FI58129B - DIAZEPINDERIVAT FOR THE FREQUENCY OF THERAPEUTIC THERAPEUTIC THERAPEUTIC (3,2-F) -S-TRIAZOLO (4,3-A) (1,4) - Google Patents

Description

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Switzerland-Switzerland (CH) 1799/73 "(71) F. Hoffmann-La Roche & Co. Aktienge sells chart, Grenzacherstr. 12U-18U,

Basel, Switzerland-Switzerland (CH) (72) Joseph Hellerbach, Basel, Paul Zeller, Allschwil, Switzerland-Switzerland (CH),

Dieter Binder, Vienna, Otto Hromatka, Vienna, Austria-Austria (AT) (7U) Oy Kolster Ab (5U) Method for therapeutically useful thieno / 3,2-f7-s-triazolo / U »3-a // l, For the preparation of U / diazepine derivatives - For the preparation of diazepine derivatives of the therapeutic route thieno / 3,2-f7-s-triazolo [kj 3-a7 / i, U7diazepine derivatives

The invention relates to a process for the preparation of useful thieno [.3-> 2- [7-s-triazolo [U, 3 ~ a7 / l ”] diazepine derivatives of the formula (I) R Ξ 'W' '" "V'V> LI „.> -K. Ϋ $ /

XC = N

R 2 is halogen or nitro, R 0 is phenyl, o-trifluoromethylphenyl, o-halophenyl, ο, ο'-dihalophenyl, o-nitrophenyl or 2-pyridyl and R 1 is alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoamino, alkoxyalkyl, alkoxybenzyloxyalkyl, morpholinoalkyl, alkyldipalkyl, cyanoalkyl, haloalkyl, alkoxycarbonylaminoalkyl, dialkylcarbamoyloxyalkyl, alkanoyloxyalkyls, and the addition of C3, alcohols, alkanoyl, alkanoyl, alkoxycarbonyl or carbamoyl,

The term "alkyl" as used herein, alone or in combination, such as in hydroxyalkyl, includes straight or branched chain hydrocarbon groups such as methyl, ethyl, propyl, isopropyl, t-butyl, and the like. The term "halogen" includes bromine, chlorine, fluorine and iodine. The term "alkoxy" describes an alkyl ring having a substituted oxygen such as nitroxy, ethoxy, propoxy and the like. The term "alkanoyl" embraces a straight-chain or branched, saturated, aliphatic carboxylic acid acyl residue such as formyl, acetyl, propionyl, and the like. The term "alkanoyloxy" embraces alkanoyl radicals having a substituted acid such as acetoxy, propionyloxy and the like. -

A preferred group of compounds of formula I is halogen, with chlorine being considered highly preferred. is preferably o-halophenyl, 0,0'-dialogenophenyl or 2-pyridyl, and when R e is o-halophenyl, fluorine and chlorine are preferred as halogens. If R 1 denotes ο, ο'-dihalophenyl, then it is preferably two identical halogen atoms and in particular two fluorine atoms. R 1 is preferably alkyl, hydroxyalkyl and aminoalkyl. A very preferred meaning of R is aminomethyl, methyl or hyroxymethyl.

A highly preferred compound is 9-aminomethyl-2-chloro-U- (o-chloro-phenyl) -6H-thieno [CB, 2H-s-triazolo [1,3], 3% (Z1, ii) diazepine .

The thienotriazolodiazepine derivatives of the formula I and their acid addition salts are prepared according to the invention in that a) a compound of the formula V> C ~ N \ O NH (II) ~

R 11 S H--C ^ TT> ^ C --ΙΓ R 2 in which R, R 0 and R have the same meaning as above are cyclized, or b) a compound of formula 58129,.

R, -C N (III)

3 \ S

Vys- \ I ί> 2

\ c_q H'N

I 2 R 2 in which R, R and R have the same meaning as above are cyclized, or 12 j ~ c) a compound of formula rq-c> (IV) 3 \ s i-d /

XC —N

R 2 wherein R 0 and R are as defined above are halogenated or nitrated, or d) to prepare a compound of formula I wherein R 1 is (lower) alkanoyl, a corresponding compound of formula I wherein R 1 is -hydroxy- (lower) alkyl, oxidized, or e) to prepare a compound of formula I wherein R is (lower) alkanoyloxy (lower) alkyl, a corresponding compound of formula I having hydroxy-lower alkyl is esterified with a corresponding alkanoylating agent, or f) a compound of formula I wherein R 1 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, the corresponding compound of formula I wherein R 1 is halogen (lower) alkyl, or the methanesulfonic acid ester of the corresponding compound of formula I or a similar reactive ester may be added n to react with a (lower) alkanol, (lower) alkoxybenzyl alcohol, (lower) thioalkanol, ammonia, (lower) alkylamine, di (lower) alkylamine or morpholine, or g) to prepare a compound of formula I wherein R is di- (lower) alkylcarbamoyloxy (lower) alkyl, the corresponding compound of formula I, wherein R 1 is hydroxy (lower) alkyl, is reacted with a reactive derivative of di (lower) alkylcarbamic acid, or h) to prepare such a compound of formula I, wherein (lower) alkoxycarbonylamino (lower) alkyl, the corresponding compound of formula I wherein R 1 is amino (lower) alkyl is reacted with a (lower) alkyl ester of chloroformic acid, or i) to prepare a compound of formula I wherein R 1 is is hydroxyethyl, the corresponding compound of formula I having (lower) alkoxycarbonyl is reduced, and j) the resulting compound is converted to the acid addition salt with shaking.

According to a first embodiment of the invention, formula I is thus prepared

by cyclizing the corresponding compound of formula II above.

The cyclization of a compound of formula II is carried out according to methods known per se, for example by heating a compound of formula II. The temperature is not critical to the successful performance of this reaction, but depends on the starting material and the reaction conditions used. This reaction can be carried out at a temperature in the range of about room temperature to 300 ° C. The cyclization according to the invention can be carried out in the presence or absence of a solvent, but preferably in the presence of an inert, organic solvent. If working in the presence of an inert organic solvent, then a reaction temperature of about 60 ° C to 180 ° C, particularly preferably a reflux temperature of the reaction mixture, is preferred. If, on the other hand, you work without a solvent, then the preferred temperature range is about 200-260 ° C. Suitable inert organic solvents include, for example, hydrocarbons such as toluene, xylene and the like, halogenated hydrocarbons such as chlorobenzene and the like, ethers such as tetrahydrofuran, dioxane, diethylene glycol dimethyl ether dimethyl ether and diethyl ether, diethylene glycol diethyl ether such as amide and the like, amide the like, dimethyl sulfoxide, and particularly preferably alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, cyclohexanol and the like. The reaction time depends on the reaction temperature used and whether a solvent is used, and is from a few minutes to U8 hours, preferably a few minutes if no solvent is used, and otherwise about 1-2 ^ + hours.

The compounds of the formula II do not and cannot in all cases be used in isolated form, since they often cyclize spontaneously under the conditions used for their preparation.

5 58129

According to another embodiment, compounds of formula I above are obtained by cyclizing the corresponding compound of formula III above. The cyclization of the compound of the formula III also takes place according to methods known per se. For example, this cyclization can take place by heating the compound of the formula III in an organic medium, in which case, however, in many cases it is preferred to work in the presence of an acid in order to obtain satisfactory yields. The cyclization can be carried out, for example, by heating a compound of formula III for several hours in a solution of an aliphatic carboxylic acid such as formic acid or acetic acid in an alcohol such as ethanol or n-propanol or by boiling for a relatively short time (about} min - 1 / For 2 hours) in an aliphatic carboxylic acid such as acetic acid, isobutyric acid or trituric acid under reflux.

The compounds of formula III do not and cannot in all cases be used in isolated form, as they often cyclize spontaneously under the conditions used in their preparation.

According to another embodiment of the invention, the compounds of formula I above can be prepared by halogenating or nitrating the corresponding thiophene ring-unsubstituted compound, i.e. the compound of formula IV above, by halogenation of a thiophene group according to a conventional method, for example with elemental chlorine, -bromo or , sulfuryl chloride, etc., wherein the reaction conditions are primarily determined by the halogenating agent used. In the case of chlorination with elemental chlorine, the reaction can be carried out, for example, in chloroform / pyridine or nitrobenzene, conveniently at room temperature. When brominated with elemental bromine, the reaction takes place in, for example, chloroform at elevated temperature, for example at reflux with cooling. Iodination with elemental iodine can be performed, for example, in chloroform and in the presence of mercury oxide at room temperature. Chlorination with sulfuryl chloride can be accomplished, for example, in chloroform or glacial acetic acid at room temperature or at elevated temperature, for example at reflux temperature.

The nitration is carried out in a conventional manner, for example with nitric acid or alkali metal nitrate in the presence of sulfuric acid, in which case the starting product is dissolved in concentrated sulfuric acid and a mixture of concentrated nitric acid and concentrated sulfuric acid is slowly added to the solution thus obtained. Low temperatures, for example, temperatures between about -10 and + 10 ° C are generally preferred for performing nitration.

'6 581 29

In another embodiment, compounds of formula I having an alkanoyl residue are obtained by oxidizing the corresponding compound wherein R 1 is a hydroxyalkyl residue according to a conventional method.

Suitable oxidizing agents are preferably carbodiimides, such as dicyclohexylcarbodiimide and the like, in dimethyl sulfoxide or a pyridine-sulfur trioxide addition compound in dimethyl sulfoxide. These reactions are performed in the presence of an organic base such as pyridine or triethylamine. Furthermore, silver oxide can also be used as an oxidizing agent, which is preferably used in a water-miscible inert solvent such as alcohols or acetone. Furthermore, the oxidation can take place in anhydrous toluene with chromium trioxide in graphite or manganese dioxide. All of these oxidation processes, with the exception of chromium trioxide or nanganese trioxide alternatives, are preferably performed at room temperature or just above or below room temperature. When chromium trioxide or manganese dioxide is used, the reaction mixture is heated - preferably to reflux.

