JP2959591B2 - Thienotriazolodiazepine compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel thienotriazolodiazepine compound having a cyclic amino side chain useful as a medicine, having both a platelet activating factor antagonistic action and an antihistamine action.

BACKGROUND OF THE INVENTION As described in U.S. Pat. No. 3,904,641, 6- (o-chlorophenyl)
-8-Ethyl-1-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] [1,4] diazepine [hereinafter referred to as etizolam [international general name (INN)]] Certain s-triazolo [3,4
It is known that -c] thieno [2,3-e] [1,4] diazepine compounds exhibit useful pharmacological activities on the central nervous system such as anxiolytic activity and anticonvulsant activity. Meanwhile, the Japanese Journal of Pharmacology (Japa
nese Journal of Pharmacology), Vol. 44, 381-
Page 391 (1987) revealed that etizolam exhibits an antagonistic effect on platelet-activating factor (hereinafter referred to as PAF).
Furthermore, according to JP-A-61-176591, 2- [4
-(2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-
a] [1,4] Diazepin-2-yl] -ethane-1-
Thienotriazolo represented by carboxylic acid morpholide
When the 1,4-diazepino-2-carboxylic acid amide compound is P
It has been shown to exhibit AF antagonism and
Nos. 81282 and 62-240686 and 6
JP-A-3-33382, JP-A-1-156982 and JP-A-2-256681 disclose various thienotriazolodiazepine compounds having a PAF antagonistic action, respectively.

[0002]

SUMMARY OF THE INVENTION Benvenis, 1972
te et al. found a factor that strongly aggregates platelets from rabbit basophils and named it platelet activating factor (PAF). By 1980, Hanahan et al.
An alkyl ether type phosphoglyceride having an acetyl group at the 1-position, that is, 1-O-hexadecyl or octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine was identified. Since then, the physiological role of PAF has been elucidated, and platelet aggregation in vivo, decreased blood pressure, immediate allergic reactions, smooth muscle contraction, inflammation, pain, edema, and respiratory, cardiovascular, and venous in vivo. It has been known to be a factor in various physiological responses including modulation of the system. In addition, histamine is a chemical mediator released from mast cells in the largest amount, and is known to cause smooth muscle contraction, dilation of capillaries, increased vascular permeability and the like, similar to PAF. It has become. Therefore, compounds having both PAF antagonistic activity and histamine antagonistic activity are useful for inflammatory diseases, allergic diseases, anaphylactic shock, septic shock, vascular diseases such as DIC (disseminated intravascular coagulation), myocardial diseases, asthma, and adulthood. P for respiratory diseases
It is extremely useful for more diseases caused by AF or histamine. Therefore, it is desired to provide a thienotriazolodiazepine compound which is effective by oral or intravenous administration, has a long-lasting effect, and has both a strong PAF antagonistic action and a histamine antagonistic action with less inhibitory action on the central nervous system. .

[0003]

Means for Solving the Problems In view of the above points, the present inventors have conducted intensive studies and as a result, in a series of studies, found that thieno [3,2-f] [1,2,4] triazolo [ 4,3-
a) [1, 4] By introducing a certain cyclic aminoalkyl side chain at the 2-position of the diazepine compound, not only PAF antagonistic effect but also strong histamine antagonistic effect is observed, and it is effective by oral and intravenous administration. The present inventors have found that the present invention exhibits a long duration of action, and further, has a small central inhibitory action such as a sedative action and a muscle relaxing action, and has completed the present invention. That is, the present invention relates to the general formula

Embedded image [Formula Note, Ar is pyridyl, phenyl or a substituent as halogen, hydroxyl, lower alkyl, lower alkoxy and formula

Embedded image (Wherein, W is _{- (CH 2) m - (} m is an integer of 1~4), -. O -, - OCH 2 - or -CH ₂ OCH ₂
And R ⁵ , R ⁶ and R ⁷ are the same or different and each represents hydrogen, halogen, a hydroxyl group, lower alkyl or lower alkoxy. ) Phenyl having 1 to 3 arbitrarily selected from the groups represented by R), R ¹ is hydrogen or lower alkyl, R ² is hydrogen, lower alkyl or cycloalkyl, R ³ is hydrogen, trifluoromethyl or lower. A represents alkyl having 1 to 6 carbon atoms, linear alkylene having 1 to 6 carbon atoms, alkylene having 1 to 6 carbon atoms substituted with lower alkyl, or 1 to 1 carbon atoms substituted with 1 to 3 hydroxyl groups.
Represents 6 straight- or branched-chain alkylenes, or A is Q-, Q-A-, or a 5- to 7-membered saturated carbon ring or nitrogen atom bonded to R ¹ and condensed to a thiophene ring. A nitrogen-containing heterocycle having a Q-CO- group can also be formed. Q is the formula

Embedded image Wherein R ⁴ is phenyl, aralkyl, arylcarbonyl, halogen as a substituent, hydroxyl, lower alkyl,
Phenyl, aralkyl or arylcarbonyl having 1 to 3 arbitrarily selected from lower alkoxy and trifluoromethyl, formula

Embedded image (Wherein R ⁸ and R ⁹ are the same or different and each represents hydrogen, halogen, trifluoromethyl, amino, nitro,
C represents a cyano, a hydroxyl group, a lower alkyl or a lower alkoxy, and B represents a hydrogen, a hydroxyl group or an esterified hydroxyl group. ) Represents a lower alkyl having a hydroxyl group and / or a carbonyl group, and X represents CH or a nitrogen atom. Or a group represented by the formula

Embedded image (Wherein R ¹⁰ and R ¹¹ are the same or different and are each independently hydrogen, halogen, trifluoromethyl, amino, nitro,
Represents cyano, hydroxyl group, lower alkyl or lower alkoxy. ). ] Or a pharmaceutically acceptable acid addition salt thereof.

