was taken up in methylene chloride, extracted several times with IN hydrochloric acid and treated dropwise with ether so that the organic phase was brought to the surface of a separating container.

After neutralizing the aqueous phase with sodium bicarbonate, the mixture was extracted with methylene chloride, dried over sodium sulphate, the solvent was evaporated and the residue was made into a paste with ethyl acetate.

By recrystallizing the obtained crystals from ethyl acetate containing activated carbon, 2-chloro-9 with a melting point of 210-212°C was obtained.
-Methyl-4-(o-nitrophenyl)-6H-cheno[3.2-f)-s-)riazolo[4.3-a)(1.
4] Colorless crystals of diazepine were obtained.

The starting material was prepared as follows: 7-chlorout3-dihydro-5(0-nitrophenyl)-2H-cheno[2.3-e)-1.4 in 30 rnl of anhydrous pyridine with nitrogen bubbling through the solution. -Diazepin-2-one 11 (0,00327 mol) was heated to reflux with phosphorus pentasulfide and 0.81.

Then silica gel C (0.05-0.2 mm) (Me
rck ) ) 50? The mixture was separated in a column filled with (in this case the product migrated first and the impurities migrated slowly).

) After concentrating the pyridine solution under vacuum, the residue was treated with methylene chloride and crystallized.

The crystallization was completed in the refrigerator, after which the mixture was filtered under vacuum and washed with a small amount of ice-cold methylene chloride.

7-Chlorotate 3-dihydro-5-(o-nitrophenyl) was then recrystallized from anhydrous methanol.
-2H-chenoC2.3''e) -1.4 diazepine-2-thione was obtained as yellow crystals with a melting point of 213-215°C.

Example 3 7-chlorout3-dihydro-5-(o-trifluoromethylphenyl) -2H-f:r-/C2・3-e
)-1,4-diazepin-2-one in 3.01 ml of ethylene glycol dimethyl ether at 80°C.
and treated with 4.22 parts of phosphorous pentasulfide and 31 parts of finely ground sodium bicarbonate and warmed to 80-85°C for 15 minutes.

The mixture was then evaporated under vacuum and added with butanol 60
It was adopted in d.

Then add 31 parts of acetylhydrazine and bring the mixture to 90
It was refluxed for a minute.

The butanol is evaporated under vacuum, the residue is taken up in methylene chloride, the organic phase is shaken several times with water and dried.
Evaporated.

This oily residue was crystallized from ether. Obtained 2-
Chlor-9-methyl-4-(o-trifluoromethylphenyl)-6H-cheno[3.2-f)-s-)riazolo(4-3-a,l(1.4)diazepine is obtained from ethyl acetate. After recrystallization it gave a melting point of 193-195°C.

Example 4 2-(2-acetylhydrazino)-7-chloro-5-(
o-fluorophenyl)-3H-cheno[2.3-e)
-1,4-diazepine 6.8♂ in anhydrous xylene 300T
The mixture was boiled under reflux for 9 hours in nl.

After cooling, the precipitated impurities were separated under vacuum, the solvent was evaporated under reduced pressure and the product was recrystallized from ethyl acetate containing activated carbon.

As a result, 2-chloro-4-(o
-fluorophenyl)-9-methyl-6H-cheno[3
・2-f)-s-) Riazolo [4.3-a] [1.4]
Obtained diazepine.

The starting material was nearchlor-5-(o-fluorophenyl)-1,3- produced as follows.
Dihydro 0-2H-chenoC;l''3-e)-1,4-diazepin-2-one is dissolved in diethylene glycol dimethyl ether 150°C at 55°C and finely ground phosphorus pentasulfide 1
40 with a mixture of 51 and 10 g of sodium bicarbonate.
Stir for a minute.

The solvent was evaporated and the residue was triturated with water, filtered under vacuum and dried.

7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-cheno[2,3-e] thus obtained
-1,4-diazepine-2-thione in methanol 200%
Boiled with 15 g of acetylhydrazine in TfLl for 30 minutes.

Then upon cooling, 2-(2-acetylhydrazino)-
7-chloro-5-(o-fluorophenyl)-3H-cheno[2.3-e)-1.4-diazepine was precipitated.

The methanol was distilled off and the residue was partitioned between methylene chloride and water.

More product precipitated during this time.

The solvent was then evaporated under reduced pressure and the residue was triturated with methanol to obtain further product.

The obtained 2-(2-acetylhydrazino)-7-chloro-5-(o-fluorophenyl)-3H-cheno[2.
3-e)-1,4-diazepine has a melting point of 207-20
It had a temperature of 9°C.

Example 5 2-(2-acetylhydrazino)-7-chloro-5-(
2-pyridyl)-3H-cheno[2.3-e)-1.4
- 2.2 fI of diazepine in 120 rIll of anhydrous xylene
The mixture was refluxed for 2 hours in a vacuum chamber.

The solution was then cooled and the precipitated impurities were filtered out.

The solvent was evaporated under reduced pressure and 2-chloro-9-methyl-4(2-pyridyl)-6H-cheno[3.2-f]-8-triazolo[4. 3-a] [1.4] Diazepine with melting point of 174~
Obtained in crystalline form at 176°C.

The starting materials were 14.6 f of dianmethyl-2-pyridylufton and 7.6 l of bismercaptoacetaldehyde prepared as follows, dissolved or suspended in 760 m of anhydrous dioxa, and treated with 5 rrL of triethylamine while stirring.

After 1.5 hours at room temperature, the mixture was poured into a 500 vLl fishing rod and extracted with methylene chloride.

The methylene chloride phase was shaken twice with 1N sodium hydroxide, dried over sodium sulfate with the addition of activated carbon, and evaporated.

Then, after recrystallization from benzene, the 2-amino-3-thenyl-2'-pyridyl-ketone was obtained with a melting point of 122-124
Obtained in the form of yellow crystals at °C.

2-Amino-3-chenyl-2'-pyridyl-ketone 6
51 was dissolved in 500 rrLl of dry dioxane, 80 g of potassium carbonate was suspended in this solution, and then treated with chloroacetyl chloride 801.

After the end of the exothermic reaction, the mixture was stirred for an additional 2 hours at room temperature,
Pour into a solution of 50 y of potassium carbonate in 21 ml of water.

The separated precipitate was then separated under vacuum, washed with water and taken up in methylene chloride.

After drying over sodium sulfate containing activated charcoal, the solvent was then distilled off under vacuum and the residue was triturated with a little methanol and filtered under vacuum.

By crystallization from methanol, 2-chloroacetylamino-3-thenyl-2'-pyridyluftone was obtained in the form of yellow needles with a melting point of 130-132°C.

2-chloroacetylamino-3-chenyl-2'-pyridyl-ketone 761 was dissolved in acetone 11, and after adding 45 g of sodium iodide, the mixture was stirred at room temperature for 15 hours.

The acetone solution was then evaporated to dryness under vacuum,
The residue was partitioned between methylene chloride and about 300 ml of water, the organic phase was converted with about 1.5 ml of concentrated ammonia and the phases were stirred for 48 hours without mixing.

After completion of the reaction the phases were separated, the organic phase was evaporated to dryness and the residue was taken up in methylene chloride.

Add this solution to 0. Thoroughly extracted with IN hydrochloric acid, neutralized the aqueous extract with potassium carbonate, and the solid material separated was filtered under vacuum and dried.

After crystallization from ethanol, 2-aminoacetylamino-3-thenyl-2'-pyridyl-ketone has a melting point of 2
Obtained in the form of yellow crystals with a temperature of 59° to 262°C.

32.4 P of 2-aminoacetylamino-3-chenyl-2'-pyridyl-ketone was heated under reflux in 350 ml of acetic acid for 15 minutes.

The solvent was then removed in vacuo, the residue triturated with a small amount of methylene chloride, and the solid material was filtered under vacuum once.

