JPH0686458B2 - A new method for preparing cheno-triazolo-diazepine derivatives. - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a thieno-triazolo-, which is particularly useful as an anti-asthma agent, an anti-allergic agent and a gastrointestinal protector.
The present invention relates to a method for producing a new derivative of diazepine.

More specifically, the present invention provides the following formula (I): (In the formula, Y represents an oxygen atom or a sulfur atom, R is a lower linear alkenyl group up to C ₅ ; a linear or branched alkyl group up to C ₂₀ ; a cyclic up to C ₆ Groups; up to C ₅ straight or branched chain alkyl groups substituted with aryl or heteroaryl groups; up to C ₅ alkyl or lower alkoxy groups, phenoxy groups, up to C ₅ lower alkyl A phenyl group substituted with one or several of a sulfonyl group, a fluorine atom, a chlorine atom or a trifluoromethyl group; a condensed bicyclic residue containing a hetero atom; and a phenyl group, a heteroaryl group or a condensed dicyclic group (Representing a sulfonyl group substituted with a cyclic group), and a method for producing a thieno-triazolo-diazepine derivative and a pharmaceutically acceptable salt thereof.

Prior art documents in the technical field of the present invention include US Pat. No. 4,621,083 (or European Patent No. 176,927), which includes PAF (platelet activating factor)-
Thieno-triazolo-diazepines having antagonistic activity have been described.

The novel compound represented by the above formula (I) produced by the method of the present invention has a PAF-antagonistic activity which is 10 to 1000 times stronger than the PAF-antagonistic activity of the diazepines described in the above patent specification. It also shows even more powerful efficacy.

According to the gist of the present invention, the following formula (I) (In the formula, Y represents an oxygen atom or a sulfur atom, R is a lower linear alkenyl group up to C ₅ ; a linear or branched alkyl group up to C ₂₀ ; a cyclic up to C ₆ Groups; up to C ₅ straight or branched chain alkyl groups substituted with aryl or heteroaryl groups; up to C ₅ alkyl or lower alkoxy groups, phenoxy groups, up to C ₅ lower alkyl A phenyl group substituted with one or several of a sulfonyl group, a fluorine atom, a chlorine atom or a trifluoromethyl group; a condensed bicyclic residue containing a hetero atom; and a phenyl group, a heteroaryl group or a condensed dicyclic group (Representing a sulfonyl group substituted with a cyclic group), which is a process for producing a thieno-triazolo-diazepine derivative represented by the following formula (A): A thieno-triazolo-diazepine compound represented by the formula (wherein Y has the above meaning) and an R-N = C = Y derivative (wherein R and Y have the above meaning) (RN =
The amount of the C = Y derivative used is a theoretical amount, preferably a slight excess over the theoretical amount) and reacted for 1/2 to 24 hours under reflux in a protic solvent under nitrogen circulation. B): (Wherein R and Y have the above-mentioned meanings) and hydrazine hydrate (theoretical amount, preferably a slight excess of the theoretical amount) is used under nitrogen circulation in an aprotic solvent. At 0 ° C. to room temperature for 5 minutes to about 1 hour, and finally the following formula (C) obtained: (Wherein R and Y have the above-mentioned meanings) and an orthoacetic acid tri (lower alkyl) ester (excess amount than theoretical equivalent amount, preferably 4 times equivalent amount) is used under nitrogen circulation under protic properties. 15 minutes to 3 hours at room temperature in a solvent,
Then, there is provided a method for producing the thieno-triazolo-diazepine derivative, which comprises cyclizing for 1/2 to 5 hours under reflux. Tri (lower alkyl) orthoacetate
The lower alkyl group of the ester is a (C ₁ -C ₆ ) alkyl group, and an ethyl group is particularly preferable.

The starting material compound represented by the above formula (A) can be produced as described in the following steps (Reference Examples I to VIII).

Reference Example I Preparation of 2-chlorobenzoylmethyl cyanide (compound of the formula below).

