CH680366A5 - - Google Patents

Description

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CH 680 366 A5

Description

The present invention relates to a process for the preparation of new derivatives of thieno-triazo-lo-diazepine which are more particularly advantageous as anti-asthmatic, anti-allergic agents and gastrointestinal protectants.

The invention relates more particularly to the preparation of thieno-triazolo-diazepine derivatives corresponding to the general formula I:

a straight or branched chain alkyl group having up to 20 carbon atoms or a cyclic group having up to 6 carbon atoms,

- an araicoyl or hetero-aralkyl group, the alkyl part of which is in a straight or branched chain and contains up to 5 carbon atoms,

- a phenyl group substituted by one or more alkyl groups or alkoxy groups having up to 5 carbon atoms, by a phenoxy group, by an alkylated sulfonyl group having up to 5 carbon atoms or by fluorine or chlorine atoms or trifluoromethyl groups or

- a condensed bicyclic residue containing a hetero atom and

- A sulfonyl group substituted by a phenyl or by a hetero-aryl or by a condensed bicyclic group, as well as their therapeutically acceptable salts.

The prior art in the field of the present invention is illustrated in American patent 4 621 083 (or B.E. 176 927) which describes compounds of the thieno-triazolo-diazepine type having PAF antagonist activity.

These new compounds exhibit a PAF antagonist activity ten to one hundred times greater than that described in the patent mentioned above and also greater efficiency.

The preparation of the compounds according to the invention consists in reacting, under nitrogen circulation, the thieno-triazolo-diazepine compound of formula A:

on a slight stoichiometric excess of the appropriate drift R-N = C = Y, in which R and Y are as defined above, in an aprotic solvent, at reflux for 1/2 hour to 24 hours,

to react, then, under nitrogen circulation and in an aprotic solvent, the compound obtained of formula B:

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CH 680 366 A5

on a slight stoichiometric excess of hydrazine hydrate, at a temperature between 0 ° C. and ambient temperature, for 5 min to one hour and, finally,

to carry out, under nitrogen circulation and in an aprotic solvent, the cyclization of the compound thus obtained of formula C:

I

NH,

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

The starting product of formula (A) is obtained by the following sequence of steps:

1 - 2-phenylphenyl cvanometh the ketone.

1

O

7 I of anhydrous THF and 115.9 g (1.36 mol) of previously dried cynoacetic acid are poured into a suitable reactor placed under a circulation of nitrogen at -70 ° C. 1715 ml (2.74 mol) of a 1.6 M solution of butyllithium in hexane are added dropwise, while allowing the temperature to rise from -70 ° C to 0 ° C. The reaction mixture is then placed under stirring for one hour and then cooled again to -70 ° C; a solution of 120 g (0.685 mol) of 2-chloro-benzoyl chloride in 1 l of anhydrous THF is then gradually added thereto. After having left the mixture under agitation for one hour at -70 ° C, the temperature is allowed to rise from -70 ° C to 0 ° C in one hour. 3 I 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 an aqueous 10% sodium bicarbonate solution and then with a saturated sodium chloride solution, and filtered. After evaporating-

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CH 680 366 A5

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

Il - Amino-2- (chloro-2 benzovle) -3- (ethoxvcarbonvD-6 tétrahvdro-4.5.6.7-pvrido r3.4-bl thiophene.

Cl

C, H

2 "5

. * Css 0

—Ori

1 V ^ No / nnh,

85.5 g (0.501 mol) of N-car-bethoxy-4-piperidone, 90 g (0.501 mol) of (I), 19.3 g are poured into a 2 I container fitted with a cooling system (0.600 mol) of flower of sulfur and 44.4 g (0.501 mol) of morpholine in solution in 550 ml of methanol. The mixture is brought to reflux 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 operation gives 155.4 g (85%) of the desired compound.

III - (bromoacetamido1-2-2-chloro-benzovlei-3-fethoxvcarbonvl) -6-tetrahvdro-4.5.6.7-pyrido f3.4-b thiophene.

2.5 I of chloroform and 146 g (0.400 mol) of (II) are poured into a 5 I reactor equipped with appropriate means and a separating funnel. 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, 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.