According to another embodiment, compounds of the formula I having an alkanoyloxyalkyl radical are obtained in such a way that the corresponding compound having a hydroxyalkyl group is esterified with an alkanoylating agent according to methods known per se. The esterification with an alkanoylating agent can be carried out, for example, by reacting a hydroxy 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 nile tetrachloride, chloroform or methylene chloride, or an organic base in excess.

The reaction is carried out at a temperature of about 0 to 80 ° C, preferably between room temperature and about 60 ° C.

In another embodiment, compounds of formula I are obtained wherein R 1 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, such that the corresponding compound of formula I wherein R 1 is halo (former) alkyl, or the methanesulfonic acid ester of the corresponding compound of formula I or a similar reactive ester is reacted with (lower) alkanol, (lower) alkoxybenzyl alcohol, (lower) thioalkanol, ammonia, (lower) alkylamine, di (lower) alkylamine or morpholine. The reaction with alkanols, alkoxybenzyl alcohols and thioalkanols is a method known per se for the formation of ether or thioether groups.

7 58129

The preparation of the thioether (compounds of formula I with alkyl-thioalkyl) can take place, for example, by reacting the methanesulfonic ester of the corresponding compound of formula I with hydroxyalkyl with thioalcohol or the corresponding mercaptide. The reaction takes place in the presence of a suitable solvent such as dimethylformamide, dioxane or tetrahydrofuran at a temperature between room temperature and 100 ° C, preferably 5 ° C.

The reaction with ammonia, alkylamines, dialkylamines or morpholine involves the formation of aminoalkyl compounds, which can take place according to methods known per se. For example, a methanesulfonic acid ester of a compound of formula I having hydroxyalkyl can be reacted with the corresponding amino compound. The reaction takes place in a manner known per se, preferably in the presence of a suitable, inert organic solvent, such as dimethylformanide, or in an alcohol such as methanol or ethanol. o. . at 0 to 100 ° C, preferably 0 to 5 ° C.

In another embodiment, compounds of formula I wherein R 1 is dialkylated aminocarbonyloxyalkyl are obtained by reacting a corresponding compound of formula I wherein R 1 is hydroxyalkyl with a reactive derivative of an acid of formula OH-CO-Ii (alkyl). Suitable reactive acid derivatives are halides, in particular chlorides.

The formation of a group of di al / tylo germs occurs in a manner known per se. This can be done, for example, by converting the hydroxyalkyl extract into the alcoholate in the presence of a suitable solvent such as dioxane and adding Η, dial-dialkylcarbamoyl chloride and finally heating for a short time.

In another embodiment, compounds of formula I wherein R is alkoxycarbonylaminoalkyl are obtained by reacting the corresponding hydroxyalkyl compound with a chloroformic acid alkyl ester in the presence of a suitable inert solvent such as dioxane. The reaction takes place in a manner known per se, preferably at room temperature.

In another embodiment, compounds of formula I having hydroxymethyl are obtained by reducing the corresponding compound of formula I having alkoxycarbonyl.

The reduction takes place in a manner known per se, preferably by treatment with complex hydrides, such as lithium aluminum hydride.

The compounds of the formula I can be converted into the corresponding salts by treatment with inorganic or organic acids, in particular pharmaceutically acceptable salts. Examples of acids which form pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, tartaric acid, citric acid, maleic acid, toluic acid, ascorbic acid, formic acid, formic acid, acetic acid, acetic acid .

The starting materials of the formula II can be prepared from the corresponding thienodiazepine derivatives of the general formula: H 0 i / w "c \ H.

= N

r2 where R., and Rg are as defined above.

The first step involves the reaction of a compound of formula V above with a sulfide, such as phosphorus pentasulfide, to form a compound of general formula: H s

I X

VV c \ i T / ¼

X! = N

R 2 wherein R 1 and R 8 are as defined above. - Sulphide is preferably used in excess in this reaction. The reaction is preferably carried out in an inert organic solvent such as pyridine, xylene and the like at a temperature between about 10 ° C and the reflux temperature of the reaction mixture, preferably at reflux temperature.

The preferred solvent for this reaction is pyridine.

The compound of formula VI above is further reacted with an organic acid hydrazide of general formula

ii2n-ni-co-r3 VII

wherein R is as defined above, 9 58129 to form a capped compound of formula II above. The condensation of the above-mentioned solid thione of formula VI with an acid hydrazide of formula VII is carried out in an inert organic solvent, preferably an alcohol such as methanol, ethanol, 1- or 2-propanol, 1- or 2-butanol and the like, at a temperature of about 60 ° to 120 ° C. preferably at the reflux temperature of the reaction mixture. In a preferred embodiment, naphydrazide is used in a 2- to 5-fold excess over the theoretically required amount. The reaction time depends on the reaction temperature and is from a few minutes to U8 hours, preferably about 1-2U hours. The crude product thus obtained usually consists of the desired compound of formula II and the already cyclized compound of formula I. However, this mixture can be separated due to the different solubility of these compounds in organic solvents such as methylene chloride, chloroform, carbon tetrachloride, ethyl acetate and the like. After separation, the compound of formula II can be converted to the compound of formula I as described above.

According to a simpler method, the mixture can be converted from the compounds of formulas I and II by heating as described above to form a uniform product of formula I. The reaction of a compound of formula VI with an acid hydrazide of formula VII preferably takes place by passing an inert gas, preferably nitrogen, through the reaction mixture so that the hydrogen sulfide formed is continuously removed.

The acid hydrazides of the formula VII are known compounds or can be easily prepared in a similar manner to the known compounds, for example by heating the ester of the formula R 1 -COO-alkyl with hydrazine hydrate under reflux, for example in methanol.

The compounds of formula V are also known compounds or can be easily prepared in a similar manner to known compounds. They can be obtained, for example, from the reaction of 2-amino-3-aroyl-thiophene derivatives with a C 1-6 halocarboxylic acid halide such as chloroacetyl chloride by treating the resulting compound with ammonia and finally cyclizing.

According to another embodiment, the compounds of formula II can also be prepared from compounds of the general formula: NH-NHO

Yv1 '= \ I_ [/ <* 2 VI11

= H

R2 10 R 58129 wherein R and R are as defined above by reacting with a carboxylic acid of formula R -C00II id j having the same meaning as above or a reactive derivative thereof. Edelläolevier. suitable reactive derivatives of carboxylic acids are, for example, esters, anhydrides, halides, amides, iminoethers, amidines and orthoesters, with orthoesters being particularly preferred. Examples of such orthoesters are orthoacetic acid trimethyl ester, orthetic acetic acid triethyl ester, orthopropionic acid triethyl ester, orthobutyric acid triethyl ester and the like.

The reaction of a compound of formula VIII with a carboxylic acid or a reactive derivative thereof preferably takes place in the presence of an inert organic solvent and an acid catalyst such as hydrohalic acids, for example, hydrochloric acid, p-toluenesulfonic acid and the like. Suitable alcohols as solvents, such as methanol, ethanol and the like, ethers such as tetrahydrofuran, diethyl ether and the like, dimethyl sulfoxide, dimethylformamide and the like, the temperature is not critical to the successful completion of this reaction step, but is preferably carried out at elevated temperature, i. at a temperature between about 30 ° C and the reflux temperature of the reaction mixture, very preferably at the reflux temperature.

In another embodiment, compounds of formula II may also be prepared from compounds of the general formula: NH-alkyl vva = li / 0¾

= N

wherein R and R. are as defined above, by reaction with an acid hydrazine of formula VII 1d. The reaction takes place in an inert organic solvent such as alcohols, for example ethanol, propanol, butanol and the like, dimethylformamide, ethers such as diglyme or methoxyethanol and the like, a strong base such as amines, for example tertiary amines such as triethylamine, methylpiperidine and the like. at elevated temperature, preferably at the reflux temperature of the reaction mixture.

581 29 11

Compounds of formula IX above may be readily prepared from the corresponding compounds of formula V by reacting a compound of formula V with an alkylamine in the presence of a Lewis acid such as titanium tetrachloride.

Compounds of formula VIII may be prepared from the corresponding compounds of formula IX by reacting a capped compound of formula IX with nitric acid in a manner known per se to form the corresponding N-nitroso compound. Reaction of this N-nitroso compound with hydrazine provides the desired compound of formula VIII. Compounds of formula VIII may further be obtained by reacting a compound of formula VI with hydrazine.

The preparation of the starting products of formula III is summarized in the following reaction scheme, which illustrates the case where in formula III is halogen, R 0 is phenyl and is methyl.

5,812 9

Reaction scheme O-alkyl

nalogen ^ ^^^^^^^ JviH ^ halogen o ϊΙ-C-CH

ίο _—> xy / Λ Λ χ χι Φ y ”\ /‘ \ hl. 013 ° \, _ / <hJo- ^ nT \ y I | j \ h2 I if Ul ^ aiocene, ^ c = o iih9 = 0 Λ Λ

O O

III Λ 58129

2-Amino-3-benzoylthiophene of formula X is converted to an ancient compound of formula XI by treatment with an orthoester of formula C 1 -C (Oalkyl) 4. The reaction is conveniently carried out in the presence of an inert organic solvent such as benzene, toluene and the like, and in the presence of an acid catalyst catalyst such as hydrochloric acid, sulfuric acid, acetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Temperature is not critical, but is usually worked at noir temperatures. 50-16q ° C, but can still be used at temperatures above or below these temperatures. Suitable solvents are hydrocarbons such as benzene or toluene and the like or the orthoester used as a reaction component in excess.

The resulting compound of formula XI is then reacted with hydrazine, preferably used as hydrazine hydrate, in an inert organic solvent. Suitable solvents are, in particular, alcohols, such as methanol, ethanol, 1-propanol, 2-propanol and the like. The reaction is carried out at a temperature between about 0 ° C and the reflux temperature of the reaction mixture, preferably about 10 ° C to 30 ° C. The reaction can be accelerated by adding an acid catalyst such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. The crude product obtained is finally reacted with an ol-halogen acid halide such as chloroacetyl chloride, bromoacetyl bromide and the like in an inert organic solvent under ice-cooling or at a temperature below the boiling point of the solvent to give a compound of formula XII. Suitable solvents are chloroform, methylene chloride, ether, dimethylformamide, pyridine, acetic acid, monochloroacetic acid or mixtures of such solvents with an error. If a neutral solvent is used, the reaction is preferably carried out in the presence of an acid acceptor such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, pyridine, triethylamine, imidazole, 2-methylimidazole and the like.

