FR2660311A1 - Process for the preparation of new thienotriazolodiazepine derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of thienotriazolodiazepine derivatives of formula: in which Y represents oxygen or sulphur and R represents various substituents, consisting - in reacting the thienotriazolodiazepine compound of formula A: with the appropriate R-N=C=Y derivative, - in then reacting the compound obtained with hydrazine hydrate and, finally, - in cyclising the compound thus obtained with triethyl orthoacetate.

Description

The present invention relates to a process for the preparation of novel thieno-triazolo-diazepine derivatives which are more particularly useful as anti-asthmatic, antiallergic and gastrointestinal protective agents.

dans laquelle Y représente l'oxygène ou le soufre et R représente - un groupement alcényle en chaîne droite ayant jusqu'à 5 atomes de carbone, - un groupement alcoyle en chaine droite ou ramifiée ayant jusqu'à 20 atomes de carbone ou cyclique ayant jusqu'à 6 atomes de carbone, - un groupement aralcoyle ou hétéro-aralcoyle dont la partie alcoyle est en chaine droite ou ramifiée et comporte jusqu'à 5 atomes de carbone, - un groupement phényle substitué par un ou plusieurs groupements alcoyles ou groupements alcoxy ayant jusqu'à 5 atomes de carbone, par un groupement phénoxy, par un groupement sulfonyle alcoylé ayant jusqu'à 5 atomes de carbone ou par des atomes de fluor, de chlore ou des groupements trifluorométhyle ou - un reste bicyclique condensé contenant un hétéro atome et - un groupement sulfonyle substitué par un phényle ou par un hétéro-aryl ou par un groupement bicyclique condensé, ainsi que de leurs sels thérapeutiquement acceptables.The invention relates more particularly to the preparation of the thieno-triazolo-diazepine derivatives corresponding to the general formula I

wherein Y represents oxygen or sulfur and R represents - a straight chain alkenyl group having up to 5 carbon atoms, - a straight or branched chain alkyl group having up to 20 carbon atoms or cyclic having up to to 6 carbon atoms, - an aralkyl or heteroaralkyl group whose alkyl part is straight or branched chain and has up to 5 carbon atoms, - a phenyl group substituted with one or more alkyl groups or alkoxy groups having up to 5 carbon atoms, with a phenoxy group, with an alkylated sulfonyl group having up to 5 carbon atoms or with fluorine, chlorine or trifluoromethyl groups or - a fused bicyclic residue containing a hetero atom and a sulfonyl group substituted with a phenyl or with a heteroaryl or with a fused bicyclic group, as well as with their therapeutically acceptable salts.

The prior art in the field of the present invention is illustrated in US Patent 4,621,083 (or B.E. 176,927) which discloses thienotriazolo-diazepine compounds having PAF antagonist activity.

These new compounds exhibit ten to one hundred times greater PAF antagonist activity than that described in the aforementioned patent and also greater efficacy.

sur un léger excès stoichiométrique du dérivé approprié
R-N=C=Y, dans lequel R et Y sont tels que définis précédemment, dans un solvant aprotique, au reflux pendant 1/2 heure à 24 heures, - à faire réagir, ensuite, sous circulation d'azote et dans un solvant aprotique, le composé obtenu de formule B

sur un léger excès stoichiométrique d'hydrate d'hydrazine, à une température comprise entre 0 C et la température ambiante, pendant 5 min à une heure et, finalement, - à effectuer, sous circulation d'azote et dans un solvant aprotique, la cyclisation du composé ainsi obtenu de formule C

avec quatre équivalents stoichiométriques d'orthoacétate triéthyle, à température ambiante, pendant 15 min à 3 heures, puis au reflux, pendant 1/2 à 5 heures. The preparation of the compounds according to the invention consists in reacting, under a nitrogen flow, the thieno-triazolo-diazepine compound of formula A

on a slight stoichiometric excess of the appropriate derivative
RN = C = Y, in which R and Y are as defined above, in an aprotic solvent, at reflux for 1/2 hour to 24 hours, then reacting under nitrogen circulation and in an aprotic solvent the compound obtained of formula B

on a slight stoichiometric excess of hydrazine hydrate, at a temperature of between 0 ° C. and room temperature, for 5 minutes to one hour and, finally, to carry out, under the circulation of nitrogen and in an aprotic solvent, the cyclization of the compound thus obtained of formula C

with four stoichiometric equivalents of orthoacetate triethyl, at room temperature, for 15 minutes to 3 hours, then at reflux for 1/2 to 5 hours.

The starting material of formula (A) is obtained by the following sequence of steps
I - (2-chloro) phenyl cyanomethyl ketone.