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CH 680 366 A5

(aminoacetamidoV2- (2-chloro benzovleì-3- (ethoxvcarbonvP-6-tetrahvdro-4.5.6.7-

IV-

pvrido T3.4-b1 thiophene.

C, HsO — C— 1

I

NH —C —CH2NH2

O

I

O

174.8 g (0.36 mol) of (III) and 3 I of THF are poured into a 5 I reactor fitted with a gas injector. The suspension is cooled to 0 ° C., then gaseous ammonia, previously dried over potassium hydroxide, is added. The addition is carried out in 8 hours (60 g of ammonia are absorbed). The mixture is then stirred overnight at 0 ° C. Then 2 I 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 evaporation on a rotary evaporator. The precipitate is kept overnight in the refrigerator. After filtration, the precipitate is washed with ethyl ether and dried. This operation gives 119 g of the desired compound. The mother liquors are concentrated and taken up with a mixture of 1.51 of ethyl ether / THF (3/1 by volume). 14.6 g of the desired compound are obtained (yield 88%).

V - (2-chloro-phenyl) -5- (ethoxvcarbonvn-8-tetrahvdro-6.7.8.9-3H-pyrido T4'.3 ':

4.51 thieno f3.2-fl diazepine-1.4 one-2.

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

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

C, HsO — C — 3

I

O

H

O

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CH 680 366 A5

VI - Preparation of Cchloro-2 phenvlei-5- (ethoxvcarbonv0-8-tétrahvdro-6.7.8.9-3H-pvrido l "4'.3 ': 4.51 thieno r3.2-fl diazepine-1.4 thione-2.

C, HsO— "C—"]

I

S y \

O

H

S

Into a reactor of 31 equipped with suitable means, 93 g (0.230 mol) of (V) and 1.75 ml of pyridine are poured. After solubilization, 56.3 g (0.25 mol) of phosphorus pentasulfide are added and the reaction mixture is stirred for 3 hours at 80-85 ° C. Then, the pyridine is evaporated and the residue obtained taken up with ice water. The mixture is then extracted with methylene chloride, dried over anhydrous magnesium sulfate, 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 min 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.

Vl - Preparation of (2-chloro phenyl V5-tetrahvdro-6.7.8.9-3H-pvrido I4'.3 ': 4.51 thieno f3.2-fl diazene-1.4 thione-2.

71.4 g (0.17 mol) of (VI), 116 g (1.30 mol) of potassium hydroxide in the form of granules and 1 l of an ethanol / water mixture (19/1 by volume). The reaction mixture is brought to reflux for 18 hours. After verifying that all the starting materials have reacted, the ethanol is 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 deprotective agent.

H —1

H

S

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CH 680 366 A5

Vili - Preparation of / chloro-2 phenvlei-5-tetrahydro-6.7.8.9.-pvrido r4'.3 ': 4.51 thieno F3.2-fl diazepine-1.4 one-2.

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 a reactor equipped with heating means and placed under nitrogen circulation. (90%) and 900 ml of ethylene glycol monoethyl ether. The mixture is heated for one hour until reaching the reflux temperature, 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 bring it 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 an aqueous solution of sodium chloride at 10%, 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 research compound are obtained (yield = 72%).

The invention will be better understood from 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 = S, R = ( 4-methoxy) 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.

40 g (0.115 mol) of (2-chloro-phenyl) -5-tetrahydro-6,7,8 are poured into a one-liter reactor equipped with stirring and cooling means and placed under nitrogen circulation, 9-3H-pyrido [4 ', 3': 4.5] thieno [3,2-f] diazepine-1,4-2 thione at 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 the mixture is brought to reflux for 2 hours. After verifying that the starting material had reacted, the mixture is cooled, filtered and the residue is washed with ethanol, with 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-6,7,8,9-3H-pyrido [4 ', 3': 4,5j thieno [3,2-f] -diazepine-1,4.