Then, by crystallizing from ethanol, 1.3
-dihydro-5-(2'-pyridyl)-2H-cheno [
2,3-e)-1,4-diazepin-2-one with melting point 2
Obtained in the form of colorless Q crystals at 63-266°C (decomposed).

■.3-Dihydro0-5-(2'-pyridyl)2H-cheno[2.3-e)-1.4-diazepin-2-one9.
81 was dissolved in 350 mA' of acetic acid and then treated dropwise with stirring at room temperature with a solution of 8.01 sulfuryl chloride in 20 ralls of acetic acid.

After the addition was complete, the mixture was stirred for an additional 15 hours.

The yellow solid material that separated was filtered under vacuum, dissolved in water, and the solution was neutralized with sodium bicarbonate.

The yellow-green solid material that separated was then filtered under vacuum, washed with water and dried.

After crystallization from ethanol, 7-chlorout3-dihydro-5-(2-pyridyl)-2H-chenoC2-3
-e) -1,4-diazepin-2-one with a melting point of 250
Obtained in the form of yellow-green crystals at ~252°C (decomposition).

7-Chloroute 3-dihydro-5-(2-pyridyl)-
2H-cheno[2.3-e)-1.4-diazepine-
3.5 l of 2-one was dissolved in 200 ml of diethylene glycol dimethyl ether at 65 DEG C. and stirred for 30 minutes with 5 g of finely ground phosphorous pentasulfide.

The solvent was then distilled off and the residue was taken up in methylene chloride and washed three times with water.

The organic phase was dried and evaporated.

7-Chloroute 3-dihydro-5-(2-pyridyl)-
2H-thieno[2,3-e,l(1,4]diazepine-
2-thione was dissolved in methanol 200a and boiled with acetylhydrazine 61 for 30 minutes.

The solvent was distilled off and the residue was taken up in methylene chloride.
Washed three times with water.

The methylene chloride was then distilled off and the crystalline residue was crushed with methanol.

After crystallization from methanol, melting point 193-195°C
2-(2-acetylhydrazino)-7-chloro-5-
(2-pyridyl)-3H-cheno(2-3-e)-1.
4-Diazepine was obtained.

Example 6 2-(2-acetylhydrazino)-7-chloro-5-(
2,6-difluorophenyl)-3H-cheno[2,3
-e,l-1.4-Diazepine 0.35P was spread on a metal plate in as thin a layer as possible and kept at 270°C for 1 minute on a sand bath.

This melt was taken up in methylene chloride and 0. The starting material was removed by shaking three times with IN hydrochloric acid.

The methylene chloride was then distilled off and the product was recrystallized from ethyl acetate containing activated carbon.

As a result, the melting point was 185-187℃ + 7) 2-chloro-4-
(2,6-difluorophenyl)-9-methyl-6H-
Cheno [3.2-f]-8-triazolo [4.3-a)
(1.4) Diazepine was obtained.

The starting material was nearchloro-5-(2,6-difluorophenyl)-1 prepared as follows.
・3-dihydro-2H-cheno[2.3-e)-1.4
- diazepin-2-one 0.06P was introduced into diethylene glycol dimethyl ether 25 rILil;
Warmed to 5°C.

Add 0.85f of finely ground phosphorus pentasulfide to this solution,
The mixture was stirred at ℃ for 35 minutes.

The solvent was then evaporated under reduced pressure and the residue was dissolved in methylene chloride 8
077Il and washed three times with water.

The organic phase was evaporated and the crude 7-chloro-5-(2,6-
Difluorophenyl)-1-3-dihydro-2H-cheno-[2.3-e,]-1.4 diazepine-2-thione was taken up in 20 ml of methanol and boiled with 11 acetylhydrazine for 40 minutes.

The product, which precipitated in crystalline form, was then filtered under vacuum and rinsed with methanol.

To obtain further product, the mother liquor is evaporated and the residue is taken up in methylene chloride and 0. Shake 3 times with IN hydrochloric acid.

The hydrochloric acid phase was neutralized with sodium bicarbonate and shaken with methylene chloride.

The organic phase was dried and evaporated under reduced pressure.

Then, by crystallization from methanol, the melting point is 2.
2-(2-acetylhydrazino)-7 at 57-260°C
-Chloro-(2,6-difluorophenyl)-3H-cheno[2,3-e)-1,4-diazepine was obtained.

Example 7 4-(0-chlorophenyl)-9-methyl-6H-cheno[3.2-f]-8-triazolo[4.3-a) (1
-4] Diazepine 3.51 (0,0111 mol) was pulverized and dissolved in sulfuric acid 35a at 5°C.

The nitrated acid mixture (65% nitric acid 0°C) was then cooled to 0°C.
．． 805 r/'Ll and 1.6 rul of sulfuric acid) were added dropwise at O'G within 0.5 hours.

The mixture was stirred for an additional 2.5 hours at 0°C, then
Pour into 00P and 500rrLl of water.

The solution was neutralized with solid sodium bicarbonate and the product precipitated in crystalline form.

The product was shaken three times with 200 parts of methylene chloride, the organic phase was washed with water and dried.

The solvent was then evaporated and the residue triturated with ethyl acetate.
The obtained 4-(o-chlorophenyl)-9-methyl-2
-nitro6H-chenoC3-2-f)-s-triazolo(4-3-a)(1.4)diazepine was recrystallized from ethanol containing activated carbon.

The product melted at 270-272°C.

The starting material was prepared as follows: 2-chloroacetylamino-3-(o-chlorobenzoyl)-thiophene 2251 (0.72 mol) was dissolved in acetone 21 and sodium iodide 1181 was added.

The solution was heated under reflux for 1.5 hours and sodium chloride precipitated immediately.

The mixture was evaporated, treated with 31 methylene chloride and 1
01 reactor with submerged ammonia 31.

The mixture was stirred for 48 hours so that the phases did not mix with each other.

At the end of the reaction the phases were separated and the aqueous phase was dissolved in methylene chloride 200
Extraction was further carried out twice with ml each, and the organic phase was washed three times with water.

The methylene chloride phase was evaporated and crystallized.

This crystal cake was treated with 200 TLl of methylene chloride,
The mixture was brought to a boil while stirring.

The product was crystallized overnight in the refrigerator, filtered under vacuum, and washed with ice-cold methylene chloride to give 2-aminoacetylamino-3-
(o-Chlorbenzoyl)-thiophene was obtained.

2-Aminoacetylamino-3-(o-chlorobenzoyl)-thiophene 150P (0.51 mol) was dissolved in 2.51 ml of absolute ethanol and 250 rul of glacial acetic acid were added.

The solution was heated under reflux with stirring until the reaction was complete (approximately 5 hours).

Completion of the reaction could be observed by thin layer chromatography (eluent: ether).

The solvent was removed in vacuo and methylene chloride 21! It was adopted in

The methylene chloride solution was shaken with dilute aqueous sodium bicarbonate solution, washed with water, and evaporated.

The product was then crystallized from 150 rI methylene chloride.
11, boiled and left in the refrigerator to crystallize.

Very pure 5-(o-chlorophenyl)-1.3-dihydro-2H-fr-/C2.3-e was then obtained by filtration under vacuum and washing with ice-cold methylene chloride.
)-1,4-diazepin-2-one with a melting point of 221-22
Obtained in the form of light yellow crystals at 3°C.

5-(o-chlorophenyl)-1,3-dihydro-2H
-Cheno[2,3-e)-1,4-diazepin-2-one 0.95P (0,0034 mol) at 80℃ in 25ml
of diethylene glycol dimethyl ether.

A finely ground mixture of 1.61 parts of P4S10 and 11 parts of sodium bicarbonate was added to this solution, during which the reaction mixture foamed strongly.

After the addition was completed, the mixture was further stirred at 80°C for 50 minutes, and the solvent was removed at 101r.
Concentrated to 1 liter and mixed with 120 TIll of water.

The precipitated product was filtered off with suction, washed with water and dried at room temperature.