In the definitions of the above symbols, halogen is chlorine,
Bromine, fluorine, iodine, lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Tertiary butyl, pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, hexyl and the like; lower siloxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy , 1-ethylpropyloxy, hexyloxy, etc., pyridyl is 2-pyridyl, 3-pyridyl, 4-pyridyl, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., and aralkyl is benzyl. And 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl and the like, and arylcarbonyl means benzoyl, thiazolylcarbonyl, imidazolylcarbonyl and the like. Hydroxymethyl and lower alkyl having group, 1-hydroxy-2-methylpropyl,
3-hydroxy-2-methylpropyl, 1-hydroxyethyl, 2-hydroxy-2-methylpropyl, isobutyryl, etc., having 1 to 6 carbon atoms substituted with linear alkylene having 1 to 6 carbon atoms or lower alkyl, Methylene, ethylene, trimethylene, tetramethylene,
Pentamethylene, hexamethylene, propylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,4-
Examples thereof include dimethyltetramethylene and the like, and the straight-chain alkylene also includes alkylenes having a double or triple bond such as vinylene, propenylene, butadiene, and propynylene. The linear or branched alkylene having 1 to 6 carbon atoms substituted with 1 to 3 hydroxyl groups is hydroxymethylene, hydroxyethylene, hydroxytrimethylene,
Hydroxytetramethylene, dihydroxytetramethylene, trihydroxytetramethylene and the like;
And R ¹ are bonded to be condensed to a thiophene ring, to form a Q-, Q-A- or Q-
The nitrogen-containing heterocycle having a CO- group means cyclopentene, cyclohexene, cycloheptene, tetrahydropyridine and the like. Esterified hydroxyl groups are acetyloxy, propionyloxy, butyryloxy,
And benzoyloxy. Pharmaceutically acceptable acid addition salts of the compounds of general formula (I) include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and nitric acid, and maleic acid, fumaric acid and malic acid And salts with organic acids such as tartaric acid, succinic acid, citric acid, acetic acid, lactic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, and pamoic acid. Where the compounds of the present invention have one or more asymmetric carbon atoms, they may exist as racemates, diastereoisomers and individual optical isomers, but the invention embraces all of them.

The compound of the general formula (I) of the present invention has the general formula

Embedded image (Wherein Y represents methanesulfonyloxy, p-toluenesulfonyloxy or a halogen such as chlorine or bromine, and other symbols are as defined above) and a compound represented by the general formula QH (III) (Wherein, Q has the same meaning as described above). The reaction is
Solvents inert to the reaction (methanol, ethanol, dimethylformamide, tetrahydrofuran, dioxane, benzene, toluene, xylene, or a mixture thereof)
The reaction proceeds from 0 ° C. to the reflux temperature of the solvent in the presence of a deacidifying agent (sodium hydrogen carbonate, sodium carbonate, pyridine, triethylamine, etc.). Here, the compound represented by the general formula (II) can be synthesized, for example, by the following method. That is, a compound represented by the general formula ArCOCH ₂ CN (IV) (where Ar is as defined above) and a general formula R—CH ₂ —CO—R ¹ (V) wherein R ¹ is And R represents methyl or ethyl alkyl carboxylate or methyl or ethyl alkyl dicarboxylate having 1 to 8 carbon atoms in the alkyl chain. (If a compound in which R is a dicarboxylic acid ester is used, one of the carboxyl groups is converted into a monocarboxylic acid by saponification at the stage of the aminoketone represented by the general formula (VI), followed by conversion to a monocarboxylic acid. Or an ethyl ester.)] In the presence of sulfur in a solvent such as methanol or ethanol, or a solvent such as dimethylformamide or dimethylacetamide, in the presence of a base such as triethylamine, pyrrolidine, piperidine or morpholine. And reacted at room temperature to 100 ° C.
General formula

Embedded image (Wherein each symbol is as defined above). Further, a) a compound represented by the general formula (VI) and

Embedded image (Wherein, Z ¹ and Z ² are the same or different and represent halogen such as chlorine or bromine, and R ³ has the same meaning as described above) to form an N-haloacetyl compound, if necessary. Further, potassium iodide, sodium iodide or the like is allowed to act thereon to form an N-iodoacetyl form, and then ammonia is caused to act to form an N-glycyl form.

