CA1049009A - 6h-thieno (3,2-f)-s-triazolo (4,3-a)-(1,4) diazepines - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to novel thienotriazolodiazepine derivatives of the general formula (I)

Description

The present invention relates to diazepine derivatives. More par-ticularly, the invention is concerned with thienotriazolodiazepine deriva-tives and a process for the manufacture thereof The thienotriazolodiazepine derivatives provided by the present invention are compounds of the general formula ~ 8 \
R4-----C~5 ~

~1 ~ 4 5 / 2 (I) wherein R1 represents a halogen atom, R2 represents a phenyl, o-trifluoro- -methylphenyl, o-halophenyl, o,o'-dihalophenyl or o-nitrophenyl group or a pyridyl or thienyl group and R4 represents a hydrogen atom or an aIkyl group or a group of the formula -alkyl-Z in which Z represents the grouping -N(R5) (R6) wherein R5 and R6 each independently represent a hydrogen atom or an alkyl group and pharmaceutically acceptable acid addition salts thereof.
As used in this description the term ~alkyl~ alone or in com_ bination such as in hydroxyalkyl, denotes a straight-chain or branched-chain hydrocarbon group containg 1-4 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, tertbutyl and the like. The term "hal-ogen" denotes bromine~ chlorine~ fluorine~ and iodine.
A preferred class of thienotriazolodiazepine derivatives provided by this invention comprises those in which R1 represents a halogen atom, es-` 20 pecially a chlorine atom, R2 preferably represents an o-halophenyl, o,o'-dihalophenyl or 2-pyridyl group. When R2 represents an o-halophenyl group, .,; ' : -1-~049009 the o-fluorophenyl and o-chlorophenyl groups are preferred. When R2 represents an o,o'-dihalophenyl group, the two halogen atoms are preferably identical and are especially fluorine atoms. R4 preferably represents an alkyl or aminoalkyl group, particularly a methyl group.
As will be evident from the foregoing, especially preferred thieno-triazolodiazepine derivatives provided by this invention are those in which Rl represents a chlorine atom, R2 represents an o-chlorophenyl or o-fluoro-phenyl group and R4 represents a methyl group.
A particularly preferred compound of formula I is 2-chloro-4-(o-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine.
Other examples of compounds of formula I are:

2-chloro-4-(o-chlorophenyl~-9-methyl-6H-thieno[3,2-f]-s-triazolo-~4,3-a~[1,4]diazepine-5-oxide, 2-chloro-9-methyl-4-(2-pyridyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a]-~1,4]diazepine, 2-chloro-9-methyl-4-(o-nitrophenyl)-4H-thieno[3,2-f]-s-triazolol4, s 3-a]~1,4]diazepine, 2-chloro-9-methyl-4-phenyl-6H-thieno~3,2-f]-s-triazolo~4,3-a]~1,4]-diazepine, 2-chloro-4-(o-fluorophenyl)-9-methyl-6H-thieno~3,2-f]-s-triazolo-[4,3-a]~1,4]diazepine, 2-chloro-4-(o,o'-difluorophenyl)-9-methyl-6H-thienol3,2-f]-s-tria-zolo[4,3-a][1,4]diazepine, 9-aminomethyl-2-chloro-4-(o-chlorophenyl)-6H-thieno~3,2-f]-s-tria-zolo[4,3-a]~1,4]diazepine, 2-chloro-4-(o-chlorophenyl)-9-dimethylaminomethyl-6H-thienor3,2-f]-s-triazolo~4,3-a][1,4]diazepine, 2-chloro-9-methyl-4-(o-trifluoromethylphenyl)-6H-thieno13,2-f]-s-~` triazolo[4,3-a]~1,4]diazepine.
According to the process provided by this invention, the thienotria-~ .
';
, ':

10491~9 zolodiazepine derivatives aforesaid, i.e. the compounds of formula I and their pharmaceutically acceptable acid addition salts, are manufactured by a process which comprises:
a) cyclising a compound of the general formula R - C - NH

O NH
S~/N=c\
CH2 (II) C = N
R

wherein Rl, R2 and R4 have the significance given earlier, or b) cyclising a compound of the general formula N \
R -C N
Rl S \N - C ~III) ~( CH2 f=o NH2 wherein Rl, R2 and R4 have the significance given earlier, or c) halogenating a compound of the formula .

, ¦ ~N
N - C IA

C = N

30 ~herein R2 and R4 have the significance given earlier, or ' - 3 -:

,. .
:
. : ' 1049(~09 d) for the manufacture of a compound of formula I in which R4 is a group of the formula -alkyl-Z in which Z has the significance given earlier, reacting a corresponding compound which carries a group of the formula -alkyl-A in place of R4 with a compound of the general formula BR; in which formulae one of the symbols A and B represent the grouping -NH-R5 in which R5 has the significance given earlier and the other symbol represents a leaving atom or group and R represents an alkyl group, provided that, when the symbol B
represents the grouping -NH-R5, R can also represent a hydrogen atom and wherein steps a) to d) may be followed by the step of e) converting a compound of formula I obtained into a pharmaceutically acceptable acid addition salt.
According to embodiment a) of the present process, compounds of formula I can be manufactured by cyclising a corresponding compound of formula II.
S The cyclisation of a compound of formula II is carried out accord-ing to methods known per se; for example, by heating a compound of formula II. The temperature at which the cyclisation is carried out is not critical, but it depends, however, on the starting material and the conditions used.
The cyclisstion can be carried out at a temperature of between about room temperature and 300C. The cyclisation can be carried out in the absence of, or, preferably, in the presence of, an inert organic solvent. If the cyclisa-tion is carried out in the presence of an inert organic solvent, the preferred temperature range lies between about 60C and 180C, preferably at the reflux ' temperature of the cyclisation mixture. If, on the other hand, the cyclisa-tion is carried out in the absence of a solvent, the preferred temperature range lies between about 200C and 260C. Suitable inert organic solvents are, for example, hydrocarbons such as toluene, xylene and the like, halogen-ated hydrocarbons such as chlorobenzene and the like, ethers such as tetra-hydrofuran, dioxane, diethyleneglycol dimethyl ether, diethyleneglycol diethyl ether and the like, amides such as hexamethylphosphoric acid triamide, dimethyl-.' ~
~, '~''~ , .
:
:~. ` , - - ~ ' .' ... . . . .

