IE900807A1 - Preparation of thieno-triazolo-diazepine derivatives - Google Patents

Abstract

This invention relates to a preparation process of the thieno-triazolo-diazepine derivatives of the formula: wherein Y stands for oxygene or sulphur and R stands for various substituents, consisting in reacting the 5 thieno-triazolo-diazepine compound of the formula A: on the appropriate R - N = Y derivative, then reacting the resulting compound on hydrazine-hydrate and, finally, cyclizing the compound thus obtained with triethylortoacetate.

Description

The present invention relates a preparation process of new derivatives of thieno-triazolo-diazepine which are more particularly interesting as anti-asthmatic, anti-allergic agent and gastro-intestinal protectors.

The invention more particularly relates to the preparation of thieno-triazolo-diazepine derivatives of the formula: wherein Y stands for oxygene or sulphur and R stands for - a lower straight alkenyl group up to Cs, - a straight or branched alkyl group up to C20, or cyclic up 10 to ce, - a aryl or hetero-aryl substituted straight or branched alkyl group up to cs, - a phenyl group substituted by one or several alkyl groups or lower alkoxy groups up to C5, a phenoxy group, a lower alkyl sulfonyl group up to C5, or fluorine or chlorine atoms, or trifluoromethyl groups or, - a condensed bicyclic rest containing an hetero-atom, - and a sulfonyl group substituted by phenyl or by hetero-aryl or by a condensed bicyclic group, and therapeutically acceptable salts thereof.

IE 90807 - 2 The prior art in the field of this invention, may be illustrated by US patent 4 621 083 (or E.P. 176 927) in which thieno-triazolo-diazepine having PAF-antagonistic activity are disclosed.

This new compound presents a PAF-antagonistic activity from ten to thousand times greater than this one of the diazepines disclosed in the above mentionned patent, and also a more potent effectiveness.

According to the invention, these compounds may be readily prepared by reacting, under nitrogen circulation, the thieno-triazolo-diazepine compound of the formula A: A. on a slight stoichiometric excess of the appropriate R - N = C = Y derivative, wherein R and Y are as defined above, in a protic solvent, under reflux for 1/2 to 24 hours, then reacting, under nitrogen circulation in an aprotic solvent, the resulting compound of the formula B: B.

IE 90807 - 3 on a slight stoichiometric excess of hydrazine-hydrate at a temperature between O’C and room temperature, for 5 mn to about one hour, and finally cyclizing, under nitrogen circulation in a protic solvent, the compound thus obtained of the formula C: with four stoichiometric equivalents of triethylortoacetate at a room temperature for 15 mn to 3 hours, and then under reflux for 1/2 to 5 hours.

The starting compound of the formula (A) can be prepared as 10 described in the following steps : I - (2-chloro)benzoylmethyl cyanide.

In an appropriate reactor placed under nitrogen circulation at - 70°C were poured 7 1 of anhydrous THF and 115.9 g (1.36 mol) of previously dried cyanoacetic acid. Then were thus added dropwise 1 715 ml (2.74 mol) of 1,6 M solution of butyllithium in hexane, while allowing temperature to rise from - 7O’C to O’C. The reactional mixture was then stirred for one hour.

IE 90807 Thereafter the reactional mixture was once more cooled at - 70“C and a solution of 120 g (0.685 mol) of chloro-2 benzoyle chloride in 1 1 of anhydrous THF, was added dropwise. After stirring for one hour at always - 70’C, the temperature was allowed to rise from - 70’C to 0’C for one hour. Then there was added dropwise 3 1 of IN HCl solution and after stirring for a few minutes, the reacted mixture was extracted by chloroform. The organic phase was washed with a 10 % aqueous sodium bicarbonate solution, then with a saturated sodium chloride solution, dried, filtered and the solvent was evaporated off to give 135 g of residue. The crystallization was effected by the addition of diisopropyl ether, and the product was filtered off, and washed with hexane to give 97.2 g of the title compound (Yield 79 %).

