CH681010A5 - - Google Patents

Description

5

10

15

20

25

30

35

40

45

50

55

CH 681 010 A5

Description

The present invention relates to processes for the preparation of new derivatives of thieno-tria-zolo-diazepine which are particularly useful as anti-ischemic, anti-asthmatic and anti-allergic agents and, as gastrointestinal protectors. The compounds of the present invention are more particularly useful for the treatment of ischemia.

The invention relates more particularly to a process for the preparation of thieno-tria-zolo-diazepine derivatives of general formula A

in which Y represents oxygen or sulfur and R represents:

- a linear or branched alkyl group having up to 20 carbon atoms,

- a phenyl group which is not substituted or substituted by a linear or branched alkyl group having up to 5 carbon atoms, an alkoxy group having up to 5 carbon atoms, a halogen atom, a trifluoromethyl group or a phenoxy group substituted or not,

- furan or thiophene and therapeutically acceptable salts derived therefrom.

According to the invention, these compounds can be easily prepared by treating the thieno-tria-zolo-diazepine compound of formula B

there is

* -CcQ

f >>

b.

with a stoichiometric amount of the derivative (C) RSCH2COOH in which R is as defined above, in an aprotic solvent, in the presence of a slight stoichiometric excess of dicyclocarbodi-imide at a temperature between 0 ° C and 60 ° C,

then reacting the resulting compound of formula

2

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 681 010 A5

r-s-ch, —c — 3

I

0

d.

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:

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 general formula A in which Y represents an oxygen atom. Also according to the invention, the derivatives of formula A in which Y is a sulfur atom can be obtained by carrying out a sulfurization reaction (step D D ′), which consists in reacting the thieno-triazolo-diazepine derivative 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. The sequence corresponding to these reactions is summarized in drawing sheet 1 of this document.

The reactions of the process for the preparation of the thieno-triazolo-diazepine derivatives of the present invention are preferably carried out under an inert atmosphere.

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

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

The production of the starting material B is described by the following sequence of preparative examples (from I to X) which is given in drawing sheet 2.

r-s-ch2

NHj

E

3

5

10

15

20

25

30

35

40

45

50

55

CH 681 010 A5

l - fchloro-2ÌDhénvl cvanométhvle kétone.

Cl c — ch2 — cn

I

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 stirring for one hour at -70 ° C, the temperature is allowed to rise from -70 ° C to 0 ° C in one hour. 31 of 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 evaporation of the solvent, 135 g of a residue are collected, which is then crystallized from di-isopropyl ether, filtered and then washed with hexane. 97.2 g (79%) of the desired compound are obtained.

Il - Amino-2-fchloro-2 benzovlei-3- (ethoxvcarbonvfl-6-tétrahvdro-4.5.6.7-pvridor3.4-b1thiophene.

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.

O

4

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 681 010 A5

III - (bromoacetamidoV2- (2-chloro benzovleì-3- (ethoxvcarbonvfl-6-

tetrahvdro-4.5.6.7-pyridor3.4-b1thiophene.

2.5 I of chloroform and 146 g (0.400 mol) of (II) are poured into a 5-liter reactor equipped with appropriate means and a separating funnel. Then 87.7 g (0.43 mol) of bromoacetyl bromide contained in the separating funnel is 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.

IV - (aminoacetamidoV2- (2-chloro benzovle1-3-fethoxvcarbonvn-6-tetrahvdro-4.5.6.7-pvridor3.4-b1thiophene.

174.8 g (0.36 mol) of (III) and 3 liters of THF are poured into a 5 liter reactor equipped 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 with 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 1.5 I of ethyl ether / THF (3/1 by volume). 14.6 g of the desired compound are obtained (yield 88%).

5

5

10

15

20

25

30

35

40

45

50

55

CH 681 010 A5

V - (chloro-2 Dhérivle1-5-fethoxvcarbonv0-8-tétrahvdro-6.7.8.9-3H-Dvridor4, .3 ': 4.51thienor3.2-fldiazepine-1.4 one-2.

c2h50 — c — 3

I

O

o

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 liter 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.

VI - 2-chloro-phenyl-5 tetrahvdro-6.7.8.9-3H-Dvridor4'.3'.4: 51thienor3.2-fldiazéDine-1.4 one-2.