1049~

formamide and the like, dimethyl sulphoxide and, especially, alkanols such as methanol, ethanol, l-propanol, 2-propanol, l-butanol, 2-butanol, cyclo-hexanol and the like. The cyclisation time depends, of course, on the tem-perature used and the fact whether a solvent is present and lies between a few minutes and 48 hours. In the absence of a solvent the reaction is pre-ferably effected in a few minutes. In the presence of a solvent the time lies preferably between 1 and 24 hours.
The compounds of formula II need not, and can not in all cases, be used in an isolated form since they frequently spontaneously cyclise under the conditions used for their preparation.
According to embodiment b) of the present process, compounds of formula I are manufactured by cyclising a compound of formula III.
The cyclisation of a compound of formula III is also carried out according to methods known per se. For example, this cyclisation can be carried out by warming a compound of formula III in an organic medium; in many cases the presence of an acid is desirable in order to obtain satisfac-tory ~ields. Thus, the cyclisation can be carried out, for example, by heating a compound of formula III to boiling under reflux for several hours ; 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 for a relatively short time (ca 5 minutes to 0.5 hour) in an aliphatic carboxylic acid such as acetic acid, isobutyric acid or pivalic acid.
The compounds of the formula III need not, and can not in all cases, be used in an isolated form since they frequently spontaneously cyclise under the conditions used for their preparation.
~ According to embodiment c) of the present process, compounds of ormula I can be manufactured by halogenating a compound of formula IA.
The halogenation is carried out according to one of the halogenation methods con~entional in thiophene chemistry; for example, using elementary chlorine, bromine or iodine, sulphuryl chloride etc, the conditions being ~ . .
'':

1049~09 primarily governed by the nature of the halogenating agent used. Chlorina-tion can be carried out using elementary chlorine, for example in chloro-form/pyridine or nitrobenzene, expediently at room temperature. Bromination can be carried out using elementary bromine, for example in chloroform, at an elevated temperature, for example at the boili~g temperature at reflux.
Iodination using elementary iodine can, for example, be carried out in chloro-form and in the presence of mercuric oxide at room temperature. Chlorination using sulphuryl chloride can, for example, be carried out in chloroform or glacial acetic acid at room temperature or at an elevated temperature, for example at the reflux temperature.
According to embodiment d) of the present process, compounds of formula I in which R4 represents a group of the formula -alkyl-Z in which Z
has the significance given earlier are manufactured by reacting a correspond-ing compound which carries a group of the formula -alkyl-A in place of R4 with a compound of the formula BR. One of the symbols A and B represents the grouping -NH-R5 in which R5 has the significance given earlier and the other symbol represents a leaving atom or group, preferably a halogen atom ~especiallr a chlorine atom) or a reactive ester group te.g. a methanesul-phonic acid ester group). R represents an alkyl group or, when B represents the grouping -NH-R5, R can also represent a hydrogen atom.
Where B represents the grouping -NH-R5 and R represents an alkyl group or has anr of the additional meanings mentioned earlier, the reaction consists in the formation of aminoalkrl-substituted compounds. This aspect ; of the process can be carried out in accordance with methods known per se.
For example, a compound of formula I in which R4 represents a hydroxyalkyl group can be converted into the methanesulphonic acid ester and this ester can be reacted with an amine of the general formula HNR5R6 in which R5 and R6 have the significance given earlier. The reaction is carried out in a manner known per se, preferably in the presence of a suitable inert organic

3~ solvent such as dimethylformamide or an alcohol such as methanol or ethanol .

' ~ ' 1049~Q9 at a temperature between 0C and 100C, preferably at 0-5C.
Compounds of formula I can be converted into pharmaceutically acceptable acid addition salts by treatment with inorganic or organic acids.
Example of acids which form pharmaceutically acceptable salts are hydro-chloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, tartaric acid, citric acid, maleic acid, ascorbic acid, formic acid, acetic acid, succinic acid, methanesulphonic acid, benzenesulphonic acid, p-toluene-sulphonic acid etc.
The starting materials of formula II can be prepared from the corresponding thienodiazepine derivatives of the general formula ,., I O
Rl ~ N - C /CH2 (IV) C = N
R2 ' .
~herein Rl and R2 have the significance given earlier.
In a first step, a thienodiazepine derivative of formula IV is reacted with a sulphide such as phosphorus pentasulphide to give a thione of the general formula Rl S N - C~

\~3( CH2 ~V) ~ = N

wherein Rl and R2 have the significance given earlier. In this reaction, the sulphide is preferably used in excess. The reaction is advantageously carried out in an inert organic solvent such as pyridine, xylene and the like at a temperature of from about 40C up to the reflux temperature of the ~ reaction mixture, preferably at the reflux temperature. Pyridine is a preferred ; 30 solvent for this reaction.