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

In a two litre-erlen fitted with a cooler, were poured 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 flower of sulfur and 44.4 g (0.501 mol) of morpholine, in 550 ml of methanol. The mixture was refluxed for one hour. After evaporation of 250 ml of solvent, the desired compound precipitates, was filtered off, washed with ethanol, then with diethyl ether and dried to yield 155.4 g (85 %) of the title compound.

IE 90807 III - 2-(bromoacetamido) - 3-(2-chlorobenzoyl) - 6-(ethoxycarbonyl) - 4,5,6,7,-tetrahydro—pyrido [3,4 - b] thiophene.

In a five litre-reactor fitted with appropriate means and with separating funnel, were poured 2.5 1 of chloroform and 146 g (0.400 mol) of (II). Then, 87.7 g (0.43 mol) of bromoacetylbromide contained in the separating funnel were added dropwise. The reactional mixture was stirred for one hour at room temperature, then washed with 3 00 ml of icy-water, and the organic phase was dried with anhydrous magnesium sulphate and filtered. The chloroform was evaporated off and the residue was treated with ethanol. The resulting precipitate was filtered off, washed with ethanol, then with diethyl ether, and dried to yield 184.6 g (95 %) of the title compound.

IV - 2-(cuninoacetamido) - 3 (2-chlorobenzoyl) - 6-(ethoxycarbonyl) - 4,5,6,7-tetrahydro-pyrido [3,4 - b] thiophene.

Cl IE 90807 - 6 In a five litre-reactor fitted with a gaz-injector were poured 174.8 g (0.36 mol) of (III) and 3 litres of THF. The suspension was cooled at O’C and then gazeous ammonia previously dried over potassium hydroxide was added. The addition was conducted in 8 hours. (60 g of ammonia were absorbed). The mixture was stirred overnight at O’C, then 2 litres of THF was evaporated off under reduced pressure, and 750 ml of ethyl acetate were added. After decantation, the organic phase was washed once with 3 00 ml of a 10 % sodium chloride solution, three times with 300 ml of water, and dried with anhydrous magnesium sulphate. After filtration, the solvent was partially evaporated off at rotavapor. The precipitate was allowed to stand overnight in refrigerator. After filtration, the precipitate was washed with diethyl ether and dried to give 119 g of the title compound.The remaining organic phase was concentrated and treated with a mixture of 1.5 1 of diethyl ether/THF (3/1 by volume) to give 14.6 g of the title compound (overall yield 88 %).

V - 5-(2-chlorophenyl) - 8-(ethoxycarbonyl) - 6,7,8,9- In a two litre-reactor fitted with stirring, cooling and warming means and placed under nitrogen circulation were poured 126.6 g (0.3 mol) (IV) and 800 ml of pyridine. The reaction mixture was refluxed for 18 hours. After having checked that all the starting material had reacted, the pyridine was partially evaporated at a rotavapor under reduced pressure.

E 90807 The obtained (dark brown) oil was dissolved with 1 litre of ethanol. After cooling in an ice-bath, there was obtained a precipitate which was filtered off, washed with ethanol and diisopropyloxide to yield 101.3 g (83.6 %) of the title compound.

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

In a three litre-reactor fitted with appropriate means, were poured 93 g (0.23 0 mol) of V and 1,75 1 of pyridine. After solubilization were added 56.3 g (0.25 mol) of phosphorus pentasulphur, and the reaction mixture was then stirred for three hours at 80-85 °C. Thereafter, the pyridine was evaporated off and the obtained residue treated with icy-water. The mixture was then extracted by methylene chloride, dried with anhydrous magnesium sulphate, filtered, evaporated and treated with diethyl-ether. Then the resulting product was filtered off, and treated with 700 ml of acetonitrile. The suspension was 0 heated at 60’C for 3 0 minutes and then allowed to cool. After filtration, and washing with acetronitrile, then with diethyl-ether, the residue was dried to yield 80.2 g (83 %) of the title compound.