Add anhydrous THF 7 to a suitable reactor placed under nitrogen circulation at -70 ° C.
1 and 115.9 g (1.36 mol) of previously dried cyanoacetic acid were added. Then 1. of butyllithium dissolved in hexane.
A 6M solution of 1,715 ml (2.74 mol) was added dropwise. During that time, the temperature rose from -70 ° C to 0 ° C. The reaction mixture was then stirred for 1 hour. Then, the reaction mixture was cooled again to −70 ° C., and a solution of 120 g (0.685 mol) of 2-chlorobenzoyl chloride in anhydrous THF1 was added dropwise thereto. -7
After stirring for 1 hour while maintaining the temperature at 0 ° C, the temperature was raised from -70 ° C to 0 ° C in 1 hour. Then, 3 L of 1N-HC1 solution was added dropwise, and after stirring for several minutes, the reaction mixture was extracted with chloroform. The organic layer was washed with 10% aqueous sodium hydrogen carbonate solution, and then with saturated aqueous sodium chloride solution,
Drying, filtration and evaporation of the solvent gave 135 g of residue. Diisopropyl ether was added to this for recrystallization, the product was filtered, and then washed with hexane to obtain 97.2 g of the title compound (yield 79%).

Reference Example II 2-Amino-3- (2-chlorobenzoyl)
-6-Ethoxycarbonyl-4,5,6,7-tetrahydro-
Preparation of pyrido [3,4-b] thiophene (compound of the following formula) In a 2 L Erlenmeyer Slasco equipped with a cooling tube, 85.5 g (0.501 mol) of N-carboethoxy-4-piperidone dissolved in 550 ml of methanol, 90 g (0.501 mol) of the compound prepared in Reference Example I and 19.3 g of sulfur flower (9.3 g) 0.600 mol) and 44.4 g (0.501 mol) of morpholine were added. The mixture was refluxed for 1 hour. After evaporating 250 ml of solvent, the resulting precipitate of the desired compound was filtered, washed with ethanol, then with diethyl ether, and then dried to obtain 155.4 g (yield 85%) of the title compound.

Reference Example III 2- (Bromoacetamide) -3- (2-
Chlorobenzoyl) -6-ethoxycarbonyl-4,6,6,
Preparation of 7-tetrahydro-pyrido [3,4-b] thiophene (compound of formula) In a 5 L reactor equipped with a suitable apparatus and a separating funnel, 2.5 L of chloroform and 146 g of the compound prepared in Reference Example II (0.40
0 mol) was added. Then, 87.7 g (0.43 mol) of bromoacetyl bromide placed in a separating funnel was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, then washed with 300 ml of ice-cold water, the resulting organic layer was dried over anhydrous magnesium sulfate and then filtered. Chloroform was evaporated from the resulting filtrate and the residue was treated with ethanol. The precipitate formed is filtered, washed with ethanol and then with diethyl ether and then dried to give the title compound 18
4.6 g (yield 95%) was obtained.

Reference Example IV Preparation of 2-aminoacetamido-3- (2-chlorobenzoyl) -6-ethoxycarbonyl-4,5,6,7-tetrahydro-pyrido [3,4-b] thiophene (compound of the following formula) 174.8 g (0.36 mol) of the compound prepared in Reference Example III and 3 l of THF were placed in a 5 l reactor equipped with a gas blowing tube.
The resulting suspension was cooled to 0 ° C. and then gaseous ammonia previously dried over potassium hydroxide was added. Ammonia was added for 8 hours (60 g of ammonia absorbed). The resulting mixture was stirred at 0 ° C. overnight, after which THF2l was evaporated under reduced pressure, then 750 ml of ethyl acetate was added. After decantation, the organic layer was washed once with 300 ml of 10% aqueous sodium chloride solution and three times with 300 ml of water,
Then, it was dried over anhydrous magnesium sulfate. After filtration, the solvent was partially evaporated on a rotary evaporator. It was then left overnight in the refrigerator to form a precipitate. The precipitate was filtered, washed with diethyl ether and then dried to obtain 119 g of the title compound. The remaining organic layer was concentrated and then treated with 1.5 l of a diethyl ether / THF mixture (3/1 by volume) to give 14.6 g of the title compound (88% overall yield).

Reference Example V 5- (2-chlorophenyl) -8-ethoxycarbonyl-6,7,8,9-tetrahydro-3H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1, 4-diazepine-2
-Production of one (a compound of the following formula) A 2 liter reactor equipped with a stirrer, a cooling device and a heating device was placed under nitrogen circulation, to which the compound 12 prepared in Reference Example IV was added.
6.6 g (0.3 mol) and 800 ml of pyridine were added. The reaction mixture was stirred for 18 hours. After confirming that all the starting materials had reacted, part of the pyridine was evaporated under reduced pressure on a rotary evaporator.

