FR2661911A1 - Process for the preparation of thienotriazolodiazepine derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of thienotriazolodiazepine derivatives of general formula A (DRAWING CF IN BOPI) in which Y represents oxygen or sulfur and R represents various substituents, which consists in reacting the compound thieno-triazolo-diazepine of formula B (CF DRAWING IN BOPI) on the derivative RSCH2 COOH, then reacting the resulting compound with hydrazine hydrate, and finally cyclizing the compound thus obtained with thiorthoacetate to obtain the compound of formula A in which Y represents oxygen and, optionally, carry out a sulfurization reaction to obtain the corresponding compound of formula A in which Y represents a sulfur atom.

Description

The present invention relates to a process for the preparation of novel

  thieno-triazolo-diazepine derivatives which are of particular interest as anti-ischemic, anti-asthmatic and antiallergic agents and, as gastrointestinal protectors The compounds of the present invention are more particularly of interest for the treatment

ischemia.

  The invention relates more particularly to a process for the preparation of the thieno-triazolo-diazepine derivatives of the general formula A ## STR2 ##

I S N

CH 3 4 N /

  Wherein Y represents oxygen or sulfur and R represents: a linear or branched alkyl group having up to carbon atoms, a phenyl group unsubstituted or substituted by a linear or branched alkyl group having up to atoms of carbon, an alkoxy group having up to 5 carbon atoms, a halogen atom, a trifluoromethyl group or an optionally substituted phenoxy group, or furan or thiophene

  and therapeutically acceptable salts derived therefrom.

  2 - According to the invention, these compounds can be easily prepared by treating the thieno-triazolo-diazepine compound of formula B o B. with a stochiometric amount of the derivative (C) RSCH 2 COOH in which R is as defined above, in an aprotic solvent, in the presence of a slight stoichiometric excess of dicyclocarbodiimide at a temperature between 0 ° C and 60 ° C, and then reacting the resulting compound of formula Cl -N

R-S-CH 2 -C-N =

| S N t

O I

H O

  D. with 3 to 5 stoichiometric equivalents of hydrazine hydrate, in a protic solvent, at a temperature between ambient temperature and 50 ° C and finally, by cyclizing in a protic solvent, the compound thus obtained of formula: 3 -

R-S-CH 2 -C-N

| S N

  With 1 to 3 stoichiometric equivalents of triorthoacetate, at a temperature between room temperature and the reflux temperature of the reaction mixture to obtain the thieno-triazolo-diazepine derivative of the general formula A in which Y is represents an oxygen atom, and optionally by carrying out a sulfurization reaction (step D -> D '), which consists in reacting the derivative of thieno-triazolo-diazepine of formula D with 3 to 5 stoichiometric equivalents of phosphorus pentasulfide in an aprotic solvent, at a temperature of between 100 ° C. and the reflux temperature of the reaction mixture, to obtain the corresponding thieno-triazolo-diazepine in which Y represents a sulfur atom. The sequence corresponding to these reactions is

  summarized in drawing sheet 1 of this document.

  The reactions of the process for the preparation of thieno-triazolodiazepine derivatives of the present invention are

  preferably conducted under an inert atmosphere.

  The prior art in the field of the present invention is illustrated in US Pat. No. 4,621,083 (or B.E. 176,927) in which the PAF antagonist activity of

  thieno-triazolo-diazepine is revealed.

  4 - These new compounds exhibit a PAF antagonist activity, ten to a thousand times greater than that of the diazepines promoted in the patent mentioned above, and

  also greater efficiency.

  Obtaining the starting material B is described by the following sequence of preparative examples (from I to X) which is

  reported in drawing sheet 2.

  I (2-chloro) phenyl cyanomethyl ketone.

this

C-CH 2-CN

  In a suitable reactor placed under a circulation of nitrogen at 700 ° C., 7 l of anhydrous THF and 115.9 g (1.36 mol) of previously dried cynoacetic acid are poured. 1715 ml (2 g) are added dropwise. 74 mol) of a 1.6 M solution of butyllithium in hexane while allowing the temperature to rise from 700 ° C. to 0 ° C. The reaction mixture is then stirred for one hour and then cooled again to 70 ° C .; a solution of 120 g (0.685 mol) of 2-chlorobenzoyl chloride in 1 l of anhydrous THF is then gradually added. After allowing the mixture to stir for one hour at 700 ° C., the temperature is allowed to rise to 700 ° C. After 1 hour stirring for a few minutes, the reaction mixture is extracted with chloroform. The organic phase is washed, with stirring. 10% aqueous solution of sodium bicarbonate and then with a solution of sodium chloride

saturated, 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 title compound.

  II Amino-2 (2-chlorobenzoyl) -3 (ethoxycarbonyl) -6

  4,5,6,7-tetrahydro-3,4-pyrido thiophene b.

ci C =

C 2 H 5 -O-C N

CO

I S NH 2

  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 g) are added. mol) of sulfur flower and 44.4 g (0.501 mol) of morpholine in solution 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

desired compound.

