WO2003080603A1 - Benzodiazepine derivative - Google Patents

Abstract

The benzodiazepine derivative represented by the following formula, which has excellent inhibitory activity against activated blood coagulation factor X; an analogue thereof; or a pharmaceutically acceptable salt of either.

Description

 Description i Background of the Invention

The present invention relates to novel orally administrable benzodiazepine derivatives which exhibit a potent anticoagulant effect by reversibly inhibiting activated blood coagulation factor X and a blood coagulation inhibitor or thrombus or embolus containing them as an active ingredient. It relates to the prevention and treatment of the diseases caused. The above-mentioned diseases to be applied include diseases in cerebrovascular disorders such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA), subarachnoid hemorrhage (vascular spasm), acute and chronic myocardial infarction, instability Diseases in ischemic heart disease such as angina pectoris, coronary artery thrombolysis, diseases in pulmonary vascular disorders such as pulmonary infarction, pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, generalized intravascular coagulation Thrombosis after vascular angioplasty and valve replacement, reocclusion and restenosis after coronary artery bypass surgery, percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary revascularization (PTCR) ), Etc.Reocclusion and restenosis after revascularization, blood clot formation during extracorporeal circulation, etc.With the westernization of lifestyle, aging of the population, etc., including myocardial infarction, cerebral thrombosis, peripheral arterial thrombosis Thromboembolic disease There is a growing trend, and the societal significance of the treatment is increasing. Anticoagulant therapy, together with fibrinolytic therapy and antiplatelet therapy, plays a part in medical treatment in the treatment and prevention of thrombosis. Conventionally, antithrombin agents have been developed as thrombus formation inhibitors.Thrombin not only regulates the activation of fibrinogen to fibrin, which is the final stage of the coagulation reaction, but also activates thrombocytes and platelets. It was also known that inhibition was at risk of causing a bleeding tendency because it was also deeply involved in aggregation. Also, oral bi Oavailability is low, and no thrombin inhibitor that can be orally administered is currently available.

 Activated blood coagulation factor X is located at the confluence of extrinsic and intrinsic coagulation cascade reactions and is located upstream of thrombin, so inhibition of this factor is more efficient and specific than thrombin inhibition May inhibit the coagulation system [Tidwell, R .; Webster, WP; Shaver, SR; Geratz, JD THROMB OSIS RESEARCH] 19 9, 33 9—3 49, 1 980]. Disclosure of the invention

 An object of the present invention is to provide a compound having an excellent activated blood coagulation factor X inhibitory action.

 An object of the present invention is to provide a compound having an inhibitory action specific to activated blood coagulation factor X which can be orally administered.

 An object of the present invention is to provide a pharmaceutical composition containing the above compound.

 An object of the present invention is to provide an anticoagulant or a prophylactic or therapeutic agent for thrombus or embolus containing the above compound.

In view of the above-mentioned circumstances, the present inventors have conducted various studies, and as a result, have found that a specific novel benzodiazepine derivative has an activated blood coagulation factor X inhibitory effect, and further studied the substituents thereof. It has been found that a compound in which the ring C of the following general formula (1) is a specific carbon ring containing a nitrogen atom has an excellent activated blood coagulation factor X inhibitory action. Furthermore, they have found that these series of compounds are useful as preventive and therapeutic agents for various diseases based on thrombosis / embolism, and have completed the present invention. That is, the present invention is represented by the general formula (1) Provided is a benzodiazepine derivative or a pharmaceutically acceptable salt thereof.

(1)

 [In general formula (1),

 Ring A represents a C 6 -C: aryl group of L 0, a C 3-carbon atom; a heteroaryl group of L 0 or a cyclic alkyl group of 4-10 carbon atoms,

R1 is a hydrogen atom, a halogeno group, a hydroxyl group, a C1-C1 alkoxyl group, a nitro group, a nitro group, a formyl group, a trifluoromethyl group, a trifluoromethoxy group, a trifluoromethyl sulfonyloxy group, Methylenedioxy group, carbamoyl group, thiocarbamoyl group, mono- or di-alkyl mono- or di-alkyl group having 2 to 7 carbon atoms, cyano group, mono- or di-alkylamino group having 1 to 6 carbon atoms, carboxyl group, alkoxycarbonyl having 2 to 7 carbon atoms Group, C3-C7 hydroxycarbonylalkenyl group, C4-C8 alkoxycarbonylalkenyl group, phosphono group, C2-C9 dialkoxyphosphoryl group, C1-C4 monoalkoxyhydroxyphosphoryl group Group, alkylthio group having 1 to 6 carbon atoms, alkylsulfonyl having 1 to 6 carbon atoms Group, aminosulfonyl group, mono- or dialkylaminosulfonyl group having 2 to 8 carbon atoms, alkyl group having 1 to 6 carbon atoms which may have a substituent, 6 to 6 carbon atoms which may have a substituent An aryl group having 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms which may have a substituent, an aryl aryl sulfonyl group having 6 to 10 carbon atoms which may have a substituent, A heteroarylsulfonyl group having 4 to 10 carbon atoms, an optionally substituted carbon number 6 to: an arylthio group having L0, having a substituent A heteroarylthio group having 4 to 10 carbon atoms, an acyl group having 1 to 8 carbon atoms which may have a substituent, an aryl group having 6 to 10 carbon atoms which may have a substituent. Substituted alkyl group having 1 to 6 carbon atoms, alkyl group having 1 to 6 carbon atoms substituted with a heterocyclic group having 5 to 10 carbon atoms which may have a substituent, and a substituent An aryl group having 6 to 10 carbon atoms substituted with an alkyl group having 1 to 6 carbon atoms, 5 to 5 carbon atoms substituted with an alkyl group having 1 to 6 carbon atoms which may have a substituent A heteroaryl group having 10 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, an amino group which may have a substituent, an amino group having 1 to 7 carbon atoms which may have a substituent, A pyrrolidine group which may have a substituent, a pyrrolidyloxy group which may have a substituent, a piperidine group which may have a substituent, A piperidyloxy group which may have a group, a piperazine group which may have a substituent, a bidazinecarbonyl group which may have a substituent, an amidino group which may have a substituent or a substituent Represents any of the guanidino groups that may have a group,

Here, when R1 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a norlogeno group, a hydroxyl group, a carbon atom having 1 to 1; an alkoxyl group having L 0, a trifluoromethyl group, and a trifluoromethoxy group. Group, carbamoyl group, mono- or dialkyl carbamoyl group having 2 to 7 carbon atoms, amino group, amino group having 1 to 7 carbon atoms, mono- or dialkylamino group having 1 to 6 carbon atoms, amidino group, carbon number Mono- or dialkylamidino group having 2 to 7 carbon atoms, trialkylamidino group having 4 to 7 carbon atoms, tetraalkylamidino group having 5 to 8 carbon atoms, guanidino group, dialkylguanidino group having 3 to 8 carbon atoms, carbon number of 4 to 4 9 trialkylguanidino groups, 6 to 10 carbon atoms, aryl groups having 1 to 10 carbon atoms, 1 carbon atoms substituted with 6 to 10 carbon atoms. C6 alkyl group, C1-6 alkyl group substituted with C5-C10 heteroaryl group, C6-C10 alkyl group substituted with C1-6 alkyl group Number of carbon atoms substituted with a alkyl group having 1 to 6 carbon atoms 5 to 10 heteroaryl groups, 6 to 10 carbon atoms arylsulfonyl group, 4 to 10 carbon atoms heteroarylsulfonyl group, carboxyl group, 2 to 7 carbon atoms alkoxy A carbon ring having 1 to 6 carbon atoms, which may be substituted with an alkyl group having 1 to 6 carbon atoms, including at least one complex atom selected from the group consisting of nitrogen, oxygen, and sulfur; and nitrogen A carbonyl group containing one or more heteroatoms selected from any of oxygen and sulfur, and a carbonyl group substituted with a carbon ring having 1 to 6 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms; An iminoalkylbiperazine carbonyl group having 7 to 10 carbon atoms, a k ° peridyloxy group, an alkylpyridyloxy group having 6 to 10 carbon atoms, an iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, Pyrrolidyloxy group, alkylpyrrolidine having 6 to 10 carbon atoms Oxy group, iminoalkylpi-lyloxy group having 7 to 10 carbon atoms, methylenedioxy group, cyano group, iminoalkyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, phosphono group, dialkoxy group having 2 to 9 carbon atoms A sulfolyl group, a monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminosulfonyl group, or a dialkylaminosulfoninole group having 2 to 8 carbon atoms,

 A ring represented by an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 3 to 10 carbon atoms;

 璟 C represents a non-aromatic carbocyclic ring having 2 to 8 carbon atoms containing at least one or more nitrogen atoms, and may contain one or more heteroatoms selected from oxygen and / or sulfur; Excluding pyrrolidyl group, piperidyl group or biperazinyl group,

R2 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, a hydroxyalkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms. Alkyl group, nitro group, formyl group, trifluoromethoxy group, trifluoromethyl group, carbamoyl group, thiocarbamoyl group, mono- or dialkyl carbamoyl group having 2 to 7 carbon atoms, amino group, amino group, having 1 to 6 carbon atoms Mono- or dialkylamino group, C1-C9 aminoamino group, C2-C9 mono- or dialkylaminoalksole group, amidino group, C2-C7 mono- or dialkylamidino group, C4-C7 Trialkylamidino group, tetraalkylamidino group having 5 to 8 carbon atoms, guanidino group, dialkylguanidino group having 3 to 8 carbon atoms, trialkylguanidino group having 4 to 9 carbon atoms, methylenedioxy group, cyano group, An iminoalkyl group having 2 to 7 carbon atoms, an acyl group having 1 to 8 carbon atoms, a piperidyloxy group, an alkylpyridyloxy group having 6 to 10 carbon atoms, an iminoalkylpiperidyloxy group having 6 to 10 carbon atoms, Alkoxy force having 8 to 14 carbon atomsRubonylpyridyloxy group, pyrrolidyloxy group, alkylpiperidyloxy group having 5 to 9 carbon atoms, carbon number 5 to 9 iminoalkylpyrrolidyloxy groups, 7 to 13 carbon atoms alkoxycarbonylpyrrolidyloxy group, pyrrolidine group, 5 to 9 carbon atoms alkyl lysine group, 5 to 9 carbon atoms iminoalkyl A lysine group, a piperidine group, an alkyl piperidine group having 6 to 10 carbon atoms, an iminoalkylpiperidine group having 6 to 10 carbon atoms, a piperazine group, an alkyl piperazine group having 5 to 13 carbon atoms, Iminoalkylpyrazine group having 6 to 9 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, arylsulfonyl group having 6 to 10 carbon atoms, 4 to 10 carbon atoms A heteroarylsulfonyl group, an iminoalkylbiperazine carbonyl group having 7 to 10 carbon atoms, an alkylpiperazinecarbonyl group having 6 to 10 carbon atoms, a piperazine sulfonyl group, an alkylpiperazine having 5 to 9 carbon atoms Sulfonyl group, iminoalkylpiperazinesulfonyl group having 6 to 9 carbon atoms, alkylsulfonyl group having 1 to 8 carbon atoms, aminosulfonyl group, mono- or dialkylaminosulfonyl group having 2 to 8 carbon atoms, piperidylalkyl group having 6 to 9 carbon atoms Or an imino anoremino reviperidyl alkyl group having 8 to 12 carbon atoms,

R3 is a hydrogen atom, a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a nitro group, a formyl group, a trifluoromethyl group, a trifluoromethoxy group , A carbamoyl group, a thiocarbamoyl group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, a methylenedioxy group, a cyano group, an iminoalkyl group having 2 to 7 carbon atoms, an acyl group having 1 to 8 carbon atoms, and a carbon number of 2 to 2 7, an alkoxycarbonyl group, a piperidyloxy group, an iminoalkylpyridyloxy group having 6 to 10 carbon atoms, an alkylpiperidyloxy group having 5 to 10 carbon atoms, an alkoxycarbonylpyridyloxy group having 8 to 14 carbon atoms, Pyrrolidyloxy group, iminoalkyl having 5 to 9 carbon atoms pyrrolidyloxy group, alkylpyrrolidyloxy group having 5 to 10 carbon atoms, alkoxycarbonylpyrrolidyloxy group having 7 to 13 carbon atoms, aryl having 6 to 10 carbon atoms Sulfonyl group, heteroarylsulfonyl group having 4 to 10 carbon atoms, carbon number? ~ 10 iminoalkylpiperazinecarbonyl group, piperazinesulfonyl group, 6 ~ 9 carbon atoms, iminoalkylpiperazinesulfonyl group, 1 ~ 6 carbon atoms which may have a substituent, 1 ~ 6 carbon atoms A mono- or dialkylamino group, an amino group which may have a substituent, an aminoamino group having 1 to 9 carbon atoms which may have a substituent, a pyrrolidine group which may have a substituent, A piperidyl group which may be substituted, a piperazine group which may have a substituent, an aryl group having 6 to 10 carbon atoms which may have a substituent, and which may have a substituent Carbon number 1 to: L 0 heteroaryl group, an optionally substituted aryl group having 6 to 10 carbon atoms substituted with an alkyl group having 1 to 6 carbon atoms, having a substituent A heteroatom having 5 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms Group, an alkyl group having 1 to 6 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms which may have a substituent, and an alkyl group having 5 to 10 carbon atoms which may have a substituent. Heteroaryl substituted alkyl group having 1 to 6 carbon atoms, optionally substituted amidino group, optionally substituted guanidino group, 6 to 9 carbon atom piperidyl Represents an alkyl group or an iminoaluminylbiperidylalkyl group having 8 to 12 carbon atoms,

When R3 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, A hydroxyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, an alkoxyalkyl group having 1 to 10 carbon atoms, a nitro group, a formyl group, a trifluoromethoxy group, Trifluoromethyl group, carbamoyl group, thiocarbamoyl group, mono- or dialkyl mono- or dialkyl group having 2 to 7 carbon atoms, amino group, mono- or dialkylamino group having 1 to 6 carbon atoms, aminoalkyl group having 1 to 9 carbon atoms Group, mono- or dialkylaminoalkyl group having 2 to 9 carbon atoms, amidino group, mono- or dialkylamidino group having 2 to 7 carbon atoms, trialkylamidino group having 4 to 7 carbon atoms, tetraalkylamidino group having 5 to 8 carbon atoms Guanidino group, dialkyl guanidino group having 3 to 8 carbon atoms, trialkyl guanidino group having 4 to 9 carbon atoms, methylene dioxo Group, cyano group, iminoalkyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, pyridyloxy group, alkylpyridyloxy group having 6 to 10 carbon atoms, imino having 6 to 10 carbon atoms Alkyl piperidyloxy group, C8-C14 alkoxycarbonylbiperidyloxy group, pyrrolidyloxy group, C5-C9 alkylpyrrolidyloxy group, C5-C9 iminoalkylpyrrolidyloxy group Group, carbon number? 13 to 13 alkoxycarbonylpyrrolidyloxy group, pyrrolidine group, 5 to 9 carbon atom alkylpiperidine group, 5 to 9 carbon atom iminoalkylpiperidine group, piperidine group, 6 to 6 carbon atoms: L 0 alkylpiperidine groups, 6 to 10 carbon atoms of iminoalkylpiperidine groups, piperazine groups, 5 to 13 carbon atoms of alkylpiperazine groups, 6 to 9 carbon atoms of iminoalkylbiperazine groups, 6 carbon atoms Aryl group having 10 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, arylsulfonyl group having 6 to 10 carbon atoms, and heteroarylsulfonyl group having 4 to 10 carbon atoms An iminoalkylpiperazinecarbonyl group having 7 to 10 carbon atoms, an alkylpiperazinecarbonyl group having 6 to 10 carbon atoms, a piperazinesulfonyl group, an alkylpiperazinesulfonyl group having 5 to 9 carbon atoms, and having 6 to 9 carbon atoms Iminoalkyl Bae Rajinsuruhoniru group, carbon 1-8 alkylsulfonyl group, Aminosuruhoniru group or carbon number 2-8 mono also Or a dialkylaminosulfonyl group,

