JP2000302765A - New diazepan derivative or its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new diazepan derivative useful as an activated blood coagulation X factor inhibitor by subjecting a diazepanylphenyl group to amide bond with a benzene ring and further subjecting the above benzene ring to amide bond with an aryl, etc. SOLUTION: This compound is represented by formula I [A is a (substituted) aryl or a (substituted)heteroaryl; B1 is a group or the like of C(=O)-NR3, B2 is a group or the like of C(=O)-NR4; and R1 to R4 are each H or a lower alkyl], e.g. N-(3-cyanobenzoyl)-N'-[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2- phenylenediamine. The compound of formula I is obtained by method, etc. mutually reacting a carboxylic acid and an amine comprising a combination of compounds of formula II and formula III (Q and W are each NH2, NH-lower alkyl or COOH; and P is a lower alkyl or the like), preferably in the presence of a condensing agent (e.g. N,N-dicyclohexylcarbobiimide).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel diazepan derivative or a salt thereof, which is useful as a drug, particularly an activated blood coagulation factor X inhibitor, and a drug therefor.

[0002]

2. Description of the Related Art In recent years, thromboembolic diseases such as myocardial infarction, cerebral thrombosis, and peripheral arterial thrombosis have been increasing year by year due to the westernization of lifestyles and aging of the population. Sex is increasing. Anticoagulant therapy, together with fibrinolytic therapy and antiplatelet therapy, plays a part in medical treatment in the treatment and prevention of thrombosis (Comprehensive Clinical 41:
2141 to 2145, 1989). In particular, in the prevention of thrombosis, safety that can withstand long-term administration and reliable and appropriate expression of anticoagulant activity are essential. Warfarin potassium is widely used worldwide as the only oral anticoagulant, but its properties based on its mechanism of action make it difficult to control its anticoagulant ability (J. Clinical Pharmacology 32,196-20
9,1992 and N.Eng.J.Med.324 (26) 1865-1875,1991),
It is a drug that is extremely difficult to use clinically, and there has been a demand for a more useful and easy-to-use anticoagulant.

[0003] Thrombin is not only involved in the conversion of fibrinogen to fibrin, which is the final stage of coagulation, but is also deeply involved in platelet activation and aggregation (Ed. Matsuo, T.
-PA and Pro-UK, Interdisciplinary Planning, pp5-40 Blood Coagulation, 1986), and their inhibitors have long been at the center of anticoagulant research as targets for drug discovery. However,
Bioavailabilit by oral administration
y) is low and there is a problem in terms of safety (Biomed. Biochim.A
cta 44, 1201-1210, 1985), and there are currently no orally available thrombin inhibitors on the market. Activated blood coagulation factor X is a Key Enzyme located at the junction of the extrinsic and intrinsic coagulation cascade reactions,
Because it is located upstream of thrombin, inhibition of this factor is more efficient than thrombin inhibition and may be able to specifically inhibit the coagulation system (THROMBOSIS RESEARCH (19), 339-
349, 1980). As a compound having an activated blood coagulation factor X inhibitory action, an amidinonaphthylalkylbenzene derivative or a salt thereof is known (JP-A-5-208946).
No. Thrombosis Haemostasis 71 (3), 314-319, 1994 and Thrombosis Haemostasis 72 (3), 393-396, 1994).

[0004] WO 96/16940 describes an amidinonaphthyl derivative represented by the following general formula or a salt thereof as a compound exhibiting an activated blood coagulation factor X inhibitory action. However, the compounds of the present invention differ from the compounds described in the publication in that they have a diazepane moiety, four cyclic moieties, that the nitrogen atom of diazepane is directly bonded to a benzene ring, and the like.

Embedded image (Refer to the gazette for symbols in the formula.) Further, WO99 / 00121 and WO99 / 00127
And WO99 / 00128 describe a phenylenediamide compound represented by the following general formula as a factor Xa inhibitor. However, the compounds of the present invention differ from the compounds in that they have a diazepane moiety.

Embedded image (Refer to the gazette for symbols in the formula.)

[0005]

As described above, an activated blood coagulation factor X inhibitor can be expected to be more effective and more specific in inhibiting the coagulation system than a thrombin inhibitor in anticoagulation therapy. Therefore, creation of a selective activated blood coagulation factor X inhibitor that has a different chemical structure from the above-mentioned known compounds, can be orally administered, and has a more excellent effect has been desired.

[0006]

Means for Solving the Problems The present inventors have found that a diazepanylphenyl group and a benzene ring are bonded through an amide bond, and the benzene ring is further bonded through an amide bond to an aryl group or a heteroaryl group. A diazepane derivative represented by the following general formula (I) or a salt thereof, characterized by having a chemical structure characterized by binding to
The present inventors have found that they have a factor inhibitory action, and completed the present invention. That is, the present invention relates to a diazepan derivative represented by the following general formula (I) or a salt thereof, and a pharmaceutical composition containing them as an active ingredient, particularly an activated blood coagulation factor X inhibitor.

[0007]

Embedded image (The symbols in the above formula have the following meanings: A: an aryl group or a heteroaryl group which may have 1 to 3 substituents, B ¹ : —C (＝ O) —NR ³ — or ^{-NR 3 -C (= O) -} , B 2: -C (= O) -NR 4 - or ^{-NR 4 -C (= O) -} , R 1, R 2, R 3 and R ^4: the same Or differently a hydrogen atom or a lower alkyl group)

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the compound (I) of the present invention will be described in detail. In the definition of the general formula herein, "lower"
The term "unless otherwise specified" means a straight or branched carbon chain having 1 to 6 carbon atoms. Accordingly, as the “lower alkyl group” exemplified by R ^{1 to} R ⁴ and the substituent described below,
For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,
2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-
Dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2 -Methylpropyl and the like. Among them, those having 1 to 3 carbon atoms are preferred, and methyl and ethyl are particularly preferred.