5-(o-chlorophenyl)-1,3-dihydro-2
H-che/C2・3-e)-1・4-diazepine-2-
I got thione.

Yellow crystals with a recrystallization contact melting point of 200°C were obtained from methanol.

A solution of 0.5 ml of hydrazine hydrate in 50 ml of anhydrous tetrahydrofuran contains 2.01 of 5-(o-chlorophenyl)-1,3-dihydro-2H-(-eno[2,
3-e)-1,4-diazepine-2-thione2. Added Oy.

After 10 minutes a red solution was obtained which was stirred for a further 20 minutes at room temperature.

The reaction product was then crystallized by addition of ether.

The crystals were separated from P, washed with ether, and dried.

5-(o-chlorophenyl)- with a melting point of 178-180°C
2-hydrazino-3H-cheno[2.3-e]-1.4
-Diazepine was obtained.

This could be recrystallized from tetrahydrofuran-ether, giving colorless crystals with a melting point of 179 DEG-180 DEG C.

5-(o-chlorophenyl)-2-hydrazino-3H-
Cheno[2-3-e)-1-4-diazepine 2P(0
,0069 mol) was suspended in 200 tnl of dry methylene chloride and treated with 101 tnl of sodium bicarbonate.

The solution was cooled to 0° C. and treated with 0.8 m of acetyl chloride while stirring.

After 45 minutes, the solid material was separated from the solution and then 10% of water was added.
Washed twice with 0rrLl each.

The organic phase was dried over sodium sulphate and then evaporated, treated with butanol 100a and 20 ml thereof evaporated under reduced pressure.

The solution was heated under reflux for 8 hours and evaporated under vacuum.

The crystals obtained after trituring the oily residue with ethanol were then boiled with a little ethanol, crystallized in the refrigerator, filtered under vacuum and dried.

As a result, 4-(o-chlorophenyl)-9-methyl 6H-cheno[3.2-f)-8- with a melting point of 221 to 223°C
) Riazolo[4.3-a) (1.4] diazepine was obtained.

Example 8 7-Chlorotate 3-dihydro-5-(o-nitrophenyl)-2H-cheno[2,3-e)-1,4-diazepin-2-one 4y prepared from 7-chlorot3-dihydro- 5-(o-nitrophenyl)-2H-cheno[2
-3-e) -1,4-Diazepine-2-thione was added to 600 rrLl of methylene chloride and treated with sodium sulfate until completely dry.

Any oily residue that may be present was dissolved in methanol 2Ornjl and the solution was filtered.

Then 6.85 f of methoxyacetic acid hydrazide (5 times the molar amount) was added and the solution was completely evaporated under reduced pressure.

This residue crystallized when treated with 200 rILl of methanol.

Apply this solution to 100mA! The solution was concentrated to 100% and crystallized in the refrigerator.

The dark red 7-chloro-2-(2-methoxyacetylhydrazino)-5-(o-nitrophenyl)3H-cheno[2. 3-e)-1,4-diazepine was obtained.

The product was refluxed in 400 ml of anhydrous xylene for 2 hours and then concentrated under reduced pressure to 150 mA'.

After crystallization, very pure colorless 2-chloro-9-methoxymethyl-4-(
o-nitrophenyl)-6H-cheno[3.2~f]-
s-triazolo[4.3-a)(t.4]diazepine was obtained.

Example 9 Unprepared from 7-chloroto-3-dihydro-5-(0-nitrophenyl)-2H-thieno[2,3-e)-1,4-diazepin-2-one 5y (0,0155 mol) Purified 7-chlororoot 3-dihydro-5-(o-nitrophenyl)-2H-cheno[2,3-e,l-1,4-diazepine-2-thione in methylene chloride 500rILl
and heated under reflux for 15 hours with stirring with 15 g of sodium bicarbonate and 7 g of acetic acid hydrazide dimethylammonium chloride.

After one filtration of the solid material, the solution was washed twice with 200 IIL each of water and dried over sodium sulfate.

After evaporating the solvent, the residue is triturated with ethyl acetate to give
7~chloro-2-(2-dimethylglycylhydrazino)
-5-(.

-nitrophenyl)-3H-cheno(2-3-e)[1
・4] Diazepine precipitated in crystalline form.

The obtained product was dissolved in 300 rrLl of absolute butanol for 2 hours.
The mixture was boiled under reflux for 4 hours, the solvent was evaporated and then triturated with ethyl acetate.

Then, by recrystallizing from ethanol, the melting point was 2.
2-chloro-9-dimethylaminomethyl-4-(.

-nitrophenyl)-6H-cheno[3.2-f]-8
-triazolo[4.3-a)C1.4]diacehine was obtained as a colorless product.

Example 10 7-Chlor-5-(0-chlorophenyl)-1,3-dihydro-2H-cheno[2,3-e]-1,4-diazepine-2-thione in anhydrous butanol with glycolic acid hydrazide. 1.51 and boiled under reflux for 8 hours.

The solvent was then distilled off and the residue was crystallized from ethyl acetate containing activated carbon.

As a result, 2-chloro-4-(o
-chlorophenyl)-6H-cheno[3.2-f)-s
-) Riazolo C4-3-a) (1,-4] diazepine -
9-methanol was obtained.

Example 11 2-chloro-4-(0-chlorophenyl)-6H-thieno[3.2-f)-s-triazolo[4.3-a)(1
-4] 0.75 r of diazepine-9-methanol was dissolved in 25 rr Ll of anhydrous chloroform, and 0.7 f of triethylamine and 0.61 l of methanesulfochloride were added thereto.

The mixture was stirred at 25°C for 25 hours, washed twice with water, and
Washed twice with saturated sodium chloride solution, dried over sodium sulphate and evaporated.

Obtained 2-chloro-4-(0-chlorophenyl)-6
H-cheno [3・2- f ) -s -) Riazolo c
+-3-a) CI-4,1 diacehine-9-methanol methanesulfonic acid ester oil was dissolved in dimethylformamide 10 mA and this solution was dissolved in a solution of liquid ammonia 1a in 5 ml dimethylformamide at 0-5°C. Added dropwise.

The mixture was stirred at room temperature for 2 hours and then partitioned between saturated sodium chloride solution and methylene chloride.

The organic phase was dried, evaporated and the residue was crystallized from ethanol.

As a result, 9-aminomethyl-2 with a melting point of 190-192°C
-Chlor-4-(o-chlorophenyl)-6H-cheno(3.2-f)-8-triazoo(4-3-a)[1
・4] Diazepine was obtained.

Example 12 2-chloro-4-(o-chlorophenyl)-6H-cheno[3.2-f)-s-)riazolo[4.3-
a) (1.4) diazepine-9-methanol 0.9'?
was dissolved in anhydrous chloroform 20 Fd, and 0.91 l of triethylamine and 0.71 l of methanesulfochloride were added.

The mixture was stirred at 25° C. for 2.5 hours, then washed twice with water, twice with saturated sodium chloride solution, dried over sodium sulphate and evaporated.

Obtained 2-chloro-4-(o-chlorophenyl)-6
H-cheno [3・2-f)-s-) Riazolo [4・3-
a, l (1,4,1-9-methanol methanesulfonic acid ester oil was dissolved in anhydrous dimethylform 73119m
7! To this was added dropwise a solution of 0.8 ml of morpholine in dimethylformamide 5 at 0-5°C.

The mixture was stirred for 2 hours and then partitioned between saturated sodium chloride solution and methylene chloride.

The organic phase was dried and evaporated.

This residue was crystallized from ethyl acetate containing activated carbon.

As a result, 2-chloro-4-(O
-chlorophenyl)-9-morpholinomethyl-6H-
Cheno [3.2-, f)-s-) Riazolo [4.3-a
) (1.4) diazepine was obtained.

Example 13 2-chloro-4-(0-chlorophenyl)-6H-cheno[3.2-f)-s-)riazolo[4.3-a)(1
・4] Dissolve 0.75f of diazepine-9-methanol in 10rIL of anhydrous chloroform, and dissolve 0.75f of diazepine-9-methanol in
．． 71 and methanesulfochloride o, sy.