IE 90807 VII - Preparation of 5-(2 chlorophenyl)-6,7,8,9 tetrahydro3H -pyrido [4*,3';4,5Ί thieno [3,2-f] 1,4 diazepine 2 thione In a two litre-reactor fitted with appropriate means, were 5 poured 71,4 g (0,17 mol) of (VI), 116 g (1,30 mol) of (85%) pelleted potassium hydroxide and 1 1 of a mixture of ethanol/water (19/1 by volume). The reaction mixture was refluxed for 18 hours. After having checked that all the starting material had reacted, ethanol was evaporated off and the residue treated with icy-water. The mixture was then extracted twice with chloroform. The aqueous phase was acidified at pH = 6,5 with acetic acid, and the pH was then ajusted at pH = 7,5 with addition of sodium bicarbonate. The precipitate was filtered off, washed twice with water, twice with ethanol and once with ether, and then washed under reflux with 500 ml of mixture of dichloromethane/ethanol (3/1 by volume) for 3 0 min. After filtration, washing with diethyl-ether and drying under reduced pressure, there was obtained 47,3 g of the title 0 compound (yield 80%) . Ε 90807 - 9 The starting compound wherein Y = S is obtained by reacting the compound (V) with a deprotecting agent.

VIII - Preparation of 5-(2-chlorophenyl) - 6,7,8, 9-tetrahydropyrido [4 *,31:4,5] thieno [ 3,2-f] 1,4-diazepine-2 one.

In a reactor fitted with warming means and placed under nitrogen circulation, were poured 94,5 g (0,234 mol) of (V), 152,1 g (2,34 mol) of pelleted 90% potassium hydroxide and 900 ml of ethylene glycol monoethylether. The mixture was warmed over one hour to reflux temperature and reflux was maintained for one hour. The solution was then added to 1,2 kg of cracked-ice and acidified with (d = 1,18) chlorhydric acid at pH 5,3. Then potassium carbonate was added to a juste pH at 8,3. The solution was then extracted three times with 500 ml of methylene chloride. The organic phase was washed with 450 ml of a 10% aqueous sodium chloride solution, dried with anhydrous magnesium sulphate, filtered and evaporated. The resulting residue was treated with diisopropyl-ether. After washing with diisopropylether and drying, there was obtained 55,9 g of the title compound (yield = 72%).

The invention will be better understood from description of the following examples: EXAMPLE 1 6-(2-chlorophenyl) - 9-[4-(methoxy)phenylthiocarbamoyl] 5 7,8,9,10-tetrahydro-l-methyl-4H-pyrido [ 4 ’,3 ' :4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = 4—(methoxy)phenyllst step A -) B: Preparation of: 5-(2-chlorophenyl) - 8-[(4-(methoxy)phenyl thiocarbamoyl] - 6,7, 8,9-tetrahydro-3H-pyrido [4',3':4,5] thieno [3,2-f] 1,4-diazepine-2-thione.

In a 1 litre-reactor fitted with stirring and cooling means and placed under nitrogen circulation, were poured 40 g (0,115 mol) of 5-(2-chlorophenyl) - 6,7,8,9 -tetrahydro-3H-pyrido [4',3':4,5] thieno [3,2-f] 1,4-diazepine-2-thione (93%) and 500 ml of methanol.

Thereafter 18,5 ml (0,123 mol) of para-methoxy-phenyl isothiocyanate were added to the orange suspension which was then refluxed for two hours. After having checked that all the starting material had reacted, the mixture was cooled. After filtration, the residue was washed with ethanol then with disopropyloxide, and dried overnight at 65’C to yield 49 g (83%) of the title compound. 2nd step B -) C: Preparation of: 5-(2-chlorophenyl)-8 - [4-(methoxy)pheny1thiocarbamoyl]-2-hydrazino - 6,7,8,9 tetrahydro-3H-pyrido [4',3':4,5] thieno [3,2-f] 1,4-diazepine.