The obtained oily substance (dark brown) was dissolved in ethanol 1. After cooling in an ice bath, the formed precipitate was filtered and washed with ethanol and diisopropyl oxide to obtain 101.3 g of the title compound (yield 83.6%).

Reference Example VI 5- (2-chlorophenyl) -8-ethoxycarbonyl-6,7,8,9-tetrahydro-3H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1, 4-diazepine-2
-Production of thione (compound of formula) In a 3 L reactor equipped with appropriate devices, 93 g (0.230 mol) of the compound prepared in Reference Example V and 1.75 L of pyridine were placed. After the above compounds were dissolved, 56.3 g of phosphorus pentasulfide (0.2
5 mol) and then the reaction mixture at 80-85 ° C.
Stir for hours. Then the pyridine was evaporated and the resulting residue was treated with ice cold water. The resulting mixture was then extracted with methylene chloride, dried over anhydrous magnesium sulfate, filtered, the methylene chloride was evaporated and then treated with diethyl ether. The product obtained was then filtered and treated with 700 ml of acetonitrile. The resulting suspension was heated at 60 ° C. for 30 minutes then left to cool. Then, filter, wash with acetonitrile, then with diethyl ether, then dry to give 80.2 g of the title compound.
(Yield 83%) was obtained.

Reference Example VII 5- (2-chlorophenyl) -6,7,8,9-tetrahydro-3H-pyrido [4 ', 3': 4,5] thieno [3,2-
f] Production of 1,4-diazepine-2-thione (compound of the following formula) In a 2 liter reactor equipped with an appropriate device, 71.4 g (0.17 mol) of the compound prepared in Reference Example VI, 116 g (1.30 mol) of pelletized potassium hydroxide (85%) and ethanol / water (volume ratio) were used.
19/1) Mixture 1 was added. The reaction mixture was refluxed for 18 hours. After confirming that all the starting materials have reacted,
Ethanol was distilled off, and the obtained residue was treated with ice-cold water. The mixture was then extracted twice with chloroform. The obtained aqueous layer was acidified with acetic acid to pH = 6.5, and then the pH was adjusted to pH = 7.5 by adding sodium hydrogen carbonate. The precipitate formed is filtered off, washed twice with water, twice with ethanol and once with ether, and then under reflux at a mixture of dichloromethane / ethanol (3/1 by volume) 500.
It was washed with m1 for 30 minutes. It is then filtered, washed with diethyl ether and then dried under reduced pressure to give the title compound.
47.3 g (yield 80%) was obtained.

The starting compound in which Y = 0 in the above formula (A) is obtained by reacting the compound obtained in Reference Example V above with a deprotecting agent.

Reference Example VIII 5- (2-chlorophenyl) -6,7,8,9-
Tetrahydro-3H-pyrido [4 ', 3': 4,5] thieno [3,
2-f] 1,4-diazepin-2-one (compound of formula) A reactor equipped with a heating device was placed under nitrogen circulation, and 94.5 g (0.234 mol) of the compound prepared in Reference Example V, 152.1 g (2.34 mol) of 90% potassium hydroxide in pellet form, and ethylene glycol monoethyl I added 900m1 of ether.
The mixture was heated to reflux temperature for 1 hour and maintained at reflux for 1 hour. The resulting solution is then crushed with ice 1.2k.
In addition to g, it was then acidified to pH 5.3 with hydrochloric acid (d = 1.18). Then potassium carbonate was added to adjust the pH to 8.3.
The solution was then extracted 3 times with 500 ml of methylene chloride.
The organic layer obtained was washed with 450 ml of 10% aqueous sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and then evaporated. The residue obtained was treated with diisopropyl ether. After washing with diisopropyl ether,
After drying, the title compound (55.9 g, yield 72%) was obtained.

The invention is illustrated by the following examples.

Example 1 6- (2-chlorophenyl) -9- [4- (methoxy)
Phenylthiocarbamoyl] -7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,
Preparation of 2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [compound in which Y = S, R = 4-methoxyphenyl group in the above formula (I)].