[0006] The reaction proceeds in a solvent such as acetone, tetrahydrofuran or dioxane under cooling, at room temperature or under heating. Or b) the amino ketone of the above general formula (VI)

Embedded image (Wherein Cbz represents a benzyloxycarbonyl group,
R ³ has the same meaning as described above. The compound represented by) is converted to a carboxylic acid halide by the action of thionyl chloride or the like in a solution of methylene chloride, chloroform, dichloroethane or the like at a low temperature to give an acetyl form. Further, the protective group is removed with hydrobromic acid or hydrochloric acid to obtain an N-glycyl form. Or c) the amino ketone of the above general formula (VI)

Embedded image (Wherein R ³ and Z ¹ have the same meanings as described above) to give an acetyl form, and the N-glycyl form can be obtained by removing the protecting group according to a conventional method. . The N-glycyl compound thus obtained is converted into a solvent inert to the reaction (ethanol, propanol, isopropyl alcohol, butanol, benzene,
Toluene, dimethylformamide, dimethylacetamide, etc.), preferably in the presence of a weak acid catalyst such as acetic acid, propionic acid, silica gel, etc., at room temperature or under heating to give a dehydration ring closure reaction,

Embedded image (Wherein each symbol is as defined above). Further, a compound represented by the general formula (X) is reacted with a thionating reagent,

Embedded image (Wherein each symbol has the same meaning as described above), and then the compound of the general formula (XI) and the general formula R ² CONHNH ₂ (XII) (wherein R ² has the same meaning as described above) Is reacted with a compound represented by the formula:

Embedded image (Wherein each symbol is as defined above), or a compound of the general formula (XI) obtained by reacting a compound of the general formula (XI) with hydrazine hydrate

Embedded image (Wherein each symbol is as defined above) and a compound represented by the general formula R ² COOH (XV) (where R ² is as defined above) or a reactive derivative thereof. Or a general formula R ² C (OR ¹² ) ₃ (XVI) wherein R ¹² represents alkyl having 1 to 5 carbons (methyl, ethyl, etc., and R ² has the same meaning as described above). By reacting the compound of formula (XIII)
Is obtained.

[0007] In the above method, the thiolating reagent is phosphorus pentasulfide, Lawesson's reagent [2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,
4-disulfide], and a compound represented by the general formula (XV)
Examples of the reactive derivative of the compound (a) include carboxylic acid halides (carboxylic acid chloride, carboxylic acid bromide, etc.), carboxylic acid anhydrides, mixed acid anhydrides (lower alkyl carbonic acid mixed acid anhydrides, alkyl phosphoric acid mixed acid anhydrides, etc.) And lower alkyl esters (eg, methyl ester, ethyl ester) and active esters (eg, benzyl ester, p-nitrobenzyl ester, p-nitrophenyl ester, p-chlorophenyl ester). The reaction of the compound of general formula (X) with the thionation reagent is usually carried out in a solvent inert to the reaction (pyridine, dimethylaniline, benzene, toluene, xylene, tetrahydrofuran, chloroform, dioxane, or a mixed solvent thereof).
Proceed at 0-100 ° C. The reaction between the compound of the general formula (XI) and the compound of the general formula (XII) is usually performed in a solvent inert to the reaction (benzene, toluene, xylene, tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropyl alcohol, etc.) The reaction proceeds from room temperature to the reflux temperature of the solvent used in the presence of an organic acid (eg, acetic acid, propionic acid), an inorganic acid (eg, hydrochloric acid, sulfuric acid) or silica gel. The reaction of the compound of the general formula (XI) with hydrazine or a hydrate thereof is usually a solvent inert to the reaction (eg, methanol, ethanol, propanol, isopropyl alcohol, butanol, tetrahydrofuran).
Medium, proceeding at 0-40 ° C. The reaction between the compound of the general formula (XIV) and the compound of the general formula (XV) or a reactive derivative thereof or the compound of the general formula (XVI) is carried out by using a solvent inert to the reaction (benzene, toluene, xylene, tetrahydrofuran, dioxane, etc.). ), Preferably proceeds in the presence of an organic acid (eg, acetic acid, propionic acid), an inorganic acid (eg, hydrochloric acid, sulfuric acid, phosphoric acid) or silica gel from room temperature to the reflux temperature of the solvent used.

The thus obtained general formula (XII)
The compound of the formula (I) is reduced by using a reducing agent such as lithium aluminum hydride and sodium borohydride to obtain a compound represented by the general formula

Embedded image (Wherein each symbol is as defined above). The reaction proceeds in a solvent such as tetrahydrofuran or diethyl ether under cooling, at room temperature or under heating. The compound of the general formula (XVII) is reacted with a compound represented by the general formula R ¹³ —SO ₂ Cl (XVIII) (where R ¹³ represents lower alkyl or substituted phenyl) in the presence of a deoxidizing agent. Or a suitable solvent without isolation (dimethylformamide,
Sodium iodide or sodium bromide in dioxane, tetrahydrofuran, or a mixed solvent thereof) can be reacted to obtain a compound of the general formula (II). The compound of the general formula (I) obtained as described above can be separated and purified from the reaction mixture by a method known per se, such as recrystallization or chromatography.
The compound of the general formula (I) can be converted into the above-mentioned pharmacologically acceptable salt by treating it with an inorganic acid or an organic acid by a conventional method. When the compound of the present invention has an asymmetric carbon atom, it is usually obtained as a racemate. The racemate can be separated into optical isomers by a conventional method. Such optical isomers can also be produced by using optically active starting compounds. Individual diastereoisomers can be purified by fractional recrystallization or chromatography.