The compound of formula XII is then treated with ammonia or hexamethylenetetramine, whereby the resulting compound of formula III can be cyclized to the corresponding compound of formula I without isolation. Namely, the compound of formula III does not need any isolation before cyclization, i. ring closure to a compound of formula I can be performed in a reaction mixture to prepare a compound of formula III without isolating this or interrupting the reaction step. For example, a compound of formula XII may be added to an alcoholic ammonia such as ethanol or methanolic ammonia, or a compound of formula XII may be dissolved in an inert organic solvent and treated with liquid ammonia or hexamethylene tetramine to give a compound of formula III. Suitable solvents for this reaction include methylene chloride, carbon tetrachloride, ether such as tetrahydrofuran or dioxane, dimethyl sulfoxide, dimethylformamide, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and the like. The resulting compound of formula III - either crude or purified - can be cyclized to form a compound of formula I as described above.

The compounds of formula III required in embodiment c) can be prepared as in embodiments a) and h) of the invention, respectively. -

The compounds of the formula I prepared according to the invention and their pharmaceutically acceptable acid addition salts have an anticonvulsant, sedative, muscle tension-triggering and tranquilizing effect, in addition to a clear anxiolytic effect, and are therefore valuable drugs. The alleviating effect of angst is demonstrated in the conflict experiment described below.

The test equipment was a Skinner touch box equipped with a food tablet dispenser.

During three pre-tests, each lasting one hour at a time, hungry female rats were taught to press the food tablet dispenser contact to obtain the food tablet (each press was rewarded); in the third preliminary experiment, the rats reached a rate of 150-200 presses / h. In the fourth pre-experiment, a short-shock electric shock to the foot was combined with the food prize following the press of the contact. Conflicted rats initially used the contact 5-10 more times and then stopped using the contact completely due to angst.

In the fifth preliminary experiment, the rats were again allowed to use the food tablet dispensing contact without preaching an electric shock, which again increased the contact speed to 150-200 presses / h.

In the sixth preliminary experiment, a selection was made among the experimental animals. Half an hour before the start of the experiment, the experimental animals were orally administered 10 mg / kg of chlorodiazepoxide; each food award was again accompanied by an electric shock. Only rats with a contact rate of 20-50 presses / hr were qualified as experimental animals to study the anesthetic-relieving effect.

The main experiment used the test substance and usually 0 rats per dose. A control group was not needed because each animal served as its own control. Test substances dissolved or suspended in a mixture of distilled vehicle (10 ml) and Tween 0 (2 drops) were administered to the experimental animals by gavage half an hour before the start of the one-hour main experiment. During the main test, when each contact press was followed by a food tablet and an electric shock, the contact operating speed of the key was recorded.

The first significant angst-relieving dose was determined according to Wilcoxon (pairwise comparison) by comparing the number of contacts used in the main experiment (shock to the foot after pretreatment with the test substance) with the number of contacts used in the control experiment (shock to the foot after saline treatment).

The experiments result in: 1. First Significant Dose (FDS); 2. Mean shock increase for increasing doses; 3. General behavior of animals with varying doses.

The test substances were 2-ethyl-N- (O-chlorophenyl) -9-methyl-6H-thieno [3,2-f] s-triazolo [1,3-a] Z1 *, known from DE application 2,229,01 + 5. D-sepiepine = compound A and the following 10 compounds prepared according to the invention: - 2-chloro-1 + - (o-chlorophenyl) -9-methyl-6H-thieno [2,3,2-f] -s-triazolo-Z Β, β-α, β, β-diazepine (Compound B); 2-bromo-N- (o-chlorophenyl) -9-methyl-6H-thieno [3,2-f] s-triazolo-3- [3-7,7-azepine] (Compound C); - 2-iodo-U- (o-chlorophenyl) -9-roethyl-6H-thienoZ3,2- [7s-triazolo-1,3-a7Z.1-> U7 (liazepine (Compound D)); - 2-chloro-9 N-methyl-1 '- (2-pyridyl) -6H-thieno [3,2-f] s-triazolo [b] Ba / Z] N / diazepine (Compound E); - 9-aminomethyl-2-chloro-U- ( o-chlorophenyl) -6H-thieno [3,2-f] s-triazolo [2,3-d] azole] azepine (Compound F); - - 2-chloro-b- (2,6-difluorophenyl) ) -9-methyl-6H-thieno [3,2,2-b] triazolo [3,3-b] azepepine (Compound G); - 2-chloro-1- + (o-fluorophenyl) -9 -methyl-6H-thieno [3,2-f] -s-triazolo [4,3-a] -1,7-diazepine (Compound H); 2-chloro-1- (o-chlorophenyl) -611-thieno 1,3,2- [7-s-triazolo [1,3-a] Z1,1 +/- diazepine-9-methanol (Compound I); - 2-chloro-1- (o-chlorophenyl) -9-dimethylaminomethyl -6H-thieno Z3,2- [7- 3-triazolo [5 +, 3-α] zazepine (Compound J) and -2-chloro-α- (o-chlorophenyl) -9-methylaminomethyl-6H-thienoZ.3-, 2- [7-s-triazolo [3,3-a] -7Z1 · iazepine (Compound K).

The results are shown in the following table.

1 (1 58129 '-' 'I —— »· η · - —p j - ... -------- -------------

Mean shock increase in one contextic dose (: 1 = 8 / dose, unless otherwise stated)

Compound FSD 0.1 0.3 1.0 3.0 10.0 30.0 ms / kc p.o nc / kG Ρ · ο. mg / kg p.o. mg / kg p.o. mg / kg p.o. rac / kf p.o. mg / kg p.o.

(Reference 3.0 0 0 0 + ^ ^ Γίο |.

\ sedation, relaxation ^ not tut- eksoftal- eksoftalnus. kittu eiu3 tangle ___________________________ness__ B 1,0 0 0 + 23 _ + 37 + I4U + 66 normal normal normal minor behavioral behavioral behavior _________ C 1,0 0 0 + 11 + _3Q + 3o + ha normal normal normal relax-behavior-behavior-behavior _______________________minen__S miner._ minen__________ D 1.0 not tut- 0 + _1 £ I {\ = 9) pJ “10) kitti normal j —®. u ^ ~ v _. ♦. ·· +, waxed relaxed behavioralaxa_.

minen,. . . '.

tio, sedation ______! information __________________ H 10.0 not tut- not tut- not tut- | +2.3 (NS) + from.6 + 16.1 (NS) putty putty putty normal normal relaxation behavioral behavioration '_____. ______________________ _________ IF 0.1 + JLiix £ + 32.5 _ ± _2Ll £ _ ± -2iLZ * 99.1 + 93.3 j normal normal normal slight sedation sedation I behavioral behavioral behavioralaxaxalaxaxate____er, _ WAftR__3ΪΙ2 £ Ι! ___ il2__1Ϊ2_ΛΪ2_- IG 1,0 not examined 0 + 6.7 + 9.8 + 97.6 not examined normal normal normal minor kitty 'I behavioral behavioral behavior _________ i H 3,0 no tut- + 2,2 (HS) + U.Ö (N3) + 11.6 + pU.5 + 6ä .7 kitti normal normal · normal minor minor behavioral behavioral behavioration sedation relaxation à ei __________ ______ ________ thio tion I 3.0 no tut- no tut- +5.7 (tIS) + 11.5 + 16.2 + 63.3 kitty kitty normal normal minor minor behavioral behavioration, sedation , minen minen minor minor ————— _________________ __relaxation relaxation J 1,0 not tut- +0,2 HS + l6.U + 20.3 + 12.7 + 36.8 kitu normal normal normal color wedding sedation, behavioral behavioral behavioral sedation slight decrease relaxation K 1.0 no tut- + 1.3 HS + 39.7 + 20.3 + Uit, 7 +36.5 (NS) kitti normal normal normal minor sedation , behavior-behavior-behavior-relaxation relaxation

_______________________making _making____making_ I

FSD - First Significant Anti-Angst Dose NS = Non-Significant Anti-Angst Dose

Underlined shock incremental values indicate significant anti-angst effect 17 58129

It is clear from the above results that all the compounds tested prepared according to the invention are more significant and / or more selective and have significantly less harmful side effects with anti-angst agents than the known compound.

The compounds of formula I and their pharmaceutically acceptable acid addition salts may be formulated according to generally known methods into pharmaceutical preparations, e.g. tablets, granules, suppositories, capsules, solutions, suspensions, emulsions, etc. talc, magnesium stearate, water, vegetable oils, polyalkylene glycols and the like, these preparations may also contain preservatives, stabilizers, wetting or foaming agents, salts for varying the osmotic pressure, buffers or other therapeutically valuable substances. If necessary, said preparations can be sterilized or subjected to other operations customary in the pharmaceutical industry.

A suitable pharmaceutical dosage unit may contain about 1 to 50 mg of a compound of the invention. Suitable daily doses for oral administration to mammals are about 0.1 mg / kg to 30 mg / kg; daily doses suitable for parenteral administration to mammals are about 0.1 mg / kg to 10 mg / kg. These doses are to be understood by way of example only; the specific dose must meet individual needs in each case.

The following examples illustrate the invention. All temperature values are in degrees Celsius.

Example 1 2.5 g of 2- (2-acetylhydrazino) -7 "chloro-5" (o-chlorophenyl) -3H-thieno [2,3-e] -1,1'-diazepine are heated under reduced pressure (water jet vacuum) in an oil bath (250 °) for 5-7 minutes until no more gas evolution is observed. The product formed is finely ground in a mortar and boiled several times with a total of 1 * 00 ml of ethyl acetate. After removal of the solvent, the crude product formed is recrystallized from ethanol with activated carbon to give 2-chloro-1- * - (o-chlorophenyl) -9-methyl-6H-thieno [3,2-f] phenyl. olo / k, 3-a7 / 1, U / diazepine as cream-colored crystals with m.p. is 205 ~ 206 °.