First step: 5- (2-chlorophenyl) -8- [4- (methoxy) phenylthiocarbamoyl] -6,7,8,9-tetrahydro-3H-pyrido [4 ', 3': 4,5] thieno. 〔3,2-
f] Production of 1,4-diazepine-thione (Production of compound of formula (B) from compound of formula (A)) One reactor equipped with a stirrer and a cooling device was placed under nitrogen circulation, and 5- (2) -Chlorophenyl) -6,7,8,9-
Tetrahydro-3H-pyrido [4 ', 3': 4,5] thieno [3,
2-f] 1,4-diazepine-2-thione (purity 93%) 40 g
(0.115 mol) and 500 ml of methanol were added. afterwards,
18.5 ml (0.123 mol) of p-methoxyphenyl isothiocyanate was added to the resulting orange suspension and then refluxed for 2 hours. After confirming that all the starting materials have reacted,
The mixture was cooled. The mixture was filtered and the residue obtained was washed successively with ethanol then diisopropyl oxide and then dried overnight at 65 ° C. to give 49 g of the title compound (yield 83
%) Was obtained.

Second step: 5- (2-chlorophenyl) -8- [4- (methoxy) phenylcarbamoyl] -2-hydrazino-6,
Preparation of 7,8,9-tetrahydro-3H-pyrido [4 ', 3', 4,5] thieno] 3,2-f] -1,4-diazepine [from compound of formula (B) to formula (c)] Production of compound of 1] One reactor equipped with a stirrer and a cooling device was placed under nitrogen circulation, and 5- (2-chlorophenyl) -8- [4-
(Methoxy) phenylthiocarbamoyl] -6,7,8,9-
Tetrahydro-3H-pyrido [4 ', 3': 4,5] thieno [3,
2-f] 40 g (0.078 mol) of 1,4-diazepine-2-thione and 350 ml of tetrahydrofuran were added. After that, the mixture was cooled to 10 ° C. and then hydrazine hydrate 4.1 ml
(0.081 mol) was added. Addition of hydrazine hydrate is 15
It took less than a minute. A reddish brown solution with a small amount of dark precipitate was thus obtained, which was then filtered. Then, 9/10 of tetrahydrofuran was distilled off from the filtration, and 400 ml of absolute ethanol was added to the residue. After adding absolute ethanol (aft
er priming) formed a precipitate. The mixture was stirred on the ice bath for 1 hour. The precipitate was then filtered, washed with ethanol, then diisopropyl oxide, and then dried under reduced pressure at 65 ° C. overnight to give 29.7 g of the title compound.
The washing solution was concentrated, and the obtained residue was treated with ethanol, filtered, and washed with ethanol and then diethyl ether to obtain 4.5 g of the title compound (total yield 86%) Third step: 6- (2- Chlorophenyl) -9- [4- (methoxy) phenylthiocarbamoyl] -7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno] 3,2- f] Production of 1,2,4-triazolo [4,3-a] -1,4-diazepine [Production of compound of formula (I) from compound of formula (c)] 1 reaction equipped with stirrer and cooling device The vessel was placed under nitrogen circulation, to which 5- (2-chlorophenyl) -8- [4-
(Methoxy) phenylthiocarbamoyl] -2-hydrazino-6,7,8,9-tetrahydro-3H-pyrido [4 ', 3':
25.5 g (0.05 mol) of 4,5] thieno [3,2-f] -1,4-diazepine and 500 ml of absolute ethanol were added. Then 37 ml of triethyl orthoacetate (0.20 mol) was added. After 30 minutes, the solution turned red and was then refluxed for 2 hours (at 70 ° C. a precipitate started to form). Then, the mixture was cooled to 10 ° C., the formed precipitate was filtered, washed successively with ethanol and then diethyl ether, and then dried under reduced pressure at 90 ° C. to obtain 24.6 g (yield 92%) of the title compound. . Melting point: 197-104
℃; appearance shape: light beige powder.

The following compounds were prepared as described in Example 1.
The compound in the above formula (I) in which Y = S was produced as described in Example 1. When Y = 0 in the above formula (I), the compound in Example 1, Step 1 is 5- (2-chlorophenyl) -6,7,8,9-tetrahydro-3H-pyrido [4 ', 3': 4,5] Thieno [3,2-f] 1,4-
5- (2-chlorophenyl) -6,7,8,9-tetrahydro-3H-pyrido [4 ', in place of diazepine-2-thione
3 ′: 4,5] thieno [3,2-f] 1,4-diazepin-2-one was used to initiate the reaction and then the appropriate isocyanate derivative was reacted in place of the isothiocyanate derivative. The reaction was carried out in 3 steps under the same conditions as described in Example 1.