The compounds included in the present invention are as shown in the following table, but it goes without saying that they are not limited to these.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[0010]

[Table 6]

[Table 7]

[Table 8]

[0011]

The compound (I) and the acid addition salt thereof of the present invention have both PAF antagonism and histamine antagonism, their effects are long-lasting, show low toxicity, and have a sedative effect. Does not substantially exhibit central inhibitory action or muscle relaxing action. Therefore, compound (I)
And pharmacologically acceptable acid addition salts thereof are useful as PAF antagonists and histamine antagonists, and various inflammatory diseases, allergic diseases,
Examples include anaphylactic shock, diseases of the myocardial system, asthma, pulmonary edema, and various diseases considered to involve PAF or histamine, such as adult respiratory disease. The compound (I) of the present invention and an acid addition salt thereof are appropriately mixed with a therapeutically effective amount thereof and a pharmaceutical additive such as an excipient, a bulking agent, a diluent, a solubilizing agent, and the like. It can be safely administered orally or parenterally as a capsule, granule, liquid, inhalant, suppository, transdermal absorbent, or injection. The dose varies depending on the compound to be selected, the severity of the disease, the age, etc., but is usually 0.1 to 1 per day per adult.
00 mg can be administered once or in several divided doses.

[0012]

EXAMPLES The present invention will now be described specifically with reference to Reference Examples and Examples, but the present invention is not limited thereto. Reference Example 1 53.5 g of 2-chlorocyanoacetophenone and 9.5 g of sulfur were suspended in 120 ml of dimethylformamide.
Under ice cooling and stirring, 71 g of dicarbethoxybutyraldehyde
Add. Then, 30 g of triethylamine is added, and the mixture is reacted at 60 to 70 ° C. for 3 hours with stirring. The reaction solution is poured into ice water, extracted with 1000 ml of ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and crystallized from isopropyl alcohol-water (7: 3) to give 2-[[5
78 g of diethyl -amino-4- (2-chlorobenzoyl) -2-thienyl] methyl] malonate are obtained. An aqueous solution of 58 g of the above compound dissolved in 350 ml of ethanol, 23 g of potassium hydroxide dissolved in 90 ml of water is added, and the mixture is heated under reflux for 2 hours with stirring. After cooling, the mixture was concentrated under reduced pressure, and ethanol was distilled off. Then, 100 ml of water was added, the mixture was acidified with hydrochloric acid, and the organic layer was extracted with 500 ml of ethyl acetate. After washing with water, it is dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and crystallized from toluene.
2-[[5-amino-4-] as yellow crystals of (decomposition)
50 g of (2-chlorobenzoyl) -2-thienyl] methyl] malonic acid are obtained. The above malonic acid (50 g) is dissolved in dimethylformamide (100 ml), toluene (240 ml) is added, and the mixture is reacted at 80 to 90 ° C. for 2 hours with stirring. After cooling,
The reaction solution was concentrated under reduced pressure and crystallized from toluene to give 3- [5-amino- as yellow crystals having a melting point of 170 to 173 ° C.
36.5 g of 4- (2-chlorobenzoyl) -2-thienyl] propionic acid are obtained. 47.5 g of the above propionic acid
Was dissolved in 900 ml of methanol, and concentrated sulfuric acid was added to the mixture under stirring.
Add 9 ml and react at 20 ° C. for 17 hours. After concentration under reduced pressure, 200 ml of water was added, and the organic layer was diluted with 600 ml of ethyl acetate.
Extract with l. After washing with a 5% potassium carbonate solution and a saline solution, the mixture is dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and crystallized from isopropyl ether to give 3- [5-amino-4-l as red crystals having a melting point of 89 to 90 ° C.
49 g of methyl (2-chlorobenzoyl) -2-thienyl] propionate are obtained. Dissolve 54 g of N-benzyloxycarbonyl-alanine in 100 ml of dimethylformamide and 300 ml of methylene chloride, and stir at -20 ° C.
Then, 18 ml of thionyl chloride is added dropwise over 10 minutes. After reacting for 1 hour at the same temperature, a solution of 39 g of the above methyl propionate in 50 ml of methylene chloride is added dropwise over 15 minutes, and the reaction is carried out at the same temperature for 5 hours. The reaction solution was poured into ice water, made alkaline with potassium carbonate, and extracted with 400 ml of chloroform.
After washing with water, it is dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and crystallized from isopropyl ether to give 3-[(5
52 g of methyl-(2-benzyloxycarbonylamino) propionylamino) -4- (2-chlorobenzoyl) -2-thienyl] propionate are obtained. Compound 5 above
2 g are suspended in 60 ml of acetic acid, 5 ml of anisole and 40 ml of 30% hydrogen bromide acetic acid solution are added, and the mixture is reacted at 20 ° C. for 2 hours. The reaction solution is poured into ice water, made alkaline with potassium carbonate, extracted with 400 ml of ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure, the residue was washed with isopropyl ether, and dissolved in 650 ml of toluene.
And heated to reflux for 4 hours using a water separator. After cooling, the silica gel is filtered and extracted with 200 ml of hot methanol. The methanol is concentrated under reduced pressure and the residue is subjected to silica gel chromatography, eluting with chloroform-methanol (100: 1 to 100: 3). The target fraction was concentrated under reduced pressure and crystallized from isopropyl ether to give 3- [5- (2-
(Chlorophenyl) -2,3-dihydro-3-methyl-2
9.5 g of methyl-oxo-1H-thieno [2,3-e] -1,4-diazepin-7-yl] propionate are obtained. Dissolve 8.4 g of the above diazepine in 80 ml of diethylene glycol dimethyl ether, add 10 g of phosphorus pentasulfide and 7.5 g of sodium bicarbonate, and add 3 g at 60 ° C.
React for 5 hours. The reaction solution is poured into ice water with stirring, and after stirring for 40 minutes, the precipitated crystals are collected by filtration and washed with water. After drying,
The mixture was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100: 1 to 100: 2). The target fraction was concentrated under reduced pressure and crystallized from isopropyl ether to give 3- [5- (2-chlorophenyl) -2,3-dihydro-3-methyl-2-thioxo- as yellow crystals having a melting point of 198 to 200 ° C. 1H-thieno [2,3-
e] 5.3 g of methyl 1,4-diazepin-7-yl] propionate are obtained. 3.2 g of the above compound is dissolved in 50 ml of tetrahydrofuran, 600 mg of 100% hydrazine hydrate is added, and the mixture is reacted at 40 to 45 ° C for 20 minutes.
The reaction solution was concentrated under reduced pressure, and the residue was dissolved in toluene (80 ml).
React for hours. After concentration under reduced pressure, crystallization from isopropyl ether-methylene chloride (1: 1) gave a melting point of 131-1.4.
3- [4- (2-chlorophenyl) -6,9-dimethyl-6H-thieno [3,2-
f] [1,2,4] triazolo [4,3-a] [1,
4] Diazepin-2-yl] methyl propionate 2.8
g. 31.7 g of the above methyl ester was dissolved in 300 ml of tetrahydrofuran, 2.9 g of lithium aluminum hydride was added, and the mixture was stirred at room temperature for about 3 hours. The reaction solution is poured into 500 ml of ice water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue is subjected to silica gel chromatography and eluted with chloroform-methanol (1-5%). The target fraction was concentrated under reduced pressure and crystallized from ethyl acetate to give a melting point of 145-145.
4- (2-chlorophenyl) as colorless crystals at 147 ° C
20.2 g of 2- (3-hydroxypropyl) -6,9-dimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine Get.