The mixture was stirred at room temperature for 2.5 hours, washed twice with water and sodium chloride solution, dried over sodium sulphate and evaporated.

Obtained 2-chloro-4-(o-chlorophenyl)-6
H-cheno [3・2-f)-s-) Riazolo [4・3-
a) [1.4] Dissolve the methanesulfonic acid ester crude product of diazepine-9-methanol in 15 Tnl of anhydrous dimethylformamide, and add 0 ml of sodium methyl mercaptide.
．． 91 and stirred at 50° C. for 1 hour.

The solution was partitioned between water and methylene chloride and the organic phase was dried and evaporated.

This residue was crystallized from ethyl acetate containing activated carbon.

As a result, 2-chloro-4-(
o-chlorophenyl)-9-methylthiomethyl-6H-
Cheno [3.2-f)-s-triazolo [4.3-a,
l(1.4) diazepine was obtained.

2-chloro-4-(0-nitrophenyl)-6H-cheno[3.2-f)-s-)riazolo[4.3-a)(1
・4] The following compound can be produced from diazepine-9-methanol and sodium methoxide in the same manner as above: 2-chloro-9-methoxymethyl-4
-(o-nitrophenyl)-6H-cheno[3・2-f
]-8-triazolo[4.3-a)(1.4]diazepine, melting point 204-205°C.

Example 14 7-chloro-5-(o-chlorophenyl)-1,3-dihydro:]-2H-cheno[12,3-e) -1-
3.27 f (0.01 mol) of 4-diazepine-2-thione are dissolved in 200 d of butanol and 5.51 g of oxalic acid ethyl ester hydrazide are dissolved while nitrogen is introduced into the solution and the butanol is slowly distilled off for the first 5 hours. with 20
Boil under reflux for an hour.

After evaporation of the solvent, the oil was then taken up in methylene chloride and treated three times with 0.2N sodium hydroxide and then with 0.2N sodium hydroxide.
Washed three times with 2N hydrochloric acid.

The organic phase was subsequently washed with sodium bicarbonate, dried and
Evaporated.

By crystallizing this residue from ethanol containing activated carbon, 2-chloro-4-(
o-chlorophenyl)-6Hthieno[3.2-f)-8
-1 Riazolo[4.3-a) (1.4]-Diazepine-
9-carboxylic acid ethyl ester was obtained.

Example 15 7-Chlorotate 3-dihydro-5-(o-nitrophenyl)-2H-cheno[2.3-e)-1. while bubbling nitrogen into the solution and slowly distilling off the solvent. 4-Diazepine-2-thio 73.37f! (0.01 mol) of 8 ethyl ester hydrazide and 15 butanol
QmA! The mixture was heated under reflux for 1 hour.

After complete evaporation of the solvent under reduced pressure, the residue was taken up in methylene chloride and treated first with water, then with 0.4N sodium hydroxide four times and then with 0.4N sodium hydroxide. Washed twice with IN hydrochloric acid.

The methylene chloride layer was washed with a dilute solution of sodium bicarbonate, dried and evaporated.

2-chloro-4-(o-nitrophenyl) was then completely crystallized from ethanol containing activated carbon.
-6H-chenoC3-2-f) -8-triazolo[
4.3-a][1.4]Diazepine-9-carboxylic acid ethyl ester was obtained in the form of colorless crystals with a melting point of 143-145°C.

Example 16 7-chloro-5-(o-
Chlorphenyl) -1,3-dihydro 2H-cheno [
2,3-e)-1,4-diazepine-2-thio 71.5
1 was boiled under reflux for 4 hours with 4 parts of 2-(p-methoxybenzyloxy)acetic hydrazide in 100 TL of absolute butanol.

The mixture was evaporated, taken up in methylene chloride, washed with water and saturated sodium chloride solution, dried and evaporated.

This residue was then crystallized from ethyl acetate containing activated carbon to give 2-chloro-4-(o-chlorophenyl)-9-C(p-methoxybenzyloxy)methyl)-6.
H-chenoC3-2-f, l-8-) Riazolo[4-
3-a) [1,4]-Diazepine was obtained.

Example 17 A suspension of 0.078 f of lithium aluminum hydride in 5 UL of anhydrous tetrahydrofuran contains 2-chloro-4-(2-chloro-4-() in 6.5 RU of anhydrous tetrahydrofuran.

-chlorophenyl)-6H-cheno[3.2--f)
A solution of 0.4N/s-)riazolo[4.3-a)(1.4]diazepine-9-carboxylic acid ethyl ester was added dropwise while cooling with water and stirring.

After stirring for 1 hour at 5° C., 0.8 d of 0.5 N sodium hydroxide was added gradually.

The solid material was then filtered off, the solvent evaporated and the residue taken up in methylene chloride.

The solution was washed with 0.5N sodium hydroxide, then water, dried and evaporated to dryness.

Crystallization of this residue from ethyl acetate yields 2-chloro-4-(o-chlorophenyl)-6H-chenoC3-2-f, l-8-4 riazo p(4- 3-a,1[1.4]diazepine-9-methanol was obtained.

Example 18 2-chloro-4-(o-chlorophenyl)-6H-cheno[3.2-f,1-s-)riazolo[4.3-a)(
1.4] 1♂ diazepine-9-methanol was dissolved in 107 rLl of anhydrous pyridine and treated with 1 ml of acetic anhydride.

The solution was kept at 30° C. for 15 hours and then evaporated under vacuum.

The residue was partitioned between methylene chloride and water.

The organic phase was then washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated.

This residue was then recrystallized from ethyl acetate to give 9-acetoxymethyl-2- with a melting point of 191-193°C.
Chlor-4-(0-chlorophenyl)-6H-cheno [
3.2-f) -s-) Riazoro [4.3-a]
[1.4] Diazepine was obtained.

Example 19 7-chloro-5-(0-chlorophenyl)-1,3-dihydro-2H-cheno[2,3-e)-1,4 diazepine-2-thione 11 was mixed with lactic acid hydrazide 21 in 50 rIL of anhydrous methanol. The mixture was boiled under reflux for 1.5 hours.

Precipitated 7-chloro-5-(o-chlorophenyl)-2
-(2-lactoylhydrazino)-3H-cheno[2.
3-e)-1,4-Diazepine was dried and boiled in 120 rrll of anhydrous xylene for 4 hours.

By evaporating the solution and crystallizing the product from ethyl acetate containing activated carbon, 2-chloro-4-(o-chlorophenyl)-9=(o-
hydroxyethyl)-6H-cheno[3.2-f]-8
-Triazolo[4.3-a)(1.4]diazepine was obtained.

Example 20 2-chloro-4-(o-chlorophenyl)-9(α-hydroxyethyl)-6H-cheno[3·2-f, 1-s
-TriazoloC4-3-a)C1-4]Diazepine 0.
41 was heated under reflux with 0.61 chromium trioxide in graphite in 80 TLl of dry toluene for 48 hours.

The solid material was then separated from the P and the solution was evaporated.

By crystallizing this residue from ethanol, 9-acetyl-2-chloro-4-(o-
Chlorphenyl)-6H-cheno[3.2-f)-s triazolo[4.3-a)(1.4]diazepine was obtained.

Example 21 7-chloro-5-(0-chlorophenyl)-1,3-dihydro-2H-cheno[2,3-e)-1,4-diazepine-2-thio 71.21 was added to 80 rIl of anhydrous methanol
The mixture was heated under reflux for 1.5 hours with 2 grams of cyanoacetic hydrazide in a 1.5-liter medium.

Nitrogen was bubbled into the solution during this time.

The solution was then concentrated to 1 OrrLl and crystallized.

Separate and dry under vacuum to give 7-chloro-5-(o-
Chlorphenyl)-2-(2-cyanoacetylhydrazino)-3Hthieno[2.3-e)-1.4-diazepine was boiled under reflux in 15 Qm of anhydrous xylene.