,:
~' ~0~9OQ~
A thione of formula V is then reacted with an organic acid hydra-zide of the general formula H2N- NH- C0 -R (VI) wherein R4 has the significance given earlier, to give a compound of formula II. The reaction of a thione of formula V with an acid hydrazide of formula VI is carried out in an inert organic solvent, preferably an alkanol such as methanol, ethanol, 1- or 2-propanol, 1- or 2-butanol and the like at a temper-ature between about 60C and 120C, preferably at the reflux temperature of the reaction mixture. In a preferred procedure, the acid hydrazide is used in a 2- to S-fold excess over the theoretically required amount. The reaction time depends on the reaction temperature and lies between a few minutes and 48 hours, preferably between about 1 and 24 hours. The thus-obtained crude product consists mainly of the desired compound of formula II and of the already cyclised compound of formula I. This mixture can be separated on the basis of the different 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 hereinbefore, the compound of formula II can be converted into the compound of formula I. According to a simpler method, the mixture of compounds of formulae I and II can be con-verted into a uniform compound of formula I by heating in the manner described earlier. The reaction of a thione of formula V with an acid hydrazide of ~ formula VI is preferably carried out while conducting an inert gas, prefer-- ably nitrogen, through the reaction mixture so that the hydrogen sulphide ; formed is continuously removed.
The acid hydrazides of formula VI are known compounds or can be readily prepared in an analogous manner to the known compounds, for example by heating an ester of the formula R4-COO-alkyl to reflux with hydrazine hydrate ~e.g. in methanol).

3Q The thienodiazepine derivatives of formula IV are also known d~,'''`
... . .
. .

~49~Q9 compounds or can be readily prepared in an analogous manner to the known compounds. Thus, they can be prepared, for example, from 2-amino-3-benzoyl-thiophene by reaction with an ~-halocarboxylic acid halide such as chloro-scetyl chloride, treatment of the resulting compound with ammonia and subse-quent cyclisation. Where thienodiazepine derivatives of formula IV are desired in which Rl and/or R3 represents other than a hydrogen atom and R2 represents other than a phenyl group, then, depending on the desired substitu-ents, the reaction can be carried out using appropriately substituted amino-aroyl-thiophene derivatives and/or substituents can be introduced at one of the subsequent stages according to generally known methods and/or substituents can be converted into other substituents.
Starting materials of formula II can also be prepared from compounds of the general formula Rl~S\~N=C/
CH2 (VII) C = N

wherein Rl and R2 have the significance given earlier, by reaction with a carboxylic acid of the general formula R4-COOH, wherein R4 has the signifi-cance given eariler, or with a reactive derivative thereof. Suitable reactive derivatives of the foregoing carboxylic acids are, for example, the esters, anh~drides, halides, amides, iminoethers, amidines and orthoesters, the orthoesters being especially preferred. Examples of such orthoesters are o~hoacetic acid trimethyl ester, orthoacetic acid triethyl ester, orthoformic ' acid triethyl ester, orthopropionic acid triethyl ester, orthobutyric acid triethyl ester and the like.
The reaction of a compound of formula VII 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 a hydrohalic acid ~e.g.

_ g _ ~.tl'.' .
., 1049~9 hydrochloric acid), p-toluenesulphonic acid and the like. Suitable solvents are alkanols such as methanol, ethanol and the like, ethers such as tetra-hydrofuran, diethyl ether and the like, dimethyl sulphoxide, dimethylform-amide and the like. The temperature is not critical, but the reaction is preferably carried out at an elevated temperature, that is to say a tempera-ture between about 30C and the reflux temperature of the reaction mixture, preferably at the reflux temperature.
Again, starting materials of formula II can be prepared from com-pounds of the general formula NH - alkyl Rl ~ N = C / (VIII) f=N

~herein Rl and R2 have the significance given earlier, by reaction with an acid hydrazide of formula VI. The reaction is carried out in an inert organic solvent such as an alkanol (e.g. ethanol, propanol, butanol and the like), dimethylformamide, an ether (e.g. diglyme and methoxyethanol) or the like in the presence of a strong base such as an amine (e.g. a tertiary amine such as triethylamine, methylpiperidine and the like) at an elevated temperature, preferably at the reflux temperature of the reaction mixture.
Compounds of formula VIII can be readily prepared from corresponding thienodiazepine derivatives of formula IV by treatment with an alkylamine in the presence of a Lewis acid such as titanium tetrachloride.
The compounds of formula VII can be prepared from the corresponding compounds of formula VIII by reaction in a manner known per se with nitrous acid to give a corresponding N-nitroso compound. By reaction of such an N-nitroso compound with hydrazine there is obtained a desired compound of formula VII. The compounds of formula VII can also be prepared by treating a ` 3Q compound of formula V with hydrazine.

- lQ _ , - .