IE 90827 - 11 In a 1 litre-reactor fitted with stirring and cooling means and placed under nitrogen circulation, were poured 40 g (0,078 mol) of 5-(2-chlorophenyl)-8- [4- (methoxy)phenylthiocarbamoyl] -6 , 7 , 8 , 9 tetrahydro-3H-pyrido [4',3':4,5] thieno [3,2-f] 1,4-diazepine-2 thione and 350 ml of tetrahydrofuran. Thereafter the mixture was cooled at 10°C, and 4,1 ml (0,081 mol) of hydrazine hydrate were added. The addition was conducted in 15 min. There was thus obtained a red-brown solution with a dark slight precipitate which was then filtered off. Thereafter 9/10 of tetrahydrofuran was evaporated off, and 400 ml of absolute ethanol were added to the residue. Precipitation occured after priming. The mixture was stirred on an ice-bath for 1 hour. The precipitate was then filtered off, washed with ethanol, then with diisopropyloxide, and dried overnight under reduced pressure at 65 “C to give 29,7 g of the title compound. The washing-liquors were concentrated and the resulting residue was treated with ethanol, filtered, washed with ethanol then with diethyl-ether to give 4,5 g of the title compound (overall yield 86%). 3rd step C -) Title compound: Preparation of 6-(2-chlorophenyl) - 9-[4-(methoxy)phenylthiocarbomoyl] - 7,8,9,10-tetrahydro-l-methyl-4H-pyrido [4',3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine.

In a 1 litre-reactor fitted with stirring and cooling means, and placed under nitrogen circulation, were poured ,5 g (0,05 mol) of 5-(2-chlorophenyl)-8-[4-(methoxy)phenylthiocarbamoyl]-2-hydrazino-6,7,3,9 tetrahydro -SHOO pyrido [4',3’:4,5] thieno [3,2-f] 1,4-diazepine and 500 ml of absolute ethanol. Then 37 ml (0,20 mol) of triethylorthoacetate were added. After 30 min, the solution became red, and was then refluxed for two hours (precipitation started at 70’C).

IE 90807 - 12 Thereafter the mixture was cooled to 10’C and the precipitate filtered off, washed with ethanol, then with diethyl-ether, and dried under reduced pressure at 90’C to yield 24,6 g (92%) of the title compound.

The following compounds have been prepared as described in example 1 when Y = S; when Y = 0, the reaction is also carried out in 3 steps in the same conditions as described in example 1 but starting with 5-(2-chlorophenyl) 6.7.8.9- tetrahydro - 3H - pyrido [4',3':4,5] thieno [3,2-f] 1,4-diazepine-2 one [instead of 5-(2-chlorophenyl)-6,7,8,9 tetrahydro - 3H - pyrido [4’,3':4,5] thieno [3,2-f] 1.4- diazepine - 2 thione] and reacting on the appropriate isocyanate derivative instead of the isothiocyanate derivative.

