JP2971902B2 - Triazolo-1,4-diazepine compounds - Google Patents

Description

The present invention relates to a 1,4-diazepine derivative having excellent action as a medicine and a pharmaceutically acceptable salt thereof.

[Background of the Invention and Prior Art]

Platelet activating factor (PAF)
r] (hereinafter simply abbreviated as PAF) has been receiving a great deal of attention in recent years, and recently its relationship with various diseases has been clarified. That is, it is presumed to be involved in inflammation, DIC, endotoxin shock, asthma, gastrointestinal ulcer, nephritis, hepatitis, and rejection at the time of organ transplantation. He is also attracting interest as a mediator of allergic reactions.

Under such circumstances, a search for compounds having a PAF inhibitory action has been conducted.

Of these, a 1,4-diazepine compound having an anti-PAF action has been proposed in, for example, JP-A-63-33382.

However, at present, no satisfactory anti-PAF agent has emerged, particularly as an anti-PAF agent targeting allergy such as asthma.

In view of such a situation, the present inventors have long been exploring and studying 1,4-diazepine derivatives which have not only an excellent PAF inhibitory action but also an excellent sustained action.

[Structure and effect of the invention]

The present inventors have made intensive studies for the above-mentioned purpose for many years, and as a result, have found that the following 1,4-diazepine derivative or a pharmacologically acceptable salt thereof can achieve the object, and have achieved the present invention. completed.

That is, the compound of the present invention is a triazolo-1,4-diazepine compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.

[Wherein, R ¹ and R ² represent the same or different hydrogen atoms or lower alkyl groups, R ³ represents a hydrogen atom or a halogen atom, and R ⁴ represents a hydrogen atom or a lower alkyl group.

X is the formula A group represented by the formula Wherein R ⁵ represents a hydrogen atom or a lower alkyl group, or a group represented by the formula: Means a group represented by

 n means an integer of 0 or 1.

Y is an alkyl group, an alkynyl group, a formula NCCH ₂
a group represented by _p (where p represents an integer of 1 to 6), ACH _{2 q} (where A is a cycloalkyl group, a morpholino group, a thienyl group, a lower alkoxy group, a substituted or unsubstituted phenyl group , An imidazolyl group or a tetrahydropyranyl group, and q represents 0 or an integer of 1 to 6); A group represented by the formula (Wherein, R ⁶ and R ⁷ may be the same or different hydrogen atoms, lower alkyl groups, or R ⁶ and R ⁷ may form a ring together with a nitrogen atom), or formula Means a group represented by Where Y is the formula (Wherein R ⁶ and R ⁷ have the above-mentioned meanings)
Or expression When the group represented by is meant, n is 0. That is, the 1,4-diazepine derivative represented by the above general formula (I) has an excellent PAF inhibitory effect, a long-lasting effect, and a high compound safety. Have.

Accordingly, an object of the present invention is to provide a novel 1,4-diazepine derivative having excellent anti-PAF activity or a pharmacologically acceptable salt thereof, and a further object of the present invention is to provide a method for producing the same. It is an object of the present invention to provide a medicament containing it.

In the above definition of the compound (I) of the present invention,
The lower alkyl group found in the definitions of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, Group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t
ert-butyl group, pentyl group (amyl group), isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methyl Pentyl group, 2-methylpentyl group, 3-methylpentyl group,
1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2
-Dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1 , 2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and the like. Among these, preferred groups include a methyl group, an ethyl group, a propyl group and an isopropyl group, and the most preferred group is a methyl group.

In the definition of Y, the alkyl group means a heptyl group, an octyl group, a nonyl group, a decyl group and the like, in addition to the lower alkyl groups described above.

In the definition of Y, the alkynyl group refers to a group having 1 to 6 carbon atoms and having a triple bond in any part. Representative alkynyl groups include, for example, the following groups.

CH≡C-CH _2- , CH≡C-CH ₂ -CH _2- , CH≡C-CH ₂ -CH ₂
-CH _2- , CH≡C-CH ₂ -CH ₂ -CH ₂ -CH _2- , CH ₃ —C≡C—CH ₂ —CH ₂ —, CH ₃ —C≡C—CH ₂ —
CH _2- , CH≡C-CH ₂ -CH _2- , CH≡C-CH ₂ -CH ₂ -CH _2- , C
H≡C—CH ₂ —CH ₂ —CH ₂ —CH ₂ — and the like.

In the formula NCCH _{2 p} , p means an integer of 1 to 6, but is preferably an integer of 1 to 3.

In the definition of A, the cycloalkyl group means a cycloalkyl group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Of these, cyclopropyl, cyclobutyl, cyclopentyl and the like are most preferred. These rings may be substituted by a methyl group or the like.

The definition of A includes a substituted or unsubstituted phenyl group, and examples of the substituent include a lower alkyl group such as a methyl group and a halogen atom such as chlorine and bromine.

The pharmacologically acceptable salt in the present invention is a conventional non-toxic salt, for example, a hydrochloride, a hydrobromide, a sulfate, an inorganic acid salt such as a phosphate, for example, an acetate, a maleate, Organic salts such as tartrate, methanesulfonate, benzenesulfonate, and toluenesulfonate, and salts with amino acids such as arginine, aspartic acid, and glutamic acid can be used.

The compound of the present invention has an asymmetric carbon in the molecule and may have various stereoisomers, but in the present invention, each of them or a mixture thereof is included in the present invention. Needless to say. In this case, the optically active substance can be produced by a conventional method.

Furthermore, it goes without saying that when some compounds form hydrates, they are also included in the present invention.

The compound of the present invention is produced by a conventional method. Among them, representative methods are as follows.

Production method [In the formula (I), X is a compound represented by the formula A group represented by or a formula Is a group represented by and n = 1. (Wherein X, Y, R ¹ , R ₂ , R ³ and R ⁴ have the above-mentioned meanings) That is, the compound represented by the formula (II) is condensed with the compound represented by the formula (III) After the reaction, a compound represented by the general formula (I '), which is one of the target substances, is obtained.

This reaction is carried out by a conventional method, but the reaction is carried out without solvent or using a solvent inert to the reaction selected from, for example, chloroform, tetrahydrofuran, diethyl ether, acetone, benzene, toluene, dimethylformamide and the like.
The reaction temperature is usually from room temperature to about 150 ° C.,
The most preferred temperature is between 100 and 130C.

In the above reaction, the compound represented by the general formula (II) used as a starting material is produced, for example, by the following method.