The "aryl group" means an aromatic hydrocarbon group containing a condensed ring, preferably an aryl group having 6 to 14 carbon atoms, more preferably phenyl, naphthyl,
And anthryl and phenanthryl. Also,
"Heteroaryl group" includes N, S, O
Means a heterocyclic aryl group having 1 to 4 identical or different hetero atoms selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl,
Tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, indolizinyl, quinolyl, isoquinolyl, quinazolinyl, quinolidinyl, quinoxalinyl, cinnolinyl, benzimidazolyl, imidazopyridyl, benzofuranyl, dihydrobenzofuranyl, naphthyridinyl, naphthyridinyl Zolyl, benzoxazolyl, benzothiazolyl, oxazolopyridyl, isothiazolopyridyl, benzothienyl and the like.

[0010] An optionally substituted aryl or heteroaryl group
The “substituent” of the “teroaryl group” has a substituent
A lower alkyl group which may have a -O-substituent
Secondary alkyl group, halogen atom, -NH_Two, -NH-lower al
Kill, -N- (lower alkyl) _Two, -C (= NH) -NH_Two,
-C (= N-OH) -NH_Two, -C (= NH) -NH-C (=
O) -O-lower alkyl, -COOH, -C (= O) -O-low
Grade alkyl, -CN, -NO_Two, -OH, -C (= O) -NH
_Two, -C (= O) -NH- (lower alkyl), -C (= O)-
N- (lower alkyl)_TwoAnd the like. Where "substituent
A lower alkyl group which may have
Rogen atom, -COOH, -C (= O) -O-lower alkyl
And the like. "Halogen atom" is a fluorine atom, salt
Elemental atom, iodine atom and bromine atom.

The compound of the present invention includes a mixture of various stereoisomers such as geometric isomers, tautomers, and optical isomers, and an isolated compound. The compound (I) of the present invention may form an acid addition salt. Further, depending on the type of the substituent, a salt with a base may be formed. As such salts, specifically, hydrochloric acid, hydrobromic acid, hydroiodic acid,
Mineral acids such as sulfuric acid, nitric acid and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid Organic acids such as, aspartic acid, acid-insoluble salts with acidic amino acids such as glutamic acid, inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, methylamine, ethylamine,
Examples thereof include salts with organic bases such as ethanolamine, basic amino acids such as lysine and ornithine, and ammonium salts. Furthermore, the present invention also includes hydrates of compound (I), various pharmaceutically acceptable solvates and polymorphs thereof. It should be understood that the present invention is not limited to the compounds described in Examples below, but includes all diazepan derivatives represented by the general formula (I) or pharmaceutically acceptable salts thereof. Is what you do.

(Production method) A typical production method of the compound of the present invention will be described below.

Embedded image Wherein A, B ¹ , B ² and R ¹ have the above-mentioned meanings,
Q and W represent, when Q represents -NH ₂ or -NH-lower alkyl, W represents -COOH; and when Q represents -COOH, W represents -NH ₂ or -NH-lower alkyl. .
P represents lower alkyl or an amino-protecting group)

Step A This is a reaction for synthesizing a compound (Ia) by reacting a carboxylic acid comprising a combination of a compound (II) and a compound (IV) with an amine, preferably in the presence of a condensing agent. This reaction may follow a conventional acylation reaction. N, N
-Dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3- (N, N-dimethylamino) propyl) carbodiimide, carbonyldiimidazole, diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide and the like are preferably used. it can. It is also possible to introduce the carboxylic acid into the corresponding active derivative of the carboxylic acid and then to condense it with the amine. Examples of the active derivative of the carboxylic acid to be used include active esters obtained by reacting with phenolic compounds such as p-nitrophenol, N-hydroxyamine compounds such as 1-hydroxysuccinimide and 1-hydroxybenzotriazole; monoalkyl ester carbonate; Or a mixed acid anhydride obtained by reacting with an organic acid or a phosphoric acid-based mixed acid anhydride obtained by reacting with diphenylphosphoryl chloride or N-methylmorpholine; obtained by reacting an ester with hydrazine or alkyl nitrite Acid azide; acid halides such as acid chloride and acid bromide;
Symmetric acid anhydrides and the like can be mentioned. Usually, the above reaction is carried out in a solvent under cooling to room temperature, but depending on the type of acylation reaction, it may be necessary to carry out the reaction under anhydrous conditions.

As the solvent, an organic solvent which does not participate in the reaction, for example, dimethylformamide, dioxane, tetrahydrofuran, ether, dichloroethane, dichloromethane, chloroform, carbon tetrachloride, dimethoxymethane,
Dimethoxyethane, ethyl acetate, benzene, acetonitrile, dimethylsulfoxide and the like, and a mixed solvent thereof can be used, but it is preferable to appropriately select according to the method to be applied. Also, depending on the method applied, N
When the reaction proceeds smoothly in the presence of a base such as -methylmorpholine, triethylamine, trimethylamine, pyridine, sodium hydride, potassium-t-butoxide, butyllithium, or sodium amide or by using these bases as a solvent. There is.

Step B This is a reaction for synthesizing a compound (Ia) by reacting a carboxylic acid comprising a combination of the compound (III) and the compound (V) with an amine. This reaction is carried out in the same manner as in Step A.