  II (bromoacetamido) -2 (2-chloro-benzoyl) -3 (ethoxy-

  carbonyl) -4,5,6,7-tetrahydro-3,4-pyrido thiophene b. C = O, C 2 HSOCN a <C I S NH-C-CH 2-Br o

O I

  6 - 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 added. 87.7 g (0, 43 mol) of bromoacetyl bromide contained in the separating funnel 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 is taken up with ethanol: the desired product precipitates. It is then filtered, washed with ethanol and then with ethyl ether. and dried to give 184.6 g

(95%) of the desired compound.

  IV (aminoacetamido) -2 (2-chloro-benzoyl) -3 (ethoxy-

  carbonyl) -4,5,6,7-tetrahydro-3,4-pyrido thiophene b. Qci C = O C 2 Hs 5 C N -t N

| N S NH -C-CH 2 NH 2

0 11

  In a 5 liter reactor equipped with a gas injector, 174.8 g (0.36 mol) of (III) and 3 liters of THF are added. The suspension is cooled to 0.degree.

  ammonia gas, previously dried on potash.

  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, firstly. with 300 ml of a 10% solution of sodium chloride, then three times with 300 ml of water, and dried over anhydrous magnesium sulfate. After filtration, the solvent is partially removed by rotavapor evaporation. the night in the refrigerator After filtration, the precipitate is washed with ethyl ether and dried This operation gives 119 g of the title 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 is obtained

  of the desired compound (Yield 88%).

  V (2-chlorophenyl) -5 (ethoxycarbonyl) -8 tetrahydro-

  6,7,8,9 3 H-pyrido 4 ', 3': 4.5 l thieno l 3,2 fl

diazepine-1,4 one-2.

Cl N

C 2 H 50 C-N

  S N u

0 H

  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 verifying that all the starting material has reacted, the pyridine is partially evaporated under reduced pressure and the oil (dark brown) thus obtained is dissolved in 1 liter of water. 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 (2-chlorophenyl) -5,6,8,8,9-tetrahydro-6H-pyrido

  1,4 ', 3', 4: 5-thieno-3,2-diazepine-1,4-one-2.

ci N H-N Qk

S N

  B. In a reactor equipped with a heating system and placed under a circulation of nitrogen, 94.5 g (0.234 mol) of V, 152.1 g (2.34 mol) of potassium hydroxide pellets are poured. 90%) and 900 ml of ethylene glycol monomethyl ether The mixture is brought to reflux in one hour and the reflux is maintained for one hour The solution is then poured into 1.2 kg of crushed ice and acidified with water. hydrochloric acid (d = 1.18) up to pH 5.3 Then, it is returned to pH 8.3 with potassium carbonate. The solution is then extracted three times with 500 ml of methylene chloride. The organic phase is washed with 450 ml of a 10% aqueous solution of sodium chloride, dried over

  anhydrous magnesium sulfate, filtered and evaporated.

  9 - The resulting residue is converted in isopropyl ether, Vé isopropyl ether and dried on

  55.9 g of the desired compound are obtained (yield 72%).

  Second sequence of preparative examples (I 'to II'): preparation of isopropylthioacetic acid (R-S-derivative)

  CH 2 CO 2 H when R represents the isopropyl radical).

Ethyl isopropylthioacetate.

  c E 3 CH 3 CH 2 CH 2 C 02 C 2 Hs

CH 3 '

  In a one-liter reactor equipped with a suitable system, 300 ml of methanol and 25.4 g (0.333 mol) of isopropylthiol are poured in. Then 57.3 g (0.333 mol) of bromoacetate are added dropwise. at room temperature, and the mixture is stirred for 4 hours, still at room temperature. 135 ml of a 2.5N sodium hydroxide solution are then added dropwise, without exceeding 7-7.5 g. The mixture is then stirred. overnight and the methanol is then evaporated The residue is taken up in 100 ml of water and the

  The mixture obtained is extracted with 350 ml of ethyl ether.

  The organic phase is washed once with a 5% sodium hydroxide solution, then three times with water and dried over anhydrous magnesium sulfate. After filtration and evaporation with a rotavapor, 46 g of the compound are obtained.

sought (85% yield).

  II 'Isopropylthio-acetic acid.

CH 3 CH S CH 2 CO 2 H

  CH 3 In a two-liter reactor equipped with appropriate systems, 40 g (0.246 mol) are poured in

  ethyl isopropylthioacetate and 380 ml of methanol.