EXAMPLE 2 6-(2-chlorophenyl) - 9-(4-methoxy)phenylthiocarbamoyl7.8.9.10- tetrahydro-l-methyl 4H-pyrido [4’,3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = 0 R = (4-methoxy)phenyl20 EXAMPLE 3 6-(2-chlorophenyl) - 9-tertbutylcarbamoyl - 7,8,9,10-tetrahydro-l-methyl 4H-pyrido [4',3':4,5] thieno [3,2-f] 1.2.4- triazolo [4,3-a] 1,4-diazepine Y = O R = tertbutyl25 EXAMPLE 4 6-(2-chlorophenyl) - 9-tertbutylthiocarbamoyl - 7,8,9,10tetrahydro-l-methyl 4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = tertbutyl13 EXAMPLE 5 6-(2-chlorophenyl) - 9-hexadecylthiocarbamoyl - 7,8,9,10tetrahydro-l-methyl 4H-pyrido [4’,3':4,5] (thieno [3,2-f] 1.2.4- triazolo [4,3-a]) 1,4-diazepine Y = S R = hexadecyl EXAMPLE 6 6-(2-chlorophenyl) - 9-isopropylcarbamoyl - 7,8,9,10-tetrahydro-l-methyl 4H-pyrido [4',3':4,5] thieno [3,2-f] 1.2.4- triazolo [4,3-a] 1,4-diazepine 10 Y = 0 R = isopropylEXAMPLE 7 6-(2-chlorophenyl) - 9-isopropylthiocarbamoyl - 7,8,9,10tetrahydro-l-methyl 4H-pyrido [4',3’:4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = -isopropylEXAMPLE 8 6-(2-chlorophenyl) - 9-(3,4,5-trimethoxy)phenylcarbamoyl7,8,9,10-tetrahydro-l-methyl 4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = 0 R = (3,4,5-trimethoxy)phenylEXAMPLE 9 6-(2-chlorophenyl) - 9-(3,4,5-trimethoxy)phenylthiocarbamoyl - 7,8,9,10-tetrahydro-l-methyl 4H-pyrido [4',3’:4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = (3,4,5-trimethoxy)phenylIE 90807 - 14 EXAMPLE 10 6-(2-chlorophenyl) - 9-(4-tertbutyl)phenylcarbamoyl - 7,8, 9.10- tetrahydro-l-methyl 4H-pyrido [4',3’:4,5] thieno [3,2-fJ 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = 0 R = (4-tertbutyl)phenylEXAMPLE 11 6-(2-chlorophenyl) - 9-(4-tertbutyl) phenylthiocarbamoyl 7.8.9.10- tetrahydro-l-methyl 4H-pyrido [ 4 ', 3 ' : 4,5 ] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = (4-tertbutyl)phenylEXAMPLE 12 6-(2-chlorophenyl) - 9-(2-trifluoromethyl)phenylthiocarbamoyl - 7,8,9,10-tetrahydro-l-methyl 4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = (2-trifluoromethyl)phenylEXAMPLE 13 6-(2-chlorophenyl) - 9-(3-trifluoromethyl)phenylthiocarbamoyl - 7,8,9,10-tetrahydro-l-methyl 4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = (3-trifluoromethyl)phenylEXAMPLE 14 6-(2-chlorophenyl) - 9-(4-trifluoromethyl)phenylcarbamoyl7,8,9,10-tetrahydro-l-methyl 4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = 0 R = (4-trifluoromethyl)phenylIE 90807 - 15 EXAMPLE 15 6-(2-chlorophenyl) - 9-(4-trifluoromethyl)phenylthiocarbamoyl - 7,8,9,10-tetrahydro-l-methyl 4H-pyrido [4',3’:4,5] thieno (3,2-f] 1,2,4-triazolo (4,3-a] 1,4-diazepine Y = S R = (4-trifluoromethyl)phenylEXAMPLE 16 6-(2-chlorophenyl) - 9-(4-fluoro)phenylthiocarbamoyl 7,8,9,10-tetrahydro-l-methyl 4H-pyrido [4’,3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = (4-fluoro)phenylEXAMPLE 17 6-(2-chlorophenyl) - 9-(2,3-dichloro)phenylcarbamoyl 7,8,9,10-tetrahydro-l-methyl 4H-pyrido [4’,3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = 0 R = (2,3-dichloro)phenylEXAMPLE 18 6-(2-chlorophenyl) - 9-(4-phenoxy)phenylcarbamoyl - 7,8,9, 10-tetrahydro-l-methyl 4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = O R = (4-phenoxy)pheny1EXAMPLE 19 6-(2-chlorophenyl) - 9-(α-methyl)phenethylthiocarbamoyl 7,8,9,10-tetrahydro-l-methyl 4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = (α-methyl)phenethylIE 