94.5 g (0.234 mol) of V, 152.1 g (2.34 mol) of potassium pellets (90%) are poured into a reactor equipped with a heating system and placed under nitrogen circulation. and 900 ml of ethylene glucol monomethyl ether. The mixture is brought to reflux in one hour and reflux is maintained for one hour. The solution is then poured into 1.2 kg of crushed ice and acidified with hydrochloric acid (d = 1.18) to pH 5.3. Then we return 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 sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated.

The resulting residue is transformed into isopropyl ether, washed with isopropyl ether and dried. 55.9 g of the desired compound are obtained (yield 72%).

Second sequence of the preparative examples (from l to II '): preparation of isopropylthio-acetic acid (derivative R-S-CH @ CO @ H when R represents the isopropyl radical).

h—]

b.

6

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 681 010 A5

I '- Ethyl isopropvlthioacetate.

ch,.

j ch - s - ch2 - c02c2h5

ch3 *

300 ml of methanol and 25.4 g (0.333 mol) of isopropylthioi are poured into a one-liter reactor equipped with an appropriate system. Then 57.3 g (0.333 mol) of ethyl bromoacetate is added dropwise at room temperature, and the mixture is stirred for 4 hours, still at room temperature. Then 135 ml of a 2.5N sodium hydroxide solution are added dropwise, without exceeding pH 7-7.5. The mixture is then stirred overnight and the methanol is then evaporated. The residue is taken up in 100 ml of water and 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 on a rotary evaporator, 46 g of the desired compound are obtained (yield 85%).

It '- Isopropylthioacetic acid.

40 g (0.246 mol) of ethyl isopropyl thioacetate and 380 ml of methanol are poured into a two-liter reactor equipped with an appropriate system.

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 taken up in about 500 ml of ice water. The solution is then acidified to pH 3 by addition of a 10% hydrochloric acid solution. The precipitate is filtered, washed with water until neutral and dried. The compound thus obtained is crystallized from 200 ml of a mixture of isopropyl acetate and isopropyl ether (4/6 by volume). The solution is filtered hot and allowed to crystallize. After filtration and washing with diisopropyloxide, 26.7 g of the desired compound are obtained (yield 80.5%).

The invention will be better understood from the description of the following examples.

(2-chloro-phenyl) -6 (isopropyl-thiomethyl-carbonyl) -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 = OR = isopropyi Pf = 122-124 ° C (Tottoli) beige powder.

1st stage B + C - »D

Preparation of (2-chloro-phenyl) -5 (isopropylthiomethylcarbonyl) -8 tetrahydro-6,7,8,9-3H-pyrido [4 ', 3', 4: 5] thieno [3,2-1] diazepine-1 , 4 one-2

s - ch2 - co2h

EXAMPLE 1:

ch-s-ch2-

7

5

10

15

20

25

30

35

40

45

50

55

CH 681 010 A5

49.8 g (0.150 ml) of (chloro-2-phenyl) -5 tetrahydro-6,7,8,9-3H-pyrido [4 ', 3'] are poured into a two-liter reactor equipped with appropriate systems , 4: 5] thieno [3,2-f] diazepine-1,4 one-2 and 250 ml of dichloroethane. The suspension is cooled to 5 ° C., then 34 g (1.65 mol) of dicyclohexyi-carbodiimide, 400 ml of dichloroethane, 20.1 g (0.150 mol) are added simultaneously, while maintaining the temperature at 10 ° C. isopropylthioacetic 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 50 ° C. to homogenize. Subsequently, the mixture is stirred overnight at room temperature and the dichloroethane is evaporated. The residue obtained is taken up in 600 ml of N, N-dimethylformamide, then 150 ml of water is added and the mixture is stirred for two hours. The dicyclohexylurea formed is filtered and the solution is washed with N, N-dimethylformamide. The N, N-dimethylformamide is partially evaporated. The residue obtained is taken up in ice water and precipitation occurs. Then 0.150 mol of acetic acid is added and the mixture is stirred.

The precipitate is filtered, washed with a 10% acetic acid solution, with water and then with a 10% sodium bicarbonate solution, 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 the desired compound are obtained (yield 68%).