(Wherein Y and X have the above-mentioned meanings, and Hal represents a halogen atom.) In this reaction, a compound represented by the general formula (IV) is converted into a compound represented by the general formula (V). The compound represented by the general formula (II) is obtained by a condensation reaction according to the method.

This reaction is preferably carried out using amines such as triethylamine and pyridine, alkali metals such as sodium hydroxide and potassium hydride, alkali metals such as metal sodium, and alkali hydroxides such as sodium hydroxide and potassium hydroxide. In the presence of a base.

This reaction is carried out without a solvent or in an ether such as tetrahydrofuran or dioxane, a halogen-based solvent such as methylene chloride or chloroform, a benzene-based solvent such as benzene, toluene, or xylene, or a solvent such as dimethylformamide or dimethylsulfoxide. .

Manufacturing method 2 (X is the formula And n is 1) (Wherein Y, R ¹ , R ² , R ³ and R ⁴ have the above-mentioned meanings) That is, a carboxylic acid represented by the general formula (VI) or a reactive derivative thereof is represented by the general formula (III) The compound represented by the formula (I) is subjected to a condensation reaction to obtain a compound represented by the general formula (I ″), which is one of the target substances.

 In this reaction, a condensation reaction is performed by a conventional method.

Reactive derivatives include acid halides such as acid chloride and acid bromide; acid azide; N-hydroxybenzotriazole; active ester with N-hydroxysuccinimide; symmetric acid anhydride; alkyl carbonic acid and p-toluenesulfonic acid And mixed acid anhydrides. Preferred reactive derivatives include acid halides such as acid chloride and acid bromide. In this reaction, for example, a dehalogenation reaction is carried out without heating or in the presence of a solvent that does not participate in the reaction such as benzene, toluene, xylene, tetravidrofuran, chloroform, carbon tetrachloride, and dimethylformamide. In this case, a favorable result can be obtained by performing the reaction in the presence of an inorganic salt such as sodium hydrogen carbonate, potassium carbonate, sodium carbonate or caustic soda, or an organic base such as triethylamine, pyridine, pyrimidine or diethylaniline.

When using a free carboxylic acid, it is preferable to carry out the reaction in the presence of a condensing agent such as dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole.

Production method 3 (in formula (I), n = 0) (In the series of formulas, Y, R ¹ , R ² , R ³ and R ⁴ have the above-mentioned meanings,
Means a halogen atom) That is, the compound represented by the general formula (VII) can be reacted with the compound represented by the general formula (III) to obtain a compound (I ′) as a target substance .

This reaction is carried out without solvent or in a dehydrohalogenation reaction under heating by an ordinary method in an organic solvent which does not participate in a reaction selected from benzene, toluene, xylene, tetrahydrofuran, chloroform, carbon tetrachloride and dimethylformamide. I do. In this case, sodium bicarbonate,
Preferred results are obtained by carrying out the reaction in the presence of inorganic salts such as potassium carbonate, sodium carbonate and caustic soda, sodium hydroxide or organic bases such as triethylamine, pyridine, pyrimidine and diethylaniline.

The starting material (III) used in the above Production Methods 1 to 3 can be produced according to the method described in Production Examples shown below.

 Next, specific effects of the present invention will be shown by experimental examples.

Experimental Example PAF receptor binding assay (receptor antagonist activity) using human platelets <Method> Platelets were obtained from a healthy male subject according to a conventional method, and a binding buffer (10 mM phosphate-
bufferes saline (pH 7.0), 0.1% (w / v) BSA, 0.9 mM CaC
l containing ₂₎ To the suspension so as to be 10 ⁸ Ke / 460μ. 20 μl of the binding buffer solution of the test compound is added to a polypropylene tube, 460 μl of platelet solution is further added, and incubated at 37 ° C. for 6 minutes after Vortex (incuba
te). Then ³ H-PAF binding buffer solution 20μ the (final ³ H-PAF concentration 0.6～1NM) was added, 6
Incubate for 10 min and wash with ice-cold wash solution (0.1% (W /
The reaction is stopped by adding 3 ml of Saline) containing BSA of V), followed by suction filtration on a glass filter (Whatman GF / C). After drying the glass filter, the radioactivity is measured with a liquid scintillation counter.

Inhibition% was calculated according to the following formula, and IC ₅₀ was obtained by interpolation from the figure.

Table 1 shows the total binding; dpm when the drug or PAF concentration was 0. non-specific binding; dpm when cold PAF 10 ^-5 M was added.

The above experimental examples clearly show that the compound of the present invention has an excellent PAF inhibitory action.

Further, it has been found that the compound of the present invention has a strong and persistent anti-PAF action as compared with conventional compounds, and is also excellent in safety, and the value of the present invention is high.

Therefore, the compound of the present invention is effective for treating / preventing any disease caused by PAF.

Representative diseases include allergic diseases, asthma, thrombosis, stroke (cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina,
It is useful as a therapeutic or prophylactic agent for human intravascular coagulation syndrome (DIC), thrombophlebitis, glomerulonephritis, anaphylactic shock, hemorrhagic shock and the like. Useful as an anti-asthmatic.

When administering the compound of the present invention as an anti-PAF agent, tablets,
It may be administered orally as a powder, granule, capsule, syrup or the like, or may be administered parenterally as a suppository, injection, external preparation, or infusion. Is preferably administered as an oral preparation.

Dosage varies significantly depending on the type of disease, degree of symptoms, age, etc.
1010 mg / kg, preferably 0.01-0.5 mg / kg.

Formulation for oral and parenteral administration is carried out by a conventional method using a usual pharmaceutically acceptable carrier.

When preparing injections, infusions, etc., add pH adjusters, buffers, stabilizers, solubilizers, etc. as necessary to the base drug, freeze-dry if necessary, and subcutaneously Intramuscular and intravenous injections and drip injections.

〔Example〕

Next, typical examples of the present invention will be described. However, it is needless to say that the present invention is not limited thereto.

 In addition, the manufacturing method of the starting material was shown as a manufacturing example.