Example 2 6- (2-chlorophenyl) -9- (4-methoxy) phenylcarbamoyl] -7,8,9,10-tetrahydro-1-
Methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f]
1,2,4-Triazolo [4,3-a] 1,4-diazepine [Compound in which Y = 0 and R = 4-methoxyphenyl group in the above formula (I)] Melting point: 202 ° C .; Appearance shape: Light yellowish white powder Example 3 6- (2-chlorophenyl) -9-tert-butylcarbamoyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] Thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [Compound in which Y = 0 and R = tert-butyl group in the above formula (I)] Melting point : 240-245 ° C; Appearance: White powder Example 4 6- (2-chlorophenyl) -9-tert-butylthiocarbamoyl-7,8,9,10-tetrahydro-1-methyl-4H
-Pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [in the above formula (I), Y = S, Compound in which R = tert-butyl Group] Melting point: 189 ° C .; appearance shape: white powder Example 5 6- (2-chlorophenyl) -9-hexadecylthiocarbamoyl-7,8,9,10-tetrahydro- 1-methyl-4H
-Pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [in the above formula (I), Y = Compound in which S, R = hexadecyl group] Melting point: 168 to 170 ° C; Appearance: Amorphous white powder Example 6 6- (2-chlorophenyl) -9-isopropylcarbamoyl-7,8,9,10-tetrahydro- 1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [the above formula ( Compound in which Y = 0 and R = isopropyl group in I)] Melting point: 214 ° C .; Appearance shape: white powder Example 7 6- (2-chlorophenyl) -9-isopropylthiocarbamoyl-7,8,9,10- Tetrahydro-1-methyl-4H
-Pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [in the above formula (I), Y = Compound in which S, R = isopropyl group] Melting point: 205 to 206 ° C; Appearance: White powder Example 8 6- (2-chlorophenyl) -9- (3,4,5-trimethoxy) phenylcarbamoyl-7,8 , 9,10-Tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,
2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [Compound wherein Y = 0 and R = 3,4,5-trimethoxyphenyl group in the above formula (I) ] Melting point: 176 to 179 ° C; Appearance form: pale yellowish white powder Example 9 6- (2-chlorophenyl) -9- (3,4,5-trimethoxy) phenylthiocarbamoyl-7,8,9,10-tetrahydro -1-Methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [the above formula Compound in which Y = S and R = 3,4,5-trimethoxyphenyl Group in (I)] Melting point: 184 ° C; Appearance shape: white powder Example 10 6- (2-chlorophenyl) -9- (tert- Butyl) phenylcarbamoyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,
2,4-Triazolo [4,3-a] 1,4-diazepine [Compound in which Y = 0 and R = 4-tert-butylphenyl group in the above formula (I)] Melting point: 218 to 220 ° C .; appearance Form: pale yellowish white powder Example 11 6- (2-chlorophenyl) -9- (4-tert-butyl) phenylthiocarbamoyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ' , 3 ′: 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [in the above formula (I), Y = S, R = 4 Compound that is -tert-butylphenyl group] Melting point: 225 to 226 ° C; Appearance: White powder Example 12 6- (2-chlorophenyl) -9- (2-trifluoromethyl) phenylthiocarbamoyl-7,8, 9,10-Tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4- Diazepine [in the above formula (I) And a compound in which Y = S and R = 2-trifluoromethylphenyl group] Melting point: 179 to 180 ° C; Appearance shape: white powder Example 13 6- (2-chlorophenyl) -9- (3-trifluoromethyl) Phenylthiocarbamoyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4, 3-a] 1,4-diazepine [compound in which Y = S and R = 3-trifluoromethylphenyl group in the above formula (I)] Melting point: 169 to 170 ° C; Appearance: White powder Example 146 -(2-Chlorophenyl) -9- (4-trifluoromethyl) phenylcarbamoyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3 , 2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [in the above formula (I), Y = 0, R = 4-trifluoromethylphenyl Compound which is a nyl group] Melting point: 212 to 217 ° C; Appearance shape: pale beige powder Example 15 6- (2-chlorophenyl) -9- (4-trifluoromethyl) phenylthiocarbamoyl-7,8,9, 10-Tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [ Compound in which Y = S and R = 4-trifluoromethylphenyl group in the above formula (I)] Melting point: 179 to 180 ° C; Appearance shape: white powder Example 16 6- (2-chlorophenyl) -9- ( 4-Fluoro) phenylthiocarbamoyl-7,8,9,10-tetrahydro-1
-Methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-
f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [compound in which Y = S and R = 4-fluorophenyl group in the above formula (I)] Melting point: 179 to 180 ° C Appearance: pale yellowish white powder Example 17 6- (2-chlorophenyl) -9- (2,3-dichloro)
Phenylcarbamoyl-7,8,9,10-tetrahydro-1-
Methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine [compound in which Y = 0 and R = 2,3-dichlorophenyl group in the above formula (I)] Melting point: 200 to 204 ° C .; Appearance shape: white powder Example 18 6- (2-chlorophenyl) -9- (4-phenoxy)
Phenylcarbamoyl-7,8,9,10-tetrahydro-1-
Methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine [compound in which Y = 0 and R = 4-phenoxyphenyl group in the above formula (I)] Melting point: 187 to 193 ° C; appearance Form: white powder Example 19 6- (2-chlorophenyl) -9- (α-methyl) phenethylthiocarbamoyl-7,8,9,10-tetrahydro-1
-Methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-
f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [compound in which Y = S and R = (α-methyl) phenethyl group in the above formula (I)] Melting point: 210- 214 ° C .; appearance: white powder Example 20 6- (2-chlorophenyl) -9- (β-methyl) phenethylthiocarbamoyl-7,8,9,10-tetrahydro-1
-Methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-
f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [Compound in which Y = S and R = (β-methyl) phenethyl group in the above formula (I)] Melting point: 200 ° C Appearance: pale yellowish white powder Example 21 6- (2-chlorophenyl) -9- (4-methylsulfonyl) phenylthiocarbamoyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [in the above formula (I), Y = S, R = (Compound which is a (4-methylsulfonyl) phenyl group] Melting point: 214 to 215 ° C; Appearance: Light beige powder Example 22 6- (2-chlorophenyl) -9- (2,4-di-tert-
Butyl) phenylthiocarbamoyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [ 4,3-a] 1,4-diazepine [in the above formula (I), Y = S, R = (2,4-di-t
Compound having an ert-butyl) phenyl group] Melting point: 146 to 148 ° C; Appearance: Light beige powder Example 23 6- (2-chlorophenyl) -9-benzylcarbamoyl-7,8,9,10-tetrahydro- 1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [the above formula ( Y in I)
= 0, compound in which R = benzyl group] Melting point: 246 to 249 ° C; Appearance shape: pale yellowish white powder Example 24 6- (2-chlorophenyl) -9- (2-furfuryl)
Thiocarbamoyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4
-Triazolo [4,3-a] 1,4-diazepine [Compound in which Y = S and R = 2-furfuryl group in the above formula (I)] Melting point: 174 ° C; Appearance: Light yellow powder Example 25 6- (2-chlorophenyl) -9- (3-quinolyl) thiocarbamoyl-7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3, 2-f] 1,2,4-
Triazolo [4,3-a] 1,4-diazepines [formula (I) above
In which Y = S and R = 3-quinolyl group] Melting point: 192-193 ° C; Appearance: Light beige powder Example 26 6- (2-chlorophenyl) -9-cyclohexylthiocarbamoyl-7,8, 9,10-Tetrahydro-1-methyl-
4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [Y in formula (I) above] = S, R = Compound of cyclohexyl group] Melting point: 209 to 214 ° C; Appearance: White powder Example 27 6- (2-chlorophenyl) -9-cyclohexylcarbamoyl-7,8,9,10-tetrahydro-1 -Methyl-4H-
Pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepines [Y = 0 in the above formula (I) , R = cyclohexyl group] Melting point: 220 ° C .; Appearance: pale yellowish white powder Example 28 6- (2-chlorophenyl) -9-allylthiocarbamoyl-7,8,9,10-tetrahydro-1- Methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [formula (I) above] At Y
= S, compound in which R = allyl group] Melting point: 224 to 226 ° C; appearance shape: pale yellowish white powder Example 29 6- (2-chlorophenyl) -9- (2,4-difluoro) phenylcarbamoyl-7, 8,9,10-Tetrahydro-
1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-
f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [compound in which Y = 0 and R = 2,3-difluorophenyl group in the above formula (I)] Melting point: 245 to 250 ° C .; Appearance form: white powder Example 30 6- (2-chlorophenyl) -9- (phenylsulfonyl) thiocarbamoyl-7,8,9,10-tetrahydro-1-
Methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine [Compound in which Y = S and R = phenylsulfonyl group in the above formula (I)] Melting point: 205 ° C; Appearance: White powder Example 31 6- (2-chlorophenyl) -9- (2-furylsulfonyl) thiocarbamoyl-7,8,9,10-tetrahydro-1
-Methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-
f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [compound in which Y = S and R = 2-furylsulfonyl group in the above formula (I)] Melting point: 222 to 226 ° C Appearance: light beige powder Example 32 6- (2-chlorophenyl) -9- (2-thienylsulfonyl) carbamoyl-7,8,9,10-tetrahydro-1-
Methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine [Compound in which Y = 0 and R = 2-thienylsulfonyl group in the above formula (I)] Melting point: 233 ° C; Appearance: White powder Example 33 6- (2-chlorophenyl) -9- (2-pyrrolylsulfonyl) thiocarbamoyl-7,8,9,10-tetrahydro-
1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-
f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [compound in which Y = S and R = 2-pyrrolylsulfonyl group in the above formula (I)] Melting point: 211-213 C .; appearance: white powder Example 34 6- (2-chlorophenyl) -9- (3-pyridylsulfonyl) carbamoyl-7,8,9,10-tetrahydro-1-
Methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine [compound in which Y = 0 and R = 3-pyridylsulfonyl group in the above formula (I)] Melting point: 184 to 189 ° C; appearance Form: light beige powder Example 35 6- (2-chlorophenyl) -9- (4-quinolylsulfonyl) thiocarbamoyl-7,8,9,10-tetrahydro-
1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-
f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [compound in which Y = S and R = 4-quinolylsulfonyl group in the above formula (I)] Melting point: 240 to 253 C .; appearance shape: white powder Example 36 6- (2-chlorophenyl) -9- (4-morpholinylsulfonyl) carbamoyl-7,8,9,10-tetrahydro-
1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-
f] 1,2,4-triazolo [4,3-a] 1,4-diazepine [compound in which Y = 0 and R = 4-morpholinylsulfonyl group in the above formula (I)] Melting point: 207 to 211 ° C; Appearance: White powder Toxicity Each of the thieno-triazolo-diazepine derivatives represented by the above formula (I) produced by the method of the present invention is toxic to mice by oral administration at a dose of 1 g / kg (body weight). I was not able to admit. For intraperitoneal (IP) administration in mice, Example 10,
Only compounds 17 and 18 and 33 have LD ₅₀ values of 0.4 to 1 g / kg (body weight)
However, no toxicity was observed for the other compounds at the total dose of 1 g / kg (body weight).