2nd stage D - »E:

Preparation of (2-chloro-phenyl) -5 (isopropyl-thiomethylcarbonyl) -8 2-hydrazino-tetrahydro-6,7,8,9-3H-pyrido [4 ', 3', 4: 5] thieno [3,2- f] 1,4-diazepine.

42.5 g (0.095 mol) of (2-chloro-phenyl) -5 (isopropyl-thiomethyl-carbonyl) -8 tetrahydro-6 are poured into a two-liter reactor equipped with appropriate systems and placed under nitrogen circulation, 7,8,9-3H-pyrido [4 ', 3', 4: 5] thieno [3,2-fl diazepine-1,4 one-2, 1 I of methanol and 19.06 g (0.376 mol) d hydrazine hydrate. After an hour and a half at room temperature (25 ° C), a CGM control shows the presence of the starting compound. Thus, to complete the reaction, the mixture is heated at 40 ° C for 30 minutes and then brought to room temperature for one hour. The mixture is filtered and, after washing with methanol and ethyl ether, 36.4 g of the desired product are obtained (yield 83%).

3rd step E -> A:

Preparation of (2-chloro-phenyl) -6 (isopropyl-thiomethylcarbonyl) -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.

32.4 g (0.070 mol) of (2-chloro-phenyl) -5 (isopropyl-thiomethyl-carbonyl) -8 are poured into a one-liter reactor equipped with a cooling system and placed under nitrogen circulation. hydrazino-2 tétra-hydro-6,7,8,9-3H-pyrido [4 ', 3', 4: 5] thieno [3,2-f] diazepine-1,4, 600 ml of methanol and 45 g (0.28 mol) of triethylorthoacetate. The suspension is brought to reflux for 90 minutes: after 15 minutes of reflux, a solution is obtained and precipitation occurs after 45 minutes of reflux. All the starting material 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, 30.3 g of the desired compound are obtained (yield 89%).

EXAMPLE 2:

(2-chloro-phenyl) -6 (isopropylthiomethyl-thiocarbonyl) -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 = isopropyl P.f. = 157-159 ° C (Tottoli); pale orange powder.

1st stage B + C D

Preparation of (2-chloro-phenyl) -5 (isopropyl-thiomethylcarbonyl) -8 tetrahydro-6,7,8,9-3H-pyrido [4 ', 3', 4: 5] thieno [3,2-f] diazepine -1.4 one-2.

8

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 681 010 A5

This reaction is described in detail in Example 1 (1st step).

2nd stage D - »D '

Preparation of (2-chloro-phenyl) -5 (isopropyl-thiomethylthiocarbonyl) -8 tetrahydro-6,7,8,9-3H-pyri-do [4 ', 3', 4: 5] thieno [3,2-1 ] diazepine-1,4 thione-2.

40.3 g (0.090 mol) of (2-chloro-phenyl) -5 (isopropyl-thiomethyl-carbonyl) -8 tetrahydro-6 are poured into a five-liter reactor equipped with appropriate systems and placed under nitrogen circulation, 7,8,9-3H-pyrido [4 ', 3', 4: 5] thieno [3,2-f] diazepine-1,4 one-2 and 1,25 1 of dimethoxy-1,2 ethane. The suspension is brought to 60 ° C. and then 87.1 g (0.392 mol) of phosphorus pentasulfide and 65.4 g (0.785 mol) of sodium bicarbonate are added over 15 minutes. The temperature is then maintained at 70 ° C for 90 minutes.

Because a TLC analysis indicates the trace of intermediate products, the mixture is then brought to reflux for 30 minutes to complete the reaction. Subsequently, the mixture is cooled to 15 ° C and 2.5 I of ice water is added. The mixture is then poured into a 5 I beaker into which a 0.4M sodium bicarbonate solution is added to reach a pH of 8 and the mixture is stirred for 30 minutes. The precipitate obtained is filtered, washed with water, ethanol and then ethyl ether, and taken up in 1 I of dichloromethane. An 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 acetronitrile and then left overnight in a cooler. After filtration, washing with acetonitrile and then with ethyl ether, 28.1 g of the desired compound are obtained (yield 85%).