~490~9 The appropriately 2-unsubstituted thienotriazolodiazepine deriva-tives required as starting materials for embodiment c) of the present process can be obtained in analogy to embodiments a) of the present invention.
The compounds of formula I and their pharmaceutically acceptable acid addition salts are valuable medicaments and can be used, for example, as anticonvulsants, sedatives, muscle-relaxants, tranquillizers and anxioly-tics. Thus, for example, 2-chloro-4-~o-chlorophenyl)-9-methyl-6H-thieno~3,2-f~-s-triazolo~4,3-a][1,4]diazepine exhibits an HD50 of 0 5 mg/kg p.o. in the rotating rod test ~mouse), an ED50 of 1.0 mg/kg p.o. in the chimney test ~mouse) and an APR2 0 of 0.03-0.1 mg/kg p.o. in the antipentetrazole test ~mouse). These tests were carried out according to generally known standard methods.
The compounds of formula I and their pharmaceutically acceptable acid addition salts can be made up into pharmaceutical preparations ~e.g.
tablets, dragées, suppositories, capsules, solutions, suspensions, emulsions etc) according to generally known procedures. Apart from the usual pharmaceu-tically inert carrier materials such as, for example, lactose, starch, talc, magnesium stearate, water, vegetable oils, polyalkyleneglycols and the like, these preparations can also contain preservatives, stabilisers, wetting agents, emulsifiers, salts for varying the osmotic pressure, buffers or other thera^
peutically~valuable materials. If necessary, the pharmaceutical preparations can be sterilised or can be subjected to other operations usual in the phar-maceutical industry. It will therefore be appreciated that the invention includes within its scope a pharmaceutical preparation containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof in association with a compatible pharmaceutical carrier material.
A suitable pharmaceutical dosage unit can contain about 1 to 50 mg of a compound provided by the present invention. Suitable daily doses for oral administration to mammals lie in the range of from about 0.1 mg/kg to about 30 mg/kg and, in the case of parenteral administration to mammals, a . . -. :
-:

suitable daily dose amounts to about 0.1 mg/kg to about 10 mg/kg. These doses are, however, given merely by way of example and the specific dosage should be adjusted in each case to the individual requirements.
The following Examples illustrate the process provided by the present invention.
Example 1 2.5 g of 2-(2-acetylhydrazino)-7-chloro-5-(o-chlorophenyl)-3H-thieno[2,3-e]-1,4-diazepine are heated under reduced pressure (water-jet vacuum) for 5-7 minutes in an oil bath ~250C) until gas evolution is no longer observed. The resulting product is finely triturated in a mortar and boiled out several times with a total of 400 ml of ethyl acetate. After removal of the solvent, the resulting crude product is recrystallised from ethanol containing active carbon to give 2-chloro-4-(o-chlorophenyl)-9-methyl-6H-thienol3,2-f]-s-triazolo~4,3-a][1,4]diazepine in the form of cream-coloured crystals of melting point 205-206C.
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-e]-1,4-diazepin-2-one are heated to reflux for 30 minutes with 2.45 g of phosphorus pentasulphide in 100 ml of absolute pyridine, dry nitro-gen being conducted through the solution. The solution is separated on a 35 cm long column ~p 3.5 cm) filled with 100 g of Kieselgel [(0.05 to 0.2 mm) tMerck)]. The separation is followed by thin-layer chromatography (eluant:
benzene/ethanol 9:2). When impurity, which runs substantially slower, appears the elution is stopped. The solvent is removed under a vacuum, whereby 7-chloro-5~(o-chlorophenyl)-1,3-dihydro-2H-thieno~2,3-e]-1,4-diazepine-2-thione ^ immediately crystallizes out in the form of yellow crystals of melting point 223-225C. This thione is not further purified prior to use in the next step.
3.3 g (0.01 mol) of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno~2,3-e~-1,4-diazepine-2-thione are heated to reflux for 30 minutes - 12 _ ~ .
'' '' - : .
. . ~ , :

under a nitrogen atmosphere with 2.5 g of acetic acid hydrazide and 150 ml of n-butanol. The solvent is removed under a vacuum, the residue treated with 200 ml of ethyl acetate and shaken out three times with 200 ml of water each time. The precipitated starting material is filtered under a vacuum and combined with the ethyl acetate phase. After concentration of the solution to 50 ml, the product is left to crystallize. Thereupon, the product is filtered under a vacuum and again recrystallized from ethyl acetate containing active carbon to give 2-(2-acetylhydrazino)-7-chloro-5-(o-chlorophenyl)-3H-thieno[2,3-e]-1,4-diazepine in the form of orange crystals of melting point 211-213~C.
Example 2 0.2 g of 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno~2,3-e]-1,4-diazepine-2-~hione are heated to reflux for 5 hours under a nitrogen atmosphere with 0.2 g of acetic acid hydrazide in 30 ml of n-butanol. After evaporation of the solvent, the product is taken up in methylene chloride and extracted several times with l-N hydrochloric acid, the organic phase being treated portionwise with ether such that it comes to the surface in the separating funnel. After neutralisation of the aqueous phase with sodium bicarbonate, the mixture is extracted with methylene chloride, the solvent evaporatet after drying over sodium sulphate and the residue made into a paste with ethyl acetate. The resulting crystals are recrystallized from eth~l acetate containing active carbon to give colourless crystals of 2-chloro-9-methyl-4-~o-nitrophenyl)-6H-thieno~3,2-f]-s-triazolo~4,3-a][1,4]diazepine of melting point 210-212C.
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-e]-1,4-diazepin-2-one are heated to reflux with 0.8 g of phosphorus pentasulphide in 30 ml of absolute pyridine, nitrogen being conducted through the solution. The mixture is separated on a column (0 3 cm) filled with 50 g of Kieselgel 1(.05 to 0.2 mm) CMerck)~ (the product travelling on the front A~ .