In a suitable reactor placed under nitrogen circulation at -70 ° C., 7 l of anhydrous THF and 115.9 g (1.36 mol) of previously dried cynoacetic acid are poured in. 1.715 g of anhydrous THF are added dropwise. ml (2.74 mol) of a 1.6 M solution of butyllithium in hexane while allowing the temperature to rise from -70 ° C. to 0 ° C. The reaction mixture is then stirred for one hour and then cooled with at -70 ° C., a solution of 120 g (0.685 mol) of 2-chlorobenzoyl chloride in 1 l of anhydrous THF is then gradually added thereto.

After allowing the mixture to stir for one hour at -70 ° C, the temperature is allowed to rise to -70 ° C to 0 ° C over one hour. 3 l of a 1N HCl solution are then added dropwise and, after stirring for a few minutes, the reaction mixture is extracted with chloroform. The organic phase is washed with a 10% aqueous sodium bicarbonate solution and then with a saturated sodium chloride solution and filtered.

After evaporation of the solvent, 135 g of a residue are collected, which is then crystallized in diisopropyl ether, filtered and then washed with hexane. 97.2 g (79%) of the desired compound are obtained.

II - Amino-2- (2-chlorobenzoyl) -3 - (ethoxycarbonyl) -6
tetrahydro-4,5,6,7-pyrido F3,4-b] thiophene.

In a 2 liter container equipped with a cooling system, 85.5 g (0.501 mol) of
N-carbethoxy-4-piperidone, 90 g (0.501 mol) of (I), 19.3 g (0.600 mol) of sulfur flower and 44.4 g (0.501 mol) of morpholine dissolved in 550 ml of methanol. The mixture is refluxed for one hour; after evaporation of 250 ml of the solvent, the desired compound precipitates. The precipitate is then separated, washed with ethanol and then with ethyl ether and dried. This gives 155.4 g (85%) of the desired compound.

III - (bromoacetamido) -2 - (2-chlorobenzoyl) -3 - (ethoxy)
carbonyl) -6-tetrahydro-4,5,6,7-pyrido F3,4-b]
thiophene.

In a 5 liter reactor equipped with appropriate means and a separating funnel, 2.5 l of chloroform and 146 g (0.400 mol) of (II) are poured. 87.7 g (0.43 mol) of bromoacetyl bromide contained in the separating funnel are then gradually added. The reaction mixture is stirred for one hour at room temperature and then washed with 300 ml of ice water. The organic phase is dried over anhydrous magnesium sulfate and filtered. The chloroform is then evaporated and the residue obtained taken up with ethanol: the desired product precipitates. It is then filtered, washed with ethanol, then with ethyl ether and dried. 184.6 g (95%) of the desired compound are obtained.

IV - (aminoacetamido) -2 - (2-chlorobenzoyl) -3 - (ethoxy)
carbonyl) -6-tetrahydro-4,5,6,7-pyrido 3,4-b]
thiophene.

In a 5 liter reactor equipped with a gas injector, 174.8 g (0.36 mol) of (III) and 3 liters of THF are poured. The suspension is cooled to 0 ° C. and gaseous ammonia, previously dried over potassium hydroxide, is then added.

The addition is conducted in 8 hours. (60 g of ammonia are absorbed). The mixture is then stirred overnight at 0 ° C. Then 2 liters of THF are evaporated under high vacuum, and 750 ml of ethyl acetate are added.

After decantation, the organic phase is washed first with 300 ml of a 10% sodium chloride solution, then three times with 300 ml of water, and dried over anhydrous magnesium sulfate. After filtration, the solvent is partially removed by rotary evaporator evaporation. The precipitate is kept overnight in the refrigerator.

After filtration, the precipitate is washed with ethyl ether and dried. This gives 119 g of the desired compound.

The mother liquors are concentrated and taken up with a mixture of 1.5 l of ethyl ether / THF (3/1 by volume). 14.6 g of the desired compound are obtained (yield 88%).

V - (2-chlorophenyl) -5 - (ethoxycarbonyl) -8-tetrahydro
6,7,8,9 - 3H-pyrido [4 ', 3': 4,5] thieno [3,2-fl]
diazepine-1,4-one-2.

In a 2 1 reactor equipped with stirring, cooling and heating means and placed under nitrogen circulation, 126.6 g (0.3 mol) of (IV) and 800 ml of pyridine are poured.

The reaction mixture is refluxed for 18 hours. After checking that all of the starting material had reacted, the pyridine was partially evaporated under reduced pressure and the oil (dark brown) thus obtained was dissolved in 1 liter of ethanol. The mixture is then cooled in an ice bath to give a precipitate which is filtered, washed with ethanol and diisopropyl ether. Yield 101.3 g (83.6%) of the title compound.