 114,115,116 ^ 7,118 and & 9 may be the same or different, each being a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, an oxo group, a hydroxyl group, a hydroxyalkyl group having 1 to 10 carbon atoms, and a carbon atom of 1 An alkoxyl group having 1 to 10 carbon atoms, an alkoxyalkyl group having 1 to 10 carbon atoms, a nitro group, a trifluoromethoxy group, a trifluoromethyl group, an amino group, a mono- or dialkylamino group having 1 to 6 carbon atoms, C1-C9 aminoalkyl group, C2-C9 mono- or dialkylaminoalkyl group, methylenedioxy group, cyano group, formyl group, carboxyl group, C2-C7 alkoxycarbonyl group, C3-C9 carbon atom An alkoxycarbonylalkyl group having 3 to 9 carbon atoms, a hydroxycarbonylalkynole group having 3 to 9 carbon atoms, a hydroxycarbonylalkenyl group having 3 to 7 carbon atoms, An alkoxycarbonylalkenyl group having 4 to 8 primes, a phosphono group, a dialkoxyphosphoryl group having 2 to 9 carbon atoms, a monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and 1 carbon atom To 6 alkylsulfonyl groups, 6 to 6 carbon atoms which may have a substituent; L 0 arylthio group, 4 to 10 heteroarylthio groups having an optionally substituted carbon atom A C1-C9 phosphorylalkyl group, a C3-C9 dialkoxyphosphorylalkyl group, a C2-C9 monoalkoxyhydroxyphosphoryl group, a 2-carboxy-12-oxoethyl group or a C1-C10 Represents any of the heteroaryl groups,

 X is an alkylene group having 1 to 6 carbon atoms (in the chain, -Η- ヽ -C (2.)-, -HC (= 0)-, -C (= 0) NH-, -NHC (= 0 ) May contain NH-), and

Z1 and Z2 may be the same or different, respectively, and include a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a hydroxy group, a hydroxyalkyl group having 1 to 6 carbon atoms, and an alkoxyalkyl having 2 to 6 carbon atoms. Group, thioalkyl group having 1 to 6 carbon atoms, alkylthioalkyl group having 2 to 8 carbon atoms, rubamoylalkyl group having 1 to 6 carbon atoms, aryl group having 6 to 10 carbon atoms, 1 to carbon atoms 10 heteroaryl groups, 1 to 6 carbon atoms A C6-C10 aryl group substituted with an alkyl group; a C4-C10 heteroaryl group substituted with a C1-C6 alkyl group; an aminoalkyl group having 1--6 carbon atoms Group, carboxyl group, alkoxycarbonyl group having 2 to 6 carbon atoms, hydroxycarbonylalkyl group having 2 to 8 carbon atoms, alkoxycarbonylalkyl group having 3 to 8 carbon atoms, aminoalkyl group having 1 to 6 carbon atoms or 2 to 10 carbon atoms And Z1 and Z2 may combine to form a ring, in which case, Z1-Z2- is an ethylene group, a trimethylene group or a tetramethylene group. Is shown. The present invention also provides a benzodiazepine derivative represented by the following general formula (1), or a pharmaceutically acceptable salt thereof.

 (1,)

(In the general formula (Γ),

 R1 ′ is a halogeno group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, an alkoxyl group having 1 to 10 carbon atoms or a hydroxyl group,

 Here, when Rl, has a substituent, the substituent is an alkyl group or a hydroxyl group having 1 to 6 carbon atoms,

璟 (T represents one of the following groups, and

R3 ⁵ is an alkyl group, a cyclic alkyl group or a heteroaryl group number 1 to 1 0 the carbon carbon number 3-8 having 1 to 6 carbon atoms. )

 The present invention also provides an activated blood coagulation factor X inhibitor comprising the benzodiazepine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

 The present invention also provides a pharmaceutical composition containing the benzodiazepine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

 The present invention also provides an anticoagulant, a prophylactic or therapeutic agent for thrombus or embolus, comprising the benzodiazepine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. BEST MODE FOR CARRYING OUT THE INVENTION

 In the present specification, the aryl group refers to an aromatic hydrocarbon ring group having 6 to 10 carbon atoms. Specific examples include a phenyl group, a 1-naphthyl group and a 2-naphthyl group. Of these, a phenyl group is preferred.

 Unless otherwise specified, “aryl” in the arylsulfonyl group and the like described in the present specification has the same meaning as the above aryl.

The heteroaryl group means an aromatic hydrocarbon ring group having 1 to 10 carbon atoms and having 1 to 3 heteroatoms selected from 0, N and S. Specifically, a pyridyl group, a pyrimidyl group, a pyridazinyl group, a birazinyl group, an imidazolyl group, a pyrrolyl group, a thiophene (chenyl) group, a virazyl group, a pyrazolyl group, a pyrrolyl group, a triazyl group, a furyl group, a isoxazolyl group , Isothiazolyl group, indolyl group, quinori And an isoquinolyl group and a tetrazole group. Among them, a heteroaryl group having 1 or 2 N and / or S and having 4 to 10 carbon atoms as a hetero atom is more preferable, and a viridyl group and a phenyl group are particularly preferable.

 Unless otherwise specified, “heteroaryl” in the heteroarylsulfonyl group and the like described in the present specification has the same meaning as the above-mentioned heteroaryl. The alkyl group refers to an alkyl group having 1 to 6 carbon atoms, and may be linear, branched or cyclic. Among them, an alkyl group having 1 to 3 carbon atoms is preferable. Specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec- and tert-butyl, n-pentyl, i-pentyl, tert-pentyl, neopentyl Groups, 2-pentyl group, 3-pentyl group, n-hexyl group, 2-hexyl group and the like. Of these, a methyl group, an ethyl group, an n-propyl group, an i-propyl group and a sec-butyl group are preferred.

 The cyclic alkyl group refers to an alkyl group having 3 to 10 carbon atoms. A cyclic alkyl group having 5 or 6 carbon atoms is preferred. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group. Of these, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group is preferred, and a cyclobutyl group and a cyclopentyl group are particularly preferred.

 Unless otherwise specified, “alkyl” in the hydroxyalkyl group, iminoalkyl group and the like described in the present specification has the same meaning as the above-mentioned alkyl. An alkenyl group refers to an alkenyl group having a straight or branched chain having 2 to 6 carbon atoms. Specific examples include a vinyl group, a propenyl group, a 2-methyl-1-propenyl group and the like.

Unless otherwise specified, “alkenyl” in the hydroxycarbonylalkenyl group and the alkoxycarbonylalkenyl group described in the present specification is also used. It has the same meaning as the above alkenyl.

 Examples of the halogeno group include a fluoro group, a chloro group, a promo group and a halide group. Of these, a fluoro group, a chloro group and a bromo group are preferred. Fluoro and chloro groups are particularly preferred.

 The alkoxyl group is an alkoxyl group having a straight or branched chain having 1 to 10 carbon atoms, an alkoxyl group having a cyclic alkyl group having 4 to 10 carbon atoms, or a cyclic carbon chain which may be condensed. Shows an alkoxyl group. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, benzyloxy, 2-phenylethoxy , 3-phenylpropyloxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, 1- Examples include an indaniloxy group and a 2-indaniloxy group. Of these, a methoxy group, an ethoxy group and an n-propoxy group are preferred.

 Unless otherwise specified, “alkoxy” in an alkoxyalkyl group, an alkoxycarbonylbiperidyloxy group, and the like described in this specification has the same meaning as the above-mentioned alkoxy.

Mono- or di-alkyl rubamoyl groups include methyl carbamoyl group, ethyl carbamoyl group, mono-alkyl rubamoyl group such as n-propylcarbamoyl group and i-propyl carbamoyl group, and dimethylcarbamoyl group, dimethylcarbamoyl group, getyl rubamoyl group, And dialkyl-powered rubamoyl groups such as di (n-propyl) -powered rubamoyl group and di (i-propyl) -powered rubamoyl group. Here, the chain length of the two alkyl groups of the dialkyl rubamoyl group may be the same or different. Further, the two alkyl groups of the dialkyl group may be combined to form a ring, or may include an unsaturated hydrocarbon group to form a ring. Also at this time-one of the CH ₂ -groups May be substituted with 0, NH or S. Specifically, a 1-pyrrolidinecarbonyl group, a 2,5-dihydro-1H-pyrroyl-1-ylcarbonyl group, a 1-pyridinepyridine carbonyl group, a 1-pyrazinecarbonyl group, a (morpholine-4- Yl) carbonyl group and (thiomorpholine-4-yl) carbonyl group. Of these, dimethylcarbamoyl group, 1-pyrrolidinecarbonyl group, (morpholin-4-yl) carbonyl group, 2,5-dihydro-1H-pyrrol-1-ylcarbonyl group and (thiomorpholine-4-yl) A carbonyl group is preferred.

 Examples of the mono- or di-alkylamino group having 1 to 6 carbon atoms include a monoalkylamino group such as a methylamino group, an ethylamino group, an n-propylamino group and an i-propylamino group, a dimethylamino group, a getylamino group, and a di (n-propyl group). And dialkylamino groups such as an amino group and a di (i-propyl) amino group. Here, the chain lengths of the two alkyl groups of the dialkylamino group may be the same or different. Further, two alkyl groups of the dialkylamino group may combine to form a ring. At this time, one of the —C-— groups may be substituted with 0, NH or S. Specific examples include a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, and a thiomorpholinyl group. Of these, a morpholinyl group and a thiomorpholinyl group are preferred.

 Examples of the alkoxycarbonyl group having 2 to 7 carbon atoms include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, a sec-butoxycarbonyl group and tert-butoxycarbodisole group and the like. Of these, a methoxycarbonyl group and an ethoxycarbonyl group are preferred.

Examples of the dialkoxyphosphoryl group having 2 to 9 carbon atoms include diethoxyphosphoryl group, di (n-propoxy) phosphoryl group, di (isopropoxy) phosphoryl group, di (n-butoxy) phosphoryl group, and di (i-butoxy) phosphoryl. Group and di (se Examples include c-butoxy) phosphoryl group and di (tert-butoxy) phosphoryl group. Of these, a diethoxyphosphoryl group is preferred.

 Examples of the monoalkoxyhydroxyphosphoryl group include a monomethoxyhydroxyphosphoryl group, a monoethoxyhydroxyphosphoryl group, a mono-n-propoxyhydroxyphosphoryl group, a monoisopropoxyhydroxyphosphoryl group, a mono-n-butoxyhydroxyphosphoryl group, a mono-i- Butoxyhydroxyphosphoryl group, monosec-butoxyhydroxyphosphoryl group, monotert-butoxyhydroxyphosphoryl group and the like. Of these, a monoethoxyhydroxyphosphoryl group is preferred.

 Examples of the alkylthio group include a methylthio group, an ethylthio group, an n-propylthio group, and an i-propylthio group. Of these, a methylthio group is preferred. Examples of the alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group, a sulfonyl group, an n-propylsulfonyl group and an i-propylsulfonyl group. Of these, a methylsulfonyl group is preferred.

Examples of the mono- or dialkylaminosulfonyl group include a monoalkylaminosulfonyl group such as a methylaminosulfonyl group, an ethylaminosulfonyl group, an n-propylaminosulfonyl group, an i-propylaminosulfonyl group, and a dimethylamino group. And dialkylaminosulfonyl groups such as a sulfonyl group, a getylaminosulfonyl group, a di (n-propyl) aminosulfonyl group and a di (i-propyl) aminosulfonyl group. Here, the chain length of the two alkyl groups of the dialkylaminosulfonyl group may be different. Further, two alkyl groups of a dialkylaminosulfonyl group may be bonded to form a ring. At this time, one of the —C-— groups may be substituted with 0, NH or S. Specific examples include a (pyrrolidine-11-yl) sulfonyl group, a (piperidine-11-yl) sulfonyl group, a (morpholine-1-4-sulfonyl) group and a (thiomorpholin-4-yl) sulfonyl group. You. Of these, a (pyrrolidine-11-yl) sulfonyl group is preferred.

 Examples of the acetyl group include an acetyl group, a propionyl group, a petyryl group, an isoptyryl group, a valeryl group, an isovaleryl group, and a bivaloyl group.

 Examples of the aminoalkyl group include an aminomethyl group, a 2-aminoethyl group, 2-aminopropyl, and 3-aminopropyl. Of these, an aminoalkyl group having 1 to 7 carbon atoms, particularly a 3-aminopropyl group, is preferred.

 Examples of the mono- or dialkylamidino group include a monoalkylamidino group such as a methylamidino group and an ethylamidino group, and a dialkylamidino group such as a dimethylamidino group and a getylamidino group. Here, the chain length of the two alkyl groups of the dialkylamidino group may be different. Further, two alkyl groups of the dialkylamidino group may combine to form a ring, or may form a ring including an unsaturated hydrocarbon group. At this time, one of the —C¾— groups may be substituted with 0, NH or S. Specifically, a (pyrrolidine-11-yl) (imino) methyl group, a (piperidine-11-yl) (imino) methyl group, a 1,4,5,6, -tetrahydro-2-pyrimidinyl group, (Morpholin-4-yl) (imino) methyl group, 2,5 dihydro-11H-pyrrole-11-yl (imino) methyl group and (thiomorpholin-4-yl) (imino) methyl group. . Of these, 2,5-dihydroxy 1 H-pyrroyl-1-yl (imino) methyl group, dimethylamidino group, (piperidine-1-yl) (imino) methyl group, (thiomorpholine-4 —Yl) (imino) methyl is preferred.

Examples of the trialkylamidino group include a trimethylamidino group, a triethylamidino group, a tri (n-propyl) amidino group, and a tri (i-propyl) amidino group. Here, the chain lengths of the three alkynole groups of the trialkylamidino group may be different. Also, two of the three alkyl groups of the trialkylamidino group may combine to form a ring. Also at this time-one of the C¾-groups May be substituted with 0, NH or S. Specific examples include a 1-methyl-1H-imidazoyl-21-yl group and a 1-ethyl-1H-imidazole-21-yl group. Of these, the 1-methyl-1H-imidazo-1-yl-2-yl group is preferred.