By evaporating this solution and crystallizing the residue from ethyl acetate containing activated carbon, a
-Chlor-4-(0-chlorphenyl)-9-cyanomethyl-6H-cheno[3.2-f)-s-)RiazoloC4-3-a)[1-4) diazepine was obtained.

Example 22 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-cheno[2,3-e)-1,4-diazepine-2-thio 70.82 ml of anhydrous methanol 40 TLl
The mixture was boiled under reflux for 1.5 hours with 1.5 hours of oxalic acid amide hydrazide.

This solution is 10171A! It was concentrated to 100% and crystallized in the refrigerator.

Then filtered and dried 7-chloro-5-(o-chlorophenyl)-2-(2--)rxalylamidehydrazino)-3H-cheno[2.3-e)-1.4
-Diazepine was boiled under reflux in anhydrous xylene 10QmA for 3 hours.

The organic phase is then evaporated and the residue is crystallized from ethanol to give 2-chloro-4-(o-chlorophenyl)-6H-cheno[3.2
-f)-s-) riazool:”4-3-a)(1・4]
Diazepine-9-carboxylic acid amide was obtained.

Example 23 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-cheno[2,3-e]-1,4-diazepine-2-thione and 7-chloro obtained from hydrazine -5-(o-chlorophenyl)-2-hydrazino-3
H-cheno[2,3-e]-1,4-diazepine 0.7
1 was introduced into 15 mA' of glacial acetic acid while cooling it to 15°C. Contains 0.0% chloroacetyl chloride.
2! It was slowly added dropwise to the solution of Ill.

The mixture was stirred for a further 2 hours and 0.3% sodium acetate was added.
1 and stirred for 1 hour.

This solution was introduced into ice water, neutralized and extracted with methylene chloride.

The solvent was then evaporated and the residue was boiled in 30 g of anhydrous xylene for 1 hour.

Subsequent evaporation of the solvent and crystallization of the residue from ethyl acetate containing activated charcoal give a melting point of 101-103.
2-chloro-9-chloromethyl-4-(o-chlorophenyl)-6H-chenoC3-2-f)-s-)riazoo(4-3-a)[1.4]diazepine was obtained at °C. .

Example 24 2-Chlor-4-(o-chlorophenyl)-9 was produced by carrying out the reaction in the same manner as in Example 23 except that iodoacetyl iodide was used instead of chloroacetyl chloride.
-iodomethyl-6H-cheno[3.2-f)-8-)
Riazolo[4.3-a][1.4]diazepine was obtained.

Example 25 2-[3.5-bis(aminomethyl)-4H1.2.4
- Triazol-4-yl-5-chloro-3-chenyl-o-chlorophenylketone-dihydrochloride (boiling point/decomposition point 230°C) 500 μl is dissolved in 10 a. of water and IN
Make alkaline with caustic soda and extract the aqueous phase with methylene chloride.

After drying over sodium sulfate and evaporating the organic phase, the residue was heated to reflux in 5-hydrous alcohol for 30 minutes.

After evaporation, the crude base was chromatographed on aluminum oxide.

9-(Aminomethyl)-2-chloro-4-(0-chlorophenyl)-6H-cheno[3.2-f)-s eluted with chloroform and crystallized from ethyl acetate.
-Triazolo[4.3-a][1.4]diazepine had a melting point of 167-168°C.

Samples from acetate ester and low boiling petroleum ether were 17
It melted at 0.5-171°C.

- The hydrochloride salt had a melting-decomposition point of 198-200°C.

Example 26 5-(o-chlorophenyl)-1H-cheno[2.3-
e] [1,4]-Diazepine-2(3K)-one 0.9
5f? (0,0034 mol) was dissolved in 25 rfLl of diethylene glycol dimethyl ether at 80°C.

A finely divided mixture of 1.61 parts of phosphorus pentasulfide and 11 parts of sodium bicarbonate was added to this solution, with vigorous bubbling of the reaction mixture.

After the addition was completed, the mixture was further stirred at 80°C for 50 minutes, and the solvent was removed at 101r.
Concentrated to Ll and decomposed with 120 ml of water.

The precipitated product was filtered off with suction, washed with water and dried at room temperature.

1.05f of 5-(o-chlorophenyl)-tH-cheno[2.3-e)(t.4]-diazepine 2(3H)-
Thione was obtained.

This product was dissolved in 5M glacial acetic acid and 2Od methanol and heated to 50°C for 1 hour with 2g acetohydrazide-dimethylammonium chloride.

After evaporation of the solvent, the oil was mixed with 150 rrLl of 5% sodium bicarbonate solution and a total of 150 rrL
Extracted portionwise with 1 liter of methylene chloride.

After drying with sodium sulfate, the solvent was removed.

The resulting oil was boiled at reflux in 70 rILl of glacial acetic acid for 1 hour.

The solvent was evaporated and the residue was partitioned between 100 ml sodium bicarbonate solution and io yd methylene chloride.

After evaporation of the organic phase, the resulting 4-(o-chlorophenyl)-9-dimethylaminomethyl-4H-cheno[3.
2-f)-s-) Riazolo [4・3-a, l(i・4]
-Diazepine was boiled with 100 TrLl ethyl acetate, impurities were filtered hot and concentrated to 20 rILl.

The precipitated product was recrystallized from ethyl acetate.

A product of 0.42 S' was obtained with a melting point of 210-212°C.

0.21 of this product was dissolved in 3QmA' of anhydrous chloroform and mixed with 0.2 TrLl of anhydrous pyridine;
It was then cooled to -5°C.

After 3 hours no starting material could be detected.

After evaporation of the solvent, the mixture was purified by acid chromatography (silica gel, eluent ethanol).

Melting point 203-205'C(7)2-J'Rollo4-(o
-chlorophenyl)9-dimethylaminomethyl-4H-
Cheno [3.2-f)-s-) Riazolo [4.3-a]
[l·4]-Diazepine was obtained.

Example 27 4-(o-chlorophenyl)-9-mef-6H-che/C3·2-f) in 100 rIL of anhydrous chloroform
-s-) lyazo0(4-3-a)-14-diazepine 1
1 (0,0032 mol) was dissolved, cooled to 0°C and mixed with 1rrLl pyridine (4-fold molar excess).

Chlorine gas was introduced into the solution for 2 hours. The solution was evaporated and the residue was taken up hot in methylene chloride and washed once with 0.1N hydrochloric acid.

The product is extracted with 4N hydrochloric acid, the methylene chloride phase being mixed with ether in such a way that it reaches the top.

Upon neutralization of the hydrochloric acid phase with solid sodium bicarbonate, the product is taken up in methylene chloride.

The methylene chloride phase was dried over sodium sulfate, evaporated and
and triturated with a small amount of ethyl acetate (Angerieben
e) I did.

The crystallized product was recrystallized from ethanol using activated carbon to give 2-chloro-4-(c
)-chlorophenyl)-9-methyl 6H-cheno[3.
2-f) -s-) Riazolo [4.3-a)-1
- 4-Diazepine was obtained.

Example 28 0.71 of 2-chloro-9-chloromethyl-4-(o-chlorophenyl)-6H-cheno[3φ2-,f)-8-triazolo[4.3-a)(1.4]diazepine 5r
ILi! Dissolved in DMF, cooled to 0 °C, 5rILl
TI (mixed with liquid NH31rILl in F, mixed with
It was left at ℃ for one week.

The reaction mixture was partitioned between saturated sodium chloride solution and methylene chloride, the organic phase was dried, evaporated and the residue was recrystallized three times from ethanol.

9-aminomethyl-2-chloro-4-(o-chlorophenyl)-6H-cheno[3.2], melting point 190-192°C
-j)-s-triazolo[4.3-a)(1.4]diazepine was obtained.