3rd stage D '-> E

Preparation of (2-chloro-phenyl) -5 (isopropyl-thiomethylthiocarbonyl) -8 2-hydrazino-tetrahydro-6,7,8,9-3H-pyrido [4 ', 3', 4: 5] thieno [3,2- 1] 1,4-diazepine.

19.7 g (0.041 mol) of (2-chloro-phenyl) -5 (isopropyl-thiomethyl-thiocarbonyl) -8 tetrahydro-6 are poured into a two-liter reactor equipped with appropriate systems and placed under nitrogen circulation, 7,8,9-3H-pyrido [4 ', 3', 4: 5] thieno [3,2-f] diazepine-1,4 thione-2, 500 ml of methanol and 8.22 g (0.162 mol) hydrazine hydrate. After an hour and a half at room temperature (25 ° C), a TLC control shows the presence of the starting compound. Thus, to complete the reaction, the mixture is heated at 40 ° C for 30 minutes and then brought to room temperature for one hour. The mixture is filtered and, after washing with methanol and ethyl ether, 16.4 g of the desired product are obtained (yield 84%).

4th step E -> A

Preparation of (2-chloro-phenyl) -6 (isopropyl-thiomethylthiocarbonyl) -9 tetrahydro-7,8,9,10 methyl-1-4H-pyrido [4 ', 3', 4: 5] thieno [3,2- f] triazolo-1,2,4 [3,4-a] diazepine-1,4.

12 g (0.025 mol) of (2-chloro-phenyl) -5 (isopropyl-thiomethyl-thiocarbonyl) -8 hydrazino- are poured into a one-liter reactor equipped with a cooling system and placed under nitrogen circulation. 2 tetrahydro-6,7,8,9-3H-pyrido [4 ', 3', 4: 5] thieno [3,2-f] diazepine-1,4, 250 ml of methanol and 16.1 g (0.100 mol) of triethylorthoacetate. The suspension is brought to reflux for 90 minutes: after 15 minutes of reflux, a solution is obtained and precipitation occurs after 45 minutes of reflux. All the starting material 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, 11.1 g of the desired compound are obtained (yield 88%).

EXAMPLE 3:

(2-chloro-phenyl) -6 (t.butylthiomethyl-carbonyl) -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 = OR = tbutyl P.f. = 169-171 ° C (Tottoli) yellow powder.

EXAMPLE 4:

(2-chloro-phenyl) -6 (t.buty! thiomethyl-thiocarbonyl) -9 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 = t.butyl P.f. = 179-181 ° C (Tottoli) pale beige powder.

EXAMPLE 5:

(2-chloro-phenyl) -6 (hexadecylthiomethyl-carbonyl) -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 = O R = hexadecyl P.f. = 292 ° C (Tottoli) creamy white powder.

EXAMPLE 6

(2-chloro-phenyl) -6 (hexadecylthiomethyl-thiocarbonyl) -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 "hexadecyl P.f. = 176-177 ° C (Tottoli) white crystalline powder.

9

5

10

15

20

25

30

35

40

45

50

55

CH 681 010 A5

EXAMPLE 7:

(2-chioro-phenyl) -6 (phenylthiomethyl-carbonyl) -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 = O R = phenyl P.f. = 243-244 ° C (Tottoli) white powder.

EXAMPLE 8:

(2-chloro-phenyl) -6 (phenylthiomethyl-thiocarbonyi) -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 = phenyl P.f. = 127-128 ° C (Tottoli) creamy white powder.

EXAMPLE 9:

(2-chloro-phenyl) -6 [(4-methoxyphenyl) thiomethyl-carbonyl] -9 tetrahydro-7,8,9,10 methyl-1-4H-pyri-do [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4

Y = O R = 4-methoxyphenyl P.f. = 180-181 ° C (Tottoli) yellow powder.

EXAMPLE 10:

(2-chloro-phenyl) -6 [(4-methoxyphenyl) thiomethyl-thiocarbonyl [-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-methoxyphenyl P.f. = 213-215 ° C (Tottoli) pale orange powder.