Embedded image (Wherein, A, B ¹ , B ² , R ¹ and P have the above-mentioned meanings) Step C Compound (Ic) having an amidino group in the compound of the present invention
Is (i) below the corresponding nitrile compound (Ib),
It can be synthesized by the methods (ii) and (iii). (I) Method of condensing nitrile into imidate and then condensing it with an amine: alcohol such as methanol or ethanol is added to nitrile form (Ib) in the presence of hydrochloric acid gas at -40 ° C to 0 ° C.
After acting at ℃ to give an imidate, an amine or an amine salt such as ammonia, ammonium carbonate, ammonium chloride or ammonium acetate is reacted. As the solvent, methanol, ethanol, acetone, tetrahydrofuran or the like is used.

(Ii) A method of converting a nitrile into a thioamide, converting it into a thioimidate, and condensing it with an amine: a nitrile (Ib) is treated with methylamine, triethylamine,
Hydrogen sulfide is allowed to act in the presence of an organic base such as pyridine and picoline to obtain a thioamide. This thioamide is converted to a dithiophosphoric acid O, O in the presence of hydrogen chloride in the form of a nitrile (Ib).
-Can also be obtained by the action of diethyl. The thioamide is reacted with a lower alkyl halide such as methyl iodide or ethyl iodide to form a thioimidate, and then reacted with an amine or an amine salt such as ammonia, ammonium carbonate, ammonium chloride or ammonium acetate. As the solvent, methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate or the like is used.

(Iii) A method of directly adding an amine, an amine salt, a metal amide, or a Grignard reagent to a nitrile:
Ammonia, ammonium chloride and ammonia, ammonium thiocyanate, alkylammonium thiocyanate, C 4 in a solvent suitable for the nitrile form (Ib) or without solvent
H ₃ Al (Cl) NH, NaNH ₂ , (CH) ₂ NMgB
It can be synthesized by adding a reagent such as r. As the solvent, chloroform, methanol, ethanol, acetone, tetrahydrofuran, toluene, dimethylformamide and the like are used. In addition, a base such as sodium hydride or an acid such as aluminum chloride or p-toluenesulfonic acid as a catalyst sometimes significantly accelerates the reaction. The reaction can be performed under cooling, at room temperature, or under heating.

Embedded image Wherein A, B ¹ , B ² , R ¹ and P have the above-mentioned meaning.

Step D Among the compounds of the present invention, the compound (Ie) having a hydroxyamidino group can be synthesized by reacting the corresponding nitrile compound (Id) with hydroxylamine or a salt thereof in a suitable solvent in the presence of a base. . As a suitable solvent, preferably, an inert organic solvent which does not participate in the reaction, for example, methanol, ethanol, dimethylformamide, dimethylamide, dioxane, tetrahydrofuran, ether,
Dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, toluene, acetonitrile, dimethylsulfoxide and the like, and a mixed solvent thereof can be used. Is preferred. As the base, triethylamine, trimethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, sodium hydride, potassium carbonate, potassium-t-butoxide and the like are used.

When P in the compound (Ia) of the present invention is a protecting group for an amine and the protecting group is not cleaved in steps A, B, C and D, it is suitable for further cleaving the protecting group P. The compound of the present invention (I) in which R ² is a hydrogen atom can be obtained by cleavage.
Here, as the protecting group for the amine exemplified by P,
There is no particular limitation as long as it is a group used for protecting the amine,
Examples include lower alkoxycarbonyl, aralkyloxycarbonyl, acyl, lower alkyl, aralkyl, and sulfonyl. “Aralkyl” refers to a group in which a hydrogen atom of the above-mentioned alkyl is substituted by aryl, and specific examples include benzyl and phenylethyl. “Acyl” specifically includes formyl, acetyl, propionyl, butyryl and the like. In addition, it is also possible to obtain a compound in which R ^{2 in the} invention compound (I) is a lower alkyl by performing a normal N-alkylation using a compound in which R ² in the invention compound (I) is a hydrogen atom.

The compound represented by the general formula (I) is
It can be produced by arbitrarily combining any other steps commonly known to those skilled in the art, such as known alkylation, acylation, oxidation, reduction, and hydrolysis. The method shown in the following reaction scheme is particularly effective for synthesizing the compound represented by the general formula (I).

Embedded image Wherein A, P, R ¹ , R ³ and R ⁴ have the above-mentioned meaning.

(Production Method of Starting Compound) Hereinafter, a typical production method of the starting compound of the compound (I) of the present invention will be described.

Embedded image (Wherein R ¹ , R ³ , R ⁴ and P have the above-mentioned meanings)

Production method 1 This is a reaction in which an amine (VI) and a carboxylic acid (Va) are condensed to form an amide bond. This reaction is carried out in the same manner as in the above step A. Production method 2 This is a reaction in which an amine (VII) and a carboxylic acid (Va) are condensed to form an amide bond. This reaction is carried out in the same manner as in the above step A. Production method 3 This is a reaction for obtaining an amine compound (IIa) from a nitro compound (VIII). This reaction can be carried out by a conventional reduction reaction. Specifically, a catalytic reduction method using palladium-carbon or the like, a method using metals such as zinc, iron and tin, Li
A method using a metal hydride such as AlH ₄ can be used. These reactions are performed in the above-mentioned inert organic solvent at room temperature or under heating.