'.

and the impurities travelling only slowly). After concentration of the pyridine solution under a vacuum, the residue is treated with methylene chloride and brought to crystallization. After completion of the crystalli-zation in a refrigerator, the mixture is filtered under a vacuum and washed with a small amount of ice-cold methylene chloride. Recrystallization from absolute methanol yields 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno-[2,3-e]-1,4-diazepine-2-thione in the form of yellow crystals of melting point 213-215C.
Example 3 3.0 g of 7-chloro-1,3-dihydro-5-(o-trifluoromethylphenyl)-2H-thieno-~2,3-e]-1,4-diazepin-2-one are dissolved in 50 ml of diethyleneglycol dimethyl ether at 80C, treated with 4.2 g of phosphorus pentasulphide and 3 g of finely triturated sodium bicarbonate and warmed for 15 minutes at 80-85C.
The mixture is then evaporated under a vacuum and taken up in 60 ml of butanol.
3 g of acetyl hydrazine are added and the mixture is heated under reflux for 90 minutes. The butanol is evaporated under a vacuum, the residue taken up in methylene chloride, the organic phase shaken out several times with water, dried and evaporated. The oily residue is brought to crystallization with ether. There is obtained 2-chloro-9-methyl-4-(o-trifluoromethylphenyl)-6H-thieno~3,2-f]-s-triazolo[4,3-a]l1,4]diazepine which, after recrystallization from eth~l acetate, has a melting point of 193-195C.
Example 4 6.8 g of 2-~2-acetylhydrazino)-7-chloro-5-(o-fluorophenyl)-3H-thienoI2,3-e]-1,4-diazepine a~e boiled under reflux for 9 hours in 300 ml of absolute xylene. After cooling, the precipitated impurities are filtered off under a vacuum. The solvent i5 then evaporated under reduced pressure and the product recrystallized from ethyl acetate containing active carbon.
~, There is obtained 2-chloro-4-~o-fluorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazoloI4,3-s]Il,4~diazepine of melting point 187-189C.
The starting material is prepared as follows:
.' .

`
~' - ,: : .
~ . ; ' ' ' . ' ' . . '' ;: . . ' ~ : . ~
:~ , . : . , . . ;

1049~09 10 g 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one are dissolved in 150 ml of diethyleneglycol dimethyl ether at 55C and stirred with a mixture of 15 g of finely triturated phosphorus pentasulphide and 10 g of sodium bicarbonate for 40 minutes. The solvent is distilled off and the residue digested with water, filtered under a vacuum and dried. The 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione thus-obtained is boiled in 200 ml of methanol with 15 g .
of acetyl hydrazine for 30 minutes. On cooling, 2-(2-acetylhydrazino)-7-chloro-5-(o-fluorophenyl)-3H-thienol2,3-e]-1,4-diazepine precipitates. The methanol is distilled off and the residue partitioned between methylene chloride and water. In so doing, additional product precipitates. The solvent is evaporated under reduced pressure and additional product is obtain-ed from the residue by digestion with methanol. The 2-(2-acetylhydrazino)-7-chloro-5-~o-fluorophenyl)-3H-thienol2,3-e]-1,4-diazepine thus-obtained has a melting point of 207-209C.
Example 5 2.2 g of 2-(2-acetylhydrazino)-7-chloro-5-(2-pyridyl)-3H-thieno-~2,3-e~-1,4-diazepine are boiled under reflux for 2 hours in 120 ml of absolute xylene. The solution is then cooled and the precipitated impurities are filtered off. The solvent is evaporated under reduced pressure and there i5 obtained 2-chloro-9-methyl-4-(2-pyridyl)-6H-thieno~3,2-f]-s-triazolol4,3-a]-

4]diazepine in the form of a crystalline product which, after recrystalli-zation from ethyl acetate, melts at 174-176C.
The starting material is prepared as follows:
14.6 g of cyanomethyl-2-pyridyl-ketone and 7.6 g of bismercapto-` acetaldehyde are dissolved or suspended in 60 ml of absolute dioxane and treated with 5 ml of triethylamine with stirring. After a period of 1.5 hours at room temperature, the mixture is poured into ea 500 ml of water and extracted ~ith meth~lene chloride. The methylene chloride phase is shaken out twice with l-N sodium hydroxide, dried over sodium sulphate with the ''`'`~ ~

: . :

1049~09 addition of active carbon and evaporated. There is obtained 2-amino-3-thienyl-2'-pyridyl-ketone which, after recrystallization from benzene, yields yellow crystals of melting point 122-124C.
65 g of 2-amino-3-thienyl-2'-pyridyl-ketone are dissolved in 500 ml of dry dioxane and 80 g of potassium csrbonate are suspended in the solution which is then treated with 80 g of chloroacetyl chloride. After the exothermic reaction has died down, the mixture is stirred for a further 2 hours at room temperature and then poured into a solution of 50 g of potas-sium carbonate in 2 litres of water. The precipitate which separates is filtered under a vacuum, washed with water and taken up in methylene chloride.
After drying over sodium sulphate containing active carbon, the solvent is distilled off under a vacuum, the residue digested with a small amount of methanol and filtered under a vacuum. There is obtained 2-chloroacetylamino-3-thienyl-2'-pyridyl-ketone which, after crystallization from methanol, yields yellow needles of melting point 130-132C.
76 g of 2-chloroacetylamino-3-thienyl-2'-pyridyl-ketone are dissolv-ed in 1 litre of acetone and, after the addition of 45 g of sodium iodide, stirred for 15 hours at room temperature. The acetone solution is then evapor-ated to dryness under a vacuum and the residue partitionet between ca 300 ml of methylene chloride and water, the organic phase covered with ca 1.5 litres of concentrated ammonia and stirred for 48 hours without mixture of the phases.
After completion of the reaction, the phases are separated, the organic phase evaporated to dryness and the residue taken up in methylene chloride. This solution is thoroughly extracted with 0.1-N hytrochloric acid, the aqueous ,~, extracts neutralised with potassium carbonate and the separated solid -material filtered under a vacuum and dried. After crystallization from ethanol, there is obtained 2-aminoacetylamino-3-thienyl-2'-pyrityl-ketone in the form of yellow crystals of melting point 259-262C.
A solution of 32.4 g of 2-aminoacetylamino-3-thienyl-2'-pyridyl-ketone in 350 ml of acetic acid is heated under reflux for 15 minutes. The solvent is then distilled off under a vacuum, the residue digested with a , ' . , ' . ',~.,.,, - '~ ,' '~ '. ' ' :- ~ - . . .
, .
.