The starting material can be prepared as follows: 3.1 g (0.01 mol) of 7 "chloro-5- (o-chlorophenyl) -1,3-dihydro-2H-thieno [2,3-b] 7 / 1,1 / 7 -diazepin-2-one is heated under reflux with 2.1 * 5 g of P 2 SO 4 in 100 ml of absolute pyridine for 30 minutes, passing dry nitrogen through the solution, which is separated by 35 cm at 100 g. silica gel / (0.05-0.2 mn) '(Merck) V packed column (0 3.5 cm) The separation is carried out by thin-layer chromatography (solvent berene / ethanol 9: 2). 18 58129 The solvent is removed in vacuo to give 7 "chloro-5- (o-chlorophenyl) -1,3-dihydro-2H-thieno [2,3-b] azepine-2- The thione immediately crystallizes as yellow crystals, mp 223-225 ° C. The product is not further purified for subsequent use.

3.3 g (0.01 mol) of 7 'chloro-5- (o-chlorophenyl) -1,3-dihydro-2H-thieno [2,3-E] -1,1'-diazepine-2-thione are heated under a nitrogen atmosphere With 2.5 g of acetic acid-Lydrazia and with 150 ml of n-butanol for 30 min at reflux. The solvent is removed in vacuo, 200 ml of ethyl acetate are added to the residue and the mixture is shaken three times with 200 ml of IIoO each time. The precipitated solid is filtered off with suction and combined with the ethyl acetate phase. After concentrating the solution to 50 ml, the product is allowed to crystallize. It is then filtered off with suction and recrystallized once more from ethyl acetate and activated carbon to give 2- (2-acetylhydrazino) -7-chloro-5- (o-chlorophenyl) -3H-thieno [2,3-e] -1,2-dia s epin as orange crystals with m.p. is 211-213 °.

Example 2 0.2 g of 7-chloro-1,3'-dihydro-5- (o-nitrophenyl) -2H-thieno [2H-s] -dia-diatnepine-2-thione is heated under nitrogen with 0.2 g of acetic acid hydrazide In 30 ml of n-butanol for 5 hours at reflux. After evaporation of the solvent, the product is dissolved in methylene chloride and extracted with 1N hydrochloric acid several times, with ether being added portionwise to the organic phase so that it is placed in a separatory funnel. After neutralization of the aqueous phase with sodium bicarbonate, it is extracted with methylene chloride; after drying over sodium sulfate, the solvent is evaporated off and the residue is triturated with ethyl acetate. The formed crystals are recrystallized from ethyl acetate and activated carbon to give 2-chloro-9-methyl-k- (o-nitrophenyl) -1 + H-thienoZ3 * 2- [7-s-triazolo [1- *, 3-% 7-] i, U / -diazepine colorless crystals, m.p. is 210-212 °. The starting material can be prepared as follows: 1 g (0.00327 mol) of 7 "chloro-1,3" dihydro-5- (o-nitrophenyl) -2H-thieno [2,3-b] -1H-diazepin-2-one is heated with 0.8 g of P 2 SO 4 in 30 ml of abs. pyridine 30 min. under reflux, during which nitrogen is passed through the solution. The reaction mixture is separated on a column packed with 50 g of silica gel ε (0.05 x 0.2 mm) (Merck) (0 3 cm) (the product runs at the edge, impurities only slowly). After concentrating the pyridine solution in vacuo, methylene chloride is added and crystallized. After complete crystallization in the refrigerator, suction is filtered off and washed with a small amount of ice-cold methylene chloride. Recrystallization of abs. Methanol is obtained as 7-chloro-1,3-dihydro-5- (o-nitrophenyl) -2H-thieno [2,3 ** ft] -1H-diazepine-2-thione as yellow crystals, m.p. is 213-215 °.

19 58129

Example 3 3.0 g of 7-chloro-1,3-dihydro-5 '(o-trifluoromethylphenyl) -2H-thieno [2,3-d] -1,1-diazepin-2-one are dissolved in 50 ml of: diethylene glycol dimethyl ether at 80 ° C, 1.2 g of phosphorus pentasulfide and 3 g of finely divided sodium hydrogen carbonate are added and the mixture is heated at 80-35 ° C for 15 minutes. It is then evaporated in vacuo, dissolved in 0 ml of butanol, 3 g of acetylhydrazine are added and the mixture is refluxed for 90 minutes. The butanol is evaporated off in vacuo, the residue is dissolved in methylene chloride, the organic phase is shaken several times with water, dried and evaporated. The oily residue is crystallized from ether. There is thus obtained 2-chloro-9-methyl-N- (o-trifluoromethylphenyl) -bH [3,2-7,7-s-triazolo [2,3-b] diazepine, m.p. 193-195 ° after recrystallization from ethyl acetate. .

Example k.8 g of 2- (2-acetylhydrazino) -7-chloro-5- (o-fluorophenyl) -3H-thieno [2,3-e] -1,1-diazepine are refluxed in 300 ml of abs. xylene for 0 hours. Impurities formed after icing are filtered off with suction. The solvent is then evaporated off under reduced pressure and the product is recrystallized from ethyl acetate and activated carbon. There is thus obtained 2-chloro-α- (o-fluorophenyl) -9-methyl-6H-thieno [3,2-f] -3-triazolo [+, 3-a7 / 1'-diazepine, m.p. is 187-130 °.

The starting material is obtained as follows: 10 g of 7-chloro-5- (o-fluorophenyl) -1,3-dihydro-2H-thieno [5,3-e] -1H-diazepin-2-one are dissolved in 150 ml of diethylene glycol dimethyl ether at 55 ° C. C and mixed with a mixture of 15 g of finely divided phosphorus pentasulfide and 10 g of sodium bicarbonate for +0 min. The solvent is distilled off and the residue is digested with water, filtered off with suction and dried. The resulting 7-chloro-5- (o-fluorophenyl) -1,3-dihydro-2H-thieno [2,3-d] diazepine-2-thione is boiled in 200 ml of methanol with 15 g of acetylhydrazine for 30 minutes. . On cooling, 2- (2-acetyldrazino) -7-chloro-5- (o-fluorophenyl) -3H-thieno [2,3-e] -1,1-diazepine precipitates. The methanol is distilled off and the residue is partitioned between methylene chloride and water. This forms another product. The solvent is evaporated off under reduced pressure and the residue is obtained by digesting another product in methanol. The resulting 2- (2-acetylhydrazino) -7-chloro-5- (o-fluorophenyl) -3H-thienoZ2,3-β7-1, β-azepine m.p. mp 207-209 °.

Example 5 2.2 g of 2- (2-acetylhydrazino) -7-chloro-5- (2-pyridyl) -3H-thieno [2,3-e] -1,1-diazepine are boiled in 120 ml of absolute xylene. 2 hours at reflux. The solution is then cooled and the precipitated impurities are filtered off. The solvent is evaporated off under reduced pressure to give 2-chloro-9-methyl-N- (2-pyryl) -8β-thieno [3,2-f] s-triazolo [3,3-a] [3,3-b] diazepine. in the form of a crystalline product which melts after recrystallization from ethyl acetate at 17-176 °.

58129 The starting material is obtained as follows: 10.6 g of cyanomethyl-2-pyridyl ketone and 7.6 g of bismercaptoacetaldehyde are dissolved or suspended in 60 ml of absolute dioxane and 5 ml of triethylaraine are added with stirring. After completion of the reaction at room temperature, after 1 1/2 hours, the reaction mixture is poured into about 500 ml of water and extracted with methylene chloride. The methylene chloride phase is shaken twice with 1 H sodium hydroxide solution, dried over sodium sulfate and treated with activated carbon and evaporated. 2-Amino-3-thienyl-2'-pyridyl ketone is obtained, from which, after recrystallization from benzene, yellow crystals are obtained, m.p. is 122-12U0.

65 g of 2-amino-3-thienyl-2'-pyridyl ketone are dissolved in 500 ml of dry dioxane, 30 g of potassium carbonate are suspended in this solution and 80 g of chloroacetyl chloride are added. After completion of the exothermic reaction, the mixture is stirred for a further 2 hours at room temperature and the reaction mixture is poured into a solution of 50 g of potassium carbonate in 2 liters of water. The precipitate which separates is then filtered off with suction, washed with water and dissolved in methylene chloride. After drying over sodium sulphate with addition of activated carbon, the solvent is distilled off under reduced pressure, the residue is digested with a small amount of methanol and filtered off with suction. 2-Chloroacetylamino-3-thienyl-2'-pyridyl ketone is obtained, which, after crystallization from methanol, gives yellow needles with m.p. is 130-132 °.

76 g of 2-chloro-3-ethylamino-3-thienyl-2'-pyridyl ketone are dissolved in 1 liter of acetone and, after adding 5 g of sodium iodide, stirred for 15 hours at room temperature. The acetone solution is then evaporated to dryness in vacuo and the residue is partitioned between about 300 ml of methylene chloride and water, the organic phase is layered with about 1.5 liters of concentrated ammonia and stirred for U8 hours without stirring the phases. After completion of the reaction, the phases are separated, the organic phase is evaporated to dryness and the residue is dissolved in methylene chloride. This solution is extracted thoroughly with 0.1 N hydrochloric acid, the aqueous extracts are neutralized with potassium carbonate, the separated solid is filtered off with suction and dried. After crystallization from ethanol, 2-aminoacetylamino-5-thienyl-2'-pyridyl ketone is obtained in the form of yellow crystals, m.p. is 259-262 °.

A solution of 32 .mu.g of 2-aminoacetylamino-3-thienyl-2'-pyridyl ketone in 350 ml of acetic acid is heated for 15 min. time to reflux. The solvent is then distilled off in vacuo, the residue is digested with a small amount of methylene chloride and the solid is filtered off with suction. After crystallization from ethanol, 1,3-dihydro-5- (2'-pyridyl) -2H-thieno [2,3-e] -1,1-diazepin-2-one is obtained as colorless crystals, m.p. is 236-266 ° (decomposes).