 Examples of the tetraalkylamidino group having 5 to 8 carbon atoms include a (dimethylamino) (dimethyliminio) methyl group and the like. Here, the chain lengths of the four alkyl groups of the tetraalkylamidino group may be the same or different. Further, two of the four alkyl groups of the tetraalkylamidino group may be bonded to form a ring. At this time, one of the —C-— groups may be substituted with 0, NH or S. Specifically, 1,3-dimethyl-1,4,5-dihydro-1H-imidazole-13-dimethyl-12-yl group and 1-ethyl-3-methyl-4,5 dihydro-1H-imidazoyl-3 —Dium 1 2— ^ f Of these, a 1,3-dimethyl-1,4,5-dihydro-1H-imidazo-1-yl-3-dim-2-yl group is preferred.

Examples of the dialkylguanidino group include a dimethylguanidino group, a getylguanidino group, a di (n-propyl) guanidino group, and a di (i-propyl) guanidino group. Here, the chain lengths of the two alkyl groups of the dialkylguanidino group may be different. Further, two alkyl groups of a dialkylguanidino group may combine to form 璟. At this time, one of the —CH ₂ — groups may be substituted with 0, NH or S. Specific examples include an imidazoline-2-amino group.

Examples of the trialkylguanidino group include a trimethylguanidino group, a triethyldanidino group, a tri (n-propyl) guanidino group, and a tri (i-propyl) guanidino group. Here, the chain lengths of the three alkyl groups of the trialkylguanidino group may be the same or different. Also, two of the three alkyl groups of the trialkylguanidino group may combine to form a ring. Also At this time, one of the —C¾— groups may be substituted with 0, NH or S. Specifically, 1-methyl-2-imidazoline-1-ylamino group, 1-ethyl-2-imidazoline-12-yl-1-amino group, and 11- (n-provyl) -2-imidazoline-12-yl And mono-amino group and 11- (i-propyl) -12-imidazoline-12-ylamino group. Of these, a 1-methyl-12-imidazoline-12-ylamino group is preferred.

 Examples of the alkylpiperazinecarbonyl group having 6 to 10 carbon atoms include methylbiperazinecarbonyl group, ethylbiperazinecarbonyl group, n-propylpiperazinecarbonyl group, i-propylpiperazinecarbonyl group, and n-butylbiperazine Examples thereof include a carbonyl group, i-butyl biperazine carbonyl group, sec-butyl biperazine carbonyl group, and tert-butyl biperazine carbonyl group. Of these, i-propylpiperazinecarbonyl group is preferred.

 Mono- or dialkylaminoalkyl groups include methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminomethyl, ethylaminoethyl, ethylaminopropyl, n-propylaminomethyl Monoalkylaminoalkyl groups such as n-propylaminoethyl group, n-propylaminopropyl group, i-propylaminomethyl group, i-propylaminoethyl group and i-propylaminopropyl group, and dimethylaminomethyl group , Dimethylaminoethyl group, dimethylaminopropyl group, acetylaminomethyl group, dimethylaminoethyl group, dimethylaminopropyl group, di (n-propyl) aminomethyl group, di (n-propyl) aminoethyl group, di ( n-propyl) aminopropyl group, di (i- Ropyl) aminomethyl group, di (i-propyl) aminoethyl group and di

(i-propyl) dialkylaminoalkyl group such as aminopropyl group. Here, the chain lengths of the three alkyl groups of the dialkylaminoalkyl group may be the same or different. Also, two alkyl groups of the dialkylaminoalkyl group are They may combine to form a ring. At this time, one of the —C¾— groups may be substituted with で, NH or S. Specifically, a (pyrrolidine-11-yl) methyl group, a (piperidine-1-yl) ethyl group, a (pyrrolidine-11-yl) propyl group, and a (pyrrolidine-11-yl) group ) Methyl group, (piperidine-1-yl) ethyl group, (piperidine-111) propyl group, (morpholine-41-yl) methyl group, (morpholine-4-yl) ethyl Group, (morpholine-4-yl) propyl group, (thiomorpholine-11-yl) methyl group, (thiomorpholine-11-yl) ethyl group and (thiomorpholine-11-yl) propyl group, etc. Is raised.

 Examples of the arylthio group include a phenylthio group and a naphthylthio group. Of these, a phenylthio group is preferred.

 Examples of the heteroarylthio group include a chenylthio group, a pyridylthio group, an indylthio group and the like. Of these, a chelylthio group is preferred.

As a carbocyclic ring having 1 to 6 carbon atoms, which may be substituted by an alkyl group having 1 to 6 carbon atoms and containing one or more heteroatoms selected from any of nitrogen, oxygen and sulfur, the following formula (3 ). The bonding position to another group is not particularly limited.

 (3)

Preferred is a structure represented by the following formula (4).

Here, it is preferable that the nitrogen atom is substituted with an alkyl group having 1 to 6 carbon atoms. '

 N, \

ノ N-

No N-

Ζ ⁰ヽ ヽ ヽ ノ,

 (Four)

In particular, a group represented by the following general formula (2) is preferable. C

(2) It may contain one or more heteroatoms selected from oxygen and z or sulfur, and has at least one carbon atom containing at least one nitrogen atom, excluding a pyridyl group, a piperidyl group or a piperazinyl group. The non-aromatic carbon ring of 8 (preferably 4 to 6) includes a structure represented by the following formula (5). Here, the non-aromatic carbocyclic ring may have a double bond. The bonding position to X, R3, R8, or R9 is not particularly limited, but it is preferable that the bonding position to X or R3 is at a nitrogen atom.

 (Five)

 More preferably, a group represented by the above general formula (2) can be mentioned.

 In the above general formula (1), ring A includes an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms (particularly, a heteroaryl group having 4 to 10 carbon atoms, and more particularly, A heteroaryl group having 3 to 5 carbon atoms) or a cyclic alkyl group having 5 or 6 carbon atoms is preferable. Of these, phenyl, pyridyl, pyrazolyl and cyclo

Two Hexyl groups are preferred. More particularly, a phenyl group is preferred.

 R1 is a hydrogen atom, a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a trifluoromethyl group, a trifluoromethyl sulfonyloxy group, a carbamoyl group, a mono- or mono-alkyl group having 2 to 7 carbon atoms. Dialkyl rubamoyl group, cyano group, nitro group, mono- or dialkylamino group having 1 to 6 carbon atoms, amino group which may have a substituent, carboxyl group, alkoxycarbonyl group having 2 to 7 carbon atoms, carbon number An alkylthio group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms which may have a substituent, and an amino group having 2 to 7 carbon atoms which may have a substituent A group, a piperazine carbonyl group which may have a substituent, an amidino group which may have a substituent and the like are preferable.

 R1 is a hydrogen atom, a fluoro group, a chloro group, a promo group, an aldehyde group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, a hydroxyl group The carbon number which may have a substituent:! An alkyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms which may have a substituent or an alkylsulfonyl group having 1 to 6 carbon atoms which may have a substituent are also preferable.

 R1 represents a hydrogen atom, a halogeno group, a carboxyl group, a cyano group, a nitro group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, or an amino group which may have a substituent Also preferred are a group, a hydroxyl group, a carbon number; an alkylthio group having! -6 and an alkyl group having 1-6 carbon atoms which may have a substituent.

When R1 has a substituent, examples of the substituent include an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, a mono- or dialkylamino group having 1 to 6 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, a carboxyl group, An alkoxycarbonyl group having 2 to 7 carbon atoms, 1 to 6 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms, including one or more heteroatoms selected from nitrogen, oxygen and sulfur Carbocycle, nitrogen, oxygen And a carbonyl or phosphono group containing at least one heteroatom selected from the group consisting of sulfur and sulfur, which may be substituted with an alkyl group having 1 to 6 carbon atoms and optionally substituted with a carbon ring having 1 to 6 carbon atoms. A C 2 -C 9 dialkoxyphosphoryl group, a C 1 -C 4 monoalkoxyhydroxyphosphoryl group, a C 1 -C 6 alkylsulfonyl group, a C 1 -C 8 acyl group and a dialkylamidino group Is preferred.

 Hydroxyl group, phosphono group, carboxyl group, alkoxy group having 2 to 7 carbon atoms, mono or dialkyl group having 2 to 7 carbon atoms, rubamoyl group, mono or dialkylamino group having 1 to 6 carbon atoms, More preferred are a perazine carbonyl group, an alkylpyrazine carbonyl group having 6 to 10 carbon atoms, an acyl group having 1 to 8 carbon atoms and an alkylsulfonyl group having 1 to 6 carbon atoms.

 Further, R1 is a hydrogen atom, a fluoro group, a chloro group, a bromo group, a sulfide group, an amino group, a carboxyl group, an ethoxycarbonyl group, a carboxyethyl group, an ethoxycarbonylethyl group, a morpholinealkyl group, a hydroxyl group. Group, methyl group, methylthio group, methylphosphoryl group, phosphonoethyl group, trifluoromethyl group, methoxy group, trifluoromethoxy group, cyano group, nitro group, morpholinecarboxyluethyl group, piperazinecarbonylethyl group, More preferred are an isopropylpiperazinecarbonyl group, a methylsulfonylaminopropyl group, a hydroxymethyl group and a hydroxypropyl group.

 R1 is a hydrogen atom, a carboxyl group, an ethoxycarbonyl group, a carboxyethyl group, an ethoxycarbonylethyl group, a morpholine alkyl group, a morpholinecarboxyletyl group, a piperazinecarbonylethyl group, an isopropylpyrazinecarbonylethyl group, It is also preferred to show a hydroxymethyl group.

R4 and R5 are preferably a hydrogen atom, a halogeno group, a trifluoromethyl group, a methoxy group and a hydroxyl group, respectively. In particular, it is preferable that R 4 is a hydrogen atom, a fluoro group, a chloro group, a methoxy group, or a methyl group. More particularly Preferably, at least one of R4 and R5 is a hydrogen atom. Preferably, M and are both hydrogen atoms.

 Rl, R4 and may be the same or different from each other, and in particular, when ring A represents a phenyl group, is preferably bonded to the phenyl group at the 6- and Z- or 8-position.

 X is preferably an alkylene group having 1 to 6 carbon atoms, more preferably a linear alkylene group having 1 to 3 carbon atoms, and further preferably a methylene group, an ethylene group or a propylene group. Ethylene groups are most preferred. As the group contained in the chain of the alkylene group X, —c (= 〇) —, C (di) N H—, and —N H C (= 0) are preferable. Ring B is preferably an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 3 to 10 carbon atoms (particularly, a heteroaryl group having 4 to carbon atoms: L0). As the aryl group, a phenyl group and a 2-naphthyl group are preferable. As the heteroaryl group, a phenyl group and a pyridyl group are preferred. More particularly, a phenyl group and a phenyl group are more preferred.

 As R2, a hydrogen atom, a halogeno group, particularly a chloro group, a bromo group; an alkoxyl group having 1 to 10 carbon atoms, particularly an alkoxyl group having 1 to 3 carbon atoms, more particularly a methoxy group; Groups, especially methyl, ethyl; and trifluoromethyl. Halogeno groups, especially chloro groups and bromo groups, and methyl groups are most preferred.

 R6 and R7 may be the same or different, and are preferably any one of a hydrogen atom, a halogeno group, a trifluoromethyl group, a methoxy group, and a hydroxyl group. More preferably, R7 and R7 are both hydrogen atoms.

R2 R6 and R7 may be the same or different from each other, and in particular, when R2 is the 3- or / and 4-position of the ring B when the ring B is a phenyl group, and 5 when the ring B is a phenyl group. At the 5-position, when ring B is a pyridyl group; When the ring B is a piperidyl group, and when the ring B is a piperidyl group, it is preferably bonded to the piperidyl group at the 1-position. It is more preferable that B is a phenyl group, R2 is bonded to the phenyl ring at the 4-position, and R6 and R7 are both hydrogen atoms.

 It is particularly preferable that B is a phenyl group, R2 is bonded to the phenyl group at the 5-position, and R6 and R7 are both hydrogen atoms.

 璟 C may contain one or more hetero atoms selected from oxygen and / or sulfur, and has at least one carbon atom containing at least one nitrogen atom, excluding a pyrrolidyl group, a piperidyl group or a piperazinyl group. Preferably, it is from ~ 8 non-aromatic carbons. In particular, a carbocycle represented by the above formula (5) is preferable.

 In particular, a carbocyclic ring represented by the above general formula (2) is more preferable.

 Further, the bonding position between ring C and X is not particularly limited.

R3 includes a halogeno group, a nitro group, an iminoalkyl group having 2 to 7 carbon atoms, a pyridyloxy group, a mono- or dialkyl group having 2 to 7 carbon atoms, a rubamoyl group, a piberidioxy group, an iminoalkyl group having 6 to 10 carbon atoms. Piperidyloxy group, alkylpiperidyloxy group having 5 to 10 carbon atoms, amino group which may have a substituent, aminoamino group having 2 to 9 carbon atoms which may have a substituent, substituent An alkyl group having 1 to 6 carbon atoms which may have a cyclic alkyl group having 3 to 8 carbon atoms which may have a substituent; an acyl group having 1 to 8 carbon atoms; An alkoxycarbonyl group, a pyrrolidine group which may have a substituent, a piperazine group which may have a substituent, a heterocyclic group having 1 to 10 carbon atoms which may have a substituent Amidino which may have a substituent or a substituent Preferably at one of the. A mono- or di-alkyl rubamoyl group having 2 to 7 carbon atoms, an alkyl group having 1 to 6 carbon atoms which may have a substituent, a cyclic alkyl group having 3 to 8 carbon atoms which may have a substituent, and An amidino group which may have a substituent is more preferred. 1 to 1 carbon atoms which may have a substituent A heteroaryl group of 0 is also preferred, especially a pyridyl group, more particularly a 4-pyridyl group. More particularly, an alkyl group having 1 to 6 carbon atoms which may have a substituent, a cyclic alkyl group having 3 to 8 carbon atoms which may have a substituent, a halogeno group, a pyridyl group (especially a 4-pyridyl group) , A nitro group, an amino group, a dialkylamino group, an amidino group which may have a substituent or a biperidyloxy group which may have a substituent are also preferable. It is also preferable to show any of a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a pyridyl group. It is also preferable to show any of a methyl group, an ethyl group, an isopropyl group, a sec-butyl group, a cyclobutyl group and a cyclopentyl group.

 When R3 has a substituent, examples of the substituent include an alkyl group having 1 to 6 carbon atoms, a mono- or dialkyl group having 2 to 7 carbon atoms, a mono- or dialkylaminoalkyl group having 2 to 9 carbon atoms. A mono- or dialkylamidino group having 2 to 7 carbon atoms, a trialkylamidino group having 4 to 7 carbon atoms, a pyrrolidine group, a piperidine group, an alkylsulfonyl group having 1 to 8 carbon atoms or a pyridyl group. It is preferable to have one. Among them, an alkyl group having 1 to 6 carbon atoms and a pyridyl group are more preferable. Further, R3 is more preferably any one of a methyl group, an ethyl group, an isopropyl group, a cyclobutyl group, a pentyl group, and a pyridyl group.

 R8 and R9 may be the same or different, respectively, a hydrogen atom, a halogeno group, carbon number:! It is preferably any one of the above-mentioned alkyl groups, oxo groups, trifluoromethyl groups, nitro groups, methoxy groups or hydroxyl groups. In particular, it is more preferably any of a hydrogen atom, a methyl group, a fluoro group, a chloro group, a promo group and an oxo group. And R9 are preferably both hydrogen atoms.