1049~09 small amount of methylene chloride and the solid material filtered under a vacuum. After crystallization from ethanol, there is obtained 1,3-dihydro-

5-(2'-pyridyl)-2H-thieno[2,3-e]-1,4-diazepin-2-one in the form of colourless crystals of melting point 263-266C (decomposition).
9.8 g of 1,3-dihydro-5-(2'-pyridyl)-2H-thieno[2,3-e]-1,4-diazepin~
-2-one are dissolved in 350 ml of acetic acid and treated dropwise at room temperature with stirring with a solution of 8.0 g of sulphuryl chloride in 20 ml of acetic acid. After completion of the addition, the mixture is stirred for a further 15 hours. The separated yellow solid material is filtered under a vacuum, dissolved in water and the solution neutralised with sodium bicarbonate. The yellow-green solid material which separates is filtered under a vacuum, washed with water and dried. After crystallization from ethanol, there is obtained 7-chloro-1,3-dihydro-5-(2-pyridyl)-2H-thieno-~2,3-e]-1,4-diazepin-2-one in the form of yellowish-green crystals of melting point 250-252C (decomposition).
3.5 g of 7-chloro-1,3-dihydro-5-(2-pyridyl)-2H-thieno[2,3-e]-1,4-diazepin-2-one are dissolved in 200 ml of diethyleneglycol dimethyl ether at 65C and stirred for 30 minutes with 5 g of finely triturated phosphorus pentasulphide. The solvent is then distilled off and the residue taken up in methy~lene chloride and shaken out three times uith water. The organic phase is dried and evaporated. The 7-chloro-1,3-dihydro-5-(2-pyridyl)-2H-thieno[2,3-e]~1,4]diazepine-2-thione is dissolved in 200 ml of methanol and boiled for 30 minutes with 6 g of acetyl hydrazine. The solvent is distilled off and the residue taken up in methylene chloride and shaken three times with water. The methylene chloride is distilled off and the crystalline residue digested with methanol. After crystallization from methanol, there is obtained 2-(2-acetylhydrazino)-7-chloro-5-(2-pyridyl)-3H-thieno[2,3-e]-1,4-diazepine of melting point 193-195C.
Example 6 3Q 0.35 g of 2-(2-acetylhydrazino)-7-chloro-5-(2,6-difluorophenyl)-3H-, thienoL2,3-e]-1,4-diazepine are distributed on a metal plate in as thin as possible a layer and maintained at 270C for 1 minute in a sand bath. The melt is taken up in methylene chloride and shaken three times with 0.1-N
hydrochloric acid in order to remove the starting material. The methylene chloride is distilled off and the product recrystallized from ethyl acetate containing active carbon. There is obtained 2-chloro-4-(2,6-difluorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazolo[4,3-a]Il,4]diazepine of melting point ` 185-l87C.
The starting material is prepared as follows:
0.06 g of 7-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-2H-thieno-~2,3-e]-1,4-diazepin-2-one are introduced into 25 ml of diethyleneglycol dimethyl ether and warmed to 85C. 0.85 g of finely triturated phosphorus pentasulphide are added to the solution which is then stirred for 35 minutes at 85C. The solvent is then evaporated under reduced pressure, the residue taken up in 80 ml of methylene chloride and shaken three times with water.
The organic phase is evaporated, the crude 7-chloro-5-~2,6-difluorophenyl)-1,3-dihydro-2H-thienol2,3-e]-1,4-diazepine-2-thione taken up in 20 ml of methanol and boiled under reflux for 40 minutes with 1 g of acetyl hydrazine.
The product which precipitates in crystalline form is filtered off under a vacuum and rinsed with methanol. In order to obtain further product, the mother liquor is evaporated, the residue taken up in methylene chloride and shaken out three times with 0.1-N hydrochloric acid. The hydrochloric acid phase is neutralised with sodium bicarbonate and shaken out with methylene chloride. The organic phase is dried and evaporated under reduced pressure.
The 2-(2-acetylhydrazino)-7-chloro-5-(2,6-difluorophenyl)-3H-thienoI2,3-e]-1, 4-diazepine thus-obtained melts at 257-260C after crystallization from methanol.
Example 7 ` Unpurified 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepine-2-thione, obtained from 5 g (0.0155 mol) of 7-chloro-1,3-dihydro-..

:, ' `~- '.-' . ' . :
; . . .
~ .. .. . . .