  - Then a solution of 20.7 g (0.369 mol) of sodium hydroxide in 380 ml of water is added dropwise. The temperature increases and is maintained at 35-38 ° C. for two hours. The methanol is then evaporated and the resulting residue is dissolved. The solution is then acidified to pH 3 by addition of a 10% hydrochloric acid solution. The precipitate is filtered off, washed with water until neutral and the compound is dried. thus obtained is crystallized in 200 ml of a mixture of isopropyl acetate and isopropyl ether (4/6 by volume) The solution is filtered hot and left to crystallize After filtration and washing with diisopropyloxide, we obtain

  26.7 g of the desired compound (yield 80.5%).

  The invention will be better understood by the description of

following examples.

EXAMPLE 1

  (2-chloro-phenyl) -6 (isopropyl-thiomethyl-carbonyl) -9-tetrahydro-7,8,9-methyl-1-4H-pyrido [4 ', 3', 4: 5] thieno [3,2] triazolo-1,2,4,4,3-aldiazepine-1,4

  Y = O R = isopropyl P f = 122-124 ° C (Tottoli) beige powder.

ci N C Hl

CH-S CH 2 N

CH / CH 3 S

1 /

1st step B + C -) D

  Preparation of (2-chloro-phenyl) -5 (isopropylthiomethyl)

  carbonyl) -6,7,8,9-3-tetrahydro-H-pyrido [4 ', 3', 4: 5] thieno [3,2-diazepine-1,4-one-2 '] - In a reactor of two liters equipped with appropriate systems, 49.8 g (0.150 ml) of (2-chlorophenyl) -6,7,8,9-tetrahydro-H-pyrido [4 ', 3', 4: 5 are added. The suspension is cooled to 5.degree. C. and then, while maintaining the temperature at 10.degree. C., 34 g are added (1.65 g). mol) of dicyclohexylcarbodiimide, 400 ml of

  dichloroethane, 20.1 g (0.150 mol) of isopropylthio-

  acetic acid and 400 ml of dichloroethane.

  The mixture is left for 30 minutes in an ice bath, then it rises to room temperature and is heated to 500 ° C. to homogenize. Thereafter, the mixture is stirred overnight at room temperature and the dichloroethane is

  The residue obtained is taken up in 600 ml of N, N

  dimethylformamide, then 150 ml of water are added and the mixture is stirred for two hours. Dicyclohexylurea

  formed is filtered and the solution is washed with N, N-

  dimethylformamide N, N-dimethylformamide is partially

  The residue obtained is taken up in ice water and the precipitation occurs.

  0.150 moles of acetic acid and the mixture is stirred.

  The precipitate is filtered, washed with a solution of 10% acetic acid, with water and then with a 10% solution of sodium bicarbonate, dried under reduced pressure and then taken up in 600 ml of ethyl acetate. The solution

  is cooled and left for three hours in the refrigerator.

  After filtration, washing with ethyl acetate and then with ethyl ether and drying, 45.7 g of

  desired compound (68% yield).

2nd step D E:

  Preparation of (2-chloro-phenyl) -5 (isopropyl-thiomethyl)

  carbonyl) -8 hydrazino-2-tetrahydro-6,7,8,9-3 H-pyrido

  1,4 ', 3', 4: 5 1 thieno-3,2-diazepine-1,4.

  12 - In a two-liter reactor equipped with appropriate systems and placed under a circulation of nitrogen, it is poured

  42.5 g (0.095 mol) of (2-chloro-phenyl) -5 (isopropylthio)

  methyl-carbonyl) -8-tetrahydro-6,7,8,9-3 H-pyrido [4 ', 3', 4: 5] thieno [1,2,3-diazepine] -1,4-one-2,1 methanol and 19.06 g (0.376 mol) of hydrazine hydrate After one hour and a half at room temperature (25 ° C.), a TLC control shows the presence of the starting compound. Thus, for the completion of the reaction, the mixture The mixture is filtered and, after washing with methanol and with ethyl ether, 36.4 g of

  product sought (yield 83%).

3rd step E -> A:

  Preparation of (2-chloro-phenyl) -6 (isopropyl-thiomethyl)

  carbonyl) -9,7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3', 4: 5] thieno [1,2,3-triazolo-1,2,4] l, 4,3 -1,4-diazepine. In a one-liter reactor equipped with a cooling system and placed under nitrogen circulation, it is poured

  32.4 g (0.070 mol) of (2-chloro-phenyl) -5 (isopropylthio)

  methyl-carbonyl) -8 hydrazino-2-tetrahydro-6,7,8,9-3 H-pyrido [4 ', 3', 4: 3 thieno] 3,2-diazepine-1,4,4,600 ml of methanol and 45 g (0.28 mol) of triethylorthoacetate The suspension is refluxed for 90 minutes: after refluxing minutes, a solution is obtained and the precipitation takes place after 45 minutes of reflux all the starting material has reacted. The mixture is then cooled and the precipitate is filtered, washed with methanol and then with ethyl ether. After drying at room temperature and then at 110 ° C. overnight under reduced pressure, the following are obtained:

  3 g of the desired compound (yield 89%).