 The substitution positions of R3, R8 and R9 are not particularly limited.

Z1 and Z2 may be the same or different, respectively, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, and a heteroaryl group having 4 to 10 carbon atoms Is preferred. In particular, it is preferable that both Z1 and Z2 are hydrogen atoms.

 In the general formula (1), ring A is an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms or a cyclic alkyl group having 5 or 6 carbon atoms,

 Is a hydrogen atom, a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a trifluoromethyl group, a trifluoromethyl sulfonyloxy group, a carbamoyl group, a mono- or di-alkyl group having 2 to 7 carbon atoms. Carbamoyl group, cyano group, nitro group, mono- or dialkylamino group having 1 to 6 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 7 carbon atoms, alkyl having 1 to 6 carbon atoms which may have a substituent An alkylthio group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminoalkyl group having 2 to 7 carbon atoms which may have a substituent, and a piperazine which may have a substituent. Represents either a carbonyl group or an amidino group which may have a substituent,

 When R1 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a hydroxyxyl group, a mono- or dialkylamino group having 1 to 6 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, or carboxyl Group, an alkoxycarbonyl group having 2 to 7 carbon atoms, 1 or more carbon atoms containing at least one heteroatom selected from nitrogen, oxygen and sulfur, and 1 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms ~ 6 carbocycles, C1 ~ C6 carbocycles which may be substituted with C1 ~ C6 alkyl groups containing one or more heteroatoms selected from any of nitrogen, oxygen and sulfur A carbonyl group, a phosphono group, a C2-C9 dialkoxyphosphoryl group, a C1-C4 monoalkoxyhydroxyphosphoryl group, a C1-C6 alkylsulfonyl group, a C1-C8 Of the acyl group or carbon number of It is preferably any one of 1 to 6 dialkylamidino groups.

 In the general formula (1), ring A represents a phenyl group;

R1 is hydrogen, fluoro, chloro, bromo, odo, carboxyl 3816

An alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, and a 1 to 6 carbon atoms which may have a substituent. An alkyl group, an alkylthio group having 1 to 6 carbon atoms which may have a substituent or an alkylsulfonyl group having 1 to 6 carbon atoms which may have a substituent;

 When M has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, a phosphono group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, or a mono or dialkyl having 2 to 7 carbon atoms. Substituted with an alkyl group having 1 to 6 carbon atoms containing at least one heteroatom selected from the group consisting of a carbamoyl group, a mono- or di-alkylamino group having 1 to 6 carbon atoms, nitrogen, oxygen and sulfur. A carbon ring which may be substituted with an alkyl group having 1 to 6 carbon atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; A carbonyl group substituted by a carbon ring having 1 to 6 carbon atoms, an acyl group having 1 to 8 carbon atoms or an alkylsulfonyl group having 1 to 6 carbon atoms; and

 M and R 5 may be the same or different, and include a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxyl group having 1 to 6 carbon atoms, a trifluoromethoxy group, It is preferably a hydroxyl group, an alkylthio group having 1 to 6 carbon atoms, or an alkylsulfonyl group having 1 to 6 carbon atoms.

 In the general formula (1), ring A represents a phenyl group;

R1 represents a hydrogen atom, a fluoro group, a chloro group, a bromo group, a halide group, an amino group, a cyano group, a nitro group, a carboxyl group, an ethoxycarbonyl group, a carboxyethyl group, an ethoxycarbonylethyl group, Morpholine alkyl, hydroxyl, methyl, methoxy, methylthio, methylsulfonyl, phosphonoethyl, morpholinecarbonylethyl, piperazinecarbonylethyl, isopropylpirazazinecarbonylethyl, methanesulfonyla Minopropyl group, hydroxy More preferably, it is a cimethyl group or a hydroxypropyl group. Here, it is more preferable that at least one of R 4 and R 5 is a hydrogen atom.

 In the general formula (1), ring B represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms;

 R2 is preferably any one of a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, and an alkoxyl group having 1 to 10 carbon atoms.

 In the general formula (1), ring B is an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms;

 Is a hydrogen atom, a chloro group, a promo group or a methyl group, and

 R6 and R7 may be the same or different, and more preferably, are any of a hydrogen atom, a halogeno group, a trifluoromethyl group, a methoxy group and a hydroxyl group. .

 In the general formula (1), ring B is an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,

 R2 is any of a chloro group, a bromo group or a methyl group,

 More preferably, R 6 and R 7 are both hydrogen atoms.

 In the general formula (1), it is preferable that ring B is any one of a phenyl group and a thiophene group.

 In the general formula (1), ring B is a phenyl group or a phenyl group,

 R2 is any of a chloro group, a bromo group or a methyl group,

 It is particularly preferred that both R 6 and R 7 are hydrogen atoms.

Further, in the general formula (1), ring C is a non-C 2-8 non-cyclic carbon atom containing at least one or more nitrogen atoms and optionally containing one or more heteroatoms selected from oxygen and Z or sulfur. Aromatic carbocycle, except pyrrolidyl, piperidyl or piperazinyl, R3 is a halogeno group, a nitro group, a C2 to C7 iminoalkyl group, a C2 to C7 mono- or dialkyl-functional rubamoyl group, a C1 to C8 acyl group, a C2 to C7 alkoxycarbonyl group, A piperidyloxy group, an iminoalkylbiperidyloxy group having 6 to 10 carbon atoms, an alkylpiperidyloxy group having 5 to 10 carbon atoms, an amino group which may have a substituent, and a substituent An aminoalkyl group having 2 to 9 carbon atoms, an alkyl group having 1 to 6 carbon atoms which may have a substituent, a cyclic alkyl group having 3 to 8 carbon atoms which may have a substituent, A pyrrolidine group which may have a substituent, a piperazine group which may have a substituent, a heteroaryl group having 1 to 10 carbon atoms which may have a substituent or a substituent. Any of the amidino groups that may be

 When R3 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a mono- or di-alkyl rubamoyl group having 2 to 7 carbon atoms, a mono- or dialkylaminoalkyl group having 2 to 9 carbon atoms, A mono- or dialkylamidino group having 2 to 7 carbon atoms, a trialkylamidino group having 4 to 7 carbon atoms, a pyrrolidine group, a piperidine group, or an alkylsulfonyl group having 1 to 8 carbon atoms or a pyridyl group; Preferred. Here, in the general formula (1), R3 is an alkyl group having 1 to 6 carbon atoms which may have a substituent or a cyclic alkyl group having 3 to 8 carbon atoms which may have a substituent. More preferred. Further, in the general formula (1), it is more preferable that the ring C is any of the groups represented by the following general formula (2). In the general formula (1), ring C is any of the groups represented by the general formula (2), and R3 is an alkyl group having 1 to 6 carbon atoms which may have a substituent or a substituent. Particularly preferred is a cyclic alkyl group having 3 to 8 carbon atoms which may have In the general formula (1), it is particularly preferable that both R 8 and R 9 are hydrogen atoms, and it is particularly preferable that both R 8 and R 9 are hydrogen atoms.

In the general formula (1), X is preferably an alkylene group having 1 to 6 carbon atoms. In the general formula (1), ring A represents a phenyl group; El is a hydrogen atom, a fluoro group, a chloro group, a promo group, an amido group, an amino group, a cyano group, a nitro group, a carboxyl group, an ethoxycarbonyl group, a carboxyethyl group, an ethoxycarbonylethyl group, a morpholine alkyl Group, hydroxyl group, methyl group, methoxy group, methylthio group, methylsulfonyl group, phosphonoethyl group, morpholinecarbonylethyl group, piperazinecarbonylethyl group, isopropylpirazazinecarbonylethyl group, methanesulfonylaminopropyl A hydroxymethyl group or a hydroxypropyl group;

 Ring B represents either a phenyl group or a thiophene group,

 R2 represents a hydrogen atom, a chloro group, a promo group or a methyl group,

 Ring C represents any of the groups represented by the above general formula (2),

 R3 represents any one of a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a pyridyl group;

 X is a methylene group, an ethylene group, or a propylene group (which may contain one C (= 0) — in the chain); and

 Preferably, Z1 and Z2 are both hydrogen atoms. Here, in the general formula (1), R 5, R 6, R 7 and R 9 are more preferably hydrogen atoms.

 In particular, in the general formula (1), ring A represents a phenyl group,

 R1 is a hydrogen atom, a carboxyl group, an ethoxycarbonyl group, a carboxyl group, an ethoxycarbonylethyl group, a morpholinealkyl group, a morpholinecarboxyleethyl group, a piperazinecarbonylethyl group, or an isopropylpyrazinecarbonylethyl group Represents a hydroxymethyl group,

 Ring B represents either a phenyl or phenyl group,

 Represents a chloro group, a bromo group or a methyl group,

璟 C represents any of the groups represented by the general formula (2), R3 represents a methyl group, an ethyl group, an isopropyl group, a cyclobutyl group, a cyclopentyl group, or a pyridyl group;

 X is a methylene group or an ethylene group or a propylene group,

 R 4 is a hydrogen atom, a fluoro group, a chloro group, a methoxy group, a methyl group, R 5, R 6, R 7 and R 9 are all hydrogen atoms, and

 More preferably, both Z1 and Z2 are hydrogen atoms.

 In the general formula (1), ring A is an aryl group having 6 to 10 carbon atoms;

 Ring B is a heteroaryl group having 3 to 10 carbon atoms,

 R2 is a halogen group;

 X is an alkylene group having 1 to 6 carbon atoms,

 R 6 and R 7 are both hydrogen atoms, and

 It is also preferred that both Z1 and Z2 are hydrogen atoms.

 In the general formula (1), ring A is a phenyl group;

 Ring B is a thiophene group,

 R2 is a black group,

 X is an ethylene group,

 R 6 and R 7 are both hydrogen atoms, and

 More preferably, both Z1 and Z2 are hydrogen atoms.

とりわけ、 R1が、 置換基を有していても良い炭素数 1〜6のアルキル基、 炭素 : 1〜1 0のアルコキシル基又はヒドロキシル基であり、 Rlが置換基を有する場合の置換基が、 炭素数 1〜 6のアルキル基又はヒドロキ シル基であり、 In particular, it is preferable that the ring C represents any of the groups represented by the general formula (2), and particularly, any of the following groups.

In particular, R1 is an alkyl group having 1 to 6 carbon atoms which may have a substituent, carbon: an alkoxyl group having 1 to 10 carbon atoms or a hydroxyl group, When Rl has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms or a hydroxy group,

 R3 is an alkyl group having 1 to 6 carbon atoms which may have a substituent, a cyclic alkyl group having 3 to 8 carbon atoms which may have a substituent or a carbon atom which may have a substituent Numerical 1-: a heteroaryl group of L 0,

 Preferably, R4, R5, R8 and R9 are all hydrogen atoms.

 More particularly, is a methoxy, hydroxyl or hydroxymethyl group,

 R3 is a methyl group, an ethyl group, an i-propyl group, a sec-butyl group, a cyclobutyl group, a cyclopentyl group or a pyridyl group;

 Preferably, R4, R5, R8 and R9 are all hydrogen atoms.

 The following compounds are particularly preferred.

本発明の化合物 (1)の代表的な製造法を説明する。 例えば、 環 Aが置換基を 有してもよいフエニル基、 Xが炭素数 1〜 6のアルキル基である場合は、 次に示 した方法を用いることにより製造できる。

A typical production method of the compound (1) of the present invention will be described. For example, when ring A is a phenyl group which may have a substituent, and X is an alkyl group having 1 to 6 carbon atoms, it can be produced by the following method.

That is, the amino acid ester (2) is treated with, for example, ethanol or the like as a solvent in the presence of a base such as sodium bicarbonate, for example, and reacted with, for example, 2-to-two-port benzyl halide (3) to obtain (4). be able to. Then, the obtained (4) is led to (6) by using, for example, dichloromethane as a solvent and reacting with, for example, an acid halide (5) in the presence of a base such as triethylamine. Can be. Using the obtained (6) as a solvent, hydrolysis is performed using, for example, tetrahydrofuran or the like in the presence of a base such as sodium hydroxide, and then, using, for example, ethanol or the like as a solvent, for example, a catalyst such as palladium-carbon. The reaction can be carried out in a hydrogen atmosphere using, for example, to lead to (7). Using the obtained (7) as a solvent, for example, dimethylformamide or the like, and by allowing a condensing agent to act in the presence of a base such as, for example, triethylamine, intramolecular condensation can be carried out to lead to (8). Using the obtained (8) as a solvent, for example, dimethylformamide or the like, and reacting with (9) in the presence of a base such as sodium hydride, the compound can be led to a benzodiazepine derivative (10). By changing the starting material (3), a compound in which ring A in formula (1) is any one of an aryl group other than a phenyl group, a heteroaryl group, and a cyclic alkyl group can also be synthesized. .

Hal represents a halogen atom.

W represents a leaving group such as a halogen atom

In addition, (6) can be led to (11) by performing a reaction using, for example, ethyl acetate or the like, for example, using a catalyst such as palladium-carbon, for example, in a hydrogen atmosphere. Subsequently, for example, dichloromethane or the like is used as a solvent, and (13) is reacted with, for example, a reducing agent such as sodium triacetoxyborohydride in the presence of an acid such as acetic acid. Obtainable. The obtained (13) is hydrolyzed using, for example, tetrahydrofuran or the like as a solvent in the presence of a base such as sodium hydroxide or the like, and then uses, for example, dichloromethane or the like as a solvent, for example, triethylamine. By reacting a condensing agent in the presence of a base such as the above, intramolecular condensation can be carried out to lead to a benzodiazepine derivative (14).

n represents an integer of 0 to 5 ₍

The compound represented by the general formula (1) and a salt thereof produced in this manner can be obtained by known separation and purification means such as extraction, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfusion, It can be isolated and purified by mouth chromatography.

 The salt of the benzodiazepine derivative represented by the general formula (1) may be any pharmaceutically acceptable salt. For the basic group in the formula, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphorus Mineral acids such as acids, formic acid, acetic acid, lactic acid, salicylic acid, mandelic acid, cunic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, 'tannic acid, malic acid, tosyl

And acid addition salts with organic acids such as benzene, acid and benzenesulfonic acid. In the case where an acid group such as a carboxyl group is present in the formula, for example, a salt with an alkali metal such as ammonium salt, sodium or potassium, or an alkaline earth metal such as calcium or magnesium may be used. Salt, aluminum Salts, zinc salts, salts with organic amines such as triethylamine, ethanolamine, morpholine, piperidine and dicyclohexylamine, and base addition salts with basic amino acids such as arginine and lysine.

 The compounds represented by the general formula (1) of the present invention also include solvates thereof, for example, hydrates and alcohol adducts.