90807 - 16 EXAMPLE 20 6-(2-chlorophenyl) - 9-(^-methyl)phenethylthiocarbamoyl 7,8,9,10-tetrahydro-l-methyl 4H-pyrido [ 4 ', 3 ': 4,5 ] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y - S R = (^-methyl)phenethylEXAMPLE 21 6-(2-chlorophenyl) - 9-(4-methylsulfonyl)phenylthiocarbamoyl - 7,8,9,10-tetrahydro-l-methyl 4H-pyrido [4',3’:4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = (4-methylsulfonyl)phenylEXAMPLE 22 6-(2-chlorophenyl) - 9-(2,4-diterbutyl)phenylthiocarbamoyl - 7,3,9,10-tetrahydro-l-methyl-4H-pyrido [4 ’,3 ’:4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = (2,4-diterbutyl)phenylEXAMPLE 23 6-(2-chlorophenyl) - 9-benzylcarbamoyl-7, 8,9,10-tetrahydro-l-methyl-4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = 0 R = benzylEXAMPLE 24 6-(2-chlorophenyl) - 9-(2-furfuryl)thiocarbamoyl - 7,8,9, -tetrahydro-l-methyl-4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = s R = (2-furfuryl)17 EXAMPLE 25 6-(2-chlorophenyl) - 9-(3-quinolyl)thiocarbamoyl - 7,8,9, -tetrahydro-l-methyl-4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = (3-quinolyl)EXAMPLE 26 6-(2-chlorophenyl) - 9-cyclohexylthiocarbamoyl - 7,8,9,10tetrahydro-l-methyl-4H-pyrido [4',3’:4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = cyclohexylEXAMPLE 27 6-(2-chlorophenyl) - 9-cyclohexylcarbamoyl - 7,8,9, 10-tetrahydro-l-methyl-4H-pyrido [4’,3’:4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = 0 R = cyclohexylEXAMPLE 23 6-(2-chlorophenyl) - 9-allylthiocarbamoyl - 7,8,9,10-tetrahydro-l-methyl-4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = allylEXAMPLE 29 6-(2-chlorophenyl) - 9-(2,4-difluoro)phenylcarbamoyl - 7,8, 9,10-tetrahydro-l-methyl-4H-pyrido [ 4 ', 3 ' : 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = O R = (2,4-difluoro)phenylIE 90807 - 18 EXAMPLE 30 6-(2-chlorophenyl) - 9-(phenylsulfonyl)thiocarbamoyl 7,8,9,10-tetrahydro-l-methyl-4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = phenylsulfonylEXAMPLE 31 6-(2-chlorophenyl) - 9-(2-furyl sulfonyl)thiocarbamoyl 7.8.9.10- tetrahydro-l-methyl-4H-pyrido [4',3’:4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = 2-(furyl)sulfonyl EXAMPLE 32 6-(2-chlorophenyl) - 9-(2-thienyl sulfonyl)carbamoyl 7.8.9.10- tetrahydro—l-methyl-4H—pyrido [4’,3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = 0 R = 2-(thienyl)sulfonyl EXAMPLE 33 6-(2-chlorophenyl) - 9-(2-pyrrolyl sulfonyl)thiocarbamoyl 7.8.9.10- tetrahydro-l-methyl-4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = 2-(pyrrolyl)sulfonyl EXAMPLE 34 6-(2-chlorophenyl) - 9-(3-pyridyl sulfonyl)carbamoyl 7,8,9,10-tetrahydro-l-methyl-4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = 0 R = 3-(pyridyl)sulfonyl IE 90807 - 19 EXAMPLE 35 6-(2-chlorophenyl) - 9-(4-quinolyl sulfonyl)thiocarbamoyl 7,8,9,10-tetrahydro-l-methyl-4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = S R = 4-(quinolyl)sulfonyl EXAMPLE 36 6-(2-chlorophenyl) - 9-(4-morpholinyl sulfonyl)carbamoyl 7,8,9,10-tetrahydro-l-methyl-4H-pyrido [4 ’ ,3 ' :4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine Y = 0 R = 4-(morpholinyl)sulphonyl TOXICITY The compounds of the invention are not toxic on the mice per os at the dose of 1 g/kg. By the IP route on the mice, only the compounds of examples 10, 17, 18 and 3 3 presented a LD 50 comprised between 0.4 and 1 g/kg and all the other were not toxic at 1 g/kg.