9.8 g of 3-dihydro-5- (2-pyryl) -2H-thieno [2,3-e] -1,1-diazepin-2-one are dissolved in 350 ml of acetic acid and the solution is added dropwise at room temperature with stirring, with 8.0 g of sulfuryl chloride in 20 ml of acetic acid. After the completion of the addition of 21 58129, stirring is continued for 15 min. The separated yellow solid is filtered off with suction, dissolved in water and the solution is neutralized with sodium bicarbonate to give a yellow-green solid. This is filtered off with suction, washed with water and dried. After crystallization from ethanol, 7 "chloro-1,3-dihydro-5" (2-pyryl) -2H-thieno Z2,3-ς7 ", op. is 250-252 ° (decomp.).

3.5 g of 7-chloro-1,3-dihydro-5- (2-pyridyl) -2H-thieno [2,3-e] 1,1 (1-diazepin-2-one) are dissolved in 200 ml of diethylene glycol dimethyl ether at 65 ° and mixed with 5 g of finely ground phosphorus pentasulphide for 30 minutes, then the solvent is distilled off and the residue is dissolved in methylene chloride and shaken three times with water, the organic phase is dried and evaporated to dryness. 2-Pyridyl) -2H-thieno [2,3-e] -1,1-diazepine-2-thione is dissolved in 200 ml of methanol and boiled with 6 g of acetylhydrazine for 30 minutes. shake three times with water, distill off the methylene chloride and digest the crystalline residue with methanol, after crystallization from methanol to give 2- (2-acetylhydrazino) -7-chloro-5- (2-pyrial) -3H-thienoZ2,3- e7_1,1-diazepine, mp 193-195 °.

Example 6 0.35 g of 2- (2-acetylhydrazino) -7-chloro-5- (2,6-difluorophenyl) -3H-thieno-Z2,3-e-1, α-diazepine is applied to a metal plate as thin as possible and kept in a sand bath for 1 minute at 270 °. The melt is dissolved in methylene chloride and shaken three times with 0.1 N hydrochloric acid to remove the starting material. The methylene chloride is distilled off and the product is recrystallized from ethyl acetate by treatment with activated carbon. 2-Chloro-N- (2,6-difluoro-phenyl) -9-methyl-6H-thieno [3,2-b] s-triazolo [2,3-b] 1,1'-diazepine is obtained, m.p. is 185-137 °.

The starting material is obtained as follows: 0.6 g of 7-chloro-5 '(2,6-difluorophenyl) -1,3-dihydro-2H-thieno [2,3-e] -1,1-diazepin-2-one is added in 25 ml: diethylene glycol dimethyl ether and heated to 85 °. 0.35 G of finely ground phosphorus pentasulfide is added to the solution and stirred for 35 minutes at 85 °. The solvent is then evaporated off under reduced pressure, the residue is dissolved in 80 ml of methylene chloride and shaken three times with water. The organic phase is evaporated to dryness, the crude 7-chloro-5- (2,6-difluorophenyl) -1,3 "dihydro-2H-thieno [2,3-s] -1,7-diazepine-2-thione is dissolved in 20 ml. methanol and reflux with 1 g of acetylhydrazine 1 (0 min. The product which precipitates as a crystal is filtered off with suction and washed with methanol.

To obtain a second product, the mother liquor is evaporated to dryness, the residue is dissolved in methylene chloride and shaken three times with 0.1 N hydrochloric acid. The hydrochloric acid phase is neutralized with sodium bicarbonate and shaken with ethylene chloride. The organic phase is dried and evaporated to dryness under reduced pressure. The obtained 2- (2-acetylhydrazino) -7-chloro-5- (2,6-difluorophenyl) -3H-thieno [2,3-e] -1,2-diazepine melts from methanol after crystallization at 257-260 °.

Example 7 3.5 g (0.0111 moles) of?-O- (chlorophenyl) -9-methyl-6H-thieno [3,2-f] -5-triazolo [1,3-f] -1,7 The azepine is finely ground and dissolved in 35 ml of sulfuric acid at 5 °. 0 ° is added dropwise at 0 ° C. cooling the nitration-napposeos (0, 65 ml of ö05 / »nitric acid and 1.6 ml of sulfuric acid) within a half hour. Stir for a further 2 1/2 hours at 0 ° and finally pour into 500 g of ice and 500 ml of water. The solution is neutralized with solid sodium bicarbonate, after which the product precipitates as crystals. Now shake three times with 200 ml of methylene chloride each time, wash the organic phase once more with water and dry. After evaporation of the solvent, the mixture is triturated with ethyl acetate and the β-o- (chlorophenyl) -9-methyl-2-nitro-6H-thieno [3,2-e] -s-tri-solo [3,3-a] tri-sol. , 1 + 7-diazepine is recrystallized from ethanol by treatment with activated carbon. The product obtained melts at 270-272 °.

The starting material is obtained as follows: 225 g (0.72 mol) of 2-chloroacetylamino-3- (o-chlorobenzoyl) thiophene are dissolved in 2 liters of acetone and 118 g of sodium iodide are added. The reaction solution is heated at reflux for 1 1/2 hours, whereupon sodium chloride soon precipitates. The reaction mixture is evaporated to dryness, 3 l of methylene chloride are added and the mixture is layered in a 10 l reaction vessel with 3 liters of concentrated aqueous ammonia. The mixture is now stirred for hQ hours so that the layers do not mix with each other. After completion of the reaction, the phases are separated, the aqueous phase is extracted twice more with 200 ml of methylene chloride each time and the organic phase is washed three times with water. The methylene chloride phase is evaporated to dryness and made to crystallize. Add 200 ml of methylene chloride to the crystal cake and boil with stirring. The product is left to crystallize overnight in a refrigerator, suction filtered and washed with ice-cold methylene chloride to give 2-aminoacetylamino-3- (o-chlorobenzoyl) thiophene, m.p. is 15o-15o °.

150 g (0.51 mol) of 2-aminoacetylamino-3- (o-chlorobenzoyl) -thiophene are dissolved in 2.5 liters of abs. ethanol and add 250 ml of glacial acetic acid. The solution is heated to reflux with stirring until the reaction is complete (about 5 hours) according to TLC control (solvent: ether). The solvent is evaporated off in vacuo and the product is dissolved in 2 liters of methylene chloride. The methylene chloride solution is shaken with dilute aqueous sodium bicarbonate solution, washed with water and evaporated to dryness. The product is crystallized, 150 ml of methylene chloride are added, the mixture is boiled and left in the refrigerator to crystallize. After suction filtration and digestion with ice-cold methylene chloride, well-prepared 5- (o-chlorophenyl) -1,3-dihydro-2H-thieno [2,3-b] -1,3-diazepin-2-one is obtained. as yellow crystals of m.p. is 221-223 °.

0.95 G (0 * 003 [mu] mol) of 5- (o-chlorophenyl) -1,3-dihydro-2H-thieno [2,3-e] -1,1,1-diazepin-2-one is dissolved in 25 ml of diethylene glycol dimethyl ether. o0 ° C. A finely ground mixture of 1.6 g of P 2 S and 1 g of sodium bicarbonate is added to the solution, whereupon the reaction mixture begins to stir vigorously.

After the addition is complete, stir for an additional 50 min at 30 °. Evaporate the solvent to 10 ml and add 120 ml of water. The precipitated product is filtered off with suction, washed with water and required at room temperature. This gives 5- (o-chlorophenyl) -1,3-dihydro-2H-thieno [2,3-d] 1,2-diazepine-2-thione. Recrystallization from methanol gives yellow crystals of m.p. is 200 °.

To a solution of 0.5 ml of hydrazine hydrate and 50 ml of abs. tetrahydrofuran, 2.0 g of 5- (o-chlorophenyl) -1,3-dihydro-2H-thieno [2,3-e] -1,1'-aziazepine-2-thione are added. After 10 min a red solution is obtained which is further stirred at room temperature for 20 min. The reaction product is crystallized by adding ether. The crystals are filtered off, washed with ether and dried. This gives 5 "(o-chlorophenyl) -2-hydrazino-3II-thieno [2,3-e] -1,1 + -diazepine, m.p.

17o "L60 °. This can be recrystallized from a mixture of tetrahydrofuran and ether to give colorless crystals, m.p. 179-1Ö0 °.

2 g (0.00o9 mol) of 5 '(o-chlorophenyl) -2-hydrazino-3H-thieno [2,5-eZ-1,1'-diazepine are suspended in 200 ml of dry methylene chloride and 10 g of sodium bicarbonate are added. The reaction solution is cooled to 0 ° and 0.3 ml of acetyl chloride is added with stirring. After 45 minutes, the reaction solution is filtered off from the solid and the reaction solution is shaken twice with 100 nl of water each time. After drying over sodium sulfate, the organic phase is evaporated to dryness, 100 ml of butanol are added, followed by evaporation of 20 ml under reduced pressure. The reaction solution is refluxed for 3 hours and evaporated to dryness in vacuo. After the oily residue is triturated with ethanol, the crystals formed are boiled with a small amount of ethanol and allowed to crystallize in a refrigerator, suction filtered and dried. There is obtained h - (o-chlorophenyl) -9-methyl-Gilthio [3,2-b] s-triazolo [2,3-b] di-sepine, m.p. is 221-223 °.