 The compound represented by the general formula (1) or a salt thereof is administered as it is or as various pharmaceutical compositions. Such pharmaceutical compositions may be in the form of tablets, powders, pills, granules, capsules, suppositories, solutions, dragees, or depots, for example, using ordinary formulation auxiliaries. It can be manufactured according to the usual method. For example, tablets may contain the active ingredient of the present invention, benzodiazepine derivative, with known auxiliary substances, such as lactose, inert diluents such as calcium carbonate or calcium phosphate, binders such as gum arabic, corn starch or gelatin, alginic acid, corn starch or Swelling agents such as pregelatinized starch, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint or cherry, moisturizing agents such as magnesium stearate, talc or ruboxymethylcellulose Obtained by mixing with the agent

—An anticoagulant containing a benzodiazepine derivative represented by the general formula (1) or a salt thereof as an active ingredient includes cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA), and subarachnoid hemorrhage Diseases in cerebrovascular disorders such as (vasospasm), diseases in acute and chronic myocardial infarction, unstable angina, ischemic heart diseases such as coronary thrombolysis, and diseases in pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism , Peripheral arterial occlusion, deep vein thrombosis, generalized intravascular coagulation, thrombosis after vascular prosthesis and valve replacement, reocclusion and restenosis after coronary artery bypass surgery, percutaneous transluminal coronary artery It can be used as a prophylactic / therapeutic agent for reocclusion and restenosis after revascularization such as plastic surgery (PTCA) or percutaneous transluminal coronary revascularization (PTCR) and thrombus formation during extracorporeal circulation. —When the benzodiazepine derivative represented by the general formula (1) is used as an anticoagulant, the administration route may be oral or parenteral, and the dosage may be the patient's age, weight, condition, The daily dose to an adult is usually 0.01 to 100 Omg, preferably 0.1 to 5 Omg for oral administration, and parenteral administration for adults. And 1 S: ~ 10 Omg \, preferably 0.01 to 10 mg. Example

 The following examples illustrate the invention in detail. These are preferred embodiments of the present invention and are not limited to these examples.

Example 1 4 — [(5-Clo-Chen-2-yl) carbonyl] —6-Fluoro-1— [2- (4 f-Sopropyl-1--1,4-diazepan—11-yl) ethyl] -1 Of 1,3,4,5 tetrahydrobenzo [e] [1,4] diazepin-2-one nitrifluoroacetate

Step 1 t-Butyl 4- [2- (Penzyloxy) ethyl]-Synthesis of 1,4-diazepane-1-carboxylate

 t-Butyl 1,4-diazepane-1-carboxylate 1.006 g (5.0 2 mmo 1), 2- (Penzyloxy) ethyl bromide 0.794 ml (5.02 mmo 1), potassium carbonate 3.135 g ( 22.7 mmo 1), 167 mg (l. 1 lmmo 1) of sodium iodide, 100 in 25 ml of toluene. The mixture was heated and stirred with C for 9.5 hours. After filtration at room temperature, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound.

Yield 752mg (2.25mmo 1) Yield 45%

MS (ESI, m / z) 335 (MH +)

H-NMR (CDC13) 51.46 (9H, s), 1.75-1.88 (2H, m), 2.63-2.78 (4H, m), 2.75 (2H, t), 3.38-3.53 (4H, m), 3.56 (2H, t), 4.53 (2H, s), 7.27-7.38 (5H, m) Step 2 t-butyl 4- (2-hydroxyethyl) ) Synthesis of 1,4-diazepane-1 carboxylate

 t-butyl 4- [2- (benzyloxy) ethyl] — 1, 4-diazepanic 1

— 748 mg (2.24 mmo 1) of carboxylate in 20 ml of ethanol

Hydrogenation was performed at 50 ° C and 4 atmospheres in the presence of 10% palladium-carbon. Post-treatment was performed according to a conventional method to obtain the title compound.

Yield 485mg (1.99mmo 1) Yield 89%

 MS (ESI, m / z) 245 (MH +)

 H-NMR (CDC13) (J1.47 (9H, s), 1.83-1.96 (2H, m), 2.68-2.85 (6H, m), 3.42- 3.58 (4H, m), 3.61 (2H, t)

Step 3 Synthesis of t-butyl 4- (2-chloroethyl) -1,4-diazepan-1-force ruboxylate

Dissolve 19 lmg (0.78 mmo1) of t-butyl 4- (2-hydroxyethyl) 1-1,4-diazepane-1-carboxylate in 5 ml of dichloromethane and add 0.07 ml of methyl sulfonyl chloride. 0.9 Ommo 1) and 0.14 ml (1. Ommo 1) of triethylamine were added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound.

Yield 156mg (0.59mmo 1) Yield 76%

 H-NMR (CDC13) dl.46 (9H, s), 1.75-1.87 (2H, m), 2.67-2.80 (4H, m), 2.87 (2H, t), 3.38-3.58 (4H, m), 3.54 (2H, t)

Step 4 Synthesis of (2-fluoro-6-nitrobenzyl) aminoethyl acetate 2-fluoro-6-nitrotoluene 5.0 g (32. mmo 1), N-bromosuccinimide 6.3 g (35.4 mmo 1), perbenzoic acid 5 Omg of the acid was dissolved in 5 Oml of benzene and stirred at 85 ° C for 2 days. After distilling off the solvent under reduced pressure, hexane was removed. In addition, the precipitated crystals were separated by filtration. The filtrate is concentrated and dried, and 100 ml of ethanol, 10.3 g (73.8 mmol) of glycineethyl ester hydrochloride and 6.2 g (73.8 mmol) of sodium hydrogen carbonate are added, and the mixture is heated at 80 ° C for 6 hours. Stirred. After evaporating the solvent under reduced pressure, the residue was partitioned between water and ethyl acetate. The mixture was extracted with 1N hydrochloric acid, and the resulting aqueous layer was made basic with a sodium hydroxide solution and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain the title compound.

Yield 5.6 g (22.Ommol) Yield 68%

 H-NMR (CDC13) 0- 1.26 (3H, t, J = 6.6Hz), 3.45 (2H, s), 4.08 (2H, s), 4.16 (2H, q, J = 6.6Hz), 7.31-7.47 ( 2H, m), 7.74 (1H, d, J = 7.8Hz)

Step 5 Synthesis of 4 — [(5-cyclopent-1-yl) carbonyl] -1-6-fluoro-1,3,4,5tetrahydrobenzo [e] [1,4] diazepin-12-one

(2-Fluoro-6-nitrobenzyl) Ethyl aminoacetate (5.6 g, 22.0 mmo 1) was dissolved in 15 Oml of dichloromethane, and triethylamine 3. Oml (22. Ommol) and di-tert-butyl dicanole 4.8 g (22.4 mmol) of Bonate was added, and the mixture was stirred at room temperature overnight. After treatment with dichloromethane as an extraction solvent, the obtained crude product was dissolved in ethanol, 10% palladium-carbon was added, and the mixture was stirred overnight at room temperature in the presence of hydrogen. After the reaction solution was filtered through celite, the solvent of the filtrate was distilled off. To the obtained crude product, 20 ml of THF and 27 ml of a 1 M lithium hydroxide solution were added, and the mixture was stirred for 4 hours. After distilling off the solvent, the residue was dissolved in 10 ml of a DMFZ dichloromethane (1/1) solution, and 4.5 g (26.5 mmo 1) of 2-chloro-1,3-dimethylimidazolinium chloride and triethylamine 4 6 ml (33.2 mmo 1) was added and stirred overnight. The mixture was treated with dichloromethane as an extraction solvent to obtain 6.4 g of a crude product. 1 g of the crude product was dissolved in 5 ml of 4N dioxane hydrochloride and stirred at room temperature for 1 hour. The solvent was distilled off to obtain 0.75 g of a crude product. Crude product Dissolve 0.32 § of this in 0 ^ [51111, and add 0.33 g (2.Ommol) of 2-chloro-1,3-dimethylimidazolinium chloride and 0.84 ml of triethylamine (6.lmmo 1 ) Was added and the mixture was stirred at room temperature for 2 hours. Extraction was performed using dichloromethane as an extraction solvent, and the precipitated crystals were collected by filtration and dried under reduced pressure.

Yield 0.16 g (0.49mmo 1) Yield 19%

MS (ESI, m / z) 325 (MH +)

 H-NMR (CDC13) 5 4.53 (2H, brs), 5.00 (2H, brs), 6.80-7.13 (3H, m), 7.20 -7.42 (2H, m), 8.22 (1H, brs)

Step 6 4 — [(5-Clot mouth—2-yl) carbonyl] 1-Fluoro 1- [2- (4-Isopropyldiazepan-1-yl) ethyl] 1 ′, 3, 4,5 Tetrahydrobenzene [e] [1,4] Synthesis of diazepin-12-one ditrifluoroacetate

4 mg (0.1 Ommol) of hexane-washed sodium hydride was suspended in 5 ml of DMF, and 4-((5-chloro (2-phenyl)) carbonyl) -6-fluoro-1,1,3,4,5 Tetrahydrobenzo [e] [1,4] diazepin-2-one (24 mg, 0.075 mmol 1) was added, and the mixture was stirred at room temperature for 30 minutes. Next, 20 mg (0.076 mmo 1) of t-butyl 4- (2-cycloethyl) -11,4-diazepane-l-carboxylate obtained in Step 3 was added, and the mixture was stirred at 65 ° C for 3 hours. After evaporating the solvent under reduced pressure, 5 ml of 4N dioxane hydrochloride was added to the residue, and the mixture was stirred for 1 hour. After distilling off the solvent under reduced pressure, 2/3 of the residue was dissolved in 8 ml of dichloromethane, and 2 ml of acetone, 2 Omg of acetic acid (0.33 mmo 1), and 8 Omg of sodium triacetoxyborohydride (0.38 mmo 1) were added. The mixture was further stirred at room temperature. The crude product obtained by distilling off the solvent was subjected to reversed-phase high-performance liquid chromatography using octadodecyl group-bonded silica gel as a filler, containing 0.1% of trifluoroacetic acid (v / v). Elution with a mixed solution of water and acetonitrile The title compound was obtained by freeze-drying the cushion.

Yield 19.4mg (0.027mmo 1) Yield 54%

MS (ESI, m / z) 493 (MH +)

 H-NMR (DMSO-d6) d 1.18 (6H, d, J = 6.6Hz), 1.88-2.18 (2H, m), 2.80-3.60 (11H, m), 4.05-4.20 (4H, m), 4.60- 4.85 (2H, m), 7.20-7.32 (2H, m), 7.42-7.60 (3H, m)

Example 2 4-[(5-Clo-cyclo-1--2-yl) carbonyl] -1-6-fluoro-1-[2- (4-Methyl-1,4-diazepan-1-yl) ethyl] — 1 , 3,, 5 Tetrahydrobenzene [e] [1,4] Synthesis of diazepin-12-one nitrifluoroacetate

 The title compound was obtained in the same manner as in Step 6 of Example 1 using paraformaldehyde instead of acetone.

Yield 11.5 mg (0.017 mmo 1) Yield 66%

MS (ESI, m / z) 465 (MH +)

 H-NMR CDMSO-d6) 5 1.88-2.18 (2H, m), 2.78 (3H, s), 2.80-3.58 (11H, m), 4.05-4.20 (4H, m), 4.60-4.4.85 (2H, m), 7.20-7.32 (2H, m), 7.42-7.60 (3H, m)

 The structural formulas of the compounds of Examples 1 and 2 are shown below.

Compound of Example 1 Compound of Example 2 Example 3 4 -— [(5-Clo-Cou-1-yl) carbonyl] —11- [2- (4-Isopropyl-1-1,4-diazepane-1-yl) ethyl] -1-6-methoxy-1, 3,4,5 Tetrahydrobenzene [e] [1,4] Synthesis of diazepin-12-one nitrifluoroacetate

Step 1 4 — [(5-Clo-Chain-1-yl) carbonyl] —1 -— [2 -— (1,4-diazepan-1-yl) ethyl] -16-methoxy-1,3,4,5 Synthesis of tetrahydrobenzo [e] [1,4] diazepin-2-one dihydrochloride

 4-[(5-cyclopent-2-yl) carbonyl] -6-methoxy-1,3-, 4-, 5-methoxy-6-toluenetoluene was obtained by the same procedure as in steps 4-5 of Example 1. Tetrahydrobenzo [e] [1,4] dazepin-2-one was obtained. This was treated with sodium hydride in the same manner as in Step 6 of Example 1 and t-butyl 4- (2-chloroethyl) -11,4-diazepane-11-carboxylate obtained in Step 3 of Example 1. T-butyl 4- (2-{4 [(5-chloro-1,2-yl) carbonyl] — 6-methoxy-12-oxo-1,3,4,5-tetrahydrazol [1,4] Dazepine-11-yl} ethyl-1,4-diazapane-11-carboxylate, followed by a 4N-dioxane hydrochloride solution to give the title compound.

 MS (ESI, m / z) 463 (MH +)

Step 2 4-[(5-chloro-1--2-yl) carbonyl] — 1— [2- (4-^^ sopropyl-l-l, 4-diazepane-l-yl) ethyl] -l-6-methoxy- 1,3,4,5 Tetrahydrobenzene [e] [1,4] Synthesis of diazepin-12-one nitrifluoroacetate

4 — [(5-Clo-guchi-1-2-yl) carbonyl]-1- [2- (1,4-diazepan-1-yl) ethyl] obtained in Step 1—6-Methoxy-1 1,3, 4,5 Tetrahydrobenzene [e] [1,4] diazepin-1-one dihydrochloride 51 mg (0.1 mmol) was dissolved in 1 ml of dichloromethane, and acetone 371 (0.5 mmol), acetic acid 3-1 (0.05 mm), sodium cyanoborohydride 10 mg (0.5 mg) were dissolved in 1 ml of dichloromethane. 15mmo 1) was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off, and the same purification procedure as in Step 6 of Example 1 was performed to obtain the title compound.

Yield 18.8mg (0.026mmol) Yield 27%

MS (ESI, m / z) 505 (MH +)

 H-NMR (DMSO-d6) 0 "1.18 (6H, d, J = 6.6Hz), 1.85-2.20 (2H, m), 2.80-3.92 (14H, m), 3.94-4.93 (6H, m), 7.01 -7.80 (5H, m)

Example 4

 The same operation as in step 2 of Example 3 was performed using acetoaldehyde instead of acetone to obtain the compounds shown in Table 1 below. '' Example 5 4-[(5-chloro-2--1-yl) carbinole]-1- [2- (4-cyclobutyl-1,4-diazepan-1-yl) ethyl] -6-methoxy Synthesis of 1,3,4,5-tetrahydro- 1 2 H- 1, 4-benzodiazepine-12-one nitrifluoroacetate

 4-[(5—Cro-guchi-1-2-yl) carbonyl] 1 1— [2 _ (1,4-4-dazepan-1-1-yl) ethyl] obtained in Step 1 of Example 3— 6-Methoxy-1,3,4,5tetrahydrobenzo [e] [1,4] diazepin-12-one dihydrochloride 32 mg (0.06 mmo 1) in N, N-dimethylformamide 1 ml After dissolving, 4 lmg (0.3 mmol) of potassium carbonate, 0.12 ml (1.2 mmol) of bromocyclobutane and 5 mg of sodium iodide were added, and the mixture was stirred at room temperature at room temperature. The solvent was distilled off, and the same purification procedure as in Step 6 of Example 1 was performed to obtain the title compound.

Yield 23.3mg (0.03mmo 1) Yield 59%

Example 6

The same operation as in Example 5 was repeated, except that promocyclobutane was replaced with eodocyclopentane. By using 6, the compounds shown in Table 1 below were obtained.