Embedded image (Wherein R ¹ , R ³ , R ⁴ and P have the above-mentioned meanings)

Process 4 This is a reaction in which the compound (VII) is reacted with the amine (Vb) to form an amide bond to obtain (IIb). The reaction is carried out in the above inert solvent at room temperature or under heating. Also, depending on the method applied, N-methylmorpholine, triethylamine, trimethylamine, pyridine, sodium hydride,
The reaction may proceed smoothly in the presence of a base such as potassium-t-butoxide, butyllithium, and sodium amide or by using these bases as a solvent.

Embedded image (In the formula, A, R ¹ , R ³ and R ⁴ have the same meanings as described above.) Process 5 A reaction in which an amine (VI) and a carboxylic acid (IVa) are condensed to form an amide bond. This reaction is carried out in the same manner as in the above step A.

Production method 6 This is a reaction in which an amine (IX) and a carboxylic acid (IVa) are condensed to form an amide bond. This reaction is carried out in the same manner as in the above step A. Production method 7 This is a reaction for obtaining an amine compound (IIIa) from a nitro compound (X). This reaction is carried out in the same manner as in the above-mentioned Production Method 3.

Embedded image (Wherein, A, R ¹ , R ³ and R ⁴ have the same meanings as described above) Production Method 8 This is a reaction in which the compound (XI) is reacted with an amine (IVb) to form an amide bond to give (IIIb). This reaction is carried out in the same manner as in the above-mentioned Production Method 4. The compound of the present invention thus produced can be isolated and purified by a known method, for example, extraction, precipitation, fraction chromatography, fractional crystallization, recrystallization and the like. The salt of the compound of the present invention can be converted into a desired salt by subjecting the salt to a usual salt formation reaction. When the compound of the present invention has an asymmetric carbon, optical isomers exist. These optical isomers can be separated by a conventional method such as fractional crystallization for recrystallization with an appropriate salt or column chromatography.

[0025]

The compound of the present invention specifically inhibits activated blood coagulation factor X and has a strong anticoagulant effect. Therefore, it is useful as a blood coagulation inhibitor or a prophylactic / therapeutic agent for diseases caused by thrombus or embolus. Suitable diseases include cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA), cerebrovascular disorders such as subarachnoid hemorrhage (vasospasm), acute and chronic myocardial infarction, unstable angina Disease, disease in ischemic heart disease such as coronary thrombolysis, disease in pulmonary vascular disorders such as pulmonary infarction, pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, generalized intravascular coagulation, after artificial vascular surgery And thrombosis after valve replacement, reocclusion and restenosis after coronary artery bypass surgery, PTCA
(Percutaneous transluminal coronary angioplasty)
Or PTCR (Percutaneous transluminal coronaryrec)
analization) post-operative reocclusion and restenosis, and diseases in various vascular disorders such as thrombosis during extracorporeal circulation. Further, the activated blood coagulation factor X inhibitory effect of the compound of the present invention suggests a possibility as a prophylactic / therapeutic agent for influenza virus infection based on the influenza virus growth inhibitory activity (JP-A-6-227971).
issue). The excellent activated blood coagulation factor X inhibitory activity of the compounds of the present invention was confirmed by the following test methods.

1) Human activated blood coagulation factor X coagulation time measurement test Human activated blood coagulation factor X (Cosmo Bio)
Dissolve in 05M Tris-HCl buffer (pH = 7.40)
Make 0.05 units / ml. 90 μl of human plasma separated by 1/10 volume of 3.8% sodium citrate and centrifuged at 3000 rpm for 10 minutes, 10 μl of a drug dissolved and diluted with physiological saline, and 50 μl of the activated blood coagulation factor X solution are added. Warm at 37 ° C for 3 minutes,
100 μl of a 0 mM CaCl solution was added and the coagulation time was measured. For measurement of coagulation time, use Amelung KC4
A was used. Coagulation time doubled dose (abbreviated as CT2)
Was calculated based on the coagulation time when 10 μl of physiological saline was added instead of the drug.

2) Bovine thrombin clotting time measurement test Human fibrinogen (lyophilized preparation, Sigma) is dissolved in 0.05 M Tris-HCl buffer (pH = 7.40) to prepare 6 mg / ml. Bovine thrombin (500
IU / vial, Mochida Pharmaceutical) is dissolved in physiological saline to prepare various concentrations of thrombin solutions. 100 μl of physiological saline was added to 100 μl of the fibrinogen solution, and the mixture was heated at 37 ° C. for 3 minutes.
0 μl was added and the coagulation time was measured to determine the concentration of thrombin that coagulated in about 20 seconds. Next, 100 μl of the drug diluted with physiological saline was added to 100 μl of the fibrinogen solution, and the coagulation time was measured. Amelung KC4A was used for the measurement of the coagulation time. The coagulation time doubled dose (abbreviated as CT2) is equal to 10 saline
It was calculated based on the coagulation time when 0 μl was added.

3) Enzyme Inhibition Assay by Synthetic Substrate Method Human activated blood coagulation factor X (Cosmo Bio Inc.)
It was dissolved in a 0.02 M Tris-HCl buffer (pH = 7.40) containing 15 M sodium chloride to prepare 6 units / ml. As a synthetic substrate, S-5222 (first chemical agent) was dissolved in purified water to prepare 0.75 mg / ml. 25 μl of a drug prepared and dissolved in physiological saline, 170 μl of 0.05 M Tris-HCl buffer (pH = 8.40), S-22225
After mixing 0 μl, add 10 ml of human activated blood coagulation factor X solution.
μl was added and incubated at 37 ° C. for 15 minutes. After stopping the reaction by adding 50 μl of 60% acetic acid, the absorbance was measured at 405 nm, and the IC ₅₀ was calculated. Bio-Rad model 3550 was used for the measurement. As a result of the above measurements 1), 2) and 3), the compound of the present invention showed that human activated blood coagulation X
It was confirmed that it specifically inhibited the factor and exhibited a strong anticoagulant effect.