PHARMACOLOGY Various pharmacological determinations have been made on these compounds ; they are summarized as follows : 1) Inhibition of platelet agregation induced by PAF This experimentation was conducted according to the method of R. KINLOUGH. RATHBONE, J.P. CAZENAVE, M. PACKHAM and F. MUSTARD, Lab. Invest. 48, 98, 1980. In this test, New Zealand rabbits were used (male New Zealand rabbits of an average weight of 5 kg).

IE 90807 - 20 The determinations are made on a chrono-log Coultronics agregometer, at 57’C coupled with a graphic recorder ; the results of these determinations (in molecular concentration) are reported on the table I on the central column. 2) Inhibition of the binding to benzodiazepine receptors The interest of the previous experimentation depends on the results obtained in this experimentation : as a compound of the invention has a benzodiazepine like structure, it is important to check whether the specific benzodiazepine activity would not appear at the dose where platelet agregation was inhibited.

Therefore, this experimentation has been conducted according to the method of MOHLER H. and RICHARD J.G.

Agonist and antagonist benzodiazepine receptor interaction in vitro, Nature, vol. 294, 763-765, 1981.

This experimentation was conducted on rat brains incubated 1 h 30 at 4’C using 3H-RO-15-1788 and 3H-RO-5-4864 (NEN) as tracers and RO-15-4788 and RO-5-4864 as reference antagonists.

The results in molecular concentration are reported in the table I, on the right hand column. 3) Action on the bronchospasm induced by the PAF The PAF intravenous injection in anaesthetized guinea-pigs induces a bronchoconstriction with a leucopeny and a thrombocytopeny, according to the method described in S. DESQUAND, C. TOUVAY, J. RANDON, V. LAGENTE, B. VILAIN, I. MARIDONNEAU-PARINI, A. ETIENNE, J. LEFORT, P. BRAQUET and B. VARGAFTIG. Interference of BN 52021 (Ginkolide B) with the bronchopulmonary effects of PAF-acether in the guinea-pig. Eur. J. Pharmacol. 127 : 83-95, 1986.

IE 90807 - 21 Male Hartley guinea-pigs (400-450 g) (Charles River) anaesthetized with urethane (2 g/kg IP), then are thracheotomized and submitted to a forced respiration with a breathing pump : 70-80 strokes/mm, 1 ml of air/100 g per stroke. A catheter is introduced in the jugular vein for the injections, an other is introduced in the carotic artery for blood takings. The initial resistance is kept constant under the pressure of 10 cm of water in accordance with the Konzett and Rossler method and the air In excess is measured with a transducor for bronchospasm UGO BASILE together with an enregistror GEMINI. The guinea-pigs had received an IV injection of pancuronium (Pavulon) to inhibit their spontaneous respiration.

The compound according to the invention and the reference compound WEB 2086 (see the above cited Boehringer patent) have been prepared as suspension in gummy water and administrated orally 1 hour before the stimulation by the PAF.

The bronchoconstriction is preparated by the calculation of the percentage of bronchoconstriction A 100 wherein A B stands for induced bronchoconstriction in mm and 3 stands for maximum bronchoconstriction in mm.

The results are reported on table II.

PRESENTATION - POSOLOGY In human therapy, the compounds of the invention are preferably administrated by oral route. Prefered forms of administration include tablets, gelatine capsules and the like. Usual posology is from 50 mg to 500 mg per diem according to the case. 0 Prefered unit dose is 50 mg, associated with appropriate carriers and agents.