Example 7 4-[(5-chloro-1-en-2-carbyl) carbonyl] -6-methoxy-1- (2- [4- (4-piberidinyl) -11,4-diazepane-11) R] ethyl} —Synthesis of 1,3,4,5-tetrahydro- 1 2H—1,4-benzodiazepine-12-one

 4 — [(5—Clo-Cou 1—2-yl) carbonyl] 1—1—1—1—1—2— (1,4—Jazepan—1—1 1) ethyl) obtained in Step 1 of Example 3— 6-Methoxy-1,3,4,5tetrahydrobenzo [e] [1,4] diazepin-12-one dihydrochloride 32mg (0.06mmo1) is dissolved in ethanol 1ml and triethylamine 0.13ml (0.9 mmo 1) and 9 mg (0.06 mmo 1) of pyridine were added, sealed, and stirred at 150 ° C. overnight. The solvent was distilled off, and the same purification procedure as in Step 6 of Example 1 was performed to obtain the title compound.

Yield 17.2mg (0.022mmo 1) Yield 42%

Table 1 shows the structure and physicochemical data of the compound of Example 3-7.

PT / JP03 / 03816

 table 1

In the table, * indicates the bonding position to the nitrogen atom. Example 8 4 — [(5-chloro-en-1-yl) carbonyl] —1-1 [2 -— (4-isopropyl-1--1,4-1) Synthesis of diazepan-1-yl) ethyl] -6-hydroxy-11,3,4,5-tetrahydro-12H-1,4-benzodiazepin-12-one

4-[(5-cyclopent-1-yl) carbonyl] -1- [2- (4-isopropyl-1,4-diazepan-1-yl) ethyl] -6 obtained in Example 3 —Met TJP03 / 03816 Xie 1,3,4,5-tetrahydro- 1 2H- 1,4-benzodiazepine 1-one 12mg (0.016mmo 1) is dissolved in 0.2ml of dichloromethane and borane tribromide dichloromethane solution (1.0 M) 1 ml was added and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off, and the same purification procedure as in Step 6 of Example 1 was performed to obtain a title compound by a purification method.

Yield 4.2 mg (0.0057 mmo 1) Yield 36%

Example 9-12

 Using the compounds obtained in Examples 4 to 7 as starting materials, the compounds shown in the following table were obtained in the same manner as in Example 8.

Table 2 shows the structures and physicochemical data of the compounds of Examples 8 to 12.

 Table 2

* In the table indicates the bonding position to the nitrogen atom.c

Example 13 1- [2- (4-azapanyl) ethyl] -4-[(5-cyclopent-2-yl) carbonyl] -6-methoxy-1-1,3,4,5-tetrahydrobenzo [e] Synthesis of [1,4] dazebine-2-one hydrochloride

Step 1 Synthesis of ethyl 1,4-dioxaspiro [4,5] dec-8-ylidene acetate

Sodium hydride washed with hexane 24 Omg (1 Ommo 1) in THF 6

1.44 ml (1 Ommo 1) of trimethyl phosphonoacetate was added dropwise to the 00 ml suspension. After stirring at room temperature for 30 minutes, 1.54 ml (1 Ommo 1) of 1,4-dioxaspiro [4,5] decane-1-one was added, and the mixture was stirred at room temperature for 3 hours. The reaction was stopped by adding 5 Oml of a saturated sodium chloride aqueous solution of ammonia, the solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water, 1N-hydrochloric acid, 1N-aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound.

Yield 2.21 g (10.4 mm o 1) Yield Quantitative

 H-NMR (CDCl3) d 1.68-1.82 (4H, m), 2.36 (2H, t, J = 6.6Hz), 2.98 (2H, t, J = 6.6Hz), 3.67 (3H, s), 3.96 (4H , s), 5.63 (1H, brs)

Step 2 Synthesis of 2- (1,4-dioxasubi [4,5] dec 8-yl) ethanol

 Ethyl 1,4-dioxaspiro [4,5] decu-8-lylidene acetate 40 Omg (1.9 mmo 1) obtained in step 1 was cooled to 0 ° C. in 40 ml of THF2 Oml, and 143 mg of lithium aluminum hydride (3. 8mmo 1) was added and the mixture was stirred for 30 minutes. After water 143/1 and 15% aqueous sodium hydroxide solution 1431 and water 4291 were sequentially added dropwise, 50 ml of ethyl ether was added, and the mixture was stirred at room temperature overnight. The precipitate was separated by filtration, and the residue obtained by concentrating the filtrate was dissolved in 2 Oml of ethanol. After adding 10% of 10% palladium on carbon and stirring overnight under a hydrogen atmosphere, the palladium on carbon was filtered off and the filtrate was concentrated to give the title compound.

Yield 29 Omg (1.56 mmo 1) Yield 82%

H-NMR, (CDC13) δ 1.20-1.36 (1H, m), 1.42-1.61 (6H, m), 1.70-1.79 (4H, m), 3.70 (2H, t, J = 6.6Hz), 3.94 (4H , s)

Step 3 Synthesis of 2- (4-oxocyclohexyl) ethyl benzoate

2 -— (1,4-dioxaspiro [4,5] dec-1-yl) ethanol 5 A solution of .00 g (26.8 mmo 1) in 50 ml of THF was cooled to 0 ° C, 3.4 ml (3 Ommo 1) of benzoyl chloride and 4.5 ml (32 mmo 1) of triethylamine were added, and the mixture was stirred for 2 hours. . Add 1.1 ml (9.5 mmo 1) of benzoyl chloride and 1.5 ml (1 lmmo 1) of triethylamine and stir at 0 ° C for 1 hour, then dilute with ethyl acetate, and add 1N hydrochloric acid and saturated aqueous sodium bicarbonate, Washed sequentially with saturated saline. After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, the main component was obtained by silica gel column chromatography. To this, 4 Oml of tetrahydrofuran and 10 ml of 3N-hydrochloric acid were added and stirred at room temperature for 1 hour. After distilling off tetrahydrofuran, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound.

Yield 3.22 g (13.lmmo 1) Yield 49%

 H-NMR (CDC13) (51.48-1.52 (2H, m), 1.79-1.84 (2H, m), 1.95 (1H, m), 2.11 -2.18 (2H, m), 2.32-2.43 (4H, m), 4.42 (2H, t), 7.46 (2H, t), 7.57 (1H, dd), 8.04 (2H, d)

Step 4 Synthesis of 2- [4- (hydroxyimino) cyclohexyl] ethyl benzoate.

 Dissolve 3.18 g (12.9 mmo 1) of 2- (4-oxocyclohexyl) ethyl benzoate in 35 ml of ethanol, and add 1.1 ml (14 mmo 1) of pyridine and 3.72 g of hydroxylamine hydrochloride (53 .5mmo 1) was added and the mixture was stirred at room temperature overnight. After concentrating the solvent, ethyl acetate and water were added and partitioned, and the ethyl acetate layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound.

Yield 3.51 g (13.4 mm o 1) Yield Quantitative

MS (ESI, m / z) 262 (MH +)

H-NMR (CDC13) d 1.20-1.28 (2H, m), 1.74-1.87 (4H, m), 1.95-2.04 (2H, m), 2.09-2.17 (1H, m), 2.42 (1H, d), 3.29 (1H, d), 4.39 (2H, t), 7.45 (2H, t), 7.57 (1H, dd), 8.03 (2H, d), 8.12 (1H, brs)

Step 5 Synthesis of 2- (7-oxazepan-1-yl) ethyl benzoate 2- [4- (Hydroxyimino) cyclohexyl] ethyl benzoate 3.4

9 g (13.4 mmo 1) was dissolved in a mixed solvent of 30 ml of toluene and 10 ml of methylene chloride, and added dropwise to 31.8 g of vigorously stirred polyphosphoric acid. After stirring at 100 ° C for 1 hour, the mixture was cooled to room temperature, diluted with methylene chloride, and partitioned by adding water. After the aqueous layer was extracted twice with methylene chloride, the combined methylene chloride layers were washed successively with saturated saline, saturated aqueous sodium bicarbonate, and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound.

Yield 3.29 g (12.6 mmo 1) Yield 94%

MS (ESI, m / z) 262 (MH +)

 H-NMR (CDC13) 51.31-1.43 (2H, m), 1.74-1.81 (3H, m), 1.93-1.96 (2H, d), 2.48-2.52 (2H, m), 3.23-3.27 (2H, m) , 4.37 (2H, t), 6.17 (1H, brs), 7.45 (2 H, t), 7.57 (1H, dd), 8.03 (2H, d)

Step 6 Synthesis of t-butyl 4- (2-hydroxyethyl) azepane-11-carboxylate

2- (7-oxosepan-1-yl) ethyl benzoate 3.21 g (12.3 mmo 1) in 50 ml of THF was cooled to 0 ° C, and lithium hydride aluminum 1.86 g (49. Ommol) Was added. After refluxing for 19 hours, the mixture was ice-cooled, 25 ml of a 1N aqueous solution of sodium hydroxide, 25 ml of saturated saline and 3.05 g of sodium chloride were added, and the mixture was stirred at room temperature for 4 hours. After adding 4.2 g (18 mmo 1) of di-t-butyldicarbonate and stirring at room temperature for 2.5 days, tetrahydrofuran was concentrated, and ethyl acetate was added for partition. After the aqueous layer was extracted three times with ethyl acetate, the combined ethyl acetate layers were washed with water and a saturated saline solution, and sulfuric anhydride- After drying, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain the title compound.

Yield 2.29 g (9.41 mmo 1) Yield 77%

MS (ESI, m / z) 244 (MH +)

 H-NMR (CDC13) d 1.18-1.37 (2H, m), 1.46 (9H, s), 1.51-1.56 (3H, m), 1.68-

I.82 (4H, d), 3.13-3.68 (6H, m)

Step 7 Synthesis of t-butyl 4- {2-[(methanesulfonyl) oxy] ethyl} azepane-11-carboxylate

 t-Butyl 4- (2-hydroxyethyl) azepane 1-carboxylate A solution of 2.27 g (9.33 mmo 1) in 25 ml of THF was cooled to 0 ° C, and 1.6 ml of triethylamine (12 mmo 1 ) And methanesulfonyl chloride 8 6 6〃 1 (

I I. 4mmo 1) was added. After stirring for 0.5 hour under ice-cooling and 0.5 hour at room temperature, the reaction was stopped by adding ice chips, and ethyl acetate and water were added for partition. The ethyl acetate layer was washed with 1N-hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Purification by silica gel column chromatography gave the title compound.

Yield 2.95 g (9.18 mm o 1) Yield 98%

MS (ESI, m / z) 322 (MH +)

 H-NMR (CDC13) 51.18-1.39 (2H, m), 1.46 (9H, s), 1.57-1.60 (2H, m), 1.69-1.74 (3H, m), 1.82-1.86 (2H, m), 3.01 (3H, s), 3.12-3.64 (4H, m), 4.25-4.28 (2H, m)

Step 8 t-Butyl 4- (2- {4 [(5-chloro-en-1-yl) carbonyl] -1-6-methoxy-12-oxo-methoxy-1,3,4,5-tetrahydrobenzo [ e] [1,4] Diazepine-1-yl} Synthesis of ethylethylazapan-1-carboxylate 4-[(5-cyclopent-2-yl) carbonyl] -1-6-methoxy-1,3,4,5-tetrahydro-benzo [e] [1,4] diazepine-12-one 224 mg (0 665 mmo 1) was dissolved in 2 ml of N, N-dimethylformamide, and 39.6 mg of sodium hydride was added at room temperature and stirred for 5 minutes. To this, a solution of 260 mg (0.81 mmol) of 1-butyl 4- {2-[(methanesulfonyl) oxy] ethyl} azepanylcarboxylate in N, N-dimethylformamide (2 ml) was added. In addition, the mixture was stirred at 70 ° C for 12 hours. After concentrating the solvent, ethyl acetate and water were added for partition, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound as a crude product.

Yield 406 mg

Step 9 1- [2- (4-azapanyl) ethyl] — 4-[(5-chloro-1-en-2-yl) carbonyl] -1-6-methoxy-1 1,3,4,5-tetrabenzo

[e] [1,4] Synthesis of diazepin-2-one hydrochloride

 t-Butyl 4 -— (2- {4 [(5-chloro-en-1-yl) carbonyl] —6-methoxy-1-1,3,4,5-tetrahydrobenzo [e] [1, 4] Jazepine

1-yl} ethylazapan-1-carboxylate (100 mg, 0.17 mmol) was mixed with 4N dioxane hydrochloride (5 ml) and stirred at room temperature. The solvent was completely distilled off with a vacuum pump.

Yield 82mg (0.17mmo 1) Quantitative

 MS (ESI, m / z) 462 (MH +)

Examples 14-17

1_ [2- (4-azapanyl) ethyl] obtained in Example 13—4 _ [(5-chloro-1-en-2-yl) carbonyl] -6-methoxy-1,3, —4,5-tetra Lahydrobenzo [e] [1,4] diazepin-12-one hydrochloride The same operation was performed using the corresponding alkyl halide to obtain the compounds shown in Table 3 below.

Examples 18, 19

 1- [2- (4-azapanyl) ethyl] obtained in Example 13-4-1 [(5-chloro-en-1-yl) carbonyl] -6-methoxy-1-1,3,4 The same operation as in step 2 of Example 3 was performed on 5-tetrahydrobenzo [e] [1,4] diazepin-2-one hydrochloride using the corresponding carbonyl compound, and the results are shown in Table 3 below. The compound was obtained.

Example 20 4-[(5-chloro-1--2-yl) carbonyl] -6-methoxy-1- {2- [1- (4-pyridyl) azapan-1-yl] ethyl} Synthesis of 1,3,4,5-tetrahydrobenzo [e] [1,4] diazepin-12-one trifluoroacetate

 1- [2-((4-azapanyl) ethyl) obtained in Example 13] —4-[(5-chloro-1-en-2-yl) carbonyl] -6-methoxy-1,3,4,5- The same operation as in Example 7 was performed on tetrahydrobenzo [e] [1,4] diazepin-12-one hydrochloride to obtain the title compound.

Table 3 shows the structure and physicochemical data of the compound of Example 13-20.

 Table 3

In the table, * indicates the bonding position to the nitrogen atom.

Example 21 4-[(5-chloro-en-2-yl) carbonyl] -1- [2- (1-cyclobutylazapan-1-yl) ethyl] -6-hydroxy-1 1,3 4, 5 Synthesis of 1-tetrahydrobenzo [e] [1,4] dazepin-12-one trifluoroacetate

 Obtained in Example 14. 4-([5-Clo-Chen-1-yl) carbonyl]-1- [2- (1-Cyclobutylazapan-1-yl) ethyl] -6 —Methoxy-1,3,4,5-tetrahydrobenzo [e] [1,4] diazepin-1-one Dissolve 4.7 mg (0.009 mmo 1) of 4.7 mg (0.009 mmo 1) in 100 L of dichloromethane and add boron tribromide in dichloromethane (1.0 M) was added, and the mixture was reacted at room temperature for 1 hour. The solvent was distilled off, and the same purification procedure as in Step 6 of Example 1 was performed to obtain the title compound. Yield 2.2 mg Yield 48.6%

MS (ESI, m / z) 502 (MH +)

Examples 22 to 27

In the same manner as in Example 21, using the corresponding starting materials, the compounds shown in Table 4 below were obtained.