VI - Preparation of (2-chlorophenyl) -5 - (ethoxy)
carbonyl) -8-tetrahydro-6,7,8,9-3H-pyrido r4,3 ':
4.51 thieno [3,2-diazepine-1,4-thione-2.

In a three-liter receiver equipped with appropriate means, 93 g (0.230 mol) of (V) and 1.75 ml of pyridine are poured. After solubilization, phosphorus pentasulfide (56.3 g, 0.25 mol) was added and the reaction mixture was stirred for three hours at 80-85 ° C. Then the pyridine was evaporated and the resulting residue was taken up with water. The mixture is then extracted with methylene chloride, dried over anhydrous magnesium sulphate, filtered, evaporated and taken up in ethyl ether The product obtained is filtered and suspended in 700 ml of acetonitrile.

The mixture is heated at 60 ° C for 30 minutes and then cooled.

After filtration and washing with acetonitrile and then with ethyl ether, the residue is dried to give 80.2 g (83%) of the desired compound.

VII - Preparation of (2-chlorophenyl) -5-tetrahydro
6,7,8,9 - 3H-pyrido [4w, 3: 4,51thieno [3,2-f]
diazepine-1,4 thione-2.

In a two-liter reactor equipped with appropriate means, 71.4 g (0.17 mol) of (VI), 116 g (1.30 mol) of potassium hydroxide in the form of granules and one liter of an ethanol / water mixture (19/1 by volume). The reaction mixture is refluxed for 18 hours.

After verifying that all the starting materials had reacted, the ethanol was evaporated and the residue taken up in ice water. The mixture is then extracted twice with chloroform. The aqueous phase is acidified with acetic acid to pH 6.5, which is then adjusted to 7.5 by adding sodium bicarbonate. The precipitate is filtered, washed twice with water, twice with ethanol and once with ether and then washed under reflux with 500 ml of a dichloromethane / ethanol mixture (3/1 by volume) for 30 min. .

After filtration, washing with ethyl ether and drying under reduced pressure, 47.3 g of the desired compound are obtained (yield 80%).

The starting compound when Y = S is obtained by reacting the compound (V) with a deprotecting agent.

VIII - Preparation of (2-chlorophenyl) -5-tetrahydro
6,7,8,9, - pyrido [4 ', 3': 4,5] thieno [3,2-fl]
diazepine-1,4-one-2.

In a reactor equipped with heating means and placed under nitrogen circulation, 94.5 g (0.234 mol) of (V), 152.1 g (2.34 mol) of potassium hydroxide in the form of granules are poured into the reactor. (90%) and 900 ml of ethylene glycol monoethyl ether. The mixture is heated for one hour until the reflux temperature is reached, the reflux is then maintained for one hour. The solution is poured onto 1.2 kg of crushed ice and acidified with hydrochloric acid (d = 1.18) to pH 5.3, then potassium carbonate is added to bring the pH to 8. 3.

The solution is extracted three times with 500 ml of methylene chloride, the organic phase, washed with 450 ml of a 10% aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue obtained is taken up in ethyl ether, washed with ethyl ether and dried. 55.9 g of the desired compound are obtained (yield = 72%).

The invention will be better understood thanks to the description of the examples which follow.

EXAMPLE 1 (2-chloro-phenyl) -6 - [(methoxy) -4-phenylthiocarbamoyl] -9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (methoxy-4) phenyl
First step A -) B
Preparation of (2-chloro-phenyl) -5 - [(methoxy) -4-phenylthiocarbamoyl] -8-tetrahydro-6,7,8,9-3H-pyrido [4 ', 3': 4,5] thieno [3 , 2-f] diazepine-1,4 thione-2.

In a one-liter reactor equipped with stirring and cooling means and placed under nitrogen circulation, 40 g (0.115 mol) of (2-chloro-phenyl) -5-tetrahydro-6,7,8,9 are poured. 3H-pyrido [4 ', 3': 4,5] thieno [3,2-f] diazepine1,4-2 thione 93% and 500 ml of methanol.

18.5 ml (0.123 mol) of para-methoxy-phenyl isothiocyanate are then added to the orange suspension and refluxed for two hours. After checking that the starting material had reacted, the mixture was cooled, filtered and the residue was washed with ethanol, diisopropyl ether and then dried overnight at 65 ° C to give 49 g (83%). of the desired compound.

Second step B -) C
Preparation of (2-chloro-phenyl) -5 - [(methoxy) -4-phenylthiocarbamoyl] -8-hydrazino-2-tetrahydro-6,7,8,9-3Hpyrido [4 ', 3': 4,5] thieno [3,2-f] - 1,4-diazepine.