Reference Example 2 90 g of 2-chlorocyanoacetophenone and 16 sulfur
g of dimethylformamide was suspended in 200 ml of dimethylformamide, and 110 g of dicarboethoxypropion aldehyde was stirred under ice-cooling and stirring.
Add. Next, 51 g of triethylamine is added, and the mixture is reacted at 70 ° C. for 3 hours with stirring. The reaction solution is poured into ice water, extracted with 1000 ml of ethyl acetate, and the extract is washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and crystallized from isopropyl alcohol-water (6: 4) to give 2- [5 as yellow crystals having a melting point of 86 to 89 ° C.
This gives 100 g of diethyl -amino-4- (2-chlorobenzoyl) -2-thienyl] malonate. Compound 10 above
0 g is dissolved in 640 ml of ethanol, an aqueous solution in which 42 g of potassium hydroxide is dissolved in 160 ml of water is added, and the mixture is heated under reflux with stirring for 2 hours. After cooling, the mixture was concentrated under reduced pressure, and after distilling off ethanol, 200 ml of water was added and acidified with hydrochloric acid. The organic layer was extracted with 500 ml of ethyl acetate, washed with water,
Dry over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, crude 2- [5-amino-4- (2
-Chlorobenzoyl) -2-thienyl] malonic acid 90 g
Get. The above malonic acid was converted to dimethylformamide 160m
, and 400 ml of toluene was added thereto.
And react for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure and crystallized from toluene to obtain 55 g of 2- [5-amino-4- (2-chlorobenzoyl) -2-thienyl] acetic acid as yellow crystals having a melting point of 172 to 182 ° C. . Acetic acid 55
g in 1000 ml of methanol, and
Add 0.9 ml and react at 20 ° C for 19 hours. After concentration under reduced pressure, add 300 ml of water and extract with 700 ml of ethyl acetate. After washing with a 5% aqueous sodium hydrogen carbonate solution and then with water, the extract is dried over anhydrous magnesium sulfate. After filtration, concentration under reduced pressure and extraction from isopropyl ether yield 47 g of methyl 2- [5-amino-4- (2-chlorobenzoyl) -2-thienyl] acetate as red crystals with a melting point of 102 to 105 ° C. N-benzyloxycarbonyl-
29 g of alanine is dissolved in 40 ml of dimethylformamide and 140 ml of methylene chloride, and 9.5 ml of thionyl chloride is added dropwise at −20 ° C. over 10 minutes with stirring. After reacting for 1 hour at the same temperature, a solution of 20 g of the above methyl acetate in 30 ml of methylene chloride is added dropwise over 15 minutes, and the reaction is carried out at the same temperature for 5 hours. The reaction mixture is poured into ice water with stirring, made alkaline with potassium carbonate, extracted with 300 ml of chloroform, washed with water and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, crude 2- [5- (2-benzyloxycarbonylamino) propionylamino-4 was obtained as a brown oil.
34 g of methyl-(2-chlorobenzoyl) -2-thienyl] acetate are obtained. 34 g of the above compound is dissolved in 30 ml of acetic acid, 1 ml of anisole and 40 ml of a 25% hydrogen bromide acetic acid solution are added, and the mixture is reacted at 20 ° C. for 3 hours. The reaction solution is poured into ice water with stirring, made alkaline with potassium carbonate, extracted with 300 ml of ethyl acetate, and washed with brine. 6 ml of diethylamine and 5 g of sodium hydrogen carbonate are added, and the mixture is stirred at 20 ° C. for 2 hours and left at the same temperature for 14 hours. The reaction solution is washed with water and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure, dissolved in 500 ml of toluene, added with 70 g of silica gel, and dried with a water separator.
Heat to reflux for hours. After cooling, the silica gel is filtered and extracted with 200 ml of hot methanol. The methanol is concentrated under reduced pressure and the residue is subjected to silica gel chromatography, eluting with chloroform-methanol (100: 1 to 100: 3). The objective fraction was concentrated under reduced pressure and crystallized from isopropyl ether to give 2- [5- (2-chlorophenyl) -3-methyl- as colorless crystals having a melting point of 185 to 190 ° C.
2,3-dihydro-2-oxo-1H-thieno [2,3
-E] -1,4-Diazepin-7-yl] methyl acetate 6.9 g are obtained. 6.8 g of the above thienodiazepine was suspended in 70 ml of diethylene glycol dimethyl ether,
6.5 g of sodium hydrogen carbonate and 8.5 g of phosphorus pentasulfide
And react at 55-60 ° C. for 4 hours. The reaction solution is poured into ice water with stirring, and after stirring for 40 minutes, the precipitated crystals are collected by filtration and washed with water. After drying, the mixture was subjected to silica gel chromatography, and chloroform-methanol (100: 1 to 1) was used.
100: 2), and the target fraction was concentrated under reduced pressure to give 2- [5- (2-
(Chlorophenyl) -2,3-dihydro-3-methyl-2
3.7 g of methyl -thioxo-1H-thieno [2,3-e] -1,4-diazepin-7-yl] acetate are obtained. 3.7 g of the above compound is dissolved in 50 ml of tetrahydrofuran, 0.7 g of 100% hydrazine hydrate is added with stirring, and the mixture is reacted at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in 70 ml of toluene, and ethyl orthoacetate was added.
6 ml is added and reacted at 80 ° C. for 4 hours. After concentration under reduced pressure,
When crystallized from isopropyl ether-methylene chloride (1: 1), colorless crystals having a melting point of 105 to 106 ° C. were obtained.
-[4- (2-chlorophenyl) -6,9-dimethyl-
3.7 g of methyl 6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] acetate are obtained. The above-mentioned methyl ester (1.2 g) is dissolved in ethanol (25 ml), sodium borohydride (1.1 g) is added, and the mixture is refluxed for about 1 hour with stirring. The reaction solution is poured into 100 ml of ice water, extracted with 100 ml of ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel chromatography,
Elute with chloroform-methanol (1-5%). The target fraction was concentrated under reduced pressure and crystallized from ethyl acetate to give 4- (2-chlorophenyl) -2- (2-hydroxyethyl) -6,9 as colorless crystals having a melting point of 150 to 152 ° C.
-Dimethyl-6H-thieno [3,2-f] [1,2,
4] Triazolo [4,3-a] [1,4] diazepine 0.9 g is obtained.