Pharmacological test Various pharmacological tests were conducted on the thieno-triazolo-diazepine derivative represented by the above formula (I) produced by the method of the present invention. The outline of the pharmacological test is as follows.

1) Aggregation-inhibiting effect on PAF-induced platelet aggregation This test was conducted by “Lab.Invest.”, 48 , 98 (1980) (R.KINLOU).
GH.RATHBON, JPCAZENAVE, M.PACKHAM and F.MUSTARD et al.). New Zealand rabbits (male New Zealand rabbits with an average weight of 5 kg) were used in this study.

The measurement was carried out at 57 ° C using a chrono-Log Coulronics aggregometer connected to a graph recorder. The measurement results (units of molecular concentration) are shown in the center column of Table I.

2) Inhibitory effect on binding to benzodiazepine receptors The interest of the previous test depends on the results obtained in this test.

That is, since the compound of the present invention has a structure similar to benzodiazepine, it is important to confirm whether or not a specific benzodiazepine activity does not appear at a dose at which platelet aggregation is suppressed.

Therefore, this test is based on the method of MOHLER H. and RICHARD JG ["N
ature, 294 , 763-765 (1981) “In vitro (in vitr
o) Interaction of agonist and antagonist with benzodiazepine receptor].

This test is ³ H-RO-15-47 as a tracer
88 and ³ H-RO-5-4864 (NEN) as a control antagonist
RO-15-4788 and RO-5-4864 were used in rat brain incubated at 4 ° C. for 1.5 hours. RO-15-47
88 and RO-5-4864 are compounds manufactured by Roche and are control antagonists of the benzodiazepine receptor. ³ H-RO-15-4788 and ³ H-RO-5-4864 are tritiated compounds of the above compounds.