EXAMPLE 11:

(2-chloro-phenyl) -6 [(3,4-dimethoxy pheny!) thiomethyl-carbonyl] -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 = O R = 3,4-dimethoxy phenyl P.f. = 120 ° C (Tottoli) pale yellow powder.

EXAMPLE 12:

(2-chloro-phenyl) -6 [(3,4-dimethoxy phenyl) thiomethyl-thiocarbonyi] -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 = 3,4-dimethoxy phenyl P.f. = 130 ° C (Tottoli) brown powder.

EXAMPLE 13:

(2-chloro-phenyl) -6 [(3,4,5-trimethoxy phenyl) thiomethylcarbonyl] -9 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 = 3,4,5,5-trimethoxyphenyl P.f. = 247-249 ° C (Tottoli) white powder.

EXAMPLE 14:

(2-chloro-phenyl) -6 [(3,4,5-trimethoxyphenyl) thiomethylthiocarbonyl] -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 = 3,4,5,5-trimethoxy phenyl P.f. = 130-131 ° C (Tottoli) beige powder.

EXAMPLE 15:

(2-chloro-phenyl) -6 [(2,3,4-trimethoxyphenyl) thiomethylcarbonyl] -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 = O R = 2,3,4,4-trimethoxy phenyl P.f. = 215-220 ° C (Tottoli) pale yellow powder.

EXAMPLE 16:

(2-chloro-phenyl) -6 [(2,3,4-trimethoxy phenyl) thiomethyl-thiocarbonyl] -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 = 2,3,4,4-trimethoxy phenyl P.f. = 175 ° C (Tottoli) orange powder.

EXAMPLE 17:

(2-chloro-phenyl) -6 [(t.-4-butyl phenyl) thiomethyl-carbonyl-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 = O R = t.-4-butylphenyl P.f. = 214-216 ° C (Tottoli) yellow powder.

10

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 681 010 A5

EXAMPLE 18:

(2-chloro-phenyl) -6 [(t-butyl-4 phenyl) thiomethyl-thiocarbonyl] -9 tetrahydro-7,8,9,10 methyl-1-4H-py-rido [4 ', 3': 4, 5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4

Y = S R = t.-4-butylphenyl P.f. = 183-186 ° C (Tottoli) pale orange powder.

EXAMPLE 19:

(2-chloro-phenyl) -6 [(2-trifluoromethyl phenyl) thiomethylcarbonyl] -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 = O R = 2-trifluoromethyl phenyl P.f. = 229 ° C (Tottoli) pale beige powder.

EXAMPLE 20:

(2-chloro-phenyl) -6 [(2-trifluoromethyl phenyl) thiomethylthiocarbonyl] -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 = trifluoromethyl-2-phenyl P.f. = 2485-249 ° C (Tottoli) orange powder.

EXAMPLE 21:

(2-chloro-phenyl) -6 [(3-trifluoromethyl phenyl) thiomethyl-carbonyl] -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 = O R = 3-trifluoromethyl phenyl P.f. = 311-313 ° C (Tottoli) yellow powder.

EXAMPLE 22:

(2-chloro-phenyl) -6 [(3-trifluoromethyl phenyl) thiomethylthiocarbonyl] -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 = 3-trifluoromethyl phenyl P.f. = 177 ° C (Tottoli) creamy white powder.

EXAMPLE 23:

(2-chloro-phenyl) -6 [(4-trifluoromethyl phenyl) thiomethylcarbonyl] -9 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 = 4-trifluoromethyl phenyl P.f. = 210-212-C (Tottoli) white powder.

EXAMPLE 24:

(2-chloro-phenyl) -6 [(4-trifluoromethyl phenyl) thiomethylthiocarbonyl] -9 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 = 4-trifluoromethyl phenyl P.f. 239-241 ° C (Tottoli) light brown powder.

EXAMPLE 25:

(2-chloro-phenyl) -6 [(4-fluoro-phenyl) thiomethyl-carbonyI] -9 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 = 4-fluoro phenyl P.f. = 200 ° C (Tottoli) pale yellow powder.

EXAMPLE 26:

(2-chloro-phenyl) -6 [(4-fluoro-phenyl) thiomethyl-thiocarbonyl] -9 tetrahydro-7,8,9,10 methyl-1-4H-py-rido [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4

Y = S R = 4-fluoro phenyl P.f. = 154-156 ° C (Tottoli) white powder.