4) Ex vivo coagulation time measurement test using mice (intravenous administration) Male ICR mice (20-30) fasted for 12 hours or more
g, SLC), a single dose of a drug dissolved in saline was administered from the tail vein, and 1 minute later, under diethyl ether anesthesia, 3.8% sodium citrate 1/1 from the posterior aorta.
0.6 ml of blood was collected at 0 volume, and the plasma was separated by centrifugation at 3000 rpm for 10 minutes. Using this plasma, the extrinsic coagulation time (PT) and the intrinsic coagulation time (APTT) were measured according to the following methods a) and b). a) Extrinsic clotting time (PT) Tissue thromboplastin (54 mg / vial, freeze-dried preparation, Ortho) is dissolved in 2.5 ml of distilled water and 3.7.
Preliminary heating at ℃. The above thromboplastin solution 50
μl was added and the clotting time was measured. Amelung KC4A was used for the measurement of the coagulation time. The coagulation time when physiological saline was administered instead of the drug was used as a control, and the activity of the drug was indicated by a relative value when this control was set to 1. b) Endogenous clotting time (APTT) 50 μl of activated thrombofax (Ortho) and 50 μl of the above plasma were heated at 37 ° C. for 3 minutes, and 37
50 µl of a 20 mM Ca ₂ Cl ₂ solution pre-warmed at ℃
Was added and the coagulation time was measured. Amelung KC4A was used for the measurement of the coagulation time. The coagulation time when physiological saline was administered instead of the drug was used as a control, and the activity of the drug was indicated by a relative value when this control was set to 1. In addition, the dose dependency and the time-dependent change of the anticoagulant effect were examined in the same manner by changing the administration dose or the blood sampling time. As a result of this measurement, the effect of prolonging the coagulation time was confirmed by intravenous administration.

5) Ex vivo clotting time measurement method using mice (oral administration) In the test of 4) above, instead of a single administration to the tail vein, oral gavage was performed using an oral probe, and blood was collected 30 minutes later. Others were performed similarly to the test of the above 4). As a result of this test, the compound of the present invention was found to have an effect of extending the coagulation time even when administered orally.

Pharmaceutical compositions containing, as an active ingredient, one or more of the compounds of the present invention represented by the general formula (I) and pharmaceutically acceptable salts thereof, can be used in pharmaceutical preparations commonly used for pharmaceutical preparations. Using carriers, excipients and other additives, tablets,
It is prepared into powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, and the like, and is orally or parenterally administered. The clinical dose of the compound of the present invention for humans is appropriately determined in consideration of the symptoms, weight, age, sex, etc. of the patient to which the compound is applied. 01-100 mg, which is administered once or in several divided doses. Since the dose varies under various conditions, a dose smaller than the above dose range may be sufficient. As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. , Mixed with magnesium aluminate. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing or solubilizing agent such as an acid may be contained. The tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, commonly used inert diluents, For example, it contains purified water and ethyl alcohol. This composition contains, in addition to an inert diluent, solubilizing or solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweetening agents, flavoring agents, flavoring agents,
Preservatives may be included. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions,
Emulsifying agents. Diluents for aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline. Examples of diluents for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysorbate 80 (trade name).
Such compositions may further comprise a tonicity agent, a preservative, a wetting agent,
Additives such as emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents may be included. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. These can also be used by preparing a sterile solid composition and dissolving in sterile water or a sterile injection solvent before use.

When the solubility of the compound of the present invention is low, it may be subjected to a solubilization treatment. As the solubilization treatment, known methods applicable to pharmaceutical preparations, for example, surfactants (polyoxyethylene hydrogenated castor oils, polyoxyethylene sorbitan higher fatty acid esters, polyoxyethylene polyoxypropylene glycols, sucrose fatty acid esters) ), A drug and a solubilizer such as a polymer (hydroxypropylmethylcellulose (HPMC),
Water-soluble polymers such as polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG), carboxymethylethylcellulose (CMEC), hydroxypropylmethylcellulose phthalate (HPMCP), methyl methacrylate-methacrylic acid copolymer (Eudragit L, S, Trade name; enteric polymers such as Rohm and Haas). Further, if necessary, a method of forming a soluble salt, a method of forming an inclusion compound using cyclodextrin, or the like can be employed. The means of solubilization can be appropriately changed according to the target drug [“Recent formulation technology and its application”, Isamu Utsumi, Pharmaceutical Journal 157-159 (1983) and “Pharmaceutical Monograph No. 1, Biology ”, Tsuneji Nagai et al., Soft Science, 78-82 (198
8)]. Of these, a method of forming a solid dispersion of a drug and a solubilizer to improve solubility is preferably employed (Japanese Patent Application Laid-Open No. 56-49314, FR2460667).
issue).

[0034]

The production method of the compound of the present invention will be specifically described below with reference to production examples of the compound of the present invention. The starting compounds of the compound of the present invention also include novel compounds, and the production methods of these compounds will be described as reference examples.