Example 29 2-chloro-9-chloromethyl-4-(O-chlorophenyl)-6H-cheno[3.2-f)-8-triazolo[4.3-a)(1.4]diazepine 0.51 5rf
5-Liquid NH31 in DMF dissolved in LlDMF
Mixed with rrLl, iron cylindrical tube (Bombenrohr
) and heated to 100° C. for 2 hours.

After cooling and opening the iron cylindrical tube, partition between saturated sodium chloride solution and methylene chloride, dry the organic phase,
Evaporated and the residue was recrystallized three times from ethanol.

9-aminomethyl-2-chloro-4(0-chlorophenyl)-6H-cheno[3,2-
f)-s-)liazolo[4.3-a][1.4]diazepine was obtained.

Example 30 2-(2-acetylhydrazino)-7-promo-5-(
o-chlorophenyl)-3H-chenoC2・3-e)
7.59 ml of -1,4-diazepine was heated to reflux in 75rILl acetic acid for 1 hour.

The solution was evaporated in vacuo.

The residue was dissolved in chloroform at 150? of aluminum oxide (activity 1, basic).

The eluate was evaporated.

The residue was crystallized from methanol-ether.

2-bromo-4(0-chlorophenyl)-9-methyl-6H-cheno[3.2-f)- with melting point 206-208°C
s-) Riazolo[4.3-a][1.4]diazepine was obtained.

The starting materials were produced as follows.

Anhydrous dioxane 590mA! 20.
27.59 of sodium bicarbonate was suspended in a solution of 75'.

The mixture was warmed to 73° C. with vigorous stirring and quickly mixed with 26.3 f of phosphorous pentasulfide.

It was stirred for an additional 50 minutes at 75°C.

Approximately 400 rILl of dioxane was then distilled off under light vacuum (temperature approximately 50°C).

After cooling to 20° C., 550 μL of acetic ester and 550 μL of water were added, and then the pH was adjusted to 10.5 with an IJ solution under ice cooling.

The organic phase was washed twice with sodium chloride solution, dried over sodium sulphate and evaporated in vacuo.

The crystalline residue was melted at 208-210°C.

- The combined aqueous phases were brought to pH 4 with acetic acid.

The precipitate precipitated therefrom was taken from house to house, washed, and dried.

Yellow crystals were obtained. -2.51 of the combined crystalline product!
Boil in ethanol and remove the insoluble portion from the heat.

The P solution was concentrated to 200 TfLl and cooled to 0°C.

7-promut-3-dihydro-5-(o
-chlorophenyl)-2H-cheno(2-3-e)
-1.,4-diazepine-2-thione was crystallized.

9.51 of 7-bromo-3-dihydro-5-(o-chlorophenyl)-2H-cheno[2.3-e)-1.4-diazepine-2-thione 9.5 in 130 rfL of anhydrous tetrahydrone run. Dissolved.

To it was added 5.751 grams of acetic hydrazide and heated to reflux temperature for 6 hours.

The solvent was then distilled off in vacuo and the residue was crystallized from ethanol.

2-(2-acetylhydrazino)-7- with melting point 198°C
From-5-(0-chlorophenyl)-3H-cheno [
2.3-e)-1.4-diazepine was obtained.

Example 31 2-(2--ycetylhydrazino)-7-iodo-5-
(o-chlorophenyl)-3H-cheno[2.3-e)
7.22 of -1,4-diazepine was heated to reflux temperature in 100 rrLl of acetic acid for 1 hour.

The solution was evaporated in vacuo.

The residue was hot dissolved in a mixture of 100 rfLl benzene and 100 rfL ethanol and decolorized with activated carbon.

After removing the charcoal, the solution was concentrated in vacuo until crystallization began.

2-Iodo-4-(0-chlorophenyl)-9-methyl-6H-1-eno[3.2-f] with a melting point of 223°C after cooling
-s-) Riazolo-C4,-3-a)-i 4-diazepine was crystallized.

The starting materials were prepared in a manner similar to that described in Example 30.
-iodo-1,3-dihydro-5-(〇-chlorophenyl)-2H-cheno[2,3-e]-1,4-diazepin-2-one.

7-iodo-1,3-dihydro-5-(0-chlorophenyl)-2H-cheno[2,3
-e) -1.47 diazepine-2-thione and melting point 18
2-(2-acetylhydrazino)-7-iodo- at 2°C
5-(0-chlorophenyl)-3H-cheno-[2.3
-6)-1,4-diazepine was obtained.

Example 32 Treated similarly to the method described in Example 11 to produce 2-chloro-4-(O-chlorophenyl)-6H-cheno[3.
2-f)-s-1 Riazolo[4.3-a)(1.4] The methanesulfonic acid ester of diazepine-9-methanol was treated with methylamine rather than with ammonia.

2-chloro-4-(o-chlorophenyl)-9-methylaminomethyl-6H-cheno[3.2-f)-s-triazolo[4.3-a)(1.4]diazepine was obtained, and this 139-14 after recrystallization from acetate ester
It melted at 1°C.

The following reference examples illustrate pharmacological preparations containing chenotriazolodiazepine derivatives provided by the present invention.

Cocoa butter and cownauba wax were melted in a glass or steel container, mixed thoroughly and cooled to 45°C.

Next, fine powder of 2-chloro-4-(o-chlorophenyl)-9-methyl-6Hthieno[3.2-f, l-5-)
Riazolo[4.3-a)(1.4]diazepine was added and the mixture was stirred until completely dispersed.

The mixture is poured into appropriately sized suppository molds, allowed to cool, and the suppositories are then removed from the molds and individually wrapped in wax paper or metal foil.

2-chloro-4-(o-chlorophenyl)-9methyl-
6H-cheno [3・2-f)-s-) Riazolo [4・3
-a) [1.4] Diazepine, lactose and maize starch were mixed first in a mixer and then in a granulator.

The mixture was returned to the mixer and Merck was added and mixed thoroughly.

This mixture was then mechanically filled into hard gelatin capsules.

In order to produce 10,000 ml of liquid for injection, 2
-Chlor-4-(o-chlorophenyl)-9-methyl-
6H-cheno [3・2-f)-s-) Riazolo [4・3
-a] [1.4] Dissolve 50 g of diazepine in 150 g of benzyl alcohol, and add 4 g of polyethylene glycol to this solution.
000- and 10,100 O of ethanol were added.

Then dissolve sodium benzoate in this mixture and add water (
For injection) Sodium benzoate 488v in 300wLl
A solution of was added.

Water (for injection) was then added to this solution to a volume of 10,000 a, filtered and placed in an appropriately sized angle.

The remaining contents of the ampoule were filled with nitrogen and the ampoule was heat sealed and sterilized in an autoclave at 0.7 atmospheres for 30 minutes.

The main embodiments and related matters of the present invention are summarized as follows.