EXAMPLE 27:

(2-chloro-phenyl) -6 [(2,3-dichloro-phenyl) thiomethyl-carbonyl] -9 tetrahydro-7,8,9,10 methyl-1-4H-py-rido [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 P.f. = 169-170 ° C (Tottoli) creamy white powder.

EXAMPLE 28:

(2-chloro-phenyl) -6 [(2,3-dichloro-phenyl) thiomethyl-thiocarbonyl] -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 = 2,3-dichloro-phenyl P.f. = 187 ° C (Tottoli) yellow powder.

11

5

10

15

20

25

30

35

40

45

50

55

CH 681 010 A5

EXAMPLE 29:

(2-chloro-phenyl) -6 [(4-phenoxyphenyl) thiomethyl-carbonyl] -9 tetrahydro-7,8,9,10 methyl-1-4H-pyri-do [4 ', 3': 4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4

Y = O R = 4-phenoxyphenyl P.f. = 292 ° C (Tottoli) brown powder.

EXAMPLE 30:

(2-chloro-phenyl) -6 [(4-phenoxyphenyl) thiomethyl-thiocarbonyl] -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-phenoxyphenyl P.f. = 192-195 ° C (Tottoli) white crystalline powder.

EXAMPLE 31:

(2-chloro-phenyl) -6 (furyI-2 thiomethyl-carbonyl) -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 = O R = furyl-2 P.f. = 121-122 ° C (Tottoli) white powder.

EXAMPLE 32:

(2-chloro-phenyl) -6 (2-furyl thiomethyl-thiocarbonyl) -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 = furyl-2 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 [3,2 -f] triazolo-1,2,4 [4,3-a] diazepine-1,4

Y = O R = 2-thienyl P.f. = 237-240 ° C (Tottoli) white powder.

EXAMPLE 34:

(2-chloro-phenyl) -6 (2-thienyl thiomethyl-thiocarbonyl) -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 = 2-thienyl P.f. = 198-199 ° C (Tottoli) creamy white powder.

TOXICOLOGY

The compounds according to the invention are not toxic to mice at a dose of 1 g / kg, by IP and oral routes.

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. ln-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 bindinq 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 where platelet aggregation is inhibited. This experiment was therefore carried out according to the method of MÖHLER H. and RICHARD J.G. "Agonist and antago-nist receptor intereaction in vitro, Nature, vol. 294.763-765.1981.

This experiment was carried out on the brains of rats incubated for 1 hour 30 minutes 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.

12

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 681 010 A5

The results, in molecular concentration, are reported in the right column of Table I. 3) Global ischemia on aerbils

For this test, male gerbils were anesthetized with brietal at a dose of 35 mg / kg PI; the two carotids were then clamped for 10 min and then released. The treated animals each received 10 mg / kg of the compounds of one of the examples.

A week later, the animals are sacrificed and the 2 seahorses are removed, weighed and frozen at -80 ° C.

After having been ground and added with a ml of TRIS-HCI buffer pH 7.4 for 30 seconds, 50 μl aliquots of this preparation are each incubated in 1 ml of TRIS-HCI buffer containing 3H-PK11 195 to 2 nM (90 Ci / mmol, NENE, Germany) for one hour at 25 ° C. For each preparation, 3 determinations were made. The density of the omega 3 sites (marked with the specific marker 3H PK 11 195) are expressed in f-moles of fresh tissue PK 11 195 / mg and converted into percentage of 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 administration forms are preferably tablets, gelatin capsules. The usual dosage is 50 mg to 500 mg per day depending on the case. The dosage unit is preferably 50 mg combined with the appropriate agents.

They can be administered by IP. The usual dosage is 5 mg to 100 mg per day depending on the case. The dosage unit is 1 to 20 mg.