 Table 4

In the table, * indicates the bonding position to the nitrogen atom.

Example 28 4-[(5-chloro-1-en-2-yl) carbonyl] -1- (hydroxymethyl) -l- [2- (4-isopropyl-l, 4-diazepan-l-yl) ethyl ] -1,3,4,5-tetrahydrobenzo [e] [1,4] diazepine-1 Of 1-one nitrifluoroacetate

Step 1 Synthesis of N- (4-methoxycarbonyl-2-nitrobenzyl) -N-t-butoxycarbonylglycineethyl ester

 Dissolve 80 g (410 mmol) of methyl 4-methyl-3-nitrobenzoate and 145 g of N-bromosuccinimide in 1 L of benzene, and heat benzoylperoxide 0.5 to 0 カ overnight. Refluxed. After cooling to room temperature, the precipitate was removed by filtration, and the filtrate was diluted with 1 L of ethyl acetate, and washed with an aqueous solution of sodium thiosulfate, a 1N aqueous solution of sodium hydroxide, and a saturated saline solution. The extract was dried over anhydrous magnesium sulfate, and the solvent was concentrated. The obtained residue was dissolved in 1 L of ethanol, 290 g (2 mol) of glycine ethyl ester monohydrochloride and 172 g (2 mol) of sodium hydrogen carbonate were added, and the mixture was stirred at 60 ° C overnight. The precipitate was removed by filtration, the solvent was concentrated, the residue was diluted with ethyl acetate, washed with water, and extracted with 4 N hydrochloric acid into the aqueous layer. The aqueous layer was made basic by the addition of 1 ON-sodium hydroxide solution, and then extracted into the organic layer with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was dissolved in 50 OmL of THF, 16.4 mL (223 mmo 1) of triethylamine and 25.6 g (117 mmo 1) of di-tert-butyl dicarbonate were added at 0 ° C, and the mixture was heated to room temperature and stirred overnight. did. 5.4 mL (49 mmo 1) of N, N-dimethylethylenediamine was added, and the mixture was stirred for 30 minutes, and the solvent was concentrated. The residue was diluted with ethyl acetate, washed successively with 3N-hydrochloric acid, 1N-sodium hydroxide solution, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (EtOAconly) to give the title compound.

Yield 29.9 g Yield 18%

H-NMR (d CDC13) δ 1.25 (3Η, t), 1.45 (9 / 2H, s), 1.46 (9 / 2H, s), 3.92 (1 H, s), 3.96 (3 / 2H, s), 3.97 (3 / 2H, s), 4.04 (1H, s), 4.19 (2H, q), 4.85 (1H, s ), 4.90 (1H, s), 7.72 (1H, t), 8.25 (1H, m), 8.63 (1H, d)

Step 2 {4— [(5-chloro-en-1-yl) carbonyl] -12-oxo-1,2,3,4,5-tetrahydro-1H—1,4-pentazodazepine-18-yl} methyl acetate Synthesis of

Dissolve 29.9 g (75.4 mmo 1) of N- (4-methoxycarbonyl-1-2-nitrobenzyl) 1N-t-methoxycarbonylglycine ethyl ester obtained in Step 1 in 30 OmL of ethanol, After adding 1.4 g of 10% palladium carbon, the mixture was stirred under a hydrogen atmosphere for 3 hours. The catalyst was filtered off, the solvent was concentrated to about 10 OmL, 100 mL of THF and 10 OmL of an aqueous solution of 12.7 g (30 Ommo 1) of lithium hydroxide were added, and the mixture was stirred at room temperature overnight. The solvent was concentrated, and the resulting residue was dissolved in 50 mL of N, N-dimethylformamide.19.1 g (113 mmo1) of 1,3-dimethyl-12-chloroimidazolinium chloride was added, and the mixture was added at room temperature for 30 minutes. Stirred. The solvent was concentrated, 5 OmL of ethyl acetate and 5 OmL of IN-hydrochloric acid were added, and the precipitate was collected by filtration and washed with ethyl acetate and water. The obtained precipitate was dried at 100 ° C under reduced pressure, dissolved in 35 OmL of THF, and 5.8 mL of triethylamine (42 mMol) and 3.7 mL of ethyl ethyl formate (39 mmo1) were added at 0 ° C. Stirred for minutes. To this was added 10 g of ice, followed by addition of 2.7 g (7 lmmo 1) of sodium borohydride, followed by stirring for 1 hour. The solvent was concentrated, the residue was diluted with ethyl acetate, washed successively with 1N-hydrochloric acid, 1N-sodium hydroxide solution, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was dissolved in THF (40 OmL), and triethylamine (7 OmL (5 Ommo 1)) and salted acetyl 3.2 mL (45 mmo 1) were added at 0 ° C, and the temperature was slowly raised to room temperature. After stirring for 1 hour, the solvent was concentrated, the residue was diluted with ethyl acetate, and washed with 1N-hydrochloric acid, 1N-sodium hydroxide solution, and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is concentrated, and the obtained residue is made up to 10 OmL of a 4N dioxane hydrochloride solution. Dissolve and stir for 1 hour. The residue obtained by concentrating the solvent was dissolved in 35 OmL of methylene chloride, and 6.8 g (42 mmol) of 5-chloro-2-carboxylic acid, ED CI 8.lg (42 mmol) s H0B t6.4 g (42 mmol) _N triethylamine 3 OmL (22 Ommo 1) was dissolved in methylene chloride 35 OmL, and the mixture was stirred overnight. Concentrate the solvent, add water, extract with ethyl acetate and concentrate. A mixed solution of hexane: ethyl acetate = 1: 1 was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound.

Yield 7.3 g Yield 27%

MS (ESI, m / z) 379 (MH +)

 NMR (d CDC13) δ 2.06 (3H, s), 4.38 (2H, br), 4.78 (2H, br), 5.03 (2H, s), 7.05 (IH, br), 7.09 (1H, br), 7.18 ( IH, d), 7.30 (IH, m), 7.46 (IH, d), 10.27 (1H, br)

Step 3 Benzyl 4- (2— {8 — [(acetoxy) methyl] —— 4 — [(5-chloro-en-1-yl) carbonyl] -12-oxo-1 1,3,4,5-tetrahydrin Benzo [e] [1,4] diazepine-1-yl} ethyl) — Synthesis of 1,4-diazepan-1-carboxylate

 15 mg (0.634 mmo 1) of sodium hydride washed with hexane was suspended in 3 ml of N, N-dimethylformamide, and {4-[(5-chloro-1,2-yl) carbonyl] -2-oxo One 1,3,4,5-tetrahydrobenzo [e] [1,4] dazevin-1-yl} methyl acetate 20 Omg (0.528 mmo 1) was added and stirred for 30 minutes. Benzyl 4- (2-chloroethyl) 1-1,4-dazepan-11-carboxylate (0.17 mg, 0.58 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours and at 50 ° C for 30 minutes. The solvent was distilled off, and the residue was extracted with ethyl acetate in a conventional manner to give the title compound as a crude product.

Step 4 {4- [(5—Black mouth chain—2-yl) carbonyl-1-1 [2— (1, 3816

4-diazepan-1-yl) ethyl 2--1-oxo-1,3,4,5-tetrahydrobenzo [e] [1,4] diazepin-1-yl} methyl acetate ditrifluoroacetate Salt synthesis

 Penzyl obtained in step 3 4- (2- {8-[(acetoxy) methyl] 1-41- [

(5-cyclopent-1-yl) carbonyl] -1-oxo-1, 3,4,5-tetrahydrobenzo [e] [1,4] diazepine-1-yl) — 1, 24-Omg (0.375 mmol) of 4-dazepan-111-carboxylate was dissolved in 0.6 ml of an acetic acid solution of hydrogen bromide at 0 ° C and stirred for 1 hour. The solvent was distilled off, and the same purification procedure as in Step 6 of Example 1 was performed to obtain the title compound.

Yield 12 Omg (0.194mmo 1) Yield 52%

Step 5 4-[(5-chloro-1--2-yl) carbonyl] -1-8- (hydroxymethyl) -1-1- [2- (4-isoprovir-1,4-diazepan-1-yl) 1,3,4,5-Tetrahydrobenzo [e] [1,4] Synthesis of diazepine-12-one ditrifluoroacetate

 {4-([5—Cro-guchi-1-2-yl) carbonyl] -1 1- [2-(1,4-Dazepan-1 1-yl) ethyl] -1 2-oxo-1 obtained in step 4 , 3,4,5-tetrahydrobenzo [e] [1,4] diazepine-18-yl} methyl acetate ditrifluoroacetate 3 Omg was dissolved in 0.5 ml of N, N-dimethylformamide and 2 —Chodopropane 26〃1 (0.26 mmo 1) and potassium carbonate 36 mg (0.26 mmo 1) were added, and the mixture was stirred at room temperature overnight. The solvent was distilled off, and the residue was extracted and concentrated using ethyl acetate according to a conventional method. The obtained residue was dissolved in methanol (0.5 ml), potassium carbonate (7.2 mg, 0.052 mmol) was added, and the mixture was treated with ultrasonic waves for 7 minutes. The solvent was distilled off, and the same purification procedure as in Step 6 of Example 1 was performed to obtain the title compound.

Yield 6.8mg (0.009mmo 1) Yield 18% 03816 Example 29 30

The same operation as in step 5 of Example 28 was performed using the corresponding alkyl halide to obtain a compound shown in Table 5.

 Example 31 4 — [(5—Chole mouth—1—yl) Carbonyl] —8— (Hydroxyxmethyl) —1——2— (4—Ethyl-1,4—Djazepan—11—yl) [Ethyl] -1- 1,3,4,5-tetrahydrobenzo [e] [1,4] Synthesis of diazepine-12-dinitrotrifluoroacetate

 {4-[(5-Clo-Chain-1-yl) carbonyl] -1 1- [2- (1,4-diazepan-1 1 ^^) ethyl] obtained in Step 4 of Example 8 —2—oxo-1,3,4,5-tetrahydrobenzo [e] [1,4] dazepine-18-yl} methyl acetate ditrifluoroacetate 3 Omg (0.048mmo 1) in dichloromethane Dissolve in lml, add acetoaldehyde 14/1 (0.24mmo l), acetic acid 601 (0.lmmo 1), sodium cyanoborohydride 4.6mg (0.07mmo 1), and add Stirred for half an hour. The solvent was distilled off and the residue was extracted with ethyl acetate according to a conventional method, and the solvent was concentrated. The obtained residue was dissolved in 0.5 ml of methanol, added with 6.7 mg (0.048 mmol) of potassium carbonate, and treated with ultrasonic waves for 7 minutes. The solvent was distilled off, and the same purification procedure as in Step 6 of Example 1 was performed to obtain the title compound.

Yield 15.2 mg (0.02 lmmo 1) Yield 44%

Example 32 4-[(5-chloro-1--2-yl) carbonyl] -18- (hydroxymethyl) 1-1- {2- (4-1- (4-pyridyl) 1-1,4-diazepan-1--1 Yl] ethyl} — 1,3,4,5-tetrahydrobenzo [e] [1,4] diazepine—2-one Synthesis of ditrifluoroacetate

{4-([5-chloro-opening-1-yl) carbonyl] -1 1- [2- (1,4-diazepan-1-yl) ethyl]-obtained in Step 4 of Example 9 2—Oxo 1 1, 3,4,5-tetrahydrobenzo [e] [1,4] diazepin-18-yl} methyl acetate ditrifluoroacetate 3 Omg (0.048mmo 1) is dissolved in 1 ml of ethanol and triethylamine 0.1 ml (0.73 mmol) and 4 mg of 4-chloropyridine (0. Immol) were added, and the tube was sealed and stirred at 150 ° C overnight. The solvent was concentrated, the obtained residue was dissolved in methanol (0.5 ml), potassium carbonate (6.7 mg, 0.048 mmol) was added, and the mixture was treated with ultrasonic waves for 7 minutes. The solvent was distilled off, and the same engraving operation as in Step 6 of Example 1 was performed to obtain the title compound.

Yield 10.lmg (0.013mmo 1) Yield 27%

Table 5 shows the structures and physicochemical data of the compounds of Examples 28 to 32.

 Table 5

実施例 33 4—[ (5—クロ口チェン一 2—ィル） カルボニル ]ー 8— (ヒドロ キシメチル） — 1ー[2— (1—シクロブチルァゼパン一 4—ィル)ェチル] 1， 3, 4， 5—テトラヒドロペンゾ [e] [1,4] ジァゼピン一 2—オン トリフルォロ 酢酸塩の合成

Example 33 4-[(5-cyclopent-1-yl) carbonyl] -8- (hydroxymethyl) -1- [2- (1-cyclobutylazepan-1-yl) ethyl] 1 Of 3,3,4,5-tetrahydrobenzo [e] [1,4] diazepin-12-one trifluoroacetate

Step 1 t-butyl 4- (2- (8-[(acetoxy) methyl) -4-] [(5-chloroten-1-yl) carbonyl] —2-oxo-1,3,4,5 —Tetrahydrobenzo [e] [1,4] diazepine 1-yl} ethyl) azepan— 1-carbo 3816 Synthesis of xylate

 1 lmg (0.47 mmo 1) of sodium hydride washed with hexane is suspended in 4 ml of N, N-dimethylformamide, and {4— [(5-chloro-en-1-yl) carbonyl] —2 —Oxo-1,3,4,5-tetrahydrobenzo [e] [1,4] diazepine-11-yl} methyl acetate 15 Omg (0.39 mmo 1) was added and stirred for 30 minutes. 139 mg (0.43 mmo 1) of t-butyl 4_ (2-chloroethyl) azepane-l-carboxylate was added, and the mixture was stirred at 50 ° C overnight. The solvent was distilled off, and the residue was extracted with ethyl acetate in a conventional manner to give the title compound as a crude product.

Yield 126mg (0.2 Ommo 1) Yield 53%

MS (ESI, m / z) 604 (MH +)

Step 2 {1— [2 -— (4-azepanyl) ethyl] —4-1-((5-chloro-en-2-yl) carbonyl) —1,2-oxo-1,1,3,4,5-tetrahydrobenzo [e ] [1,4] Synthesis of diazepine-8-yl} methyl acetate

 t-butyl 4- (2-{8-[(acetoxy) methyl] -4-] ((5-chloro-1-2-yl) carbonyl] — 2-oxo-1, 3,4,5- Tetrahydrobenzo [e] [1,4] dazepine-11-yl} ethyl) 126 mg (0.2 Ommo1) of azepan-11-carboxylate was dissolved in 6 ml of a 4N-dioxane hydrochloride solution and stirred at room temperature. The solvent was distilled off to obtain the title compound.

Yield l O Omg (0.2 Ommo 1) Yield Quantitative

 MS (ESI, m / z) 504 (MH +)

Step 3 4-[(5-chloro-en-1-yl) carbonyl] -1- 8- (hydroxymethyl) -1-1 [2- (1-cyclobutylazepan-1-yl) ethyl] 1, 3,4,5-Tetrahydrobenzene [e] [1.4] Synthesis of diazepin-12-one trifluoroacetate {1— [2- (4-azepanyl) ethyl] 1—4 — [(5-chlorocene-1-yl) carbonyl] —2—oxo-1 1,3,4,5 obtained in step 2 —Tetrahydropenzo [e] [1,4] diazepine-180-methyl} acetate was subjected to the same operation as in step 5 of Example 28 using butyl mocyclobutane to obtain the title compound.