Production Example 1 1-benzyloxycarbonyl-4- (2-hydroxyethyl) piperidine 50 g of 4-piperidineethanol and 49.2 g of sodium hydrogen carbonate were dissolved in 480 ml of water, and 55.2 ml of benzyloxycarbonyl chloride was slowly added dropwise under ice cooling, followed by stirring for 1 hour. Extracted with chloroform and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: hexane = 30: 70) to obtain 66.0 g (yield: 65%) of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.75 to 1.85 (m, 7H), 2.5 to 3.0 (m, 2H), 3.4 to 3.8 (m,
2H), 3.9-4.3 (m, 2H), 5.11 (s, 2H), 7.1-7.4 (m, 5
H) Production Example 2 1-benzyloxycarbonyl-4- (formylmethyl) piperidine Dissolve 159 g of oxalic acid chloride in dichloromethane 1 and add 195.8 g of dimethyl sulfoxide dropwise at -67 ° C.
After stirring for 1 minute, 1-benzyloxycarbonyl-
200 ml of dichloromethane in which 66 g of 4- (2-hydroxyethyl) piperidine was dissolved was added dropwise. Then, 380 g of triethylamine was added dropwise at -67 ° C, and the mixture was stirred for about 1 hour. After evaporating the solvent, ethyl acetate was added, insolubles were removed by filtration, and the filtrate was washed with water and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: hexane = 20: 80) to obtain 55.0 g (yield 84%) of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.8 to 1.85 (m, 4H), 1.85 to 2.45 (m, 1H), 2.36 (dd, J
= 6.1Hz, 1.8Hz, 2H), 2.5 ~ 3.0 (m, 2H), 3.9 ~ 4.35 (m, 2
H), 5.07 (s, 2H), 7.1-7.5 (m, 5H), 9.67 (t, J = 1.8H
z, 1H) Production Example 3 2-Amino-5- [4- (1-benzyloxycarbonyl) piperidyl] -3- (2-chlorobenzoyl) thiophene 1-benzyloxycarbonyl-4- (formylmethyl) piperidine (55.0 g), sulfur (6.75 g) and 2-chlorocyanoacetophenone (37.87 g) were mixed with N, N-dimethylformamide 2
Suspend in 50 ml, add triethylamine 7.75 at 40 ° C, and add 1.
Stir for 5 hours. After evaporating the solvent, ethyl acetate was added, and water and
Then, it was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: hexane = 30: 70) to give the title compound (67.9 g, yield 76).
%)Obtained. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.15 to 2.1 (m, 4H), 3.4 to 4.05 (m, 3H), 3.95 to 4.35
(M, 2H), 5.06 (s, 2H), 6.04 (bs, 1H), 6.94 (bs, 2H),
7.1 to 7.55 (m, 9H) Production Example 4 2- [4- (1-benzyloxycarbonyl) piperidyl] -5- (bromoacetylamino) -4- (2-chlorobenzoyl) thiophene To 67.9 g of the compound obtained in Production Example 3, toluene 1.5 and water 350 m
l, 27 g of sodium hydrogencarbonate was added, and 48.61 g of bromoacetic bromide was added at 60 ° C.
The organic layer was separated, washed with saturated saline, and dried over anhydrous magnesium sulfate. This was filtered and the solvent was distilled off to obtain the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.1 to 2.2 (m, 4H), 2.55 to 3.05 (m, 3H), 4.07 (s, 2
H), 4.0 ~ 4.45 (m, 2H), 5.06 (s, 2H), 6.36 (bs, 1H),
7.1-7.6 (m, 9H), 12.47 (bs, 1H) Production Example 5 2- (aminoacetylamino) -5- [4- (1-benzyloxycarbonyl) piperidyl] -3- (2-chlorobenzoyl) thiophene Ethyl acetate 2 was added to the total amount of the compound obtained in Production Example 4,
After passing ammonia gas for 3 hours while stirring at room temperature, stirring was continued for 12 hours. After passing nitrogen gas for about 30 minutes, the organic layer was separated under salting out, the aqueous layer was extracted with chloroform under salting out, and both organic layers were dried over anhydrous magnesium sulfate. This was filtered and the solvent was distilled off to obtain the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.1 to 2.15 (m, 4H), 2.5 to 3.05 (m, 3H), 4.61 (bs, 2
H), 3.9-4.4 (m, 2H), 5.06 (s, 2H), 6.32 (bs, 1H), 7.
1 to 7.6 (m, 9H) Production Example 6 2- [4- (1-benzyloxycarbonyl) piperidyl] -4- (2-chlorophenyl) -thieno [3,2-
f] [1,4] diazepin-7-one To the total amount of the compound obtained in Production Example 5, benzene (600 ml), pyridine (1.5) and acetic acid (9.6 g) were added.
Heated to reflux for an hour. After evaporating the solvent, the residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: hexane = 60: 40) to obtain 61.21 g of the title compound (total yield over three steps: 77%). ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.0 to 2.15 (m, 4H), 2.35 to 3.0 (m, 3H), 3.9 to 4.4 (m,