Reference Example 1 4- (4-methyl-1,4-diazepan-1-yl) benzonitrile 1
8.86 g was dissolved in 185 ml of 12N hydrochloric acid, stirred at 80 ° C. for 12 hours, and concentrated under reduced pressure. After adding water and stirring at room temperature, the resulting precipitate was filtered and washed with water. The obtained solid was dried under reduced pressure to obtain 18.25 g of 4- (4-methyl-1,4-diazepan-1-yl) benzoic acid hydrochloride. Reference Example 2 1080 mg of 4- (4-methyl-1,4-diazepan-1-yl) zoic acid hydrochloride was dissolved in 50 ml of N, N-dimethylformamide, and 1650 mg of 1,2-phenylenediamine and 1-hydroxy 680 mg of benzotriazole, 960 mg of 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride and 870 ml of N, N-diisopropylethylamine were added, and the mixture was stirred at room temperature for 13 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform: methanol (8: 2) as an eluting solvent to give 2′-amino-4- (4-methyl-1,4-
750 mg of diazepan-1-yl) benzanilide were obtained. Reference Example 3 3.89 g of 4-fluorobenzonitrile was dissolved in 30 ml of N, N-dimethylformamide, and 9.7 g of 1,4-diazepane and 9.3 g of potassium carbonate were added thereto, followed by stirring at 80 ° C. for 12 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water and saturated saline, dried over sodium sulfate,
After concentration under reduced pressure, 7.63 g of 4- (1,4-diazepan-1-yl) -benzonitrile was obtained.

Reference Example 4 4- (1,4-Diazepan-1-yl) -benzonitrile 5.1
3 g was dissolved in 15 ml of concentrated hydrochloric acid, and the mixture was stirred for 4 hours while heating under reflux.
After concentration of the reaction solution, the residue was dissolved in 30 ml of methanol, and sulfuric acid was added.
5 ml was added and the mixture was heated under reflux for 18 hours. After concentrating the reaction solution, saturated aqueous sodium hydrogen carbonate and chloroform were added, and the organic layer was separated. The organic layer was washed with water and saturated saline, dried over sodium sulfate,
It was concentrated under reduced pressure. The obtained residue was dissolved in 50 ml of 1,4-dioxane, 4.47 ml of triethylamine and 8.75 g of di-t-butyl carbamate were added, and the mixture was stirred at room temperature for 12 hours. After concentrating the reaction solution, saturated aqueous sodium hydrogen carbonate and chloroform were added, and the organic layer was separated. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was treated with methanol 10
The mixture was dissolved in 0 ml, 25 ml of a 1 N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 5 days. After concentrating the reaction solution, a 10% aqueous solution of citric acid was added, and the generated precipitate was filtered off and dried under reduced pressure.
7.24 g of -t-butoxycarbonyl-1,4-diazepan-1-yl) benzoic acid was obtained. Reference Example 5 4- (4-t-butoxycarbonyl-1,4-diazepan-1
-Yl) benzoic acid (2 g) was dissolved in N, N-dimethylformamide (30 ml).
-Ethyl-3-dimethylaminopropylcarbodiimide
1.5 g of hydrochloride was added, and the mixture was stirred at room temperature for 17 hours. Water in the reaction solution,
Ethyl acetate was added and the organic layer was separated. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, a 10% aqueous solution of citric acid, and a saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain 2 '.
-Amino-4- (4-t-butoxycarbonyl-1,4
-Diazepan-1-yl) benzanilide (740 mg) was obtained.

Reference Example 6 N- (2-Aminophenyl) -4- (4-t-butoxycarbonyl-1,4-diazepan-1-yl) benzamide (2.35 g) was dissolved in pyridine (20 ml), and 4-methoxybenzoyl chloride was dissolved. 1.17 g was added, and the mixture was stirred at room temperature for 15 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography using chloroform: methanol (30: 1) as an eluting solvent to give N- [4- (4-t
-Butoxycarbonyl-1,4-diazepan-1-yl) benzoyl] -N ′-(4-methoxybenzoyl) -1,2
3.07 g of phenylenediamine were obtained. Reference Example 7 4- (4-methyl-1,4-diazepan-1-yl) aniline
1 g was dissolved in 10 ml of toluene, and 800 mg of isatoic anhydride was added thereto, followed by stirring for 5 hours while heating under reflux. The insolubles were filtered, and the solution was concentrated under reduced pressure. The obtained residue was subjected to chloroform: methanol: aqueous ammonia (10: 1:
Purified by silica gel column chromatography using 0.1) as an eluting solvent, and 2-amino-4 '-(4-methyl-1,4-
816 mg of diazepan-1-yl) benzanilide were obtained. Reference Example 8 4- (4-methyl-1,4-diazepan-1-yl) benzoic acid hydrochloride (500 mg) was dissolved in thionyl chloride (5 ml), one drop of N, N-dimethylformamide was added, and the mixture was stirred at 60 ° C. for 2 hours. . The reaction solution was concentrated under reduced pressure, toluene was added, and the mixture was concentrated again under reduced pressure. The obtained residue was dissolved in 5 ml of N, N-dimethylformamide,
-Methyl-6-nitroaniline (648 mg) was added at 50 ° C.
For 13 hours. Water was added to the reaction solution, which was washed with ethyl acetate, made alkaline with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and concentrated to 2'-methyl-4- (4-methyl-1,
507 mg of 4-diazepan-1-yl) -6′-nitrobenzanilide were obtained.