(2) General formula [In the formula, R1 represents a halogen atom or a nitro group, R
2 is phenyl, 0-)lifluoromethylphenyl, 0-
Halofueni/L/, O-0'-dihalophenyl or 0-nitrophenyl group or hapyridyl group, R3 is lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino- lower alkyl, lower alkoxy
Lower alkyl, lower alkoxybenzyloxy-lower alkyl, morpholino-lower alkyl, lower alkylthio-lower alkyl, cyano-lower alkyl, halo-lower alkyl, lower alkokinecarbonylamino-lower alkyl, di-lower alkylcarbamoyloxy-lower alkyl, lower alkanoyl oxy-lower alkyl, lower alkameyl, lower alkoxycarbonyl or carbamoyl group] In producing chenotriazolodiazepine derivatives and acid addition salts thereof, (a) the general formula [wherein R1, R2 and R3 are (b) cyclizes a compound of the general formula [wherein R1, R2 and R3 have the same meanings as above]; or (e) cyclizes a compound of the general formula [in the formula] , R2 and R3 are as defined above], or (d) to produce a compound of formula (I) in which R3 represents a lower alkanoyl group, R3 is α-hydroxy lower alkyl. or (e) to prepare compounds of formula (I) in which Rs represents a lower alkanoyloxy lower alkyl group, or (e) compounds of formula (I) in which R3 represents a hydroquine lower alkyl group. ) is esterified with a suitable alkanoylating agent, or (f) Ra is lower alkoxy-lower alkyl, lower alkoxybenzyloxy-lower alkyl, lower alkylthio-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl , di-lower alkylamino-lower alkyl or morpholino-lower alkyl group, the corresponding compounds of formula (I) in which R3 represents a halo-lower alkyl group or R
The reactive ester of the corresponding compound of formula (I) in which 3 represents a hydroxy-lower alkyl group can be substituted with a lower alkanol,
treatment with lower alkoxybenzyl alcohol, lower alkyl mercaptan, ammonia, lower alkyl amine, di-lower alkyl amine or morpholine, or (g) producing a compound of formula (I) in which R3 represents a di-lower alkylcarbamoyloxy-lower alkyl group. (h) R3 represents a lower alkoxycarbonylamino-lower alkyl group by reacting the corresponding compound of formula (I) with a reactive ester of di-lower alkylcarbamic acid in order to In order to prepare compounds of formula (I), the corresponding compounds of formula (I) in which R3 represents an amino-lower alkyl group are reacted with a lower alkyl ester of chloroformic acid, or (i) R3 is a hydroxymethyl group. Formula (I) representing
reducing a compound of formula (I) in which R3 represents a lower alkoxycarbonyl group, and (j) optionally converting the resulting compound of formula (I) into an acid addition salt. A method for producing a chenotriazolodiazepine derivative of the general formula (I).

and Embodiment a), (b), (c) according to the above item 1, provided that in embodiment (a), R3 represents a lower alkanoyl or lower alkanoyloxy-lower alkyl group,
(d), (e) or (j), characterized in that R1 and R2 have the meaning as defined in paragraph 1 above, and R3
is lower alkyl, hydroxy lower alkyl, amino lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, lower alkoxy-lower alkyl, lower alkoxybenzyloxy-lower alkyl, morpholino-lower alkyl, lower alkylthio-
Production of a Cheno)IJ azolodiazepine derivative of the general formula (I) according to item 1 above, which represents a lower alkyl, cyano-lower alkyl, halo-lower alkyl, lower alkanoyloxy-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or carbamoyl group. Method.

3. The method according to item 1 or 2 above, wherein R1 represents a halogen atom.

4. The method according to item 3 above, wherein R1 represents a chlorine atom.

5. The method according to any one of items 1 to 4 above, wherein R3 represents a lower alkyl group, a hydroxy lower alkyl group, or an amino lower alkyl group.

6. The method according to item 5 above, wherein R3 represents a methyl or hydroxymethyl group.

7. The method according to any one of items 1 to 6 above, wherein R2 represents 0-halophenyl, o'o'-dihalophenyl or 2-pyridyl group.

8. The method according to item 7, characterized in that R2 represents o-chlorophenyl, 0-fluorophenyl or o-o'-cyfluorophenyl.

9. The method according to any one of items 4 to 8 above, wherein R1 represents a chlorine atom, R2 represents O-chlorophenyl or O-fluorophenyl, and R3 represents a methyl group.

10.2-chloro-4-(0-chlorophenyl)-9-
2. The method according to item 1 above, characterized in that methyl-6H-cheno[3.2-f)-s-triazoloC-triazol.3-a)(1.4]diazepine is produced.

11.2-chloro-4-(o-chlorophenyl)-9-
The method according to item 1 above, characterized in that methyl-6H-cheno[3.2-f)-s-triazolo[4.3-a]diazepine-5-oxide is produced.

12.4-(o-chlorophenyl)-9-methyl2-nitro-6H-cheno[3.2-f)-s-triazolo[
4.3-a,l(1.4) diazepine is produced in the method of item 1 above.

13.2-chloro-9-methyl-4-(2-pyridyl)
-6H-cheno [3・2-f)-s-) Riazolo [4・
3-The method according to item 1 above, characterized in that a,l(1.4) diazepine is produced.

14. To produce 2-chloro-9-methyl-4-(o-nitrophenyl)-6H-cheno(3,2-f]-s triazolo[4,3-a)(1,4]diazepine The method according to item 1 above.

15.2-chloro-9-methyl-4-phenyl-6H-
Cheno [3.2-f)-s-) Riazolo [4.3-a)
(1.4) The method according to item 1 above, which comprises producing diazepine.

16.2-chloro-4-(o-fluorophenyl)-9
-Methyl-6H-cheno[3.2-f)-s-)riazolo[4.3-a)I:1.4]diazepine is produced.

17.2-chloro-4-(o-o'-difluorophenyl)-9-methyl-6H-cheno[3.2-f)-s-
) The method according to item 1 above, characterized in that liazolo[4.3-a][1.4]diazepine is produced.

18. Produce 9-acetyl-2-chloro-4-(o-chlorophenyl)-6H-cheno[3.2-f)-s-)riazolo[4.3-a)(1.4]diazepine The method according to item 1 above, characterized in that:

19, 9-tert-butyl-2-chloro-4
−(.

-chlorophenyl)-6H-cheno[3.2f)-s-
The method according to item 1 above, characterized in that triazoDC4-3-a]CI, 4) diazepine is produced.

and 9-carbamoyl-2-chloro-4-(o-chlorophenyl)-6H-cheno[3.2-f]-8-triazo0C4-3-a)[”1-4,1 diazepine is produced. The method according to item 1 above, characterized in that:

21. 9-Aminomethyl-2-chloro-4-(o-chlorophenyl)-6H-cheno[3,2-f]-8-triazoloC4-3-a)[”1-4) Produce diazepine The method according to item 1 above, characterized in that:

22. To produce 9-carbetoxy-2-chloro-4-(o-chlorphenyl)-6H-cheno[3,2-f]-8-triazolo[4,3-a)CI・4]diazepine The method according to item 1 above.

23.2-chloro-4-(0-chlorophenyl)-9-
The method of item 1 above, characterized in that cyanomethyl-6H-cheno[3.2-f]-8-triazoloC4-3-a) CI-4,1 diazepine is produced.

24.2-chloro-4-(o-chlorophenyl)-9-
Methylthiomethyl-6H-cheno[3.2-f, 1-s
-) Riazooc4-3-a) [1-4] The method according to item 1, characterized in that it produces diazepine.

25.2-chloro-4-(o-chlorophenyl)9-morpholinomethyl-6H-cheno[3.2-f)-s-
2. The method according to item 1 above, characterized in that lyazo-o(4-3-a, 1(1-4) diazepine) is produced.

26. Produce 2-chloro-4-(o-chlorophenyl)9-methoxymethyl-6H-cheno[3.2-f)-8-)liazolo[4.3-a][1.4]diazepine The method according to item 1 above, characterized in that:

27.2-Chlor-4-(o-chlorophenyl)-9-
Hydroxymethyl-6H-cheno[3.2-f)-s-
The method according to item 1 above, characterized in that triazolo[4.3-a][1.4]diazepine is produced.

28.2-chloro-4-(o-chlorophenyl)9-dimethylaminomethyl-6H-cheno[3.2-f)-s
-) Riazolo(4-3-a, 1(1-4) diacehine).

29.2-Chlor-9-chloromethyl-4-(o-chlorophenyl)-6H-cheno[3.2-f]-8-triazoloC4-3-a) CI-4,1 diazepine is produced. The method according to item 4 above.

30, (2-chloro-4-(o-chlorophenyl)6H
-Ceno [3.2-f) -s-) Riazolo [4.3-a
)(1.4)Diazepin-9-yl]-methyl-carbamic acid ethyl ester is produced.

3tl: 2-chloro-4-(0-chlorophenyl)-6
H-cheno[3.2-f)-8-triazolo[4.3-
a) (1,4) diazepine-9-ylyomethyl-N-
4. The method according to item 4, characterized in that N-dimethyl carbamate is produced.