2H), 4.43 (s, 2H), 5.7 (s, 2H), 6.16 (bs, 1H), 7.05〜
7.55 (m, 9H), 8.93 (bs, 1H) Production Example 7 2- [4- (1-benzyloxycarbonyl) piperidyl] -4- (2-chlorophenyl) -thieno [3,2-
f] [1,4] diazepine-7-thione 61.21 g of the compound obtained in Production Example 6, sodium hydrogen carbonate 1
3.35 g, 27.54 g of phosphorus pentasulfide in 1,2-dimethoxyethane 1
And stirred at 80 ° C. for 1.5 hours. The reaction solution was filtered through a celite membrane, and the filtrate was subjected to chloroform: methanol (Ca 7:
Washed in 3) and combined with the filtrate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; dichloromethane containing 2 to 8% of methanol) to obtain 62.6 g (yield: 99%) of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.15 to 2.1 (m, 4H), 2.5 to 3.1 (m, 3H), 3.95 to 4.45
(M, 2H), 4.83 (bs, 2H), 5.07 (bs, 2H), 6.18 (bs, 1
H), 7.0-7.6 (m, 9H) Example 1 2- [4- (1-benzyloxycarbonyl) piperidyl] -4- (2-chlorophenyl) -9-methyl-6H-
Thieno [3,2-f] [1,2,4] triazolo [4,3-a]
(1,4) diazepine 62.6 g of the compound obtained in Production Example 7 was suspended in 3.5 of methanol, 33.5 g of hydrazine monohydrate was added, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent, triethyl orthoacetate was added, and the mixture was stirred at 80 ° C for 1 hour. After evaporating the solution, the residue was subjected to silica gel column chromatography (developing solvent; dichloromethane: methanol = 98: 2) to give the title compound in 21.5%.
g (33% yield). ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.2 to 2.2 (m, 4H), 2.6 to 3.05 (m, 3H), 2.67 (s, 3H),
4.0 to 4.4 (m, 2H), 4.88 (bs, 2H), 5.07 (bs, 2H), 6.34
(Bs, 1H), 7.1 to 7.5 (m, 9H) Production Example 8 4- (2-chlorophenyl) -9-methyl-2- (4-
Piperidyl) -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 6.65 g of the compound obtained in Example 1 was dissolved in 140 ml of dichloromethane, 17 ml of trimethylsilyl iodide was added under a nitrogen stream, and the mixture was stirred with nitrogen for 25 minutes. After cooling, methanol (40 ml) was added, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; dichloromethane: methanol:
Triethylamine = 94.5: 5: 0.5) to give the title compound.
4.45 g (90% yield) was obtained. ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.1 to 2.05 (m, 4H), 2.35 to 3.2 (m, 5H), 2.60 (s, 3
H), 4.77 (bs, 2H), 6.37 (bs, 1H), 7.2-7.6 (m, 4H) MS m / z (Pos. FAB); 398 (M + H) ⁺ Example 24. 4- (2-chlorophenyl) -9-methyl-2- [4-
(1-phenylpropiolylpiperidyl)]-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4]
Diazepine 50 mg of phenylpropiolylic acid, 110 mg of the piperidine derivative obtained in Production Example 8 and 1-hydroxybenzotriazole
50 mg of monohydrate was dissolved in 8 ml of N, N-dimethylformamide, and N, N′-dicyclohexylcarbodiimide 7 was dissolved under ice cooling.
0 mg was added, and the mixture was stirred at 4 ° C overnight and at room temperature for 1 hour. After evaporating the solvent, a saturated aqueous solution of sodium hydrogen carbonate was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue was subjected to silica gel column chromatography (developing solvent; dichloromethane: methanol = 99: 1) to obtain 130 mg (yield: 89%) of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.4 to 2.4 (m, 4H), 2.55 to 3.5 (m, 3H), 2.68 (s, 3H),
4.35 to 4.9 (m, 2H), 4.88 (bs, 2H), 6.37 (bs, 1H), 7.05
7.67.65 (m, 9H) MS m / z (Pos. FAB); 526 (M + H) ⁺ Example 3 4- (2-chlorophenyl) -2- [4- {1- (3-
Cyanopropionyl) piperidyl {] -9-methyl-6H
-Thieno [3,2-f] [1,2,4] triazolo [4,3-a]
(1,4) diazepine 10 ml of methanol in 1 g of methyl 3-cyanopropionate,
1 ml of water and 1.34 g of potassium carbonate were added, and the mixture was stirred at 60 ° C. for 2 hours. After evaporating the solvent, chloroform was added, and the insolubles were collected by filtration and washed with chloroform. Methanol was added to the crystals, insolubles were removed by filtration, and the solvent was distilled off to obtain 1.31 g of a mixture of potassium 3-cyanopropionate and an inorganic salt.