EXAMPLE 2

  13 - (2-chloro-phenyl) -6 (isopropylthiomethyl-thiocarbonyl) -9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3', 4: 5] thieno [3,2-fl] triazolo-1,2,4 1,4-allyl 1,4-diazepine Y = SR = isopropyl P f = 157-159 ° C (Tottoli); pale orange powder. I c CH 3 CH C CH 2-C N a

CH 3 S

S

CH 3 - N

1st step B + C ->) D

  Preparation of (2-chloro-phenyl) -5 (isopropyl-thiomethyl)

  carbonyl) -8-tetrahydro-6,7,8,9-3 H-pyrido [4 ', 3', 4: 5] thieno

1,3-diazepine-1,4-one-2.

  This reaction is described in detail in Example 1 (1st step). 2nd stage D -) D '

  Preparation of (2-chloro-phenyl) -5 (isopropyl-thiomethyl)

  thiocarbonyl) -8,6,8,8,9-3-tetrahydro-4H-pyrido [4 ', 3', 4: 5]

  thieno-3,2-diazepine-1,4-thione-2.

  In a five-liter reactor equipped with appropriate systems and circulated with nitrogen,

  , 3 g (0.090 mol) of (2-chloro-phenyl) -5 (isopropylthio)

  methyl-carbonyl) -8-tetrahydro-6,7,8,9-3 H-pyrido [4 ', 3', 4: 5]

  thieno l 3,2-fl diazepine-1,4-one-2 and 1.25 l of dimethoxy-

  The suspension is heated to 60 ° C. and 87.1 g (0.392 mol) of pentasulphide are then added over a period of 15 minutes.

  phosphorus and 65.4 g (0.785 mol) of sodium bicarbonate.

  The temperature is then maintained at 700 ° C. for

90 minutes.

  Because a TLC analysis indicates the trace of intermediate products, the mixture is then refluxed for 30 minutes to complete the reaction. Thereafter, the mixture is cooled to 15 ° C. and 2.5 l of ice water. The mixture is then poured into a 5-beaker in which a 0.4 M solution of sodium bicarbonate is added to reach a pH of 8 and the mixture is stirred for 30 minutes. The precipitate obtained is filtered off, washed with water, ethanol and then ethyl ether, and taken up in 1 l of dichloromethane. Insoluble material is filtered. The mixture is then washed with 300 ml of dichloromethane and the dichloromethane is evaporated. The resulting residue is taken up with water. acetonitrile and then left overnight in a cooler After filtration, wash with acetonitrile and then with diethyl ether,

  28.1 g of the desired compound are obtained (yield 85%).

3rd step D '-> E

  Preparation of (2-chloro-phenyl) -5 (isopropyl-thiomethyl)

  thiocarbonyl) -8 hydrazino-2-tetrahydro-6,7,8,9-3 H-pyrido

  1,4 ', 3', 4: 5 1 thieno-3,2-diazepine-1,4.

  In a two-liter reactor equipped with appropriate systems and placed under nitrogen circulation, 19.7 g (0.041 mol) of (2-chloro-phenyl) -5 (isopropyl-thiomethyl-thiocarbonyl) -8-tetrahydro-6 are added. 7, 8, 9-3 Hpyrido [4 ', 3', 4: 5] thieno [3,2-diazepine] -l, 4-thione-2, 500 ml of methanol and 8.22 g (0.162 mol) of Hydrazine hydrate After one hour and a half at room temperature (25 ° C.), a TLC control shows the presence of the starting compound. Thus, for the completion of the reaction, the mixture is heated at 40 ° C. for 30 minutes and then brought to temperature. The mixture is filtered and, after washing with methanol and ethyl ether, 16.4 g of the product are obtained.

searched (84% yield).

- 4th stage E -> A

  Preparation of (2-chloro-phenyl) -6 (isopropyl-thiomethyl)

  thiocarbonyl) -9-tetrahydro-7,8,9,10 methyl-1-4 H-pyrido [4 ', 3', 4: 5] thieno [1,2,3-triazolo-1,2,4] 3,4 -1,4-diazepine. In a one-liter reactor equipped with a cooling system and placed under nitrogen circulation, it is poured

  12 g (0.025 mol) of (2-chloro-phenyl) -5 (isopropylthio)

  methyl-thiocarbonyl) -8 hydrazino-2-tetrahydro-6,7,8,9-3 H-

  pyrido [4 ', 3', 4: 5] thieno [1,2,3-diazepine-1,4,250 ml of methanol and 16.1 g (0.100 mol) of triethylorthoacetate. The suspension is refluxed for 90 minutes: After refluxing for a minute, a solution is obtained and the precipitation takes place after 45 minutes of reflux. All the starting material has reacted. The mixture is then cooled and the precipitate is filtered off, washed with methanol and then with ethyl ether. at room temperature and then at 110 C overnight under reduced pressure, we obtain

  11.1 g of the desired compound (yield 88%).