32, (2-chloro-4-(o-chlorophenyl)-6
H-cheno [3・2-f) -s -) Riazolo [4
・3-a]:4.4] The method according to the above item 1, characterized in that diazepin-9-yl-to-methyl acetate is produced.

33.2-chloro-4-(o-chlorophenyl)-9-
(1-hydroxyethyl)-6H-chenoC3-2-f
) -8-triazo o(4.3-a)[1.4]diazepine is produced by the method according to the above item 1.

34.2-chloro-4-(o-chlorophenyl)-9-
The method according to item 1 above, characterized in that iodomethyl-6H-cheno[3.2-f]-8-triazolo[4.3-a)(1.4]diazepine is produced.

35.2-chloro-9-methoxymethyl-4-(.

Nitrophenyl)-6H-cheno[3.2-f)-s-
Triazo I:I [4-3-a) [1-4) The method according to item 1 above, characterized in that diazepine is produced.

36, (2-chloro-4-(o-nitrophenyl)-6
H-cheno [3・2-f, l-5-) Riazolo [4・3
-a) The method according to item 1 above, characterized in that it produces (1.4) diazepin-9-yltucarboxylic acid ethyl ester.

37.2-chloro-4-(o-chlorophenyl)-9-
(p-methoxybensiloquine methyl)-6H-cheno [
3.2-f, 1-8-triazolo[4.3-a:](1
・4] The fourth above, characterized in that it produces diazepine.
Section method.

38.2-chloro-9-dimethylaminemethyl-4-(
o-nitrophenyl)-6H-cheno[3.2-f)-
2. The method according to item 1 above, characterized in that s-triazolo(4-3-a)CI''4]diazepine is produced.

39.2-chloro-9-methyl-4-(o-trifluoromethylphenyl)-6H-cheno[3.2-f)-
s-) Riazolo[4.3-a][1.4]diazepine is produced.

Claims (1)

[Scope of Claims] 1 General formula [wherein R1 represents a halogen atom or a nitro group, R
2 is phenyl, o-trifluoromethylphenyl, 0-
Halophenyl □ m □'-dihalophenyl or 0-nitrophenyl group or pyridyl group, R3 is lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, lower Alkoxy
Represents lower alkyl, lower alkoxybenzyloxy-lower alkyl, morpholino-lower alkyl, lower alkylthio-lower alkyl, cyano-lower alkyl, halo-lower alkyl, lower alkanoyloxy-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or carbamoyl group] Chenotriazolodiazepine derivatives and their patents characterized in that the compound is cyclized and the resulting compound is optionally converted into an acid addition salt, wherein R1, R2 and R3 have the same meanings as above. Method for producing acid addition salts. 2 General formula [wherein R1 represents a halogen atom or a nitro group, R
2 is phenyl, 0-)lifluoromethylphenyl, 0-
Halophenyl, 0・o'-dihalophenylmodi< is 0-
Represents a nitrophenyl group or a pyridyl group, R3 is lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, lower alkoxy-lower alkyl, lower alkoxybenzyloxy- lower alkyl, morpholino-lower alkyl, lower alkylthio-lower alkyl, cyano-lower alkyl, halo-lower alkyl, lower alkanoyloxy-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or carbamoyl group] and obtain A process for producing a chenotriazolodiazepine derivative of the general formula [wherein R1, R2 and R3 have the same meanings as above] and an acid addition salt thereof, which comprises converting the compound obtained by converting the compound into an acid addition salt, if desired. 3 general formula [wherein R2 represents phenyl, o-trifluoromethylphenyl, 0-halophenyl, o-o'-dihalophenyl or 0-nitrophenyl group or hahyridyl group,
R3 is lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, lower alkoxy-lower alkyl, lower alkoxybenzyloxy-
lower alkyl, morpholino-lower alkyl, lower alkylthio-lower alkyl, cyano-lower alkyl, halo-lower alkyl, lower alkanoyloxy-lower alkyl,
a lower alkanoyl, lower alkoxycarbonyl or carbamoyl group], and optionally converting the resulting compound into an acid addition salt [wherein R1□ represents a halogen atom, R2 and R3
has the same meaning as above] A method for producing a chenotriazolodiazepine derivative and an acid addition salt thereof. 4 General formula [wherein R2 represents phenyl, 0-)rifluoromethyl A/phenyl, 0-halophenyl, 0.o'-dihalophenyl or 0-nitrophenyl group or pyridyl group, R2 represents lower alkyl, hydroxy-lower alkyl ,
Amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, lower alkoxy-lower alkyl, lower alkoxybenzyloxy-lower alkyl, morpholino-lower alkyl, lower alkylthio-lower alkyl, cyano-lower alkyl, halo A compound of the general formula [representing a lower alkyl, lower alkanoyloxy, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or carbamoyl group] is nitrated, and the resulting compound is optionally converted into an acid addition salt. In the formula, R1 represents a nitro group, and R2 and R3 have the same meanings as above. A method for producing a chenotriazolodiazepine derivative and an acid addition salt thereof. 5 General formula [wherein R1 represents a halogen atom or a nitro group, R
2 is phenyl, 〇-trifluoromethylphenyl, 0-
Halophenyl, o-o'-dihalophenyl or 0-
Represents a nitrophenyl group or a pyridyl group, R31 is α
-hydroxy-representing a lower alkyl group] and optionally converting the resulting compound into an acid addition salt [wherein R3
2 represents a lower alkanoyl group, and R1 and R2 have the same meanings as above.] A method for producing a chenotriazolodiazepine derivative and an acid addition salt thereof. 6 general formula [wherein R1 represents a halogen atom or a nitro group, R
2 is phenyl, o-trifluoromethylphenyl, 0-
Halophenyl, OaO'-dihalophenyl or 0-
nitrophenyl group or pyridyl group, and R33 represents a hydroxy-lower alkyl group] is esterified with a suitable alkanoylating agent, and the resulting compound is optionally converted into an acid addition salt. A method for producing a chenotriazolodiazepine derivative of the formula [wherein R34 represents a lower alkanoyloxy lower alkyl group, and R1 and R2 have the same meanings as above] and an acid addition salt thereof. 7 General formula [In the formula, R1 represents a halogen atom or a nitro group, R
2 is phenyl, o-trifluoromethylphenyl, 0-
Halophenyl, o-o'-dihalophenyl or 0-
nitrophenyl group or pyridyl group, and X represents a halogen atom or a reactive ester group] is treated with a lower alkanol or lower alkyl mercaptan or the corresponding alkoxide or mercaptide, and the resulting compound is optionally converted into an acid addition salt. In the general formula C, R35 represents lower alkoxy-lower alkyl or lower alkylthio-lower alkyl group, and R1 and R
2 has the same meaning as above] A method for producing a chenotriazolodiazepine derivative and an acid addition salt thereof. 8 General formula [wherein, Ro represents a halogen atom or a nitro group, R
2 is phenyl, 0-)lifluoromethylphenyl, 0-
Halophenyl, o-o'-dihalophenylmodi< is 0-
a nitrophenyl group or a pyridyl group, and X represents a halogen atom or a reactive ester group] is treated with ammonia, lower alkylamine, di-lower alkylamine, or morpholine, and the resulting compound is optionally converted into an acid addition salt. [wherein R36 represents an amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl or morpholino-lower alkyl group,
1 and R2 have the same meanings as above] and an acid addition salt thereof. 9 General formula [In the formula, R1 represents a halogen atom or a nitro group, R
2 is phenyl, 0-trifluoromethylphenyl, 0-
Halophenyl, o-o'-dihalophenyl or 0-
represents a nitrophenyl group or a pyridyl group, and R37 represents a lower alkoxycarbonyl group], and optionally converts the resulting compound into an acid addition salt [wherein R38 represents represents a hydroxymethyl group, and R1 and R2 have the same meanings as above.] A method for producing a chenotriazolodiazepine derivative and an acid addition salt thereof.