In a one-liter reactor equipped with stirring and cooling means and placed under nitrogen circulation, 40 g (0.078 mol) of (2-chloro-phenyl) -5 (4-methoxy) -8-phenylthiocarbamoyl are poured into the reaction vessel. tetrahydro-6,7,8,9-3H-pyrido [4 ', 3': 4,5] thieno [3,2-f] diazepine-1,4-thione-2 and 350 ml of tetrahydrofuran. The mixture is then cooled to 10 ° C. and 4.1 ml (0.081 mol) of hydrazine hydrate is added.The addition is carried out in 15 minutes to give a solution (reddish brown) with a fine dark precipitate. The mixture is filtered and then 9/10 of tetrahydrofuran are evaporated and 400 ml of absolute ethanol are added to the residue.The precipitation is carried out after priming and the mixture is stirred on an ice bath for one hour.

The precipitate obtained is filtered, washed with ethanol then with diisopropyl ether and dried overnight under reduced pressure at 65 ° C., to give 29.7 g of the desired compound. The residue obtained is taken up in ethanol, filtered, washed again with methanol and then with ethyl ether to give 4.5 g of the desired compound (yield 86%).

Third step C -) Compound sought
Preparation of (2-chloro-phenyl) -6 - [(methoxy) -4-phenylthiocarbamoyl] -9-tetrahydro-7,8,9,10-methyl-1H-pyrido [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4.

In a 1-liter reactor equipped with stirring and cooling means and placed under nitrogen circulation, 25.5 g (0.05 mol) of (2-chloro-phenyl) -5 [(methoxy) -4 2-phenylthiocarbamoyl] -8-hydrazino-2-tetrahydro-6,7,8,9-3H-pyrido [4 ', 3': 4,5] thieno [3,2-f] diazepine-1,4 and 500 ml of absolute ethanol. 37 ml (0.20 mol) of triethyl orthoacetate are then added. After 30 minutes, the solution turns red and refluxed for two hours (precipitation begins at 70 ° C).

The mixture is then cooled to 10 ° C. and the precipitate is filtered off, washed with methanol and then with ethyl ether and dried under reduced pressure at 90 ° C. to give 24.6 g (92%) of the desired compound.

The compounds of the following examples were prepared as described in Example 1 when Y = S. When
Y = 0, the reaction is also carried out in three stages under conditions analogous to those described in Example 1 but starting from the (2-chloro-phenyl) -5,7,8,8-tetrahydro-9H-pyridine [4 ', 3': 4,5] thieno [3,2-f] diazepin-1,4-one-2 [instead of (2-chlorophenyl) -5,6,7,8,6-tetrahydro 3H-pyrido [4 ', 3': 4,5] thieno [3,2-f] diazepine-1,4-thione-2] which is treated with the appropriate isocyanate instead of isothiocyanate.

EXAMPLE 2 (2-chloro-phenyl) -6- (4-methoxy) phenyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [ 3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (methoxy-4) phenyl
Mp: 197-204 ° C (Tottoli), pale beige powder.

EXAMPLE 3 (2-chlorophenyl) -6- (tert-butyl) -9-carbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3,2- f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = OR = terbutyl
Mp: 240-245 ° C (Tottoli), white powder.

EXAMPLE 4 (2-chloro-phenyl) -6- (tert-butyl) -9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3, 2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = terbutyl
Mp: 189 ° C (Tottoli), white powder.

EXAMPLE 5 (2-chloro-phenyl) -6- (hexadecyl) -9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3, 2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = hexadecyl
Mp: 168-170 ° C (Tottoli), amorphous white powder.

EXAMPLE 6 (2-chloro-phenyl) -6- (isopropyl) -9-carbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3, 2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = OR = isopropyl
Mp: 214 ° C (Tottoli); White powder
EXAMPLE 7 (2-chloro-phenyl) -6- (isopropyl) -9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3, 2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = isopropyl
Mp: 205-206 ° C (Tottoli), white powder.

EXAMPLE 8 (2-chloro-phenyl) -6- (3,9-trimethoxy) -9-phenylcarbamoyltetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5 ] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = OR = (3,4,5-trimethoxy) phenyl
Mp: 176-179 ° C (Tottoli), creamy white powder.

EXAMPLE 9 (2-chloro-phenyl) -6- (3,9-trimethoxy) -phenyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4 , 5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (3,4,5-trimethoxy) phenyl
Mp: 184 ° C (Tottoli), white powder.

EXAMPLE 10 (2-chloro-phenyl) -6- (4-tertbutyl) -9-phenyl-carbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [ 3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = OR = (terbutyl-4) phenyl
Mp 218-220 ° C (Tottoli); creamy white powder.