EXAMPLE 3

  (2-chloro-phenyl) -6 (t-butylthiomethyl-carbonyl) -9 tetra-

  7,8,9,10-Hydroxy-4-methyl-4H-pyrido [4 ', 3']: 4,5-thieno-3,2-triazolo-1,2,4,4,3-al diazepine- l, 4

  Y = O R = t butyl P f = 169-171 ° C (Tottoli) yellow powder.

EXAMPLE 4

  (2-chlorophenyl) -6- (tert-butylthiomethyl-thiocarbonyl) -9,8,8,9-tetrahydro-1-methyl-4H-pyrido [4 ', 3']: 4,5-thieno [3,2-] triazolo-1,2,4 1,4-allyl diazepine-1,4 Y = SR = t-butyl P f = 179-1810 ° C (Tottoli) beige powder

blade.

16 -

EXAMPLE 5

  (2-chloro-phenyl) -6 (hexadecylthiomethyl-carbonyl) -9 tetra-

  7,8,9,10-Hydroxy-4-methyl-4H-pyrido [4 ', 3']: 4,5-thieno-3,2-triazolo-1,2,4,4,3-al diazepine- 1.4 Y = OR = hexadecyl P = 292 C (Tottoli) creamy white powder.

EXAMPLE 6

  (2-chloro-phenyl) -6 (hexadecylthiomethyl-thiocarbonyl) -9,8,8,9-tetrahydro-1-methyl-4H-pyrido [4 ', 3']: 4,5-thieno [3,2-fl] triazolo-1,2,4 1,4-allyl diazepine-1,4 Y = SR = hexadecyl P f = 176-1770 ° C (Tottoli) powder

white crystalline.

EXAMPLE 7

  (2-chloro-phenyl) -6 (phenylthiomethyl-carbonyl) -9 tetra-

  7,8,9,10-Hydroxy-4-methyl-4H-pyrido [4 ', 3']: 4,5-thieno [3,2-di] triazolo [1,2,4] -4,3-al diazepine- l, 4

  Y = O R = phenyl P f = 243-244 C (Tottoli) white powder.

EXAMPLE 8

  (2-chloro-phenyl) -6 (phenylthiomethyl-thiocarbonyl) -9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3']: 4,5-thieno [3,2-fl] triazolo-1,2,4 1,4-diazepine-1,4 Y = SR = phenyl P f = 127-1280 ° C (Tottoli) creamy white powder.

EXAMPLE 9

  (1-chloro-phenyl) -6 (4-methoxyphenyl) thiomethyl-car-

  9,9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3']: 4,5-thieno] 3,2-triazolo-1,2,4,4,3,4-triol al diazepine-1,4, Y = OR = 4-methoxy phenyl P = 180-181 ° C (Tottoli)

yellow powder.

17 -

EXAMPLE 10

  (1-chloro-phenyl) -6 (4-methoxyphenyl) thiomethyl-thiocarbamate

  9,9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3']: 4,5-thieno] 3,2-triazolo-1,2,4,4,3,4-triol al diazepine-1,4, Y = SR = 4-methoxy phenyl P = 213-215 ° C (Tottoli)

pale orange powder.

EXAMPLE 11

  (1-chloro-phenyl) -6 (3,4-dimethoxyphenyl) thiomethyl-car-

  9,9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3']: 4,5-thieno] 3,2-triazolo-1,2,4,4,3,4-triol α-1,4-diazepine = OR = 3,4-dimethoxyphenyl P f = 120 ° C (Tottoli)

pale yellow powder.

EXAMPLE 12

  (1-chloro-phenyl) -6 (3,4-dimethoxyphenyl) thiomethylthio-

  9-carbonyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3']: 4,5-thieno [3,2-t] triazolo [1,2,4] -4,3 1,4-diazepin-1,4-Y = SR = 3,4-dimethoxyphenyl P f = 130 ° C (Tottoli)

brown powder.

EXAMPLE 13

  (2-chloro-phenyl) -6 (3,4,5-trimethoxyphenyl) thiomethyl-

  9-carbonyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3']: 4,5-thieno [3,2-t] triazolo [1,2,4] -4,3 1,4-diazepine Y = OR = 3,4,5-trimethoxy phenyl P f = 247-249 ° C

(Tottoli) white powder.

EXAMPLE 14

  (2-chloro-phenyl) -6 (3,4,5-trimethoxyphenyl) thiomethyl-

  9-thiocarbonyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3']: 4,5-thieno [3,2-fl] triazolo [1,2,4] -4,3-al diazepine-1,4, Y = SR = 3,4,5-trimethoxy phenyl P f = 130-131 ° C

(Tottoli) beige powder.