Example 3 U g (0.013 mol) of 7-chloro-1,3-dihydro-5-o- (nitrophenyl) -2H-thieno-1,2,3-e-1,1-cyazepin-2-one 7-Chloro-1,3-dihydro-5- (o-nitrophenyl) -2H-thieno [2,2,3-e] -1,2-diazepine-2-thione is dissolved in 600 ml of methylene chloride and sodium sulfate is added to completion. to dry. The oily residue, if any, is dissolved in 20 ml of methanol and the solution is filtered. 6.35 g (five times the molar amount) of methoxyacetic acid hydrazide are now added and the solution

2U

58129 is completely evaporated to dryness under reduced pressure. The residue crystallizes on addition of 200 ml of methanol. The solution is concentrated to 100 ml and allowed to crystallize in the refrigerator. After suction filtration and drying, dark red 7-chloro-2- (2-methoxyacetylhydrazino) -5- (o-nitrophenyl) -3H-thieno [2,3-e] -1,1-diazepine is obtained, melting at 193-200 ° . The product is boiled in 100 ml of absolute xylene for 2 hours under reflux and finally evaporated under reduced pressure to 150 ml. After complete crystallization, a very pure colorless, colorless 2-chloro-9-methoxy-ethyl-U- (o-nitrophenyl) -6n-thieno [3,2-f] s-triazolo [1,3-a] T-diazepine is obtained, melting at 20 ° C. ^ -205 ° C.

Example 9-3 g (0.0199 mol) of Y-chloro-1,3-dihydro-5- (o-nitrophenyl) -2H-thieno [2,3-e] -1H-diazepin-2-one obtained The crude 7-chloro-1,3-dihydro-9- (o-nitro-phenyl) -2H-thieno72,3-e7-1,2-diazepine-2-thione is dissolved in 900 [mu] l of methylene chloride and boiled with stirring. g of sodium bicarbonate and 7 g of acetnyrazide diacetylammonium chloride for 19 hours at reflux. After filtration of the solid, the solution is washed twice with 200 ml of water each time and dried over sodium sulfate. After evaporation of the solvent, it is triturated with ethyl acetate, whereupon 7-chloro-2- (2-dimethyl-6-lysylhydrazino) -9- (o-nitrophenyl) -3H-thieno [2H-n-N] -diazepine is crystallized.

The quality product is boiled in 300 ml of dry butanol for 2 hours at reflux and, after evaporation of the solvent, triturated with ethyl acetate.

After recrystallization, 2-chloro-9-dimethylaminomethyl-U- (o-nitrophenyl) -6H-thieno [3,2-b] s-triazolo [2,3-b] 7β-diazepine is obtained as a colorless product, by sp. is 23 ^ -236 °.

Example 10 1.1 g of 7-chloro-9- (o-chlorophenyl) -1,3-dihydro-2H-thieno-Z2,3-e7-1'-cylazepine-2-thione is refluxed under cooling with 1.9 S with glycolic acid hydrazide in absolute butanol for 0 hours. The solvent is then distilled off and the residue is recrystallized from ethyl acetate by treatment with activated carbon. There is thus obtained 2-chloro-1- (o-chlorophenyl) -6H-thieno [3,2-f] s-triazolo [3-ol-diazepine-9-methanol, m.p. is 219 ”221 °.

Example 11 0.75 S 2-chloro-1 * - (o-chlorophenyl) -6H-thieno [3,2-b] -s -triazolo [1,3-a] - / l, The + 7-diazepine-9-methanol is dissolved in 25 ml of absolute chloroform and 0.7 g of triethylamine and 0.6 g of methanesulfofoyl chloride are added. The mixture is stirred for 2.5 hours at 25 °, then washed twice with water and twice with brine, dried over sodium sulfate and evaporated to dryness. The oily methanesulfonic acid ester of 2-chloro-N- (o-chlorophenyl) -6H-thieno [3,2-f] s-triazolo [1,3-a] [1,1] -diazepine-9-methanol is dissolved in 10 ml of 581 29 DMF and the solution is added dropwise to a solution of 1 ml of liquid ammonia in 5 ml of Di • iF. Stir for 2 hours at room temperature and partition the reaction mixture between saturated sodium chloride solution and methylene chloride. The organic phase is dried and evaporated to dryness and the residue is crystallized from ethanol. 9-Aminomethyl-2-chloro-1- (o-chlorophenyl) -6H-thieno [3,2- [7-s-triazolo-Z, 1,3-a7] -7-diazepine is obtained, m.p. is 190-192 °.

Example 12 0.93 2-Chloro-N- (o-chlorophenyl) -6H-thieno [3,2-7-7-s-triazolo [1,3-a] -Z11,1 +/- diazepine-9-methanol is dissolved in 20 ml of: absolute chloroform and 0.9 g of triethylamine and 0.7 g of methanesulphonyl chloride are added. The mixture is stirred for 2.5 hours at 25 DEG C., then washed twice with water and twice with saturated brine, dried over sodium sulfate and evaporated to dryness. The oily methanesulfonic acid ester of 2-chloro-β- (o-chlorophenyl) -6H-thieno [3,2-7,7-s-triazolo [1,3-a] [2,7] diazepine-9-methanol is dissolved in 10 ml of dry DI -1F and a solution of 0.0 ml of morpholine in 5 ml of DMF at 0-5 ° is added dropwise. Stir for 2 hours and partition the reaction mixture between saturated sodium chloride solution and methylene chloride. The organic phase is dried and evaporated to dryness. The residue is recrystallized from ethyl acetate by treatment with Akti i vihi i. There is thus obtained 2-chloro-1- + (o-chlorophenyl) -Q-morpholinomethyl-GH-thieno [3,2-f] s-triazolo [1,3-a] [1,7] diazepine, m.p. is 22h-226 °.

Example 13 0.75 g of 2-chloro-N- (o-chlorophenyl) -6H-thieno [3,2-f] -s-triazolo [1,3-a] [1,3] -diazepine-9- methanol is dissolved in 10 ml of absolute chloroform and 0.7 g of triethylamine and 0.8 g of methanesulfonyl chloride are added. The reaction mixture is stirred for 2 hours at room temperature and washed with water and brine, dried over sodium sulfate and evaporated to dryness.

Crude 2-chloro-N- (o-chlorophenyl) -6H-thieno [3,2,2-f] s-triazolo [4,3-a] 2,7,7'-azepine-9-methanol the methanesulphonic acid ester is dissolved in 15 ml of absolute UMF and 0.9 g of sodium methyl mercaptide are added and stirred at 50 ° for 1 hour.

The reaction solution is partitioned between water and methylene chloride, the organic phase is dried and evaporated to dryness. The residue is recrystallized from ethyl acetate by treatment with activated carbon. 2-Chloro-N- (o-chlorophenyl) -9-methylthiomethyl-O-thieno [3,2-f] triazolo [3,3-b] diazepine, m.p. 200-202 °, is obtained. .

Example lU

3.27 g (0.01 mol) of 7-chloro-5- (o-chlorophenyl) -1,3'-dihydro-2H-thieno-Z2,3-s7,11'-cyano-zepine-2-thione dissolved in 200 ml of butanol JSt is refluxed with 5.5 G of oxalic acid ethyl ester hydrazide for 20 hours, passing a stream of nitrogen through the solution and slowly distilling off the butanol for the first 5 hours. After evaporation of the solvent 2b 58129, the oil is dissolved in methylene chloride, shaken three times with 0.2 N sodium hydroxide solution and then three times with 0.2 N hydrochloric acid. Finally, the organic phase is washed with sodium bicarbonate solution, dried and evaporated to dryness. Crystallization of the residue from ethanol and treatment with activated carbon gives 2-chloro-4- (o-chlorophenyl) -6H-thieno [3,2-f] s-triazolo [1,3-a] [1,1 '] - diazepine-9 "carbon -acetic acid ethyl ester, m.p. is 180-1Ö2 °.

Example 15 3.37 g (0.01 mol) of 7-chloro-1,3-dihydro-5 '(o-nitrophenyl) -2H-thieno [2,3-e] -1,1'-diazepine-2-thione boil with 8 g of oxalic acid ethyl ester hydrazide and 150 ml of butanol for 1 hour under reflux, passing a stream of nitrogen through the solution and slowly distilling off the solvent. After complete evaporation of the solvent under reduced pressure, the residue is dissolved in methylene chloride. and shaken with water, finally five times with 0.1 N sodium hydroxide solution and then twice with 0.1 N hydrochloric acid. The methylene chloride phase is shaken with dilute sodium bicarbonate solution, dried and evaporated to dryness. After complete crystallization from ethanol with a handful of activated carbon, 2-chloro-k- (o-nitro-phenyl) -6-thieno [2,3-f] s-triazolo [1,3-a] [1,7] diazepine-9-carboxylic acid-ethyl] is obtained. ester as colorless crystals, m.p. is lU3-ll + 5 °.

Example 16 1.5 g of 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-2H-thieno - [2,3-e] -1,3-diazepine-2-thione are boiled in U g of 2- (p-methoxybenzyloxy) -acetic acid hydrazide in 100 ml of absolute butanol at reflux for k hours, passing a stream of nitrogen through the solution. The reaction mixture is evaporated to dryness, dissolved in methylene chloride, washed with water and saturated sodium chloride solution, dried and evaporated to dryness by recrystallization from ethyl acetate with treatment with activated carbon to give 2-chloro-U- (o-chlorophenyl) -9 "/" methyl / -6H-thieno [3,2-b] -s-triazolo [3x, 3-a] - (1H) diazepine.

Example 17

A solution of 0.4 l of 2-chloro-1- + (o-chlorophenyl) -6H-thieno [3,2-b] s-triazolo [1,3-a] [1,1 '] -diazepine-9 -carboxylic acid ethyl ester in 6.5 ml of absolute tetrahydrofuran is added dropwise under ice-cooling and with stirring to a suspension of 0.078 lithium aluminum hydride in 5 ml of absolute tetrahydrofuran, and after stirring for 1 hour at 3 °, 0.8 ml of 0 is added dropwise. .5 N sodium hydroxide. After the solid is filtered, the solvent is evaporated and the residue is dissolved in methylene chloride.

27 58129

The solution is washed with Ο, ρίΙ sodium hydroxide solution and finally with water and, after drying, evaporated to dryness. Crystallization of the residue from ethyl acetate gives 2-chloro-N- (o-chlorophenyl) -bK-thieno Z3,2-7-s-triazolo [2,3-b] 1H-diazepine-9-methanol, m.p. is 219-221 °.