Similarly, the following compounds can be obtained. 4- (2-chlorophenyl) -2-hydroxymethyl-6,9-dimethyl-6H-thieno [3,2-f]
[1,2,4] triazolo [4,3-a] [1,4] diazepine ◎ 2- (2-hydroxyethyl) -4- (2-methylphenyl) -6,9-dimethyl-6H-thieno [ 3,2
-F] [1,2,4] triazolo [4,3-a] [1,
4] Diazepine ◎ 2- (2-hydroxyethyl) -4- (2-methoxyphenyl) -6,9-dimethyl-6H-thieno [3,
2-f] [1,2,4] triazolo [4,3-a]
[1,4] diazepine ◎ 4- (3-chlorophenyl) -2- (2-hydroxyethyl) -6,9-dimethyl-6H-thieno [3,2
-F] [1,2,4] triazolo [4,3-a] [1,
4] Diazepine ◎ 4- (4-chlorophenyl) -2- (2-hydroxyethyl) -6,9-dimethyl-6H-thieno [3,2
-F] [1,2,4] triazolo [4,3-a] [1,
4] diazepine ◎ 4- (3-chlorophenyl) -2- (3-hydroxypropyl) -6,9-dimethyl-6H-thieno [3
2-f] [1,2,4] triazolo [4,3-a]
[1,4] diazepine ◎ 4- (4-chlorophenyl) -2- (3-hydroxypropyl) -6,9-dimethyl-6H-thieno [3,4
2-f] [1,2,4] triazolo [4,3-a]
[1,4] diazepine ◎ 4- (2-chlorophenyl) -2- (4-hydroxybutyl) -6,9-dimethyl-6H-thieno [3,2
-F] [1,2,4] triazolo [4,3-a] [1,
4] Diazepine