Example 1 4- (4-Methyl-1,4-diazepan-1-yl) benzoic acid hydrochloride (1.1 g) was dissolved in thionyl chloride (5 ml) and stirred at 60 ° C. for 90 minutes. After concentrating the reaction solution, it was suspended in 10 ml of 1,2-dichloroethane, and 900 mg of 2′-amino-3-cyanobenzanilide was added to the reaction solution in which 10 mg of pyridine was dissolved. The reaction solution was stirred at room temperature for 2 hours, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using chloroform: methanol: aqueous ammonia (15: 1: 0.1) as an eluent to give N- 822 mg of (3-cyanobenzoyl) -N '-[4- (4-methyl-1,4-diazepan-1-yl) benzoyl] -1,2, -phenylenediamine were obtained. Example 2 N- (3-cyanobenzoyl) -N '-[4- (4-methyl-1,4-diazepan-1-yl) benzoyl]-
350 mg of 1,2-phenylenediamine in ethanol 3
The mixture was dissolved in 50 ml, and saturated by introducing hydrogen chloride at -20 ° C or lower under stirring, and then heated to 3 ° C and stirred for 17 hours. The reaction solution was distilled off under reduced pressure, and the obtained residue was ethanol 15m
1190 mg of ammonium acetate, and
Stirred at C for 5 hours. After filtering the precipitate, the reaction solution was distilled off under reduced pressure. The obtained residue is treated with water: methanol (96: 4-6).
0:40) as an elution solvent (YMC-GE1)
ODS-A 120-S150, hereinafter the same). After adding a small amount of 1N HCl aqueous solution, the mixture was distilled off under reduced pressure, further dissolved in water, and freeze-dried to give N- (3-carbamimidylbenzoyl)-
N '-[4- (4-methyl-1,4-diazepan-1-
Yl) benzoyl] -1,2-phenylenediamine hydrochloride (190 mg) was obtained.

The compound of Example 3 was synthesized in the same manner as in Example 2. Example 4 N- (3-cyanobenzoyl) -N '-[4- (4-methyl-1,4-diazepan-1-yl) benzoyl]-
448 mg of 1,2-phenylenediamine was dissolved in 15 ml of ethanol, 1.43 ml of triethylamine and 104 mg of hydroxylamine hydrochloride were added, and the mixture was stirred under heating and reflux for 2 hours. After the reaction solution was concentrated, 1N hydrochloric acid was added, and the mixture was concentrated again. The obtained residue is eluted with water: methanol (90:10).
Purified by ODS column chromatography. After adding a small amount of a 1N aqueous hydrochloric acid solution, the mixture was evacuated under reduced pressure, dissolved in water, freeze-dried, and subjected to N- [3- (N-hydroxycarbamimidyl) benzoyl) -N '-[4- (4-methyl −
1,4-diazepan-1-yl) benzoyl] -1,2
-456 mg of phenylenediamine hydrochloride were obtained.

The compound of Example 5 was synthesized in the same manner as in Example 4. Example 6 810 mg of 2'-amino-4- (4-methyl-1,4-diazepan-1-yl) benzanilide was dissolved in 20 ml of pyridine, and 470 mg of 4-methoxybenzoyl chloride was added.
Stirred at room temperature for 26 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography using chloroform: methanol (10: 1) as an eluent.
A small amount of a 4N hydrochloric acid / ethyl acetate solution was added, and the mixture was taken out, dissolved in water, freeze-dried, and N- (4-methoxybenzoyl) -N ′-[4- (4-methyl-1,4-diazepane). -1-yl) benzoyl] -1,2-phenylenediamine hydrochloride (1.176 g) was obtained.

The compounds of Examples 7 to 10 were synthesized in the same manner as in Example 6. Example 11 N- [4- (4-t-butoxycarbonyl-1,4-diazepan-1-yl) benzoyl] -N '-(4-methoxybenzoyl) -1,2-phenylenediamine was converted to 465 m.
g was dissolved in 10 ml of ethyl acetate, 5 ml of a 4N hydrochloric acid / ethyl acetate solution was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. . The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is chloroform: methanol (5: 1)
Was purified by silica gel column chromatography using as an elution solvent, a small amount of a 4N hydrochloric acid / ethyl acetate solution was added, and the mixture was distilled to give N- [4- (1,4-diazepan-1-yl).
Benzoyl] -N '-(4-methoxybenzoyl)-
280 mg of 1,2-phenylenediamine hydrochloride was obtained.

The compound of Example 12 was synthesized in the same manner as in Example 11. Example 13 1.1 g of N- [4- (4-t-butoxycarbonyl-1,4-diazepan-1-yl) benzoyl] -N '-(5-chlorothenoyl) -1,2-phenylenediamine in 1,4
-Dissolved in 10 ml of dioxane, added 5 ml of 4N hydrochloric acid / ethyl acetate solution, and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. . The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 10 ml of 1,2-dichloroethane, and 0.5 ml of a 35% aqueous solution of formalin and 0.5 ml of acetic acid were added thereto, followed by stirring at room temperature for 10 minutes. 590 mg of sodium triacetoxyborohydride was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic layer was separated. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform: methanol (15: 1) as an eluent. Four
After adding a small amount of a normal hydrochloric acid / ethyl acetate solution, the mixture was tumbled, further dissolved in water, and freeze-dried to give N- (5-chlorothenoyl) -N '-[4- (4-methyl-1,4-diazepane). -1-yl) benzoyl] -1,2-phenylenediamine hydrochloride (264 mg) was obtained.

The compounds of Examples 14 and 15 were synthesized in the same manner as in Example 6. Example 16 1.1 g of 4- (4-methyl-1,4-diazepan-1-yl) benzoic acid hydrochloride was dissolved in 10 ml of thionyl chloride, and the mixture was stirred at 60 ° C. for 2 hours. After concentration, the reaction solution was suspended in 1,2-dichloroethane (10 ml) and added to a reaction solution prepared by dissolving 930 mg of 2-amino-4′-methoxybenzanilide in pyridine (10 ml). After the reaction solution was stirred at room temperature for 4 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was chloroform: methanol.
Purification was performed by silica gel column chromatography using (8: 1) as an eluting solvent, and a small amount of a 4N hydrochloric acid / ethyl acetate solution was added, and the mixture was distilled. The obtained residue is crystallized from ethanol to give 4′-methoxy-2-{[4- (4-methyl-1,
620 mg of 4-diazepan-1-yl) benzoyl] amino {benzanilide were obtained.