100 mg of this mixture and 150 m of the piperidine derivative obtained in Production Example 8
g, 1-hydroxybenzotriazole monohydrate 80mg
Was dissolved in 10 ml of N, N-dimethylformamide, and N, N
80 mg of N'-dicyclohexylcarbodiimide was added and 4
The mixture was stirred at ℃ overnight and at room temperature for 4 hours. After evaporating the solvent, a saturated aqueous solution of sodium hydrogen carbonate was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. Filter this,
After evaporating the solvent, the residue was subjected to silica gel column chromatography (developing solvent; dichloromethane: methanol = 99: 1) to obtain 140 mg (yield 78%) of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.1 to 2.3 (m, 4H), 2.67 (s, 3H), 2.4 to 3.4 (m, 7H),
3.5-4.2 (m, 1H), 4.4-5.9 (m, 1H), 4.88 (bs, 2H), 6.
35 (bs, 1H), 7.1-7.5 (m, 4H) MS m / z (Pos. FAB); 479 (M + H) ⁺ Example 4 4- (2-chlorophenyl) -9-methyl-2- [4-
(1-morpholinoacetylpiperidyl)]-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 150 mg of piperidine derivative and 150 mg of triethylamine obtained in Production Example 8 were dissolved in 4 ml of N, N-dimethylformamide,
This was added dropwise at −60 ° C. to 4 ml of N, N-dimethylformamide in which 60 mg of chloroacetyl chloride was dissolved. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. This was filtered, and only chloroform was distilled off. 40 mg of morpholine and 100 mg of potassium carbonate were added thereto, and the mixture was stirred at 60 ° C. for 1.5 hours. After evaporating the solution, water was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. Filter this,
After evaporating the solvent, the residue was subjected to silica gel column chromatography (developing solvent; dichloromethane: methanol = 98: 2) to obtain 130 mg of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.2 to 2.25 (m, 4H), 2.3 to 2.65 (m, 4H), 2.68 (s, 3
H), 2.65 to 3.4 (m, 5H), 3.5 to 3.8 (m, 4H), 3.95 to 4.36
(M, 1H), 4.36 to 4.9 (m, 1H), 4.89 (s, 2H), 6.35 (bs, 1
H), 7.1-7.5 (m, 4H) MS m / z (Pos. FAB); 525 (M + H) ⁺ Example 5 4- (2-chlorophenyl) -9-methyl-2- [4-
{1- (4-pentinoyl) piperidyl}]-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4]
Diazepine 4-pentynic acid 40 mg, piperidine derivative 15 obtained in Production Example 8
0 mg and 1-hydroxybenzotriazole monohydrate 6
0 mg was dissolved in N, N-dimethylformamide (10 ml) and the mixture was cooled on ice.
N, N'-dicyclohexylcarbodiimide 80 mg was added,
The mixture was stirred at 4 ° C overnight and at room temperature for 6 hours. After evaporating the solvent, a saturated aqueous solution of sodium hydrogen carbonate was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. Filter this,
After evaporating the solvent, the residue was subjected to silica gel column chromatography (developing solvent; dichloromethane: methanol = 99: 1) to obtain 140 mg (yield 78%) of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.3 to 2.3 (m, 5H), 2.3 to 2.7 (m, 4H), 2.5 to 3.4 (m, 3
H), 2.67 (s, 3H), 3.65 to 4.15 (m, 1H), 4.4 to 5.0 (m, 1
H), 4.88 (bs, 2H), 6.35 (bs, 1H), 7.05-7.6 (m, 4H) MS m / z (Pos. FAB); 478 (M + H) ⁺ Example 62- [4- 〔1 -(4-Bromophenylacetyl) piperidyl}]-4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-
a) [1,4] diazepine It was synthesized by the method of Example 2 using 4-bromophenylacetic acid. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.15 to 2.2 (m, 4H), 2.49 to 3.3 (m, 5H), 2.87 (s, 3
H), 3.55-4.1 (m, 1H), 4.45-5.0 (m, 1H), 4.88 (bs, 2
H), 6.34 (bs, 1H), 6.6 ~ 7.11 (m, 4H), 7.11 ~ 7.6 (m, 4
H) MS m / z (Pos. FAB); 596 [(M + H) ⁺ , Cl = 35, Br = 81] Example 7 4- (2-chlorophenyl) -2- [4- (1-cyanoacetylpiperidyl) ] -9-methyl-6H-thieno [3,
2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine It was synthesized by the method of Example 2 using cyanoacetic acid. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.4 to 2.4 (m, 4H), 2.45 to 3.55 (m, 3H), 2.67 (s, 3
H), 3.47 (s, 2H), 3.55-4.0 (m, 1H), 4.4-4.9 (m, 1
H), 4.87 (bs, 2H), 6.37 (bs, 1H), 7.1-7.5 (m, 4H) MS m / z (Pos. FAB); 465 (M + H) ⁺ Example 8 4- (2-chlorophenyl) -9-methyl-2- [4-
[1- {4- (2-thienyl) piopionyl} piperidyl]]-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine It was synthesized by the method of Example 2 using 4- (2-thienyl) butanoic acid. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.1 to 2.2 (m, 6H), 2.4 to 3.32 (m, 3H), 2.67 (s, 3H),
3.32 to 4.45 (m, 4H), 4.45 to 5.05 (m, 2H), 4.88 (bs, 2
H), 6.32 (bs, 1H), 6.95-7.6 (m, 7H) MS m / z (Pos. FAB); 550 (M + H) ⁺ Example 9 4- (2-chlorophenyl) -2- [4- ( 1-cyclopropanecarbonylpiperidyl)]-9-methyl-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4]
Diazepine 700 mg of piperidine derivative and 900 mg of triethylamine obtained in Production Example 8 were dissolved in 5 ml of N, N-dimethylformamide,
10 ml of an N, N-dimethylformamide solution in which 650 mg of 3-bromopropionyl chloride was dissolved was added dropwise at -60 ° C. After evaporating the solvent, a saturated aqueous solution of sodium hydrogen carbonate was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue was subjected to silica gel column chromatography (developing solvent; dichloromethane: methanol = 99: 1) to give 400 mg of the title compound.
(Yield 49%). ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.6 to 1.15 (m, 4H), 1.2 to 2.25 (m, 5H), 2.4 to 3.5 (m,
3H), 2.68 (s, 3H), 3.7-5.0 (m, 2H), 4.89 (bs, 2H),
6.36 (bs, 1H), 7.1 to 7.5 (m, 4H) Example 10 4- (2-chlorophenyl) -9-methyl-2- [4-
(1-Pentanoyl) piperidyl] -6H-thieno [3,2
-F] [1,2,4] triazolo [4,3-a] [1,4] diazepine It was synthesized by the method of Example 2 using valeric acid chloride. ^{1 H-NMR (90MHz, CDCl} 3) δ; 0.91 (t, J = 6.5Hz, 3H), 1.1~2.3 (m, 8H), 2.31 (t, J
= 7.2Hz, 2H), 2.67 (s, 3H), 2.5-3.4 (m, 3H), 3.7-4.
2 (m, 1H), 4.45 to 5.0 (m, 1H), 4.88 (bs, 2H), 6.35 (b
s, 1H), 7.1-7.5 (m, 4H) MS m / z (Pos. FAB); 482 (M + H) ⁺ Example 11 4- (2-chlorophenyl) -9-methyl-2- [4-
(1-Octanoyl) piperidyl] -6H-thieno [3,2
-F] [1,2,4] triazolo [4,3-a] [1,4] diazepine It was synthesized by the method of Example 2 using octanoyl chloride. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.7 to 1.1 (m, 3H), 1.1 to 2.5 (m, 14H), 2.31 (t, J = 7.
5Hz, 2H), 2.68 (s, 3H), 2.5 ~ 3.35 (m, 3H), 3.7 ~ 4.15
(M, 1H), 4.45 to 5.0 (m, 1H), 4.88 (bs, 2H), 6.35 (bs,