Example 10 0.6 g of 9-aminomethyl-2-chloro-α- (o-chlorophenyl) -6H-thieno-Z, 3,2-7,7-s-triazolo [2,3-a] [1,7] diazepine are dissolved in 15 ml to absolute dioxane. 1.5 S of potassium carbonate are suspended in the solution and 0.18 g of chloroformic acid ethyl ester are added with stirring. The reaction solution is filtered after 3 hours from the solid. The residue obtained after evaporation of the filtrate is recrystallized from ethyl acetate by treatment with activated carbon to give 9-ethoxycarbonylaminomethyl-2-chloro-1- (o-chlorophenyl) -6H-thienoZ3,2-7-s-triatolo [2,3-a] (1.4) diazepine.

Example 19 1,2 β 2-Chloro-N- (o-chlorophenyl) -6H-thieno [3,2-b] -s-triazolo [2,2,7] diazepine-9-methanol is dissolved in 20 ml of absolute dioxane and heated With 0.1 g of 80 [mu] l of sodium hydride suspension for 2 hours at 50 [deg.] C. After cooling, 0.1 g of N, N-dimethylcarbamoyl chloride is added with stirring. The reaction solution is heated for 1 hour in a water bath and, after evaporation, partitioned between sodium bicarbonate solution and methylene chloride. The product from the organic phase is recrystallized from ethanol to give 2-chloro-4- (o-chlorophenyl) -9-N, N-dimethylcarbamoyloxymethyl-6H-ieno [2,3-f] s-triazolo [3-7,7]. 7äiatsepiini.

Example 20 1 g of 2-chloro-N- (o-chlorophenyl) -6H-thieno [3,2-e] -s-triazolo - [? - 3-a] -Z1,7-diazepine-9-methanol is dissolved in 10 ml of: absolute pyridine and add 1 ml of acetic anhydride. The reaction solution is kept at 30 ° for 15 hours and evaporated to dryness in vacuo. The residue is partitioned between methylene chloride and water. The organic phase is washed with saturated brine and dried over sodium sulfate and evaporated to dryness. After recrystallization of the residue from ethyl acetate, 9-acetoxyethyl-2-chloro-b- (o-chlorophenyl) -6H-thienoZ3,2- [7-s-triazolo [2,3-b] 1,1'-diazepine is obtained, m.p. is 191-193 °.

Example 21 1 g of 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-2H-1-eno-Z2,3-e71, di-s-e-silin-2-thione is refluxed at 50 ral: 3 in absolute methanol with 2 g of lactic acid hydrazide for 1.5 hours. The precipitated 7-chloro-5- (o-chlorophenyl) -2-lactoylhydratino) -3H-thieno [2,3-e] 1,1-k-diazepine is dried and boiled in 120 ml of absolute xylene for k hours. The solution is evaporated to dryness 28,581 29 and the product is recrystallized from ethyl acetate by treatment with activated carbon to give 2-chloro-U- (o-chlorophenyl) -9- (N-hydroxyethyl) -6H-thieno [3,2-f] -5-triazolo / ^, 3_% 7 / l> * tZdiazepine, m.p. is 118-120 °.

Example 22 0.1 g of 2-chloro-N- (o-chlorophenyl) -9- (C 1-4 hydroxyethyl) -6H-thieno [2,3-b] triazolo [3-a] [ the diazepine is refluxed in 80 ml of dry toluene with 0.6 g of crane trioxide in graphite for 1 hour. The solid is filtered off and the solution is evaporated to dryness. The residue is recrystallized from ethanol to give 9-acetyl-2-chloro-N- (o-chlorophenyl) -6H-thieno [3,2-f] -3-trisolo [1,3-a] [1,1 '].

Example 23 1.2 g of 7 "chloro-5- (o-chlorophenyl) -1,3-dihydro-2II-thieno-Z2,3-e / 1,1'-diazepin-2-thione are boiled together with 2 g: with cyanoacetic acid hydrazide in 30 [mu] l of absolute ethenol for 1.5 hours under reflux, passing a stream of dried nitrogen through the solution, concentrating the reaction solution to 10 ml and allowing it to crystallize Suction-filtered and dried 7-chloro-5- (o-chlorophenyl). A solution of 2- (2-cyanoacetylhydrazino) -3H-thieno [2,3-b] -1H-diazepine is refluxed in 130 ml of absolute xylene for 2 tonnes, the solution is evaporated to dryness and the residue is recrystallized from ethyl acetate to give activated carbon. 2-Chloro-U- (o-chlorophenyl) -9-cyanomethyl-6-thieno-Z3,2- [7-s-triazolo], 3-α7 / 1'-clazazepine, mp 217-220 °.

Example 2k To 0.8 g of 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-2H-thieno [2,3-Q] 1-diazepine-2-thione is boiled in 10 ml of absolute methanol 1, With 5 g of oxalic acid amide hydrazide for 1.5 hours at reflux. The solution is concentrated to 10 ml and allowed to crystallize in the refrigerator. The filtered and dried 7-chloro-5- (o-chlorophenyl) -2- (2-oxalylamide hydrazino) -3U-thieno [2,3-e] -1H-diazepine is refluxed. The organic phase is evaporated to dryness and the residue is recrystallized from ethane to give 2-chloro-N- (o-chlorophenyl)-] -thieno [1,2- b] triazolo [2,3-b] diazepine-9-carboxylic acid amide, m.p. is 2 ^ 8-251 °.

Example 25 0.7 g of 7-chloro-5- (o-chlorophenyl) -2-hydrazino-3H-thieno [2,3-e] -1H-diazepine obtained from 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-2H-thienoZ2,3- (7-1,1 + -diadiepin-2-thione and hydrazine) and m.p. is 236 °, is added with cooling to 15 ° to 15 ml of glacial acetic acid and a solution of 0.25 g of chloroacetyl chloride in 5 ml of glacial acetic acid is slowly added dropwise. Stir for 2 hours, add 0.3 g of sodium acetate and stir for 1 hour. The reaction solution is poured into ice water, neutralized and shaken with methylene chloride.

29 58129 After evaporation of the solvent, the residue is boiled in 30 ml of absolute xylene for 1 hour. After evaporation of the solvent, the residue is recrystallized from ethyl acetate by treatment with activated carbon to give 2-chloro-9-chloromethyl-U- (o-chlorophenyl) -6H-thieno [3,2-f] -s-triazolo [1,3-a]. ? ~ A, U7-diazepine, m.p. is 101-103 °.

Example 26

By proceeding in the same manner as in Example 25, but using iodoacetyl iodide instead of chlorine instead of the original, 2-chloro-1- (o-chlorophenyl) -9-iodomethyl-6H-thieno [2- [7-s-triatolo [3-a] A »·

Example 27 500 1¾ 2- [3,5-bis (aminomethyl) -1 + H1,2'-triazol-U-yl] -5-3-thienyl-o-chlorophenyl ketone hydrochloride (melting point / decomposition point 230 °) is dissolved in 10 ml: water and basified with 1N sodium hydroxide; the aqueous phase is extracted with methylene chloride. After drying over sodium sulfate and evaporation of the organic phase, the residue is refluxed in 5 nl of absolute alcohol. After evaporation to dryness, the crude base is chromatographed on alumina. Elution with chloroform and crystallization from acetic acid ester gives 9 "(aminomethyl) -2-chloro-U- (o-chlorophenyl) -6h-thieno [3,2-f] s-triazolo [1,3-a] alpha] diisepine having a melting point of 167-168 °. A recrystallized sample of acetic acid ester and low boiling petroleum ether melts at 170.5-171 °. The melting-decomposition point of the monohydrochloride is 198-200 °.

Example 2ö 0.95 G (0.003 + + moles) of 5- (o-chlorophenyl) -1H-thieno [2,3-e] A-7- [d] azepin-2 (3H) -one is dissolved in 25 ml of diethylene glycol dimethyl ether. in.

A finely triturated mixture containing 1.6 g of phosphorus pentosulfide and 1 g of sodium bicarbonate is added to the solution, whereupon the reaction mixture begins to stir vigorously. When the addition is complete, the reaction mixture is stirred for a further 50 minutes in CoA, the solvent is evaporated to 10 ml and __ 120 ml of water are added to the reaction mixture. The precipitated product is filtered off with suction, washed with water and dried at room temperature to give 1.05 β 5 - (o-chlorophenyl) -11-thienoZ2,3-s7 / 1,7-uiazepin-2 (3h) -thione. This product is dissolved in a solvent mixture of 50 ml of glacial acetic acid and 20 ml of methanol and the solution is heated with 2 g of acethydrazide diacetate / excess ammonium chloride for 1 hour at 50 °. The solvent is evaporated off and 150 ml of 5% sodium bicarbonate solution are added to the residue and the mixture is extracted with 150 ml of methylene chloride, which is used in several portions. The solution is dried over sodium sulfate and the solvent is evaporated off. The resulting oil is refluxed in 70 ml of glacial acetic acid for 1 hour. The solvent is evaporated off and the residue is taken up in a mixture of 100 ml of sodium bicarbonate and 100 ml of methylene chloride. The organic phase is evaporated to dryness and the resulting li- (o-chlorophenyl) -9-dimethylaminomethyl-U1-thieno [3,2-f] s-triazolo [3,3-a] 7,7-diazepine is boiled with 100 [mu] l of ethyl acetate, the impurities are evaporated off and the solution is evaporated to 20 ml. The precipitated product is recrystallized from ethyl acetate to give 0.2 g of product, m.p. 210-212 °. 0.2 g of this product is dissolved in 30 ml of anhydrous chloroform, 0.2 nl of anhydrous pyridine is added to the solution and cooled to -5 °. Dry chlorine gas is slowly introduced into the solution.

After 3 hours, no more starting materials can be detected. The solvent is evaporated off and the mixture is purified by column chromatography (silica gel, eluent ethanol).

This gives 2-chloro-1 + - (o-chlorophenyl) -9-dimethylaminomethyl-U1-thieno [3,2-7-7-s-triazolo], 3-% 7H-diazepine, m.p. 203-205 °.

Example 29 1 E (0.0032 mol) of N- (o-chlorophenyl) -9-methyl-6H-thieno [3,2-f] s-triazolo [1,3-a] -1,3-diazepine dissolved in 100 lanes abs. chloroform, the solution is cooled to 0 ° and 1 ml of pyridine (^-fold excess) is added to the solution.