Table IA

Examples

IC50

BDZ receivers

1

2

3

4

5

6

7

8

9

10

11

12

2.53 10-8 2.81 10 "8 1.6810" ® 4.9710 ~ 7 7.4310 "® 9.4610" 9 5.11 10 ~ 7 1.0510 "8 3.3710" 8 1, 71 10 "7 2.6410" ® 3.1410 "8

6.710 "6 4.8210" 5 2.3 10 "6 1.55 10" 6 1.21 10 ~ 7 9.1 10 ~ 7 2.1 10 "6 7.3310" 6 2.710T6

6.61er5

1,410T6 8,710 ~ 7

13

5

10

15

20

25

30

35

40

45

50

55

CH 681 010 A5

IQ table

Examples

ICso

BDZ receivers

13

1.8510 "®

5.510T5

14

9.2210 "®

1,510 "®

15

1.2 1CT7

3,610T6

16

5.3510 "8

61 (T7

17

8.7510 "9

4.710 "®

18

2.3 10 "8

4.41 10 "5.

19

6.3610 "®

2,710 "7

20

1.4610 ~ 7

1.610 "®

21

8.6610 "®

8.1 10 "7

22

8.1810 "®

6.1 10 ~ 7

23

1.2410 "®

1,210 "6

24

3.2710 "®

3.3 10 "®

Table l C

Examples

ICso

BDZ receivers

25

1.1310-®

6.3 10 ~ 7

26

6.56 10 ~ 9

6.1 10-7

27

8.4510 "®

4.8 10 "5

28

9.0610 "®

4.310 "®

29

9.0510 "®

1.2310 "®

30

1.0410-7

3,610-7

31

7.1010 "®

2.3 10 ~ 7

32

8.7510 "9

1.3 10 "®

33

4.1210 "®

. 5.710 "®

34

1.2810 "7

7.210 "7

14

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 681 010 A5

Table li A

Examples

Overall protection in%

1

54.2 "*

2

36.3 **

S

34.3 **

4

$

CO co

5

29.4 **

6

27.8 **

7

14.8 NS

8

26.2 *

9

31.2 **

10

10.3 NS

11

46.5 ***

12

34.1 **

13

32.1 **

14

19.7 NS

15

35.8 **

16

29.3 **

17

11.1 NS

18

12.6 NS

19

45.6 ***

20

32.7 **

Table II B

Examples

Overall protection in%

21

34.1 ** -

22

48.1 ***

23

37.5 **

24

38.7 **

25

14.7 NS

26

26.5 *

27

33.3 **

28

35.3 **

29

51.6 ***

30

16.1 NS

31

36.2 **

32

30.3 **

33

24.8 *

34

34.7 **

15

5

10

15

20

25

30

35

40

45

50

55

CH 681 010 A5

Claims (3)

Claims 1) Process for the preparation of thieno-triazolo-diazepine derivatives of general formula A - a phenyl group unsubstituted or substituted by a linear or branched alkyl group having up to 5 carbon atoms, an alkoxy group having up to 5 carbon atoms, a halogen atom, a trifluoromethyl group or a phenoxy group substituted or not, - furan or thiophene and, of their therapeutically acceptable salts, which consists in treating the thieno-triazolodiazepine compound of formula B yu with a stoichiometric amount of the derivative (C) RSCH2COOH in which R is as defined above, in an aprotic solvent, in the presence of a slight stoichiometric excess of dicyclocarbodi-imide at a temperature between 0 ° C and 60 ° C, then reacting the resulting compound of formula 16 5 10 15 20 25 30 35 40 45 50 55 60 65 CH 681 010 A5 in which 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 from formula: NHj E. 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 general formula A in which Y represents an oxygen atom. 2. Process for the preparation of thienotriazolo-diazepine derivatives of general formula A according to claim 1 and their therapeutically acceptable salts, which consists in treating the thieno-triazolodiazepine compound of formula B according to claim 1 with a stoichiometric amount of the derivative ( C) RSCH2COOH 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, to react the resulting compound of formula D according to claim 1 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 an atom of sulfur, then reacting the compound thus obtained with 3 to 5 stoichiom equivalents tric of hydrazine hydrate in a protic solvent at a temperature between room temperature and 50 ° C and finally, cyclizing, in a protic solvent, the compound thus obtained of formula: 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 general formula A in which Y represents a sulfur atom. 3. Preparation process according to claim 1 or claim 2 wherein the reaction steps are carried out under an inert atmosphere. 17