Embodiments 17 and 18 in the same manner as Embodiment 16.
Was synthesized. Example 19 2'-methyl-4- (4-methyl-1,4-diazepan-1-
Yl) -6'-nitrobenzanilide 500 mg in TH
The resultant was dissolved in 10 ml of F, and 50 mg of 10% palladium-carbon powder was added, followed by stirring at room temperature for 3 hours under a hydrogen atmosphere.
The reaction solution was filtered through celite and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform: methanol (30: 1-6: 1) as an eluent, and N- (2-amino-6-methylphenyl) -4 was obtained.
300 mg of a crude product of-(4-methyl-1,4, -diazepan-1-yl) benzamide was obtained. 295 mg of the obtained crude product was dissolved in 4 ml of tetrahydrofuran,
A solution of 223 mg of 4-methoxybenzoyl chloride in 3 ml of tetrahydrofuran and 183 μl of triethylamine were added, and the mixture was stirred at room temperature for 21 hours. 80 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
After washing with saturated saline and drying over anhydrous sodium sulfate,
It was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform: methanol (20: 1) as an elution solvent. After adding a small amount of a 4N hydrochloric acid / ethyl acetate solution, the mixture was taken up, further dissolved in water, freeze-dried, and N ^1- (4-methoxybenzoyl) -3-N ^2-
132 mg of [4- (4-methyl-1,4, -diazepan-1-yl) benzoyl] -1,2-phenylenediamine hydrochloride were obtained.

Example 20 was synthesized in the same manner as in Example 19. Examples 21 to 78 N- (2-aminophenyl) -4- (4-methyl-1,
4-Diazepan-1-yl) benzamide (10 mg) was dissolved in N, N-dimethylformamide (500 ml), and various carboxylic acids (5-10 mg, about 40 mM) in 1% 1-hydroxybenzenetriazole-N, N-dimethylformamide solution were added. 500 ml, N, N-diisopropylethylamine 7 ml and a resin carrying carbodiimide (N-Cyclohexylcarbodiimid manufactured by novabiochem)
e, N'-methylpolystyrene HL (200-400mesh), 2% DVB) 40-7
0 mg (about 90 mM) was added, and the mixture was shaken at room temperature for 13 hours. The reaction mixture was filtered, and ethyl acetate and a 1N aqueous sodium hydroxide solution were added to the obtained solution, and the organic layer was separated. The organic layer was concentrated under reduced pressure to obtain the target compound.

The structural formulas and physicochemical properties of the compounds of Reference Examples and Examples are shown in the attached table. The symbols in the table have the following meaning. Rf: Reference example number Ex: Example number structure: Structural formula salt: Salt free: Free form DATA: Physical property data NMR: Nuclear magnetic resonance spectrum (TMS internal standard) FAB-MS: Mass spectrometry value Me: Methyl group Boc: t -Butoxycarbonyl group T. : Retention time in HPLC analysis. (Using Wakosil-II 5C18 AR 4.6X30mm, 254nm, 35 ℃,
4.0ml / min, 5mM TFA-MeOH / 5mM TFA-H2O = 1/9 (0min) -9/1
The analysis was performed under the condition of a linear gradient of (5 min). )

[Table 1]

[Table 2]

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[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

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[Table 8]

[Table 9]

[Table 10]

The compounds in Tables 11 and 12 can be readily prepared in much the same way as described in the above examples and preparations, or by applying some variations which are obvious to those skilled in the art. It is possible to

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[Table 11]

[Table 12]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 405/12 C07D 405/12 409/12 409/12 (72) Inventor Norio Seki Miyuki, Tsukuba, Ibaraki Hill 21 Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Tsukasa Ishihara 21 Miyukigaoka, Tsukuba City, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Keizo Sugasawa 21 Miyukigaoka, Tsukuba City, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Shun-ichiro Hachiya 21 Miyukigaoka, Tsukuba-shi, Ibaraki Prefecture Inside Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Yuta Yuchi 21 Miyukigaoka, Tsukuba-shi, Ibaraki Prefecture Inside Yamanouchi Pharmaceutical Co., Ltd. Yuzo 21 Miyukigaoka, Tsukuba-shi, Ibaraki F-term in Yamanouchi Pharmaceutical Co., Ltd. (reference) 04 GA07 GA08 MA01 MA04 NA14 ZA54 ZC41

Claims (3)

[Claims] 1. A diazepan derivative represented by the following general formula (I) or a salt thereof. Embedded image (The symbols in the above formula have the following meanings, respectively.
A: an aryl group or a heteroaryl group which may have 1 to 3 substituents, B ¹ : —C (＝ O) —NR ³ — or —NR ³ —C (＝ O) —, B ² : —C (＝ O) —NR ⁴ — or —NR ⁴ —C (＝ O) —, R ¹ , R ² , R ³ and R ⁴ : the same or different hydrogen atom or lower alkyl group) 2. A pharmaceutical composition comprising the diazepan derivative or its salt according to claim 1 as an active ingredient. 3. An activated blood coagulation factor X inhibitor comprising the diazepan derivative or its salt according to claim 1 as an active ingredient.