EXAMPLE 11: (2-chloro-phenyl) -6- (4-tertbutyl) phenyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (terbutyl-4-phenyl)
Mp: 225-226 ° C (Tottoli), white powder.

EXAMPLE 12 (2-chloro-phenyl) -6- (trifluoromethyl-2) -phenyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (trifluoromethyl-2) phenyl
Mp 179-180 ° C (Tottoli), white powder.

EXAMPLE 13 (2-chloro-phenyl) -6- (trifluoromethyl-3) -phenyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (trifluoromethyl-3) phenyl
Mp: 169-170 ° C (Tottoli), white powder.

EXAMPLE 14: (2-chloro-phenyl) -6- (trifluoromethyl-4) -phenyl-9-carbamoyltetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [ 3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = OR = (trifluoromethyl-4) phenyl
Mp: 212-217 ° C (Tottoli), pale beige powder.

EXAMPLE 15 (2-chloro-phenyl) -6- (trifluoromethyl-4) -phenyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (4-trifluoromethyl) phenyl
Mp: 178-180 ° C; White powder.

EXAMPLE 16 (2-chloro-phenyl) -6- (4-fluoro) -phenyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [ 3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (4-fluoro) phenyl
Mp 179-180 ° C (Tottoli), creamy white powder.

EXAMPLE 17 (2-chloro-phenyl) -6- (2,3-dichloro) -9-phenyl-carbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4 Y = OR = (2,3-dichloro) phenyl-
Mp: 200-204 ° C (Tottoli), white powder.

EXAMPLE 18 (2-chloro-phenyl) -6- (4-phenoxy) -phenyl-9-carbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = OR = (phenoxy-4) phenyl
Mp: 187-193 ° C (Tottoli); White powder.

EXAMPLE 19 (2-chloro-phenyl) -6- (o-methyl) phenethyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [ 3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (α-methyl) phenethyl
Mp: 210-214 ° C (Tottoli); White powder.

EXAMPLE 20 (2-chloro-phenyl) -6- (ss-methyl) phenethyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [ 3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (ss-methyl) phenethyl
Mp: 200 ° C (Tottoli), creamy white powder.

EXAMPLE 21: (2-chloro-phenyl) -6- (methylsulfonyl-4) -phenyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (methylsulfonyl-4) phenyl
Mp: 214-215 ° C (Tottoli), pale beige powder.

EXAMPLE 22 (2-chloro-phenyl) -6- (2,4-diterbutyl) phenyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5 ] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (2,4-diterbutyl) phenyl
Mp: 146-148 ° C (Tottoli), pale beige powder.

EXAMPLE 23: (2-chloro-phenyl) -6- (benzyl) -9-carbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3 , 2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = o R = benzyl
Mp: 246-249 ° C (Tottoli), creamy white powder.

EXAMPLE 24: (2-chloro-phenyl) -6- (furfuryl-2) -9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (furfuryl-2)
Mp: 174 ° C (Tottoli), pale yellow powder.

EXAMPLE 25 (2-chloro-phenyl) -6- (3-quinolyl) -9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (3-quinolyl)
Mp: 192-193 ° C (Tottoli), pale beige powder.

EXAMPLE 26 (2-chloro-phenyl) -6- (cyclohexyl) -9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3 , 2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = cyclohexyl
Mp 209-214 ° C (Tottoli); White powder.