The results obtained are shown in the right column of Table I in units of molecular concentration. BDZ in the table means benzodiazepine.

3) Effects on PAF-induced bronchospasm "Eur. J. Pharmacol.", 127 , 83-95 (1986) [S. DESQUAN
D, C.TOUAY, J.RANDON, V.LAGENTE, B.VILAIN, I.MARIDONNEA
U-PARINT, A.ETIENNE, J.LEFORT, P.BRAQUET and B.VARGAFT
IG et al. “Interference of BN 52021 (Ginkolide B) wit
h the bronchopulmonary effects of PAF-acether in t
PAF was administered intravenously to anesthetized guinea pigs to induce bronchial stenosis with leukopenia and thrombocytopenia.

Then, a male Hartley guinea pig (body weight 400 to 450 g) (Charles River breed) anesthetized with urethane (2 g / kg body weight, IP administration) was tracheotomized, and 70 to 80 times / min using a respiratory pump, Insufflation rate: Air 1m1 / weight 100g
I made a forced breath on the condition. A catheter for drug injection was inserted into the jugular vein, and a catheter for blood collection was inserted into the carotid artery. According to the method of Konzett and Rssler, the initial resistance was kept constant under a pressure of 10 cm of water, and a bronchospasm exchange (transducor): UGO BASIRE and recorder (enregistror): G
Excess air was measured using EMINI. Guinea pigs have pancuronium (pan) to control their natural respiration.
curonium) [Pavulon] was administered intravenously (IV).

The thieno-triazolo-diazepine derivative represented by the above formula (I) prepared by the method of the present invention and the reference compound WEB2
086 (see above Boehringer patent; U.S. Pat. No. 4,621,083) were each prepared as a viscous aqueous suspension, administered orally and stimulated with PAF one hour later.

Bronchial stenosis has the following formula: (Where A represents the induced bronchial stenosis in mm,
B represents the maximum bronchial stenosis in mm) and was evaluated by calculating the bronchial stenosis rate.

Dosage Form-Dose: In the treatment of humans, the thieno-triazolo-diazepine derivative of the above formula (I) produced by the method of the present invention is preferably administered orally. Preferred dosage forms include tablets, gelatin capsules and the like. In the above case, the dose to be administered is usually 50 mg to 500 mg per diem.

The unit dose is preferably 50 mg combined with the appropriate carrier and drug.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Laurent, Jean-Pierre France. 75015-Paris. Liu Brome. 159 (72) Inventor Laurent, Alain France. 91120 Paraiso. Liu De Piveert 10

Claims (2)

[Claims] 1. The following formula (I): (In the formula, Y represents an oxygen atom or a sulfur atom, R is a lower linear alkenyl group up to C ₅ ; a linear or branched alkyl group up to C ₂₀ ; a cyclic up to C ₆ Groups; up to C ₅ straight or branched chain alkyl groups substituted with aryl or heteroaryl groups; up to C ₅ alkyl or lower alkoxy groups, phenoxy groups, up to C ₅ lower alkyl A phenyl group substituted with one or several of a sulfonyl group, a fluorine atom, a chlorine atom or a trifluoromethyl group; a condensed bicyclic residue containing a hetero atom; and a phenyl group, a heteroaryl group or a condensed dicyclic group (Representing a sulfonyl group substituted with a cyclic group), which is a process for producing a thieno-triazolo-diazepine derivative represented by the following formula (A): A thieno-triazolo-diazepine compound represented by the formula (wherein Y has the above meaning) and an RN = C = Y derivative (wherein R and Y have the above meaning) under nitrogen circulation. The reaction was carried out in a protic solvent under reflux for 1/2 to 24 hours, and then the obtained formula (B): (Wherein R and Y have the above-mentioned meanings) and hydrazine hydrate are reacted in an aprotic solvent under nitrogen circulation at a temperature of 0 ° C. to room temperature for 5 minutes to about 1 hour. Finally, the following equation (C) obtained: (Wherein R and Y have the above-mentioned meanings) and an orthoacetic acid tri (lower alkyl) ester under nitrogen circulation in a protic solvent at room temperature for 15 minutes to 3 hours,
Then, the method for producing the thieno-triazolo-diazepine derivative, which comprises cyclizing for 1/2 to 5 hours under reflux. 2. The method of claim 1 wherein the orthoacetic acid tri (lower alkyl) ester is triethyl orthoacetate.