18 -

EXAMPLE 15

  (2-chloro-phenyl) -6 (2,3,4-trimethoxyphenyl) thiomethyl-

  9-carbonyl-7,8,9,10-tetrahydro-4-methyl-4H-pyrido [4 ', 3']: 4,5-thieno] 3,2-triazolo-1,2,4-l, 4,3- 1,4-diazepine Y = OR = 2,3,4-trimethoxyphenyl P f = 215-220 ° C

(Tottoli) pale yellow powder.

EXAMPLE 16

  (2-chloro-phenyl) -6 (2,3,4-trimethoxyphenyl) thiomethyl-

  9-thiocarbonyl-7,8,9,10-tetrahydro-1- [4H-pyrido] -4 ', 3': 4,5-thieno] 3,2-triazolo-1,2,4-l, 4,3- 1,4-diazepine Y = SR = 2,3,4-trimethoxy phenyl P = 175 ° C (Tottoli)

orange powder.

EXAMPLE 17

  1- (4-chlorophenyl) -1- (4-tert-butylphenyl) thiomethylcarbonyl 7,8,9,10-tetrahydro-methyl-1-4H-pyrido [4 '], 3': 4,5-thieno 3,2-triazolo-1,2,4,4,3-al-1,4-diazepine Y = OR = 4-tert-butyl phenyl P = 214-216 ° C (Tottoli)

yellow powder.

EXAMPLE 18

  (1-chloro-phenyl) -6- (4-tert-butylphenyl) thiomethyl-thiocarbamate

  9,9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3']: 4,5-thieno [1,2,3-triazolo-1,2,4] -4,3-triol; 1,4-diazepine Y = SR = 4-tert-butylphenyl P f = 183-186 ° C (Tottoli)

pale orange powder.

EXAMPLE 19

  (2-chloro-phenyl) -6 (trifluoromethyl-2-phenyl) thiomethyl-

  9-carbonyl-7,8,9,10-tetrahydro-4-methyl-4H-pyrido [4 ', 3']: 4,5-thieno] 3,2-triazolo-1,2,4-l, 4,3-al 1,4-diazepine Y = OR = trifluoromethyl 2 phenyl P f = 229 C (Tottoli)

pale beige powder.

19 -

EXAMPLE 20

  (2-chloro-phenyl) -6 (trifluoromethyl-2-phenyl) thiomethyl-

  9-thiocarbonyl-7,8,9,10-tetrahydro-1- [4H-pyrido] -4 ', 3': 4,5-thieno] 3,2-triazolo-1,2,4-l, 4,3- 1,4-diazepine Y = SR = 2-trifluoromethylphenyl P f = 2485-249 ° C

(Tottoli) orange powder.

EXAMPLE 21

  (1-chloro-phenyl) -6 (trifluoromethyl-3-phenyl) thiomethyl-

  9-carbonyl-7,8,9,10-tetrahydro-4-methyl-4H-pyrido [4 ', 3']: 4,5-thieno] 3,2-triazolo-1,2,4-l, 4,3- 1,4-diazepine Y = OR = 3-trifluoromethyl phenyl P = 311-313 ° C

(Tottoli) yellow powder.

EXAMPLE 22

  (1-chloro-phenyl) -6 (trifluoromethyl-3-phenyl) thiomethyl-

  9-thiocarbonyl-7,8,9,10-tetrahydro-1- [4H-pyrido] -4 ', 3': 4,5-thieno] 3,2-triazolo-1,2,4-l, 4,3- 1,4-diazepine Y = SR = 3-trifluoromethyl phenyl P = 177 C (Tottoli)

cream white powder.

EXAMPLE 23

  (1-chloro-phenyl) -6 (trifluoromethyl-4-phenyl) thiomethyl-

  9-carbonyl-7,8,9,10-tetrahydro-4-methyl-4H-pyrido [4 ', 3']: 4,5-thieno] 3,2-triazolo-1,2,4-l, 4,3-al 1,4-diazepine Y = OR = trifluoromethyl phenyl P f = 210-212 ° C

(Tottoli) white powder powder.

EXAMPLE 24

  (1-chloro-phenyl) -6 (trifluoromethyl-4-phenyl) thiomethyl-

9-thiocarbonyl-7,8,9,10-tetrahydro-4-methyl-4H-pyrido [4 ', 3']: 4,5-thieno] 3,2-triazolo-1,2,4-l, 4,3 α-1,4-diazepine Y = SR = 4-trifluoromethyl phenyl P f =

  239-241 C (Tottoli) light brown powder.

-

EXAMPLE 25

  (1-chloro-phenyl) -6 (4-fluoro-phenyl) thiomethyl-carbohydrate

  9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3']: 4,5-thieno-1,3,2-triazolo-1,2,4,4,3,3-triol; al diazepine-1,4 Y = OR = 4-fluorophenyl P f = 200 C (Tottoli) powder

pale yellow.

EXAMPLE 26

  (1-chloro-phenyl) -6 (4-fluoro-phenyl) thiomethyl-thiocarbamate

  9,9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3']: 4,5-thieno] 3,2-triazolo-1,2,4,4,3,4-triol 1,4-diazepine-1 = SR = 4-fluorophenyl P f = 154-1560 ° C (Tottoli) white powder.