40 g (0.078 mol) of (2-chlorophenyl) -5- (4-methoxy) phenyl-8 thiocarbamoyl are poured into a 1 l reactor equipped with stirring and cooling means and placed under nitrogen circulation. -tetra-hydro-6,7,8,9 3H-pyrido [4 ', 3': 4,5] thieno [3,2-f | -diazepine-1,4-thione-2 and 350 ml of tetrahydrofuran- born. 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. A solution (red-brown) is obtained with a fine dark precipitate, which is filtered. 9/10 of the tetrahydrofuran are then evaporated and 400 ml of absolute ethanol are added to the residue. Precipitation occurs after initiation. 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, which gives 29.7 g of the desired compound. The washing liquors are concentrated and the residue obtained is taken up in ethanol, filtered, washed again with ethanol and then with ethyl ether, which gives 4.5 g of the desired compound (yield 86%).

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CH 680 366 A5

Third step C-) Compound sought:

Preparation of (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.

25.5 g (0.05 mol) of (2-chloro-phenyl) -5 - [(methoxy) - are poured into a 1 l reactor equipped with stirring and cooling means and placed under nitrogen circulation. 4 phenylthiocarbamoyl] -8-hydra-zino-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. Then added 37 ml (0.20 mol) of triethyl orthoacetate. After 30 minutes, the solution turns red and is brought to reflux for 2 hours (precipitation begins at 70 ° C).

The mixture is then cooled to 10 ° C and the precipitate is filtered, washed with ethanol 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 = O, the reaction is also carried out in three stages under conditions analogous to those described in example 1 but from (2-chloro phenyi) -5-tetrahydro-6,7,8,9-3H-pyrido [4 ', 3': 4,5] thieno [3,2-f] -diazepine-1, 4 one-2 [instead of (2-chloro-phenyl) -5-tetrahydro-6,7, 8,9-3H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,4-diazepine-thione-2] which is treated with the appropriate isocyanate instead of isothiocyanate.

EXAMPLE 2:

(2-chloro phenyl) -6- (4-methoxy) 9-phenyl 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 = S, R = (4-methoxy) phenyl-

M.p .: 197-204 ° C (Tottoli); pale beige powder

EXAMPLE 3:

(2-chloro-phenyl) -6- (terbutyl) -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 = terbutyl-

M.p .: 240-245 ° C (Tottoli): white powder EXAMPLE 4:

(2-chloro-phenyl) -6- (terbutyl) -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 = S, R = terbutyl-

M.p .: 189 ° C (Tottoli); White powder

EXAMPLE 5:

(2-chloro-phenyl) -6- (hexadecyl) -9 thiocarbamoyI-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 = S, R = hexadecyl-

M.p .: 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 = O, R = isopropyl-

M.p .: 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 = S, R = isopropyl-

M.p .: 205-206 ° C (Tottoli); White powder

EXAMPLE 8:

(2-chloro-phenyl) -6- (trimethoxy-3,4,5) phenyl-9 carbamoyltétrahydro-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 = (3,4,5-trimethoxy) phenyl-

M.p .: 176—179 ° C (Tottoli); creamy white powder

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CH 680 366 A5

EXAMPLE 9:

(2-chloro-phenyl) -6- (trimethoxy-3,4,5) 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 = S, R = (3,4,5-trimethoxy) phenyl-m.p .: 184 ° C (Tottoli); White powder

EXAMPLE 10:

(2-chloro-phenyl) -6- (terbutyl-4) -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 = O, R = (4-terbutyl) phenyl-

M.p .: 218-220 ° C (Tottoli); creamy white powder

EXAMPLE 11:

(2-chloro phenyl) -6- (terbutyl-4) 9-phenyl 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 = S, R = (terbutyl-4) phenyl-

M.p .: 225-226 ° C (Tottoli); White powder

EXAMPLE 12:

(2-chloro-phenyI) -6- (trifluoromethyl-2) 9-phenyl thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3 , 2-1] triazolo-1,2,4 [4,3-a] diazepine-1,4

Y = S, R = (2-trifluoromethyl) phenyl-m.p .: 179-180 ° C (Tottoli); White powder

EXAMPLE 13:

(2-chloro-phenyl) -6- (trifluoromethyl-3) 9-phenyl 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 = S, R = (trifluoromethyl-3) phenyl-m.p .: 169-170 ° C (Tottoli); White powder

EXAMPLE 14:

(2-chloro-phenyl) -6- (trifluoromethyl-4) 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 = O, R = (trifluoromethyl-4) phenyl-

M.p .: 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 , 2-1] triazolo-1,2,4 [4,3-a] diazepine-1,4

Y = S, R = (trifluoromethyl-4) phenyl-m.p .: 178-180 ° C; White powder

EXAMPLE 16

(2-chloro-phenyl) -6- (fluoro-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 = S, R = (fluoro-4) phenyl-

M.p .: 17 & -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 = O, R = (2,3-dichloro) phenyl-

M.p .: 200-204 ° C (Tottoli); White powder

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CH 680 366 A5

EXAMPLE 18:

(2-chloro phenyl) -6- (phenoxy-4) phenyl-9 carbamoyl tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3, 2-f] triazoio-1,2,4 [4,3-a] diazepine-1,4

Y = O, R = (phenoxy-4) phenyl-

M.p .: 187—193 ° C (Tottoli); White powder

EXAMPLE 19:

(2-chloro-phenyl) -6- (a-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 = S, R = (a-methyl) phenethyl-

M.p .: 210-214 ° C (Tottoli); White powder

EXAMPLE 20:

(2-chloro phenyl) -6- (p-methyl) phenethyl-9 thiocarbamoyl-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3': 4,5] thieno [3 , 2-1] triazolo-1,2,4 [4,3-a] diazepine-1,4

Y = S, R = (p-methyl) phenethyl-

M.p .: 200 ° C (Tottoli); creamy white powder

EXAMPLE 21:

(2-chloro-phenyl) -6- (4-methylsulfonyl) 9-phenyl thiocarbamoyI-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 = S, R = (methylsulfonyl-4) phenyl-

M.p .: 214-215 ° C (Tottoli); pale beige powder

EXAMPLE 22:

(2-chloro-phenyl) -6- (2,4-diterbutyl) 9-phenyl 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 = S, R = (2,4-diterbutyl) phenyl-

M.p .: 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-

M.p .: 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 = S, R = (furfuryl-2) -

M.p .: 174 ° C (Tottoli); pale yellow powder

EXAMPLE 25:

(2-chloro-phenyl) -6- (quinolyl-3) -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 = S, R = (quinolyi-3) -

M.p .: 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 = S, R = cyclohexyl-Mp: 209-214 ° C (Tottoli); White powder

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CH 680 366 A5

EXAMPLE 27:

(2-chloro-phenyl) -6-cyc! ohexyl-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 = cyclohexyl-

M.p .: 220 ° C (Tottoli): creamy white powder

EXAMPLE 28:

(2-chloro-phenyl) -6-allyl-9 thiocarbamoyl-tetrahydro-7,8,9,10 methyl-1 4H-pyrido [4 ', 3': 4,5] thieno [3,2-1] triazolo- 1,2,4 [4,3-a] 1,4-diazepine

Y = S, R = aliyl-

M.p .: 224-226 ° C (Tottoli): creamy white powder EXAMPLE 29:

(2-chloro-phenyl) -6- (2,4-difluoro) 9-phenyl carbamoyl-tetrahydro-7,8,9,10 methyl-1 4H-pyrido [4 ', 3': 4,5] thieno [3 , 2-1] triazolo-1,2,4 [4,3-a] diazepine-1,4

Y = O, R = (2,4-difluoro) phenyl-

M.p .: 245—250 ° C (Tottoli): white powder

EXAMPLE 30:

(2-chloro-phenyl) -6- (phenylsulfonyl) -9 thiocarbamoyl-tetrahydro-7,8,9,10 methyl-1 4H-pyrido [4 ', 3': 4,5] thieno [3,2-1] triazolo-1,2,4 [4,3-a] diazepine-1,4

Y = S, R = (phenylsulfonyl) -

M.p .: 205 ° C (Tottoli); White powder

EXAMPLE 31:

(2-chloro-phenyl) -6- (furyl-2) -9-sulfonyl-thiocarbamoyl-tetrahydro-7,8,9,10 methyl-1 4H-pyrido [4 ', 3': 4,5] thieno [3,2 -1] triazolo-1,2,4 [4,3-a] diazepine-1,4