Example 1 4- (2-chlorophenyl) -2- (3-hydroxypropyl) -6,9-dimethyl-6H-thieno [3,2-
f] [1,2,4] triazolo [4,3-a] [1,
4] 3.9 g of diazepine is dissolved in 50 ml of methylene chloride, 2.7 g of methanesulfonic acid chloride is added, 2.4 g of triethylamine is added dropwise with stirring under ice cooling, and the mixture is stirred for about 2 hours. The reaction solution is poured into ice water, the methylene chloride layer is separated, and dried over anhydrous magnesium sulfate. After concentration, the residue is dissolved in 50 ml of dioxane, 7.5 g of N-diphenylmethylpiperazine is added, and the mixture is heated under reflux for 4 hours. After cooling, the mixture is poured into 200 ml of ice water, the oily substance is extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After concentration, the residue was subjected to silica gel chromatography, and ethyl acetate-
Elute with methanol (5-10%). The desired fraction was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate.
2- [3- (4-diphenylmethyl-1-piperazinyl) propyl] -4- (2
-Chlorophenyl) -6,9-dimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-
a) 1.2 g of [1,4] diazepine 1/4 hydrate are obtained.

The following compounds are obtained in the same manner as in the above Examples. ◎ 4- (2-chlorophenyl) -2- [4-bis (4
-Fluorophenyl) methyl-1-piperazinylmethyl] -6,9-dimethyl-6H-thieno [3,2-f]
[1,2,4] triazolo [4,3-a] [1,4] diazepine / 3/2 oxalate, melting point 149 ° -151 ° C. 4- (2-chlorophenyl) -2- [2- (4 -Diphenylmethyl-1-pidrazinyl) ethyl] -6,9
-Dimethyl-6H-thieno [3,2-f] [1,2,
4] triazolo [4,3-a] [1,4] diazepine
1/4 hydrate, melting point 191-192 ° C 4- (2-chlorophenyl) -2- [2- (4-bis (4-fluorophenyl) methyl-1-pidrazinyl) ethyl] -6,9 -Dimethyl-6H-thieno [3,
2-f] [1,2,4] triazolo [4,3-a]
[1,4] diazepine dioxalate 1/2 hydrate,
Melting point 148 to 150 ° C ◎ 4- (2-chlorophenyl) -2- [2- (4-
(4-Chlorophenyl) phenylmethyl-1-piperazinyl) ethyl] -6,9-dimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-
a) [1,4] diazepine dioxalate, melting point 142-152 ° C 4- (2-
Chlorophenyl) -2- [3- (4-bis (4-fluorophenyl) methyl-1-pidrazinyl) propyl]-
6,9-dimethyl-6H-thieno [3,2-f] [1,
2,4] triazolo [4,3-a] [1,4] diazepine oxalate monohydrate, melting point 151-153 ° C