EXAMPLE 27

  (2-chloro-phenyl) -6 (2,3-dichlorophenyl) thiomethyl-car-

  9,9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3']: 4,5-thieno] 3,2-triazolo-1,2,4,4,3,4-triol 1,4-diazepine-1,4 = OR = 2,3-dichlorophenyl P f = 169-170 ° C (Tottoli)

cream white powder.

EXAMPLE 28

  (1-chloro-phenyl) -6- (2,3-dichloro-phenyl) -thiomethyl-thio-carbonyl-9,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4, 5 th théno

  1,2,3-triazolo-1,2,4,4-allyl-1,4-diazepine Y = S R = 2,3-dichlorophenyl P = 187 ° C (Tottoli) powder

yellow.

EXAMPLE 29

  (1-chloro-phenyl) -6 (4-phenoxyphenyl) thiomethyl-car-

  9,9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3']: 4,5-thieno] 3,2-triazolo-1,2,4,4,3,4-triol 1,4-diazepine = Y = OR = 4-phenoxy phenyl = 292 ° C (Tottoli) brown powder. 21 -

EXAMPLE 30

  (1-chloro-phenyl) -6 (4-phenoxyphenyl) thiomethyl-thiocarbamate

  9,9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3']: 4,5-thieno [1,2,3-triazolo-1,2,4] -4,3 1,4-diazepine Y = SR = 4-phenoxy phenyl P = 192-195 ° C (Tottoli)

white crystalline powder.

EXAMPLE 31

  (2-chloro-phenyl) -6 (2-furyl-thiomethyl-carbonyl) -9 tetra-

  7,8,9,10-Hydroxy-4-methyl-4H-pyrido [4 ', 3']: 4,5-thieno-3,2-triazolo-1,2,4,4,3-al diazepine- 1.4 Y = OR = 2-furyl P f = 121-122 C (Tottoli) white powder.

EXAMPLE 32

  (2-chloro-phenyl) -6 (2-furyl-thiomethyl-thiocarbonyl) -9,8,8,9-tetrahydro-1-methyl-4H-pyrido [4 ', 3']: 4,5-thieno l 3, 2-fl triazolo-1,2,4 1,4-diazepine-1,4-allyl

  Y = S R = 2-furyl P f = 246 C (Tottoli) beige powder.

EXAMPLE 33

  (2-chloro-phenyl) -6 (2-thienyl-thiomethyl-carbonyl) -9-tetrahydro-7,8,9,10-methyl-1-4H-pyrido [4 ', 3']: 4,5-thieno l 3, 2-triazolo-1,2,4,4-triazolo diazepine-1,4 Y = OR = 2-thienylP f = 237-240 C (Tottoli) white powder.

EXAMPLE 34

  (2-chloro-phenyl) -6- (2-thienyl-thiomethyl-thiocarbonyl) -9,8,8,10-tetrahydro-7-methyl-1H-pyrido [4 ', 3']: 4,5-thieno l 3, 2-triazolo-1,2,4,4-allyl-1,4-diazepine Y = SR = 2-thienylp F = 198-199 C (Tottoli) powder

White cream.

22 -

TOXICOLOGY

  The compounds according to the invention are not toxic on the

  mice at a dose of 1 g / kg, by IP and oral routes.

PHARMACOLOGY

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

the 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. CAZENAVE, M. PACKHAM and F. MUSTARD,

Lab Invest 48,98,1980.

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

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 This experiment was therefore carried out according to the method of MOHLER H and RICHARD JG "Agonist and antagonist receptor intereaction in vitro, Nature, vol.

294, 763-765, 1981.

  23 - This experiment was conducted on rat brains incubated for -1H 30 at 40 C using 3 H-RO-15-4788 and 3 H-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) Overall Ischemia on gerbils For this test, male gerbils were anesthetized with brietal at a dose of 35 mg / kg IP; both carotids were then clamped for 10 min and then released. The treated animals each received 10 mg / kg of the compounds of a

examples.

  One week later, the animals are sacrificed and the 2 hippocampi are removed, weighed and frozen at 800 C. After crushing and adding 1 ml of TRIS-HCl buffer pH 7.4 for 30 seconds, aliquots 50 μl of this preparation are each incubated in 1 ml of TRIS-HCl buffer containing 3 H-PK 11195 at 2 nM (90 Ci / mmole, NENE, Germany) for one hour at 250 ° C. For each preparation, 3 determinations The densities of the omega 3 sites (labeled with the specific marker 3H PK 11195) were expressed in f-moles of fresh tissue PK 11195 / mg and converted to percent protection compared to the control. The results of this experiment are reported in

Table II.

PRESENTATION DOSAGE

  In human therapy, the compounds according to the invention

  are preferably administered orally.