1H), 7.1-7.5 (m, 4H) MS m / z (Pos. FAB); 524 (M + H) ⁺ Example 12 4- (2-chlorophenyl) -2- [4- (1-methoxyacetylpiperidyl)] -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine It was synthesized by the method of Example 2 using methoxyacetic acid chloride. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.4 to 2.3 (m, 4H), 2.4 to 3.2 (m, 3H), 2.68 (s, 3H),
3.39 (s, 3H), 3.7 to 4.2 (m, 1H), 4.06 (s, 2H), 4.4 to 4.
9 (m, 1H), 4.89 (s, 2H), 6.36 (bs, 1H), 7.1 to 7.55 (m,
4H) MS m / z (Pos. FAB); 470 (M + H) ⁺ Production Example 9 2-morpholinoethylphenyl carbonate 2 g of 4- (2-hydroxyethyl) morpholine and 3.6 g of pyridine were dissolved in 40 ml of dichloromethane, and 5.97 g of phenyl chloroformate was added dropwise under ice-cooling, followed by stirring for about 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added, the organic layer was separated, the aqueous layer was extracted with chloroform, the two were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate.
This was filtered and the solvent was distilled off. The residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: hexane =
30:70) to give 3.39 g (89% yield) of the title compound. ^{1 H-NMR (90MHz, CDCl} 3) δ; 2.35~2.7 (m, 4H), 2.69 (t, J = 6.1Hz, 2H), 3.55~3.
85 (m, 4H), 4.34 (t, J = 6.1 Hz, 2H), 6.95 to 7.5 (m, 4H) Example 13 4- (2-chlorophenyl) -9-methyl-2- [4-
{1- (2-morpholinoethyloxycarbonyl) piperidyl}]-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 170 mg of the piperidine derivative and 290 mg of 2-morpholinoethylphenyl carbonate obtained in Production Example 8 were mixed with 6 ml of chloroform.
And dried at 80 ° C. while stirring. The operation of adding chloroform and distilling off to dryness was performed two to three times to complete the reaction. This was subjected to silica gel column chromatography (developing solvent; dichloromethane: methanol = 97: 3), dichloromethane was added to the obtained fraction, and insolubles were removed by decantation. After distilling off dichloromethane, a small amount of dichloromethane was added again to remove insolubles, and dichloromethane was distilled off to obtain 170 mg of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.2 to 2.2 (m, 4H), 2.25 to 3.15 (m, 7H), 2.54 (t, J =
6.1Hz, 2H), 2.68 (s, 3H), 3.55 to 3.85 (m, 4H), 3.95 to
4.45 (m, 2H), 4.18 (t, J = 6.1Hz, 2H), 4.89 (bs, 2H),
6.36 (bs, 1H), 7.1 to 7.55 (m, 4H) MS m / z (Pos. FAB); 555 (M + H) ⁺ Production Example 10 2-cyanoethylphenyl carbonate It was synthesized in the same manner as in Production Example 9. ^{1 H-NMR (90MHz, CDCl} 3) δ; 4.83 (s, 2H), 6.9~7.5 (m, 5H) Example 14 4- (2-chlorophenyl) -2- [4- {1- (2-
Cyanoethyloxycarbonyl) piperidyl {] -9-
Methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 150 mg of the piperidine derivative and 180 mg of 2-cyanoethylphenyl carbonate obtained in Production Example 8 were dissolved in 5 ml of chloroform, and dried under stirring at an external temperature of 110 ° C. The operation of adding chloroform again, stirring and heating to dryness was repeated until the reaction was completed. This was subjected to silica gel column chromatography (developing solvent: dichloromethane) to obtain 90 mg of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.3 to 2.2 (m, 4H), 2.5 to 3.2 (m, 3H), 2.68 (s, 3H),
2.69 (t, J = 6.1 Hz, 2H), 3.9 to 4.45 (m, 2H), 4.25 (t, J
= 6.1Hz, 2H), 4.88 (bs, 2H), 6.36 (bs, 1H), 7.1 ~ 7.6
(M, 4H) MS m / z (Pos. FAB); 495 (M + H) ⁺ Example 15 4- (2-chlorophenyl) -2- [4- (1-cyanomethyloxycarbonylpiperidyl)]-9-methyl. −
6H-thieno [3,2-f] [1,2,4] triazolo [4,3-
a) [1,4] diazepine ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.1 to 2.4 (m, 4H), 2.6 to 3.3 (m, 3H), 2.68 (s, 3H),
3.9 to 4.5 (m, 2H), 4.70 (s, 2H), 4.89 (bs, 2H), 6.36
(Bs, 1H), 7.1-7.5 (m, 4H) MS m / z (Pos. FAB); 481 (M + H) ⁺ Example 16 4- (2-chlorophenyl) -2- [4- {1- (3 −
Cyanopropyloxycarbonyl) piperidyl {] -9
-Methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.1 to 2.3 (m, 6H), 2.42 (t, J = 6.8 Hz, 2H), 2.68 (s, 3
H), 2.6-3.3 (m, 3H), 3.85-4.45 (m, 2H), 4.16 (t, J
= 5.8Hz, 2H), 4.48 (bs, 2H), 6.35 (bs, 1H), 7.1 ~ 7.55
(M, 4H) MS m / z (Pos. FAB); 509 (M + H) ⁺ Example 17 2- [4- {1- (3-butynyloxycarbonyl) piperidyl}]-4- (2-chlorophenyl). -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3
-A] [1,4] diazepine ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.2 to 2.2 (m, 4H), 1.96 (t, J = 2.9 Hz, 1H), 2.3 to 3.15
(M, 3H), 2.51 (td, J = 6.8Hz, 2.9Hz, 2H), 2.68 (s, 3
H), 3.9-4.5 (m, 2H), 4.15 (t, J = 6.8Hz, 2H), 4.89 (b
s, 2H), 6.35 (bs, 1H), 7.1-7.6 (m, 4H) MS m / z (Pos. FAB); 494 (M + H) ⁺ Example 18 2- [4- (1-butoxycarbonyl) piperidyl ]-
4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.92 (t, J = 6.1 Hz, 3H), 1.1 to 2.2 (m, 8H), 2.68 (s, 3
H), 2.5 ~ 3.15 (m, 3H), 3.9 ~ 4.4 (m, 2H), 4.03 (t, J =
6.5Hz, 2H), 4.88 (bs, 2H), 6.35 (bs, 1H), 7.1 ~ 7.55
(M, 4H) MS m / z (Pos. FAB); 498 (M + H) ⁺ Production Example 11 2-bromoethyl t-butyldimethylsilyl ether 2 g of ethylene bromohydrin and 2.4 g of imidazole were N,
It was dissolved in 40 ml of N-dimethylformamide, and 2.65 g of t-butylmethylsilyl chloride was added at room temperature. After completion of the reaction, benzene was added, washed with water and a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. This was filtered and the solvent was distilled off to give 3.60 g of the title compound (yield 94
%)Obtained. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.13 (s, 6H), 0.94 (s, 9H), 3.38 (t, J = 6.5 Hz, 2H),
3.88 (t, J = 6.5Hz, 2H) Production Example 12 1- (2-hydroxyethyl) imidazole Dissolve 3.56 g of 2-bromoethyl t-butyldimethylsilyl ether and 1.97 g of imidazole in 70 ml of N, N-dimethylformamide, add 4 g of potassium carbonate, and add
The mixture was stirred for 40 minutes. After evaporating the solvent, ethyl acetate was added, washed with water and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue was dissolved in tetrahydrofuran,
12.6 ml of tetrabutylammonium fluoride (1M solution in tetrahydrofuran) was added, and the mixture was stirred at room temperature. After completion of the reaction, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent: dichloromethane) to obtain 0.59 g (yield 35%) of the title compound. ^{1 H-NMR (90MHz, CDCl} 3) δ; 3.28 (bs, 1H), 3.6~4.2 (m, 4H), 6.84 (bs, 1H), 7.2
8 (bs, 1H) Production example 13 It was synthesized from the compound obtained in Production Example 12 in the same manner as in Production Example 9.