Y = S, R = (furyl-2) sulfonyl-

M.p .: 222-226 ° C (Tottoli); pale beige powder

EXAMPLE 32:

(2-chloro-phenyl) -6- (2-thienyl) 9-sulfonyl-carbamoyl-tetrahydro-7,8,9,10 methyl-1 4H-pyrido [4 ', 3: 4,5] thieno [3,2- 1] triazolo-1,2,4 [4,3-a] diazepine-1,4

Y = O, R = (2-thienyl) sulfonyl-

M.p .: 233 ° C (Tottoli); White powder

EXAMPLE 33:

(2-chloro-phenyl) -6- (pyrrolyl-2) sulfonyl-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 = S, R = (2-pyrrolyl) sulfonyl-

M.p .: 211-213 ° C (Tottoli); White powder

EXAMPLE 34:

(2-chloro-phenyl) -6- (3-pyridyl) sulfonyl-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 = (pyridil-3) sulfonyl-

M.p .: 184-189 ° C (Tottoli); beige powder

EXAMPLE 35

(2-chloro-phenyl) -6- (quinolyl-4) -9-sulfonyl 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 = S, R = (quinolyI-4) sulfonyl-

M.p .: 240-253 ° C (Tottoli); White powder

11

5

10

15

20

25

30

35

40

45

50

55

CH 680 366 A5

EXAMPLE 36:

(2-chloro-phenyl) -6- (morpholinyl-4) sulfonyl-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 = (morphoIinyl-4) sulfonyl-Mp: 207-211 ° C (Tottoli); White powder

TOXICOLOGY

The compounds according to the invention are not toxic to mice at a dose of 1 g / kg. By the IP route in the mouse, only the compounds of Examples 10, 17, 18 and 33 exhibited an LD 50 of between 0.4 and 1 g / kg and none of the others was toxic at 1 g / kg.

PHARMACOLOGY

The pharmacological interest of the compounds according to the invention has been established by the experiments summarized below:

1Ì Inhibition of the aggregation of platelets induced by PAF.

The experiment was carried out on New Zealand rabbits (male rabbits with an average weight of 5 kg) according to the method of R. KINLOUGH. RATHBONE, J.P. CAZENAVE, M. PACKHAM and F. MUSTARD, Lab. In-vest. 48, 98.1980.

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

2) Inhibition of bindino on benzodiazepine receptors.

The interest of the previous experiment depends on the results obtained in this experiment: given that 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 at the dose or platelet aggregation is inhibited.

This experiment was therefore carried out according to the method of MÖHLER H. and RICHARD J.G. "Agonist and antagonist receptor interaction in vitro", Nature, vol. 294.763-765.1981.

This experiment was carried out on the brains of rats incubated for 1 h 30 min 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 a reference antagonist.

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

3) Action on the PAF-induced bronchospasm.

The intravenous injection of PAF in anesthesia guinea pigs induces bronchoconstriction with leukopenia and thrombocytopenia according to the method described by S. DESQUAND, C. TOUVAY, 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 brochopulmonary effects of PAF-acether in guinea pigs". Eur. J. Pharmacol. 127: 83-95.1986.

Male Hartley guinea pigs (400-500 g) (Charles River) anesthetized with urethane (2 g / kg PI), are then thracheotomized and subjected 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 samples. The initial resistance is kept constant under the pressure of 10 cm of water according to the Konzett and Rössler method and the excess air is measured with a UGO BASILE bronchospasm transducer and a GEMINI recorder. The guinea pigs had received an IV injection of pancuronium (Pavulon) to inhibit their spontaneous breathing.

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

The bronchoconstriction is determined by calculating the percentage of bronchoconstriction A X 100 in which A represents the induced bronchoconstriction in mm and B represents the bron-

B

maximum choconstriction in mm.

The results are reported in Table II.

12

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 680 366 A5

PRESENTATION - DOSAGE.