  These dosage forms are preferably tablets, gelatin capsules. The usual dosage is 50 mg to 500 mg per day as appropriate. The dosage unit is preferably 50 mg combined with the appropriate agents. They can be administered by IP The usual dosage is from 5 mg to 100 mg per day as appropriate.

dosage is from 1 to 20 mg.

-

TABLE I A

EXAMPLES IC 50 BDZ receivers

1 2.53 10-8 6.7 10-6

2 2,81 10-o 8 4,82 10-5

3 1.68 10-8 2.3 10-6

4 4.97 10-7 1.55 10-6

7.43 10-9 1.21 1 0-

6 9.46 10-9 9.1 10-7

7 5,11 10-7 2.1 10-6

8 1.05 10-8 7.33 10-6

9 3.37 10-8 2.7 10-6

1.71 10-7 6.6 10-5

11 2.64 10-8 1.4 10-6

12 3.14 10-8 8.7 10-7

26 -

TABLE I B

EXAMPLES IC 50 BDZ receivers

13 1.85 10-8 5.5 10-5

14 9.22 10-9 1.5 10-6

1,2 10-7 3,6 10-6

16 5.35 10-8 6 10-

17 8.75 10-9 4.7 10-6

18 2.3 10-o 8 4.41 10-5

19 6.36 10-9 2.7 10-7

1.46 10-7 1.6 10-6

21 8.66 10-9 8.1 10-7

22 8.18 10-9 6.1 10-7

23 1.24 10-8 1.2 10-6

24 3.27 10-8 3.3 10-6

27 -

TABLE I C

EXAMPLES IC 50 BDZ receivers

1.13 10-8 6.3 10-7

26 6.56 10-9 6.1 10-7

27 8.45 10-9 4.8 10-5

28 9.06 10-9 4.3 10-6

29 9.05 10-9 1.23 10-6

1.04 10-7 3.6 10-7

31 7.10 10-9 2.3 o 10-7

32 8.75 10-9 1.3 10-6

33 4.12 10-8 5.7 10-6

34 1.28 10-7 7.2 10-7

28 -

TABLE II A

EXAMPLES Overall protection in%

1 54.2 ***

2 36.3 **

3 34.3 **

4 38.1 **

29.4 **

6 27.8 **

7 14.8 NS

8 26.2 *

9 31.2 **

10.3 NS

It 46.5 ***

12 34.1 **

13 32.1 **

14 19.7 NS

35.8 **

16 29.3 **

17 11.1 NS

18 12.6 NS

19 45.6 **

32.7 **

29 -

TABLE II B

EXAMPLES Overall protection in%

21 34.1 **

22 48.1 ***

23 37.5 **

24 38.7 **

14.7 NS

26 26.5 *

27 33.3 **

28 35.3 **

29 51.6 ***

16.1 NS

31 36.2 **

32 30.3 **

33 24.8 *

34 34.7 **

-

Claims (2)

R E V E N D I C A T IO NS   1) Process for the Preparation of Thieno-Triazolo-diazepine Derivatives of General Formula A and N% C R S NCH 2 -   wherein Y represents oxygen or sulfur and R represents: a linear or branched alkyl group having up to 20 carbon atoms, a phenyl group unsubstituted or substituted by a linear or branched alkyl group having to carbon atoms, an alkoxy group having up to 5 carbon atoms, a halogen atom, a trifluoromethyl group or an optionally substituted phenoxy group or, furan or thiophene and,   of their therapeutically acceptable salts.   which consists in treating the thieno-triazolo-   diazepine of formula B B. H 31 - with a stoichiometric amount of the derivative (C) RSCHCOOH in which R is as defined above, in an aprotic solvent, in the presence of a slight stoichiometric excess of dicyclocarbodiimide at a temperature between OC and 60 ° C, and then reacting the resulting compound of the formula ## STR1 ## wherein R is defined above, with 3 to 5 stoichiometric equivalents of hydrazine hydrate, in a protic solvent, at a temperature between room temperature and 50 ° C and finally, by cyclizing, in a protic solvent, the compound thus obtained of formula: ## STR2 ##   with 1 to 3 st Ochiometric equivalents of triortho-   acetate, at a temperature between room temperature and the reflux temperature of the reaction mixture to obtain the thieno-triazolo-diazepine derivative of general formula A wherein Y represents an oxygen atom, and optionally by carrying out an sulfurization reaction (step D -) D '), which comprises reacting the derivative of the thieno-triazolo-diazepine of formula D with 3 to 5 stoichiometric equivalents of phosphorus pentasulfide in an aprotic solvent at a temperature between 10 C and the reflux temperature of the reaction mixture, to obtain the corresponding thieno-triazolo-diazepine in which Y represents a sulfur atom.   2) A preparation method according to claim 1 wherein the reaction steps are conducted from   preferably under an inert atmosphere.