5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepin-2-one, is dissolved in 500 ml of methylene chloride and boiled under reflux for 15 hours with stirring with 15 g of sodium bicarbonate and 7 g of acetic hydrazide dimethylammonium chloride After filtration of the solid material, the solution is washed twice with 200 ml of water each time and dried over sodium sulphate. After evaporation of the solvent, the residue is triturated with ethyl acetate, whereupon 7-chloro-2-(2-dimethylglycylhydrazino)-5-(o-nitrophenyl)-3H-thieno-[2,3-e]~1,4]diazepine precipitates in crystalline form. The product obtained is boiled under reflux in 300 ml of dry butanol for 24 hours and, after evaporation of the solvent, triturated with ethyl acetate. After recrystal-lization from ethanol, there is obtained 2-chloro-9-dimethylaminomethyl-4-(o-nitrophenyl)-6H-thieno[3,2-f]-s-triazolo~4,3-a][1,4]diazepine as a colour-less product of melting point 234-236C.
Example 8 0.75 g of 2-chloro-4-(o-chlorophenyl)-6H-thienol3,2-f]-s-triazolo-' ~4,3-a]~1,4]diazepine-9-methanol are dissolved in 25 ml of absolute chloroform and there are added thereto 0.7 g of triethylamine and 0.6 g of methanesulpho-; chloride. The mixture is stirred for 2.5 hours at 25C, then washed twice with water and twice with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The resulting oily methanesulphonic acid ester of 2-chloro-4-~o-chlorophenyl)-6H-thieno~3,2-f]-s-triazolol4,3-a~1,4~-diazepine-9-methanol is dissolved in 10 ml of dimethylformamide and the solution added dropwise at 0-5C to a solution of 1 ml of liquid ammonia in 5 ml of dimethylformamide. The mixture is stirred for 2 hours at room temper-ature and then partitioned between saturated sodium chloride solution and meth~lene chloride. The organic phase is dried and evaporated and the residue recrystallized from ethanol. There is obtained 9-aminomethyl-2-chloro-4-(o-chlorophenyl)-6H-thieno~3,2-f]-s-triazolol4,3-a]~1,4]diazepine of melting point 190-192C.
3Q The following Examples illustrate pharmaceutical preparations con-.~ ~ .

~049009 taining the thienotriazolodiazepine derivatives provided by this invention:
Example A
Manufacture of suppositoriesper suppository 2-Chloro-4-(o-chlorophenyl)-9--methyl-6H-thieno[3,2-f]-s--triazolo[4,3-a][1,4]diazepine0.010 g Cocoa butter ~melting point 36-37C) 1.245 g Carnauba wax 0.045 g Suppository weight: 1.3 g The cocoa butter and carnauba wax are melted in a glass or steel vessel, thoroughly mixed and cooled to 45C. Finely powdered 2-chloro-4-(o-chlorophenyl)-9-methyl-6H-thieno~3,2-f]-s-triazolo~4,3-a][1,4]diazepine - is then added and the mixture stirred until it is completely dispersed. The mixture is poured into suppository moulds of suitable size, allowed to cool, the suppositories then removed from the moulds and packed individually in wax paper or metal foil.
Example B
Manufacture of capsules per capsule ; 20 2-Chloro-4-(o-chlorophenyl)-9- --methyl-6H-thienoI3,2-f]-s--triazoloI4,3-a]Il,4]diazepine10 mg Lactose 165 mg Maize starch 30 mg Talc 5 mg Total capsule content 210 mg ,' :', ~ , 1 The 2-chloro-4-(o-chlorophenyl)-9-methyl-6H-thienol3,2-f]-s-tria-zolol4,3-a~l1,4]diazepine, lactose and maize starch are first mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer, :.

.
.:, - - , ,- :

,~ : , - :

~049009 the talc added and thoroughly mixed. The mixture is mechanically filled into hard gelatine capsules.

Example C

Manufacture of an injection solution per ml 2-Chloro-4-(o-chlorophenyl)-9--methyl-6H-thieno[3,2-f]-s--triazolo[4,3-a][1,4]diazepine5.0 mg Propyleneglycol 0.4 ml Benzyl alcohol (benzaldehyde-free)0.015 ml Ethanol (95%) 0.10 ml Sodium benzoate 48.8 mg Benzoic acid 1.2 mg Water for injection q.s. ad 1.0 ml , For the manufacture of 10,000 ml of an injection solution, 50 g of 2-chloro-4-(o-chlorophenyl)-9-methyl-6H-thieno~3,2-f]-s-triazolo[4,3-s]~1,4]-diazepine are dissolved in 150 ml of benzyl alcohol and there are added thereto 4000 ml of propyleneglycol and 1000 ml of ethanol. 12 g of benzoic acid are then dissolved in the foregoing mixture and a solution of 488 g of sotium benzoate in 300 ml of water (for injection) is added. The solution obtained is made up to a volume of 10,000 ml by the addition of water ~for injection), filtered and filled into ampoules of a suitable size; the remain-ing volume of the ampoules is filled with nitrogen, the ampoules are heat-sealed and sterilised for 30 minutes in an autoclave at 0.7 atmospheres.

. ~ .