４− 4- (2-chlorophenyl) -2-
[2- (4-bis (4-fluorophenyl) methylpiridino) ethyl] -6,9-dimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-
a] [1,4] diazepine MS (m / z); 641 NMR
(CDCl ₃ ) δ (ppm); 2.1 (d, 3H, 7 Hz), 2.72 (s, 3H), 1.0-
3.2 (m, 13H), 3.50 (d, 1H, 11Hz), 4.35 (q, 1H, 7Hz), 6.42
(s, 1H), 6.8-7.5 (m, 12H) 4- (2-chlorophenyl) -2- [2- (4-diphenylmethylpyridino) ethyl] -6,9-dimethyl-6H-thieno [ 3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine MS (m / m
z); 605 NMR (CDCl ₃ ) δ (ppm); 2.1 (d, 3H, 7 Hz),
2.70 (s, 3H), 1.0-3.2 (m, 13H), 3.50 (d, 1H, 11Hz), 4.35
(q, 1H, 7Hz), 6.42 (s, 1H), 7.25 (m, 14H) ◎ 4- (2-chlorophenyl) -2- [3- (4-
(4-Chlorophenyl) phenylmethyl-1-piperazinyl) propyl] -6,9-dimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-
a] [1,4] diazepine MS (m / z); 654 NMR
(CDCl ₃ ) δ (ppm); 2.1 (d, 3H, 7 Hz), 2.68 (s, 3H), 1.8-
2.9 (m, 13H), 4.20 (s, 1H), 4.35 (q, 1H, 7Hz), 6.39 (s, 1
H), 7.0-7.6 (m, 13H) ４− 4- (2-chlorophenyl) -2- [3- (4-diphenylmethylpiperidino) propyl] -6,9-dimethyl-6H-thieno [3,2 -F] [1,2,4] triazolo [4,3-a] [1,4] diazepine MS (m /
z); 619 NMR (CDCl ₃ ) δ (ppm); 2.1 (d, 3H, 7 Hz),
2.68 (s, 3H), 1.8-3.1 (m, 15H), 3.48 (d, 1H, 11Hz), 4.35
(q, 1H, 7Hz), 6.39 (s, 1H), 7.0-7.6 (m, 12H) ◎ 4- (2-chlorophenyl) -2- [3- (4-bis (4-fluorophenyl) methylpiperidino ) Propyl] -6,9-dimethyl-6H-thieno [3,2-f]
[1,2,4] triazolo [4,3-a] [1,4] diazepine MS (m / z); 655 NMR (CDCl ₃ ) δ (ppm)
; 2.1 (d, 3H, 7Hz), 2.68 (s, 3H), 1.8-3.0 (m, 15H), 3.47
(d, 1H, 11Hz), 4.35 (q, 1H, 7Hz), 6.39 (s.1H), 6.8-7.6
(m, 12H) 4- (2-chlorophenyl) -2- [3- (4-diphenylmethylenepiperidino) propyl] -6,9-dimethyl-6H-thieno [3,2-f] [1, 2,4] triazolo [4,3-a] [1,4] diazepine MS (m
/ Z); 617 NMR (CDCl ₃ ) δ (ppm); 1.87 (m, 2H), 2.
1 (d, 3H, 7Hz), 2.3-2.6 (m, 10H), 2.69 (s, 3H), 2.82 (t, 2
H, 7Hz), 4.35 (q, 1H, 7Hz), 6.43 (s, 1H), 7.1-7.5 (m, 14H)
◎ 4- (2-chlorophenyl) -2- [3- (4-
(Hydroxydiphenylmethyl) piridino) propyl] -6,9-dimethyl-6H-thieno [3,2-f]
[1,2,4] triazolo [4,3-a] [1,4] diazepine MS (m / z); 634 NMR (CDCl ₃ ) δ (ppm)
; 1.1-3.1 (m, 14H), 2.08 (d, 3H, 7Hz), 2.66 (s, 3H), 3.5
4 (m, 1H), 3.68 (s, 1H), 4.32 (q, 1H, 7Hz), 6.36 (s, 1H),
6.9-7.5 (m, 14H) 4- (2-chlorophenyl) -2- [3- (4-bis (4-fluorophenyl) methylenepiridino) propyl] -6,9-dimethyl-6H-thieno [3 , 2-
f] [1,2,4] triazolo [4,3-a] [1,
4] Diazepine MS (m / z); 653 NMR (CDCl ₃ ) δ
(ppm); 1.4-2.0 (m, 2H), 2.1 (d, 3H, 7 Hz), 2.2-2.6 (m, 10
H), 2.68 (s, 3H), 2.80 (t, 2H, 7Hz), 4.32 (q, 1H, 7Hz), 6.
38 (s, 1H), 6.7-7.5 (m, 14H)

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 495/14 A61K 31/55 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula [Wherein Ar is pyridyl, phenyl or a halogen, a hydroxyl group, a lower alkyl, a lower alkoxy and a compound represented by the formula: (Wherein, W is _{- (CH 2) m - (} m is an integer of 1~4), -. O -, - OCH 2 - or -CH ₂ OCH ₂
And R ⁵ , R ⁶ and R ⁷ are the same or different and each represents hydrogen, halogen, a hydroxyl group, lower alkyl or lower alkoxy. ) Phenyl having 1 to 3 arbitrarily selected from the groups represented by R), R ¹ is hydrogen or lower alkyl, R ² is hydrogen, lower alkyl or cycloalkyl, R ³ is hydrogen, trifluoromethyl or lower. A represents alkyl having 1 to 6 carbon atoms, linear alkylene having 1 to 6 carbon atoms, alkylene having 1 to 6 carbon atoms substituted with lower alkyl, or 1 to 1 carbon atoms substituted with 1 to 3 hydroxyl groups.
Represents 6 straight- or branched-chain alkylenes, or A is Q-, Q-A-, or a 5- to 7-membered saturated carbon ring or nitrogen atom bonded to R ¹ and condensed to a thiophene ring. A nitrogen-containing heterocycle having a Q-CO- group can also be formed. Q is the formula Wherein R ⁴ is phenyl, aralkyl, arylcarbonyl, halogen as a substituent, hydroxyl, lower alkyl,
Phenyl, aralkyl or arylcarbonyl having 1 to 3 arbitrarily selected from lower alkoxy and trifluoromethyl, having the formula: (Wherein, R ⁸ and R ⁹ are the same or different and each represents hydrogen, halogen, trifluoromethyl, amino, nitro,
C represents a cyano, a hydroxyl group, a lower alkyl or a lower alkoxy, and B represents a hydrogen, a hydroxyl group or an esterified hydroxyl group. ) Represents a lower alkyl having a hydroxyl group and / or a carbonyl group, and X represents CH or a nitrogen atom. Or a group represented by the formula: (Wherein R ¹⁰ and R ¹¹ are the same or different and are each independently hydrogen, halogen, trifluoromethyl, amino, nitro,
Represents cyano, hydroxyl group, lower alkyl or lower alkoxy. ). A thienotriazolodiazepine compound or a pharmaceutically acceptable acid addition salt thereof.