EXAMPLE 27 (2-chloro-phenyl) -6-cyclohexyl-9-carbamoyl-tetrahydro-7,8,9,10-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] triazolone 1,2,4 [4,3-a] diazepine-1,4
Y = OR = cyclohexyl
Mp: 220 ° C (Tottoli); creamy white powder
EXAMPLE 28 (2-chloro-phenyl) -6-allyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] diazepine-1,4
Y = SR = allyl
Mp: 224-226 ° C (Tottoli); creamy white powder
EXAMPLE 29
(2-chlorophenyl) -6- (2,4-difluoro) -9-phenyl-carbamoyl-7,8,9,10-tetrahydro-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3, 2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = OR = (2,4-difluoro) phenyl
M: 245-250 ° C (Tottoli), white powder
EXAMPLE 30 (2-chloro-phenyl) -6- (phenylsulfonyl) -9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] ] 1,2,4-triazolo [4,3-a] diazepine-1,4
Y = SR = (phenylsulfonyl)
Mp: 205 ° C (Tottoli); White powder
EXAMPLE 31 (2-chloro-phenyl) -6- (2-furyl) -sulfonyl-9-thiocarbamoyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4,1,3,5] thieno [3,2] 1,2,4 [4,3-a] diazepine-1,4-triazolo
Y = SR = (2-furyl) sulfonyl
Mp: 222-226 ° C (Tottoli); pale beige powder
EXAMPLE 32 (2-chloro-phenyl) -6- (2-thienyl) -9-sulfonyl carbamoyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3', 4,5] thieno [3,2] 1,2,4 [4,3-a] diazepine-1,4-triazolo
Y = OR = (thienyl-2) sulfonyl
Mp: 233 ° C (Tottoli); White powder
EXAMPLE 33 (2-chloro-phenyl) -6- (2-pyrrolyl) -sulfonyl-9-thiocarbamoyl-tetrahydro-7,8,9,10-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3, 2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (2-pyrrolyl) sulfonyl
M: 211-213 ° C (Tottoli) white powder
EXAMPLE 34 (2-chloro-phenyl) -6- (3-pyridyl) -9-sulfonyl carbamoyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3, 2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4 Y = OR = (pyridyl-3) sulfonyl
M.p. 184-189 ° C (Tottoli), beige powder
EXAMPLE 35 (2-chloro-phenyl) -6- (4-quinolyl) -sulfonyl-9-thiocarbamoyl-tetrahydro-7, α, 9,10-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3, 2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = SR = (4-quinolyl) sulfonyl
Mp 240-253 ° C (Tottoli); White powder
EXAMPLE 36 (2-chloro-phenyl) -6- (4-morpholinyl) -9-carbamoyltetrahydro-7,8,9,10-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3, 2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4
Y = OR = (morpholinyl-4) sulfonyl
M: 207-211 ° C (Tottoli), white powder
TOXICOLOGY
The compounds according to the invention are not toxic in the mouse at a dose of 1 g / kg. By the IP route in the mouse, only the compounds of Examples 10, 17, 18 and 33 have an LD 50 of between 0, 4 and 1 g / kg and none of the others was toxic at 1 g / kg.

PHARNACOLOGIE
The pharmacological interest of the compounds according to the invention was established by the experiments summarized below: 1) Inhibition of platelet aggregation induced by
the PAF.

The experiment was conducted on New Zealand rabbits (male rabbits with an average weight of 5 kg) according to the method of
R.KINLOUGH. RATHBONE, JPCAZENAVE, M.PACKHAM and F.MUSTARD,
Lab. Invest.48,98,1980.

The determination is carried out at 57 ° C on an aggregometer
Cronolog Coultronics coupled to a chart recorder the results of these determinations (in molecular concentration) are reported in the central column of Table I.

2) Inhibition of the binding on benzodiazepine receptors.

The interest of the previous experiment depends on the results obtained in this experiment: since a compound according to the invention has a benzodiazepine structure, it is important to check whether the specific activity of the benzodiazepine does not appear in the dose where platelet aggregation is inhibited.

This experiment was therefore conducted according to the method of
MOHLER H. and RICHARD JG "Agonist and antagonist receptor interaction in vitro, Nature, vol 294, 763-765, 1981.

This experiment was conducted on rat brains incubated for 1H30 at 4 ° C using 3H-RO-15-4788 and 3H-RO-5-4864 (NEN) as tracers and RO-15-4788 and
RO-5-4864 as reference antagonist.

The results, in molecular concentration, are reported in the right column of Table I.

3) Action on bronchospasm induced by PAF.

Intravenous injection of PAF into anesthetized guinea pigs induces bronchoconstriction with leukopenia and thrombocytopenia according to the method described by S.DESQUAND, C.TOWAY, J.RANDON, V.LAGENTE, B.VILLAIN,
I.MARIDONNEAU-PARINI, A.ETIENNE, J.LEFORT, P.BRAQUET and
B.VARGAFTIG. in "Interference of BN 52021 (Ginkgolide B) with the effects of pyopulmonary PAF-acether in guinea pigs". Eur. J. Pharmacol., 83-95, 1986.

Male guinea pigs of Hartley strain (400-500 g) (Charles
River) anesthetized with urethane (2 g / kg IP), are then thracheotomized and submitted to forced breathing with a respiratory pump: 70-80 strokes / min, 1 ml of air / 100 g per stroke. A catheter is inserted into the jugular vein for injections and another into the carotid artery for blood collection. The initial resistance is kept constant under the pressure of 10 cm of water according to the Konzett and Rosser method and the excess air is measured with a UGO BASILE bronchospasm transducer and a GEMINI recorder.

The guinea pigs received an IV injection of pancuronium (Pavulon) to inhibit their spontaneous respiration.

The compounds according to the invention and the reference compound WEB 2086 (see the Boehringer patent cited above) were prepared in suspension in gummed water and administered orally one hour before stimulation with PAF.