Chlorine gas is bubbled into the solution for 2 hours. The solution is evaporated to dryness and the residue is taken up in methylene chloride and washed once with 0.1 N hydrochloric acid.

The product is extracted with U-hydrochloric acid, with ether being added to the methylene chloride phase to rise above. Hydrochloric acid is neutralized with solid sodium bicarbonate and the product is taken up in methylene chloride. The methylene chloride phase is dried over sodium sulfate, evaporated to dryness and the residue is triturated with a small amount of ethyl acetate. The crystallized product is recrystallized from the activated carbon used by me from ethanol to give 2-chloro-U- (o-chlorophenyl) -9-methyl-t-yl-thieno [3,2-f7-s-triazolo [2,3-f] 1,2-diazepine, m.p. 205-206 °.

Example 30 0.7 g of 2-chloro-9'-chloromethyl-U- (o-chlorophenyl) -6H-thieno [3 ', 2- [7-triazolo-β, 1,3'-b], β-diazepine are dissolved in 5 ml. DMF, the solution is cooled to 0 °, 1 ml of liquid NH 4 dissolved in 5 ml of TIIF is added to the solution and the mixture is allowed to stand at 0 ° C. The reaction mixture is partitioned between saturated sodium chloride solution and methylene chloride, the organic phase is dried, evaporated to dryness and the residue is recrystallized three times from ethanol. There is thus obtained 9-aminomethyl-2-chloro-N- (o-chlorophenyl) -6H-thieno Z3,2- [7-s-triazolo-Z, -3-e7-1 ', fc-diazepine, m.p. 190-192 °.

Example 31 0.5 g of 2-chloro-9-chloromethyl-1 + - (o-chlorophenyl) -6H-thieno [3,2-7] -s-triazolo [1,3-a] -1,1'-diazepine is dissolved in? Ml: DMF, 1 L of liquid ammonia dissolved in 5 mL of DMF is added to the solution, the mixture is sealed in a piston tube and the mixture is heated for 2 hours at 100 ° C. The bomb is cooled and opened and the reaction mixture is partitioned between saturated sodium chloride solution and methylene chloride. The organic phase is dried, evaporated to dryness and the residue 31 58129 is recrystallized three times from ethanol to give 9 "aminomethyl-2-chloro-k- (o-chlorophenyl) -6H-thieno [3,2-f] -5-triazolo [E] , 3-α7-1β-diazepine, m.p. 190-192 °.

Example 32 7.5 G of 2- (2-acetylhydrazino) -7-bromo-5- (o-chlorophenyl) -3H-thieno-Z2,3-e7-1,2-diazepine are dissolved in 75 ml of acetic acid and a solution boil for 1 hour at reflux. The solution is evaporated to dryness in vacuo. The residue is dissolved in chloroform and filtered through 150 g of alumina (activity I, basic). The eluates are evaporated to dryness. The residue is crystallized from a mixture of methanol and ether. 2-Bromo-α- (o-chlorophenyl) -9-methyl-6H-thieno-Z, 3,2-f-s-triazolo [7 H, 3-8-1'-diazepine is obtained, m.p. 206-200 °.

The starting material is obtained as follows: To a solution of 20.7 δ 7-bromo-1,3-dihydro-5- (o-chlorophenyl) -2H-thieno [2,3-e] -1,2-diazepin-2-one In 590 ml of abs. dioxane, suspended in 27.5 lbs of sodium bicarbonate. The mixture is heated to 73 ° with vigorous stirring and 26.3 g of phosphorus pentasulfide are added rapidly. The mixture is stirred for a further 50 min at 75 °. Then distill off at slightly reduced pressure äQO ml of dioxane (temperature about 50 °). The mixture is cooled to 20 ° and 550 ml of acetic acid ester and 550 ml of water are added and the pH of the mixture is adjusted to 10.5 with dilute sodium hydride solution while cooling with ice.

The organic phase is washed twice with brine, dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue melts at 208-210 °. The pH of the combined aqueous phases is adjusted to acetic acid. The precipitate formed is filtered off, washed and dried to give yellow crystals. The combined crystalline products are boiled in 2.5 l of ethanol and the insoluble matter is filtered off while hot. The filtrate is concentrated to 200 ml and cooled to 0 °. In this case, 7-bromo-1,3-dihydro-5 '(o-chlorophenyl) -2H-thieno [2,3-e] -1,1'-diazepine-2-thione crystallizes, m.p. 2LU °. 9.5 g of 7-bromo-1,3-dihydro-5- (o-chlorophenyl) -2H-thieno [2,3-e] -1,1-diazepine-2-thione are dissolved in 130 ml of abs. tetrahydrofuran.

5.75 g of acetic acid hydrazine are added to the solution and the solution is refluxed for 6 hours. The solvent is then evaporated off in vacuo and the residue is crystallized from ethanol. This gives 2- (2-acetylhydrazino) -7 "bromo-5- (o-chlorophenyl) -3H-thieno [2,3-e] -1,1-diazepine, m.p. 193 °.

Example 33 7 »5 g of 2- (2-acetylhydrazino) -7-iodo-5- (o-chlorophenyl) -3H-thieno / (2,3-β-1,1'-diatoepir dissolved in 100 Mira acetic acid) poa boil for 1 hour at reflux. The solution is evaporated to dryness in vacuo. The residue is dissolved in a hot mixture of 32,581 29 ml of benzene and 100 ml of ethanol and decolorized with activated carbon. The carbon is filtered off and the solution is concentrated by evaporation in vacuo until crystallization begins. After cooling, 2-iodo-N- (o-chlorophenyl) -9-methyl-6H-thieno [3,2-b] -s-triazolo [1,3-a] -1,1'-diazepine crystallizes, m.p. 223 °.

The starting material is obtained from 7-iodo-1,3-dihydro-5- (o-chlorophenyl) -2H-thieno [2,3-e] -1,1'-diazepin-2-one as shown in Example 32. This gives 7-iodo-1,3-dihydro-5- (o-chlorophenyl) -2H-thieno [2,3-e] -1,1,1-diazepine-2-thione, m.p. 200-202 ° and 2- (2-acetylhydrazino) -7'-iodo-5- (o-chlorophenyl) -3H-thieno [2,3-e] -1,1 * -di- ... foazepuniu, m.p. . 102.

Example 3 ^

Work as in Example 11, except that the methane of 2-chloro-U- (o-chloro-renyl) -6H-thieno [5,2-e] -5-triazolo [2,3-q] -1-diazepine-9-methalone sulfonic acid esters are treated with methyl amine instead of ammonia. This gives 2-chloro-α- (o-chlorophenyl) -9-methylaminomethyl-6H-thieno [3,2-b] 5-s-triazolo [3- (7-yl) azepepine, which is re-run from acetic acid ester. after crystallization, it melts at 139-1 ^ 1 °.

Claims (3)

A process for the preparation of therapeutically used thieno / 3,2-f7-s-triazolo [1, 3-a7Z1> k / oiazepine derivatives of the formula r-c * w (i) Wherein R, is halogen elder nitro, R £ is phenyl, o-trifluoromethylphenyl, o-halophenyl, ο, '-dihalophenyl, o-nitrophenyl or 2-pyridyl, and dr alkyl , alkylaminoalkyl, dialkylarainoalkyl, alkoxyalkyl, alkoxibenzyloxyalkyl, morpholinoalkyl, alkylthioalkyl, cyanoalkyl, haloalkyl, alkoxycarbonylaninoalkyl, dialkylcarbamoyloxyalkyl, alkanoyloxyalkyl, alkanoyl, alkanoyl, alkanoyl, alkoxyl atoms, and their acid addition salts, characterized in that: a) a compound of the formula R3 - c - hn O / "" (II) νγ "" \ 1- / 2 R2 where R 1, R 2 and R are as defined above; cyclized, or x B) a compound of the formula /, R 2 yS N-C (III) II cho -L 2 c = or C 37 581 2 9 where R 1, and R 2 are as defined above, are cyclized, or c ) a compound of formula Π - CN (IV) C = w R2 where R0 and R are as defined above, halogenated or nitrated, or d) to produce a compound of formula I wherein R is lower alkanoyl, a corresponding is a compound of formula I wherein R (is (3-hydroxy (lower) alkyl, oxyucras, or e) for the preparation of a compound of formula I, wherein R lä is lower-alkanoyloxy (lower) alkyl, a corresponding compound of formula I , wherein is hydroxy (lower) alkyl, is esterified with a corresponding alkanoylating agent, or f) to produce a compound of formula I, wherein R 1 is (lower) alkoxy (lower) alkyl, (lower) alkoxy (lower) alkyl , (lower) alkylthio (lower) alkyl, amino (lower) alkyl, (lower) alkyl amino (lower) alkyl, di (lower) alkylamino (lower) alkyl or morpholino (lower) alkyl, a corresponding compound of the formula I, wherein is halogen (lower) alkyl, or a methanesulfonic acid ester or a similar reactive ester of a corresponding compound of formula I, wherein R is hydroxy (lower) alkyl, gre) alkanoi, a (lower) alkoxybenzyl alcohol, a (lower) thioalkanol, ammonia, a (lower) alkylamine, a di (lower) alkylamine or morpholine, or g) to prepare a compound of formula I wherein R is di (lower) -alkyl 11 · arbarnoyloxy (lower) alkyl, a corresponding compound of formula I, wherein Π is hydroxy (lower) alkyl, is reacted with a reactive derivative of a di (lower) alkylcarbanoic acid, or h) to prepare of a compound of formula I wherein R 2 is (lower) -alkoxycarbonylamino (lower) alkyl, a corresponding compound of formula I, wherein is amino (lower) alkyl, is reacted with a chloroformic acid (lower) alkyl ester, or i) to prepare of a compound of formula I, wherein ΐγ is hydroxymethyl, a corresponding compound of formula I, wherein (lower) alkoxycarbonyl is reduced, and j) o :; Su wished, there. Rarely does no one lead to an acid addition