Example 19 4- (2-chlorophenyl) -2- [4- [1- {2-
(Imidazoyl) ethyloxycarbonyl {piperidyl]]-9-methyl-6H-thieno [3,2-f] [1,2,4]
Triazolo [4,3-a] [1,4] diazepine ¹ H-NMR (90 MHz, CD ₃ OD) δ; 1.2 to 2.2 (m, 4H), 2.4 to 3.1 (m, 3H), 2.68 (s, 3H),
3.9 to 4.5 (m, 6H), 4.87 (bs, 2H), 6.36 (bs, 1H), 6.75
-7.1 (m, 2H), 7.1-7.6 (m, 4H), 7.42 (bs, 1H) MS m / z (Pos. FAB); 536 (M + H) ⁺ Example 20 4- (2-chlorophenyl) -9 -Methyl-2- [4-
{1- (tetrahydropyran-4-yloxycarbonyl) piperidyl}]-6H-thieno [3,2-f] [1,2,4]
Triazolo [4,3-a] [1,4] diazepine ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.0 to 2.2 (m, 8H), 2.5 to 3.2 (m, 3H), 2.68 (s, 3H),
3.25 to 3.67 (m, 2H), 3.67 to 4.0 (m, 2H), 4.0 to 4.39 (m,
2H), 4.5 ~ 5.05 (m, 1H), 4.88 (s, 2H), 6.35 (bs, 1H),
7.05-7.55 (m, 4H) MS m / z (Pos. FAB); 526 (M + H) ⁺ Production Example 14 Phenyl 3-phenylpropyl carbonate Obtained in a yield similar to that of Production Example 9 in a yield of 70%. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.8 to 2.25 (m, 2H), 2.74 (dd, J = 9.0 Hz, 6.5 Hz, 2H),
4.23 (d, J = 6.5 Hz, 2H), 6.95 to 7.55 (m, 10H) Example 21 4- (2-chlorophenyl) -9-methyl-2- [4-
{1- (3-Phenylpropyloxycarbonyl) piperidyl}]-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.0 to 2.2 (m, 6H), 2.4 to 3.2 (m, 5H), 2.68 (s, 3H),
3.8 to 4.4 (m, 2H), 4.07 (t, J = 6.5 Hz, 2H), 4.89 (bs, 2
H), 6.36 (bs, 1H), 6.7-7.6 (m, 9H) MS m / z (Pos. FAB); 560 (M + H) ⁺ Example 22 4- (2-chlorophenyl) -9-methyl-2-. [4-
{1- (2-morpholinoethylaminocarbonyl) piperidyl}]-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 170 mg of the piperidine derivative obtained in Production Example 8 and 4- [2-
(Phenyloxycarbonylamino) ethyl] morpholine (210 mg) dissolved in chloroform (4 ml)
Stirred at 80 ° C. The operation of adding chloroform and distilling off to dryness was repeated twice to complete the reaction. This was subjected to silica gel column chromatography (developing solvent; dichloromethane: methanol = 95: 5), a small amount of dichloromethane was added to the obtained fraction, and insolubles were removed by decantation.
After distilling off dichloromethane, a small amount of dichloromethane was added again, insolubles were filtered off, and dichloromethane was distilled off to obtain 160 mg of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.0 to 2.25 (m, 4H), 2.25 to 3.1 (m, 9H), 2.67 (s, 3
H), 3.1-3.5 (m, 2H), 3.5-3.85 (m, 4H), 3.85-4.2
(M, 3H), 4.88 (bs, 2H), 6.35 (bs, 1H), 7.1 to 7.6 (m, 4
H) MS m / z (Pos. FAB); 554 (M + H) ⁺ Production Example 15 4- (phenyloxycarbonyl) morpholine It was synthesized by the method of Production Example 9 and silica gel column chromatography (developing solvent; ethyl acetate: hexane = 5:
95). ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 3.4 to 3.9 (m, 8H), 6.9 to 7.5 (m, 5H) Example 23 4- (2-chlorophenyl) -9-methyl-2- [4-
(1-morpholinocarbonylpiperidyl)]-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4]
Diazepine Chloroform 5 was added to 180 mg of the piperidine derivative obtained in Production Example 8 and 250 mg of 4- (phenyloxycarbonyl) morpholine.
The mixture was stirred at an external temperature of 130 ° C. for 12 hours while distilling off to dryness. This was subjected to silica gel column chromatography (developing solvent: dichloromethane) to obtain 38.8 mg of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.2 to 2.4 (m, 4H), 2.6 to 3.2 (m, 3H), 2.68 (s, 3H),
3.0 to 3.45 (m, 4H), 3.45 to 3.95 (m, 6H), 4.88 (bs, 2
H), 6.36 (bs, 1H), 7.05-7.5 (m, 4H) Production Example 16 2-ethoxyethyl p-toluenesulfonate Dissolve 2 g of 2-ethoxyethanol in 40 ml of pyridine,
Under ice cooling, p-toluenesulfonyl chloride (5.66 g) was added, and the mixture was stirred and heated to room temperature. Ethyl acetate was added, washed with water and a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: hexane = 5: 95) to give the title compound (3.69).
g (yield 56%). ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.12 (t, J = 7.2 Hz, 3H), 2.42 (s, 3H), 3.42 (q, J = 7.
2Hz, 2H), 3.4 to 3.7 (m, 2H), 4.0 to 4.2 (m, 2H), 7.26 (b
d, J = 8.3 Hz, 2H), 7.73 (bd, J = 8.3 Hz, 2H) Example 24 4- (2-chlorophenyl) -2- [4- {1- (2-
Ethoxyethyl) piperidyl {] -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,
4) diazepine 150 mg of the piperidine derivative and 140 mg of 2-ethoxyethyl p-toluenesulfonate obtained in Production Example 8 were dissolved in 5 ml of N, N-dimethylformamide, and 100 mg of potassium carbonate was added.
Stirred at 90 ° C. for 2 hours. After evaporating the solvent, water was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue was subjected to silica gel column chromatography (developing solvent; dichloromethane: methanol = 98: 2) to obtain 120 mg (yield: 68%) of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.20 (t, J = 7.2 Hz, 3H), 1.5 to 2.4 (m, 6H), 2.4 to 3.0
(M, 1H), 2.64 (t, J = 6.1Hz, 2H), 2.71 (s, 3H), 2.8 ~
3.25 (m, 2H), 3.51 (q, J = 7.2Hz, 2H), 3.59 (t, J = 6.1H
z, 2H), 4.95 (bs, 2H), 6.44 (bs, 1H), 7.2 ~ 7.6 (m, 4
H) MS m / z (Pos. FAB); 470 (M + H) ⁺ Production Example 17 Obtained in a yield similar to that of Production Example 16 in a yield of 70%. ^{1 H-NMR (90MHz, CDCl} 3) δ; 1.95 (t, J = 2.9Hz, 1H), 2.27 (s, 3H), 2.53 (td, J =
7.2Hz, 2.9Hz, 2H), 4.06 (t, J = 7.2Hz, 2H), 7.25 (bd, J
= 8.3Hz, 2H), 7.73 (bd, J = 8.3Hz, 2H) Example 25 2- [4- {1- (3-butynyl) piperidyl}]-4
-(2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.4 to 3.0 (m, 11H), 1.97 (t, J = 2.5 Hz, 1H), 2.68 (s,
3H), 2.8-3.2 (m, 2H), 4.88 (bs, 2H), 6.35 (bs, 1H),
7.1-7.5 (m, 4H) MS m / z (Pos. FAB); 450 (M + H) ⁺ Example 26 4- (2-chlorophenyl) -4- [1- (dimethylaminosulfonyl) piperidyl] -9-methyl -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4]
Diazepine 100 mg of the piperidine derivative obtained in Production Example 8 and 80 mg of triethylamine were dissolved in 3 ml of N, N-dimethylformamide, and this was dissolved in 50 mg of dimethylsulfamoyl chloride.
It was added dropwise at −60 ° C. to 4 ml of N-dimethylformamide. Since a large amount of the raw material remained, triethylamine and dimethylsulfamoyl chloride were added at room temperature until the raw material disappeared. After evaporating the solvent, a saturated aqueous solution of sodium hydrogen carbonate was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue was subjected to silica gel column chromatography (developing solvent; dichloromethane: methanol = 99: 1) to give 90 mg of the title compound.
(71% yield). ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.5 to 2.2 (m, 4H), 2.5 to 3.1 (m, 3H), 2.68 (s, 3H),
2.80 (s, 6H), 3.55 to 3.9 (m, 2H), 4.89 (bs, 2H), 6.32
(Bs, 1H), 7.1-7.5 (m, 4H) MS m / z (Pos. FAB); 505 (M + H) ⁺ Example 27 4- (2-chlorophenyl) -9-methyl-2- [4-
{1- (2-thiophenesulfonyl) piperidyl}]-
6H-thieno [3,2-f] [1,2,4] triazolo [4,3-
a) [1,4] diazepine Example 2 using 2-thiophenesulfonyl chloride
Was synthesized by the method described above. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.5 to 2.3 (m, 4H), 2.3 to 2.95 (m, 1H), 2.44 (td, J = 1
2.2Hz, 3.6Hz, 2H), 2.67 (s, 3H), 3.65-4.15 (m, 2H),
4.88 (bs, 2H), 6.33 (bs, 1H), 6.8 to 7.7 (m, 7H) MS m / z (Pos. FAB);