Bronchoconstriction is determined by calculating the percentage of bronchoconstriction A x 100 in which A
B represents the bronchoconstriction induced in mm and B represents the maximum bronchoconstriction in mm.

The results are reported in Table II.

PRESENTATION - DOSAGE.

In human therapy, the compounds according to the invention are preferably administered orally. These most appropriate forms of administration are tablets or capsules. The usual dosage is 50 mg to 500 mg per day as appropriate.

The dosage unit is preferably 50 mg in combination with the appropriate excipients and agents.

TABLE IA

<tb> EXAMPLES <SEP> IC50 <SEP> Receptors <SEP> BDZ
<tb><SEP> 1 <SEP> 3.01 <SEP> 10-7 <SEP> 2 <SEP> 10-6
<tb><SEP> 2 <SEP> 1.27 <SEP> 10-7 <SEP> 7.7 <SEP> 10-5 <SEP>
<tb><SEP> 3 <SEP> 1.71 <SEP> 10-8 <SEP> 4.3 <SEP> 10-7
<tb><SEP> 4 <SEP> 8.82 <SEP> 10-9 <SEP> 1.35 <SEP> 10-7
<tb><SEP> 5 <SEP> 2.97 <SEP> 10-7 <SEP> 6.3 <SEP> 10-5
<tb><SEP> 6 <SEP> 2.35 <SEP> 10-8 <SEP> 6.6 <SEP> 10-5
<tb><SEP> 7 <SEP> 3.28 <SEP> 10-8 <SEP> 7 <SEP> 10-6 <SEP>
<tb><SEP> 8 <SEP> 1.15 <SEP> 10-8 <SEP> 1.5 <SEP> 10-6
<tb><SEP> 9 <SEP> 3,87 <SEP> 10-8 <SEP> 4,5 <SEP> 10-6 <SEP>
<tb><SEP> 10 <SEP> 8.8 <SEP> 10-9 <SEP> 5.25
<tb><SEP> 11 <SEP> 9.44 <SEP> 10-9 <SEP> 1.2 <SEP> 10-6
<tb><SEP> 12 <SEP> 1.71 <SEP> 10-7 <SEP> 3.5 <SEP> 10-6 <SEP>
<Tb>
TABLE IB

<tb> EXAMPLES <SEP> IC50 <SEP> Receptors <SEP> BDZ
<tb><SEP> 13 <SEP> 1.71 <SEP> 10-7 <SEP> 6.25 <SEP> 10-6
<tb><SEP> 14 <SEP> 1.5 <SEP> 10-7 <SEP> 7.05 <SEP> 10-5
<tb><SEP> 15 <SEP> 2.2 <SEP> 10-7 <SEP> 1.25 <SEP> 10-6
<tb><SEP> 16 <SEP> 6.4 <SEP> 10-8 <SEP> 7 <SEP> 10-7
<tb><SEP> 17 <SEP> 5.5 <SEP> 10-8 <SEP> 9.2 <SEP> 10-7
<tb><SEP> 18 <SEP> 3.3 <SEP> 10-8 <SEP> 8.6 <SEP> 10-7
<tb><SEP> 19 <SEP> 4.25 <SEP> 10-8 <SEP> 3.6 <SEP> 10-7
<tb><SEP> 20 <SEP> 6.17 <SEP> 10-9 <SEP> 7.2 <SEP> 10-7
<tb><SEP> 21 <SEP> 2.4 <SEP> 10-8 <SEP> 1.1 <SEP> 10-6
<tb><SEP> 22 <SEP> 3.66 <SEP> 10-7 <SEP> 6.3 <SEP> 10-7
<tb><SEP> 23 <SEP> 6.68 <SEP> 10-8 <SEP> 1.6 <SEP> 10-6
<tb><SEP> 24 <SEP> 4.8 <SEP> 10-8 <SEP> 6.5 <SEP> 10-7
<Tb>
TABLE IC

<tb> EXAMPLES <SEP> IC50 <SEP> Receptors <SEP> BDZ
<tb><SEP> 25 <SEP> 1.82 <SEP> 10-7 <SEP> 3.5 <SEP> 10-7
<tb><SEP> 26 <SEP> 5.33 <SEP> 10-8 <SEP> 4.1 <SEP> 10-6
<tb><SEP> 27 <SEP> 4.52 <SEP> 10-8 <SEP> 2 <SEP> 10-6
<tb><SEP> 28 <SEP> 9.05 <SEP> 10-9 <SEP> 1.4 <SEP> 10-7
<tb><SEP> 29 <SEP> 5.86 <SEP> 10-8 <SEP> 2.2 <SEP> 10-7
<tb><SEP> 30 <SEP> 1.1 <SEP> 10-8 <SEP> 6.3 <SEP> 10 <SEP> -7
<tb><SEP> 31 <SEP> 8,15 <SEP> 10-9 <SEP> 6,15 <SEP> 10-7
<tb><SEP> 32 <SEP> 6.66 <SEP> 10-8 <SEP> 4.33 <SEP> 10-6
<tb><SEP> 33 <SEP> 2,, 5 <SEP> 10 <SEP> -7 <SEP> 9.1 <SEP> 10-6
<tb><SEP> 34 <SEP> 1.0 <SEP> 10-7 <SEP> 4 <SEP> 10-5
<tb><SEP> 35 <SEP> 3,4 <SEP> 10-8 <SEP> 2,2 <SEP> 10-6
<tb><SEP> 36 <SEP> 6.10 <SEP> 10-9 <SEP> 7.25 <SEP> 10-6
<tb> TABLE II