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

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

Table IA

Examples

CI50

BDZ receivers

1

3.01

10 ~ 7

. 2

10 "6

2

1.27

10 ~ 7

7.7

10 ~ 5

3

1.71

10 "8

4.3

10 ~ 7

4

8.82

10 "9

1.35

10 ~ 7

5

2.97

10 ~ 7

6.3

10 ~ 5

6

2.35

10 "8

6.6

10 ~ 5

7

3.28

10 "8

7

10 "6

8

1.15

10 "8

1.5

10 "6

9

3.87

10 "8

4.5

10 "6

10

8.8

10 "" 9

5.25

10 "6

11

9.44

10-9

1.2

10 "6

12

1.71

10 ~ 7

3.5

10 "6

Table IB

Examples

CI50

BDZ receivers

13

1.71

10 ~ 7

6.25

10-6

14

1.5

10-7

7.05

10-5

15

2.2

10 "7

1.25

10 "6

16

6.4

10 "8

7

10 ~ 7

17

5.5

10 "8

9.2

10 ~ 7

18

3.3

10 "8

8.6

10 ~ 7

19

4.25

10 "6

3.6

10 "7

20

6.17

10 "9

7.2

10 "7

21

2.4

10 "6

1.1

10 "6

22

3.66

10 ~ 7

6.3

10 ~ 7

23

6.68

10 "8

1.6

10 "6

24

4.8

10 "8

6.5

10 "7

13

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 680 366 A5

Table IC

Examples

Clso

BDZ receivers

25

1.82

10 "7

3.5

10 ~ 7

26

5.33

10 "8

4.1

10 "6

27

4.52

10-8

2

10 "6

28

9.05

10-9

1.4

10 ~ 7

29

5.86

10 "8

2.2

10 ~ 7

30

1.1

10 "8

6.3

10 ~ 7

31

8.15

10 "9

6.15

10 "7

32

6.66

10 "8

4.33

IO "6

33

2.05

10 ~ 7

9.1

10 "6

34

1.0

10 ~ 7

4

10.5

35

3.4

IO "8

2.2

10 "6

36

6.10

10 "9

7.25

10-6

Table II

Examples

Percentage of bronchoconstriction

Percentage of action

Witnesses

79 ± 5.55

-

WEB 2086

25.3+ 11.56 ***

-68.0

1

13 ± 4.39 ***

-83.5

3

28.7+ 9.30 ***

-63.7

5

30.3+ 8.80 ***

-61.6

7

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 ± 11.25 ***

-81.8

22

25.5+ 13.2 ***

-67.7

24

33.3 ± 12.8 ***

-57.9

30

37.2+ 14.95 ***

-52.9

33

22.4 ± 9.8 ***

-71.7

Claims (1)

Claims 1. Process for the preparation of thieno-triazolo-diazepine derivatives of formula: 14 5 10 15 20 25 30 35 40 45 50 55 60 65 CH 680 366 A5 X R — NH— < in which 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 a cyclic group having up to 6 carbon atoms, - an aralkyl or heteroalkyl group, the alkyl part of which is in a straight or branched chain and contains up to 5 carbon atoms, - a phenyl group substituted by one or more alkyl groups or alkoxy groups having up to 5 carbon atoms, by a phenoxy group, by an alkylated sulfonyl group having up to 5 carbon atoms or by fluorine or chlorine atoms or trifluoromethyl groups or - a condensed bicyclic residue containing a hetero atom, - And a sulfonyl group substituted by a phenyl or by a hetero-aryl or by a condensed bicyclic group, consisting in reacting, under nitrogen circulation, the thieno-triazolo-diazepine derivative of formula A: on a slight stoichiometric excess of the appropriate derivative R-N = C = Y, in which R and Y are as defined above, in an aprotic solvent, at reflux for 1/2 hour to 24 hours, to react, then, under nitrogen circulation and in an aprotic solvent, the compound obtained of formula B: AT. H Y 15 5 10 15 20 25 30 35 40 45 50 55 CH 680 366 A5 on a slight stoichiometric excess of hydrazine hydrate, at a temperature between 0 ° C. and ambient temperature, for 5 min to one hour and, finally, to carry out, under nitrogen circulation and in an aprotic solvent, the cyclization of the compound thus obtained of formula C: I NH, with four stoichiometric equivalents of triethyl orthoacetate, at room temperature, for 15 min to 3 hours, then at reflux, for 1/2 to 5 hours. 16