; - 21 -~,,,~;,.
:.; - , , , ; , ' . ' ,

Claims (23)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing thienotriazolodiazepine derivatives of the general formula (I) wherein R1 represents a halogen atom, R2 represents a phenyl, o-trifluoro-methylphenyl, o-halophenyl, o,o'-dihalophenyl or o-nitrophenyl group or a pyridyl or thienyl group and R4 represents a hydrogen atom or an alky group or a group of the formula -alkyl-Z, in which Z represents the grouping -N(R5)(R6) wherein R5 and R6 each independently represent a hydrogen atom or an alkyl group and pharmaceutically acceptable acid addition salts there-of, which process comprises a) cyclising a compound of the general formula (II) wherein R1, R2 and R4 have the significance given above, or b) cyclising a compound of the general formula (III) wherein R1, R2 and R4 have the significance given above, or c) halogenating a compound of the formula IA
wherein R2 and R4 have the significance given earlier, or d) for the manufacture of a compound of formula I in which R4 represents a group of the formula -alkyl-Z in which Z has the significance given earlier, reacting a corresponding compound which carries a group of the formula -alkyl-A in place of R4 with a compound of the general formula BR; in which formulae one of the symbols A and B represents the grouping -NH-R5 in which R5 has the significance given earlier and the other symbol represents a leaving atom or group and R represents an alkyl group, provided that, when the symbol B
represents the grouping -NH-R5, R can also represent a hydrogen atom and where steps a) to d) may be followed by the step of e) converting a compound of formula I obtained into a pharmaceutically acceptable acid addition salt.

2. A process according to claim 1, wherein R4 represents an alkyl or aminoalkyl group.

3. A process according to claim 2, wherein R4 represents a methyl group.

4. A process according to claim 1, wherein R2 represents an o-halo-phenyl, o,o'-dihalophenyl or 2-pyridyl group.

5. A process according to claim 4, wherein R2 represents an o-chloro-phenyl, o-fluorophenyl or o,o'-difluorophenyl group.

6. A process according to any one of claims 1 to 3, wherein R1 represents a chlorine atom, R2 represents an o-chlorophenyl or o-fluorophenyl group and R4 represents a methyl group.

7. A process as claimed in claim 1, wherein 2-(2-acetylhydrazino)-7-chloro-5-(o-chlorophenyl)-3H-thienol2,3-e]-1,4-diazepine is cyclised.

8. A process as claimed in claim 1, wherein 2-(2-acetylhydrazino)-7-chloro-s-(o-fluorophenyl)-3H-thieno[2,3-e]-1,4-diazepine is cyclised.

9. A process as claimed in claim 1, wherein 2-(2-acetylhydrazino)-7-chloro-5-(2-pyridyl)-3H-thieno[2,3-e]-1,4-diazepine is cyclised.

10. A process as claimed in claim 1, wherein 2-(2-acetylhydrazino)-7-chloro-5-(2,6-difluorophenyl)-3H-thieno[2,3-e]-1,4-diazepine is cyclised.

11. A process as claimed in claim 1, wherein 7-chloro-2-(2-dimethyl-glycylhydrazino)-5-(o-nitrophenyl)-3H-thienol2,3-e][1,4]diazepine is cyclised.

12. A process as claimed in claim 1, wherein the methanesulphonic acid ester of 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]-diazepine-9-methanol is reacted with ammonia.

13. Thienotriazolodiazepine derivatives of the general formula (I) wherein R1 represents a halogen atom, R2 represents a phenyl, o-trifluoro-methylphenyl, o-halophenyl, o,o'-dihalophenyl or o-nitrophenyl group or a pyridyl or thienyl group and R4 represents a hydrogen atom or an alkyl group or a group of the formula -alkyl-Z, in which Z represents the grouping -N(R5)(R6) wherein R5 and R6 each independently represent a hydrogen atom or an alkyl group and pharmaceutically acceptable acid addition salts there-of, whenever prepared according to the process claimed in claim 1 or by an obvious chemical equivalent thereof.

14. Thienotriazolodiazepine derivatives according to claim 13, where in R4 represents an alkyl or aminoalkyl group, whenever prepared according to the process claimed in claim 2 or by an obvious chemical equivalent thereof.

15. Thienotriazolodiazepine derivatives according to claim 13, wherein R4 represents a methyl group, whenever prepared according to the process claimed in claim 3 or by an obvious chemical equivalent thereof.

16. Thienotriazolodiazepine derivatives according to claim 13, wherein R2 represents an o-halophenyl, o,o'-dihalophenyl or 2-pyridyl group, whenever prepared according to the process claimed in claim 4 or by an obvi-ous chemical equivalent thereof.

17 Thienotriazolodiazepine derivatives according to claim 13 wherein R2 represents an o-chlorophenyl, o-fluorophenyl or o,o'-difluorophenyl group, whenever prepared according to the process claimed in claim 5 or by an obvious chemical equivalent thereof.

18. 2-Chloro-4-(o-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazolo-[4,3-a][1,4]diazepine, whenever prepared according to the process claimed in claim 7 or by an obvious chemical equivalent thereof.

19. 2-Chloro-4-(o-fluorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazolo-14,3-a][1,4]diazepine, whenever prepared according to the process claimed in claim 8 or by an obvious chemical equivalent thereof.

20. 2-Chloro-9-methyl-4-(2-pyridyl)-6H-thieno[3,2-f]-s-triazolol4,3-a]-[1,4]diazepine, whenever prepared according to the process claimed in claim 9 or by an obvious chemical equivalent thereof.

21. 2-Chloro-4-(o,o'-difluorophenyl)-9-methyl-6H-thieno[3,2-f]-s-tria-zolo[4,3-a][1,4]diazepine, whenever prepared according to the process claimed in claim 10 or by an obvious chemical equivalent thereof.

22. 2-Chloro-9-dimethylaminomethyl-4-(o-nitrophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, whenever prepared according to the process claimed in claim 11 or by an obvious chemical equivalent thereof.

23. 9-Aminomethyl-2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-tria-zolol4,3-a][1,4]diazepine, whenever prepared according to the process claimed in claim 12 or by an obvious chemical equivalent thereof.