<tb> Percentage <SEP> of
<tb> EXAMPLES <SEP> bronchoconstriction <SEP> Percentage <SEP> of <SEP> action
<tb> Cookies <SEP> 79 <SEP> + <SEP> 5.55
<tb> WEB <SEP> 2086 <SEP> 25.3 <SEP> + <SEP> 11.56 <SEP> *** <SEP> - <SEP> 68.0
<tb><SEP> 1 <SEP> 13 <SEP> + <SEP> 4.39 <SEP> *** <SEP> - <SEP> 83.5
<tb><SEP> 3 <SEP> 28.7 <SEP> + <SEP> 9.30 <SEP> *** <SEP> - <SEP> 63.7
<tb><SEP> s <SEP> 30.3 <SEP> + <SEP> 8.80 <SEP> *** <SEP> - <SEP> 61.6
<tb><SEP> 23.4 <SEP> + <SEP> 10.50 <SEP> *** <SEP> - <SEP> 70.4
<tb><SEP> 8 <SEP> 16.2 <SEP> + <SEP> 8.38 <SEP> * $ * <SEP><SEP> - <SEP> 79.5
<tb><SEP> 10 <SEP> 26.7 <SEP> + <SEP> 11.0 <SEP> *** <SEP> - <SEP> 66.2
<tb><SEP> 14 <SEP> 48.6 <SEP> + <SEP> 14.32 <SEP> ** <SEP> - <SEP> 38.5
<tb><SEP> 18 <SEP> 14.1 <SEP> + <SEP> 11.25 <SEP> *** <SEP><SEP> - <SEP> 81.8
<tb><SEP> 22 <SEP> 25.5 <SEP> + <SEP> 13.2 <SEP> *** <SEP> - <SEP> 67.7
<tb><SEP> 24 <SEP> 33.3 <SEP> + <SEP> 12.8 <SEP> *** <SEP> - <SEP> 57.9
<tb><SEP> 30 <SEP> 37.2 <SEP> + <SEP> 14.95 <SEP> *** <SEP> - <SEP> 52.9
<tb><SEP> 33 <SEP> 22.4 <SEP> + <SEP> 9.8 <SEP> *** <SEP> - <SEP> 71.7
<Tb>

Claims (1)

 CLAIM 1 ") Process for the preparation of thieno-triazolo-diazepine derivatives of formula

 wherein Y represents oxygen or sulfur and R represents - a straight chain alkenyl group having up to 5 carbon atoms, - a straight or branched chain alkyl group having up to 20 carbon atoms or cyclic having up to to 6 carbon atoms, - an aralkyl or heteroaralkyl group whose alkyl part is straight or branched chain and has up to 5 carbon atoms, - a phenyl group substituted with one or more alkyl groups or alkoxy groups having up to 5 carbon atoms, with a phenoxy group, with an alkylated sulfonyl group having up to 5 carbon atoms or with fluorine, chlorine or trifluoromethyl groups or - a condensed bicyclic hetero atom-containing residue and a sulfonyl group substituted with a phenyl or a heteroaryl or a fused bicyclic group, consisting in reacting, under nitrogen circulation, the derivative of thieno-triazolo-diazepine of formula A

 on a slight stoichiometric excess of the appropriate derivative RN = C = Y, in which R and Y are as defined above, in an aprotic solvent, at reflux for 1/2 hour to 24 hours, then reacting under nitrogen circulation and in an aprotic solvent the compound obtained of formula B

 on a slight stoichiometric excess of hydrazine hydrate, at a temperature between 0; C and the ambient temperature, for 5 minutes to one hour and finally - to perform, under nitrogen circulation and in an aprotic solvent, the cyclization of the compound thus obtained of formula C

 with four stoichiometric equivalents of triethyl orthoacetate at room temperature for 15 minutes to 3 hours and then at reflux for 1/2 to 5 hours.