IE 90807 TABLE I A EXAMPLESIC50 BDZ receptors 1 3.01 io-7 -> 10'6 2 1.27 io-7 7.7 IO5 3 1.71 io-8 4.3 ,o-7 4 8.82 10“9 1.35 io-7 5 2.97 .0-7 6.3 IO’5 6 2.35 IO'8 6.6 1 o-5 *7 / 3.28 10‘8 7 l io-6 3 1.15 io-8 1.5 10“6 9 3.37 io-8 4.5 1O'S 10 8.8 10’9 5.25 io6 1 1 9.44 io-9 1.2 io6 12 1.71 io*7 3.5 io’6 IE 90807 - 23 TABLE I B EXAMPLESIC50 BDZ receptors 13 1.71 io’7 6.25 o 1 O 14 1.5 io’7 7.05 !- in 1 O 15 . 2.2 io'7 1.25 IO'6 16 6.4 1 OO 1 O 7. 10-7 17 5.5 io'8 9.2 io_/ 18 3.3 io-8 8.6 io-7 19 4.25 io8 3.6 10-7 20 6.17 io'9 7.2 io-7 21 2.4 o 1 oo 1.1 <5 1 o 22 3.66 io-7 6.3 io-7 23 6.68 io-8 1.6 io-6 24 4.8 OO 1 o 6.5 10-7 IE 90807 - 24 TABLE I C EXAMPLESIC50 BDZ receptors 25 1.82 io-7 3.5 io’7 26 5.33 10-8 4.1 io-6 27 4.52 1O-S 2. io'0 28 9.05 σ\ 1 O 1.4 io-7 29 5.86 oo 1 O 2.2 io-7 1 30 1.1 io8 6.3 10-7 31 8.15 10'9 6.15 io7 32 6.66 io-8 4.33 O t o 33 2.05 io-7 9.1 io-6 34 1.0 10-7 4. io-·5 35 3.4 io-8 2.2 10-6 36 6.10 o 1 7.25 10-6 IE 90807 TABLE II Examples Percentage of bronchoconstriction Percentage of action Controls 79. 5.55 - WEB 2086 25.3 + 11.56 « «« - 68.0 1 13 -r 4.39 **♦ - 83.5 3 28.7 9.30 **· - 63.7 5 30.3 + 8.80 **· - 61.6 I ί 23.4 10.50 *** - 70.4 8 16.2 . 8.38 »♦* - 79.5 10 26.7 11.0 *** - 66.2 14 48.6 14.32 ** - 38.5 18 14,1 + 1 1.25 *♦» - SI.8 ί --- 4 22 25.5 13.2 *** - 67.7 24 33.3 + 12.8 - 57.9 30 37.2 14.95 « * * 1 - 52.9 33 22.4 + 9.3 - 71.7 IE 90807

Claims (2)

1. CLAIM 1) Preparation process of the thieno-triazolo-diazepine derivatives of the formula: wherein Y stands for oxygene or sulphur and R stands for 5 - a lower straight alkenyl group up to C s , - a straight or branched alkyl group up to C 20 , or cyclic up to C e , - a aryl or hetero-aryl substituted straight alkyl group up to C 5 , said aryl being optionnally methyl substituted, 10 - a phenyl group substituted by one or several alkyl groups or lower alkoxy groups up to C 5/ a phenoxy group, a lower alkyl sulfonyl group up to C 5 , or fluorine or chlorine atoms, or trifluoromethyl groups or, - a condensed bicyclic rest containing an hetero-atom, 15 - and a sulfonyl group substituted by phenyl or by hetero-aryl or by a condensed bicyclic group, consisting in reacting, under nitrogen circulation, the thieno-triazolo-diazepine compound of the formula A: IE 90807 on a slight stoichiometric excess of the appropriate R - N = C = Y derivative, wherein R and Y are as defined above, in a protic solvent, under reflux for 1/2 to 24 hours, then reacting, under nitrogen circulation in an 5 aprotic solvent, the resulting compound of the formula B: on a slight stoichiometric excess of hydrazine-hydrate at a temperature between 0‘C and room temperature, for 5 mn to about one hour, and finally cyclizing, under nitrogen circulation in a protic solvent, ’the compound thus obtained 10 of the formula C: with four stoichiometric equivalents of triethylortoacetate at a room temperature for 15 mn to 3 hours, and then under reflux for 1/2 to 5 hours. IE 90807 -282) Process according to claim 1, substantially as described herein by way of Example.

2. 3) Thieno-triazolo-diazepine derivatives as defined in claim 1 when prepared by a process according to claim 1 or 2.