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 243: 00 249: 00) (72) Inventor Tetsuya Kawahara 2-23-5 Akubo, Tsukuba, Ibaraki Pref. ) Inventor Naoyuki Shimomura 2-2-5, Akubo, Tsukuba, Ibaraki Pref. Mezon Gakuen 207 (72) Inventor Osamu Asano Massachusetts, USA 01810 Andover No. 211, Bull Finch Drive 700 (72) Inventor Hiroyuki Yoshimura 4-4-2-18 Ninomiya, Tsukuba, Ibaraki Prefecture Sunny Hill Terrace 301 (72) Inventor Mitsuaki Miyamoto 13-3-205, Higashizaki-cho, Tsuchiura-shi, Ibaraki (72) Inventor Yoshinori Sakuma 25, right paddy, large section of Tsuchiura City, Ibaraki Pref. 2-23-5 Mezon Gakuen 307 (72) Inventor Kokichi Harada 2-11-2-3-2-2, Matsushiro, Tsukuba City, Ibaraki Prefecture (72) Inventor Sou Kakuda 1-10-4, Tokodai, Tsukuba City, Ibaraki Prefecture (72) ) Inventor Satoshi Katayama 1-16-7 Kannondai, Tsukuba City, Ibaraki Prefecture (72) Koji Yamada 5-8-8 Kariyacho, Ushiku City, Ibaraki Prefecture (72) Inventor Shigeru Shigeta 1687-21 Ushikucho, Ushiku City, Ibaraki Prefecture (72) Inventor Yoshimasa Machida 500-81 Shimohirooka, Tsukuba City, Ibaraki Prefecture (72) Inventor Koichi Katayama 2-30-3 Umezono, Tsukuba City, Ibaraki Prefecture (72) Inventor Isao Yamazu 3605-669, Kashiwada-cho, Ushiku-shi, Ibaraki (56) References JP-A-2-256682 (JP, A) JP-A-61-87684 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB Name) C07D 495/14 A61K 31/55 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) General formula [Wherein, R ¹ and R ² represent the same or different hydrogen atoms or lower alkyl groups, R ³ represents a hydrogen atom or a halogen atom, and R ⁴ represents a hydrogen atom or a lower alkyl group. X is the formula A group represented by the formula Wherein R ⁵ represents a hydrogen atom or a lower alkyl group, or a group represented by the formula: Means a group represented by n means an integer of 0 or 1. Y is an alkyl group, an alkynyl group, a formula NCCH ₂
a group represented by _p (where p represents an integer of 1 to 6),
Formula ACH _{2 q} (where A represents a cycloalkyl group, a morpholino group, a thienyl group, a lower alkoxy group, a substituted or unsubstituted phenyl group, an imidazolyl group or a tetrahydropyranyl group, and q represents 0 or 1 to 6) A group represented by the formula: A group represented by the formula (Wherein, R ⁶ and R ⁷ may be the same or different hydrogen atoms, lower alkyl groups, or R ⁶ and R ⁷ may form a ring together with a nitrogen atom), or formula Means a group represented by Where Y is the formula (Wherein R ⁶ and R ⁷ have the above-mentioned meanings)
Or expression When the group represented by is meant, n is 0. ] A triazolo-1,4-diazepine compound represented by the formula: or a pharmacologically acceptable salt thereof. 2. An anti-PAF agent comprising the triazolo-1,4-diazepine compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. An agent for treating / preventing a disease in which an anti-PAF effect is effective, comprising the triazolo-1,4-diazepine compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.