 MS (ESI, m / z) 530 (MH +)

Examples 34-35

 The same operation as in step 3 of Example 33 was performed using the corresponding alkyl halide to obtain compounds of Examples 34 to 35 shown in Table 6 below.

Example 36 4-[[(5-chloro-1-en-2-carbyl) carbonyl] -8- (hydroxymethyl) 1-1- [2- (1-ethylethylazepan-41-yl) ethyl] -1, Synthesis of 3,4,5-tetrahydrobenzo [e] [1,4] diazepin-2-one trifluoroacetate

 {1— [2- (4-azepanyl) ethyl] one obtained in Step 2 of Example 33

4-[[(5—Chloro-2-yl) carbonyl] —2-oxo-1,3,4,5-tetrahydrobenzo [e] [1,4] diazepine-1-yl} methyl The acetate was subjected to the same operation as in step 2 of Example 3 using acetoaldehyde in place of acetone, and then the resulting composition was dissolved in methanol, and carbon dioxide was added to the acetic acid. Treated with sound waves for 5 minutes. The solvent was distilled off, and the same purification procedure as in Step 6 of Example 1 was performed to obtain the title compound.

 MS (ESI, m / z) 490 (MH +)

Example 37 4 -— [(5-chloro-1--2-yl) carbonyl] —8- (hydroxymethyl) 1-111 {2 -— (1- (4-pyridyl) azepan-1-yl) Ethyl} —Synthesis of 1,3,4,5-tetrahydrobenzo [e] [1,4] diazepine-12-one trifluoroacetate {1- [2- (4-azepanyl) ethyl] i obtained in step 2 of Example 33

4— [(5—Chain 1-2-yl) Carbonyl] — 2—Oxo 1, 3, 4,

Dissolve 49 mg (0.1 lmmo 1) of 5-tetrahydrobenzo [e] [1,4] diazepine-1-yl} methyl acetate in 1 mL of ethanol and add 30 mg of 4-chloropyridin hydrochloride (0 mg). 2 mmol) and triethylamine 279 L (2 Ommo 1) were added, and the mixture was sealed and stirred at 160 ° C overnight. After evaporating the solvent, the same purification procedure as in step 6 of Example 1 was performed to obtain the title compound.

Yield 9.7mg (0.018mmo 1) Yield 18%

MS (ESI, m / z) 525 (MH +)

Table 6 shows the structures and physicochemical data of the compounds of Examples 33 to 37.

JP03 / 03816

 Table 6

* In the table indicates the position of the bond to the nitrogen atom.

To 100% aqueous solution of the evaluation compound was added 130% of 100 mM Tris-hydrochloric acid buffer adjusted to ρ8.4, and then human activated blood coagulation factor X (Enzyme Research) was added to pH8.4 Tris-HCl. The buffer solution was heated to 0.5 units / ml of a solution prepared at 0.5 units / ml and incubated at room temperature for 10 minutes. Next, N-Benzy L-Iso-isocyanate-L-glucamyl-glycyl-L-arginyl-P-nitroanilide hydrochloride (manufactured by Peptide Research Institute) adjusted to 0.8 mM with pH 8.4 Tris-HCl buffer 5 μl was added, the absorbance was measured, and the initial reaction rate was determined, and a control obtained by adding Tris-monohydrochloride buffer 101 adjusted to pH 8.4 instead of the solution of the evaluation compound was used as a control. Was measured using a MICROPLATE REA DER Model 3550-UV (BIO RAD) at a wavelength of 405 nm at intervals of 15 seconds for 16 minutes. The negative logarithmic value of the concentration of the compound to be evaluated when inhibiting 50% of the rate (abbreviated as pIC50) was used as an index of activated blood coagulation factor X inhibitory activity. Table 7 shows the blood coagulation factor X inhibitory activity.

Example 39 Measurement of thrombin inhibitory activity

 Aqueous solution of test compound 10〃] 100 mM Tris-HCl buffer 1301 adjusted to J :: pH 8.4, and then human thrombin (manufactured by SIGMA) was treated with Tris-hydrochloride buffer (pH 8.4) for 2 units Zm 10〃1 of the solution prepared in 1 was added and incubated at room temperature for 10 minutes. Then, a solution of D-phenylalanil L-pipecolyl-L-arginyl-P-nitroanilidoni hydrochloride (Daiichi Pure Chemicals, S-2238) adjusted to 0.4 mM with pH 8.4 Tris-HCl buffer 501 was added, the absorbance was measured, and the initial reaction rate was determined. A control was prepared by adding 10〃1 of Tris-monohydrochloride buffer adjusted to pH 8.4 instead of the solution of the evaluation compound. The absorbance was measured using a MICROPLATE READER Model 3550-UV (BIO RAD) at a wavelength of 405 ηm at intervals of 15 seconds for 16 minutes. Calculate the negative logarithm of the concentration of the test compound when inhibiting the thrombin activity (initial velocity) by 50% without adding the test compound.

(abbreviated as pIC50) was used as an index of thrombin inhibitory activity. Table 7 shows the tombin inhibitory activity of representative compounds.

Example 40 Measurement of anticoagulant activity Anticoagulant activity was determined using a prothrombin time (PT) assay. PT measurement was performed as shown below. That is, blood was collected from a healthy person, and 1/10 volume of a 3.8% aqueous solution of trisodium citrate was added thereto, and plasma was separated by centrifugation. Five liters of a DMSO solution containing the evaluation product was added to the plasma 4 and incubated at room temperature for 2 minutes. After placing the test tube containing the plasma solution in a Sysmex CA-3000 fully automatic blood coagulation analyzer (Toa Medical Electronics), incubate at 37 ° C for 3 minutes, and then use Sy smex PT II (Toa Medical Electronics, Osagi Brain). Tissue thromboplastin, 13.2 mM calcium chloride) 100〃1 was added. PT was measured automatically by the same device. Using a control to which DMSO 51 was added instead of the solution of the evaluation compound as a control, a negative logarithm of the concentration of the evaluation compound that prolongs the control PT by a factor of 2 was obtained (abbreviated as pPT2). Index.

 Table 7

この結果より本発明のベンゾジァゼビン誘導体は、 活性化血液凝固第 X因子に 特異的な高い阻害活性を示し、 これに基づく高い抗凝固活性を示すことがわかる 本発明化合物又はその塩を有効成分とする抗血液凝固剤は優れた活性化血液凝 固第 X因子阻害作用に基づく抗血液凝固作用を示す。 本発明の化合物又はその塩 を有効成分とする抗血液凝固剤はまた、 経口吸収性にも優れる。従って、 本発明 化合物は脳梗塞、 脳血栓、 脳塞栓、 一過性脳虚血発作 （T I A) 、 くも膜下出血 (血管れん縮） 等の脳血管障害における疾病、 急性及び慢性心筋梗塞、 不安定狭 心症、 冠動脈血栓溶解等の虚血性心疾患における疾病、 肺梗塞、 肺塞栓等の肺血 管障害における疾病、 末梢動脈閉塞症、 深部静脈血栓症、 汎発性血管内凝固症候 群、 さらに人工血管術及び人工弁置換後の血栓形成、 冠動脈バイパス術後におけ る再閉塞及び再狭窄、 経皮的経管式冠動脈形成術 (P T C A) または経皮的経管 式冠動脈再開通療法 （P T C R) 等の血行再建後の再閉塞及び再狭窄、 体外循環 時の血栓形成などの予防 ·治療剤として利用できる。

The results show that the benzodiazebine derivative of the present invention exhibits a high inhibitory activity specific to activated blood coagulation factor X and a high anticoagulant activity based on the same. The compound of the present invention or a salt thereof is used as an active ingredient. Anticoagulant is an excellent activated coagulant It shows an anticoagulant effect based on a solid factor X inhibitory effect. The anticoagulant containing the compound of the present invention or a salt thereof as an active ingredient is also excellent in oral absorbability. Therefore, the compounds of the present invention are useful for diseases in cerebrovascular disorders such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA), subarachnoid hemorrhage (vascular spasm), acute and chronic myocardial infarction, unstable narrowing Heart disease, diseases in ischemic heart disease such as coronary thrombolysis, diseases in pulmonary vascular disorders such as pulmonary infarction, pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, generalized intravascular coagulation, and artificial Thrombus formation after angioplasty and valve replacement, reocclusion and restenosis after coronary artery bypass surgery, percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary revascularization (PTCR) It can be used as a prophylactic / therapeutic agent for reocclusion and restenosis after revascularization and thrombus formation during extracorporeal circulation.

7

Claims

The scope of the claims 1. A benzodiazepine derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof.

(1)  [In general formula (1),  Ring A represents 6-carbon atoms: an aryl group of L 0, 3-carbon atoms; a heteroaryl group of L 0 or a cyclic alkyl group of 4-10 carbon atoms; Are a hydrogen atom, a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a nitro group, a formyl group, a trifluoromethyl group, a trifluoromethoxy group, a trifluoromethyl sulfonyloxy group, and a methylenedioxy group. Group, carbamoyl group, thiocarbamoyl group, mono- or di-alkyl mono- or di-alkyl group having 2 to 7 carbon atoms, cyano group, mono- or di-alkylamino group having 1 to 6 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 7 carbon atoms A C3-C7 hydroxycarbonylalkenyl group, a C4-C8 alkoxycarbonylalkenyl group, a phosphono group, a C2-C9 dialkoxyphosphoryl group, a C1-C4 monoalkoxyhydroxyphosphoryl group An alkylthio group having 1 to 6 carbon atoms, an alkylsulfonyl having 1 to 6 carbon atoms Group, aminosulfonyl group, mono- or dialkylaminosulfonyl group having 2 to 8 carbon atoms, alkyl group having 1 to 6 carbon atoms which may have a substituent, An aryl group having 6 to 10 carbon atoms which may have a substituent; a heteroaryl group having 1 to 10 carbon atoms which may have a substituent; and 6-1 carbon atom which may have a substituent. An arylsulfonyl group of 0, a heteroarylsulfonyl group of 4 to 10 carbon atoms which may have a substituent, an arylthio group of 6 to 10 carbon atoms which may have a substituent, A heteroarylthio group having 4 to 10 carbon atoms which may have a group; an acyl group having 1 to 8 carbon atoms which may have a substituent; and 6 to 10 carbon atoms which may have a substituent. An alkyl group having 1 to 6 carbon atoms substituted by a aryl group; an alkyl group having 1 to 6 carbon atoms substituted by a heteroaryl group having 5 to 10 carbon atoms which may have a substituent; 6 to 6 carbon atoms substituted with an alkyl group which may have 1 to 6 carbon atoms: substituted with an aryl group of L 0 and an alkyl group having 1 to 6 carbon atoms which may have a substituent. 5 to 10 carbon atoms, a heteroaryl group having 1 to 6 carbon atoms, a mono or dialkylamino group having 1 to 6 carbon atoms, an amino group which may have a substituent, 1 carbon atom which may have a substituent To 7, an optionally substituted pyrrolidine group, an optionally substituted pyrrolidyloxy group, an optionally substituted piperidine group, an optionally substituted piperidyloxy group Group, a piperazine group which may have a substituent, a piperazine carbonyl group which may have a substituent, an amidino group which may have a substituent or a guanidino which may have a substituent Represents one of the groups Here, when Rl has a substituent, the substituent is: Alkyl group, hydrogeno group, hydroxyl group, alkoxyl group having 1 to 10 carbon atoms, trifluoromethyl group, trifluoromethoxy group, carbamoyl group, mono- or dialkyl carbamoyl group having 2 to 7 carbon atoms Group, amino group, C1 to C7 aminoalkyl group, C1 to C6 mono or dialkylamino group, amidino group, C2 to C7 mono or dialkylamidino group, C4 to C7 trialkyl Amino dino group, tetraalkylamidino group having 5 to 8 carbon atoms, guanidino group, dialkylguanidino group having 3 to 8 carbon atoms, trialkylguanidino group having 4 to 9 carbon atoms, 6 to 10 carbon atoms Aryl groups having 1 to 10 carbon atoms, alkyl groups having 1 to 6 carbon atoms substituted with aryl groups having 6 to 10 carbon atoms, and 5 to 10 carbon atoms. C1-C6 alkyl group substituted with teraryl group, C6-C10 aryl group substituted with C1-C6 alkyl group, C1-C6 alkyl group substituted with C1-C6 alkyl group A heteroaryl group having 5 to 10 carbon atoms, an arylsulfonyl group having 6 to 10 carbon atoms, a heteroarylsulfonyl group having 4 to 10 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, A carbon ring having 1 to 6 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms, including one or more complex atoms selected from nitrogen, oxygen and sulfur, nitrogen, oxygen and sulfur A C1-6 alkyl group containing one or more heteroatoms selected from A carbonyl group substituted with a carbon ring having 1 to 6 carbon atoms, an iminoalkylpyrazine carbonyl group having 7 to 10 carbon atoms, a pyridyloxy group, an alkylpyridyloxy group having 6 to 10 carbon atoms , Iminoalkylpyridyloxy group having 7 to 10 carbon atoms, pyrrolidyloxy group, alkylpyrrolidyloxy group having 6 to 10 carbon atoms, iminoalkylpiridyloxy group having 7 to 10 carbon atoms, methylenedioxy group, cyano group, carbon number 2-7 iminoalkyl group, C1-8 carbon group, phosphono group, C2-9 dialkoxyphosphoryl group, C1-4 monoalkoxyhydroxyphosphoryl group, C1-6 alkylsulfonyl Represents an aminosulfonyl group or a dialkylaminosulfonyl group having 2 to 8 carbon atoms,  Ring B represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 3 to 10 carbon atoms,  A non-aromatic carbon having a carbon number of 2 to 8 containing at least one nitrogen atom, and may contain one or more heteroatoms selected from oxygen and / or sulfur, provided that a pyrrolidyl group , Excluding a piperidyl group or a biperazinyl group, Is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, Hydroxyalkyl group having 1 to 10 carbon atoms, alkoxyl group having 1 to 10 carbon atoms, alkoxyalkyl group having 1 to 10 carbon atoms, nitro group, formyl group, trifluoromethoxy group, trifluoromethyl group, and valvamoyl Group, thiocarbamoyl group, mono- or dialkyl group having 2 to 7 carbon atoms, amino group, mono- or dialkylamino group having 1 to 6 carbon atoms, amino group having 1 to 9 carbon atoms, mono- or mono-alkyl group having 2 to 9 carbon atoms Or dialkylaminoalkyl group, amidino group, mono- or dialkylamidino group having 2 to 7 carbon atoms, trialkylamidino group having 4 to 7 carbon atoms, tetraalkylamidino group having 5 to 8 carbon atoms, guanidino group, 3 to carbon atoms 8 dialkylguanidino groups, 4 to 9 carbon atoms trialkylguanidino groups, methylenedioxy groups, cyano groups, charcoal Iminoalkyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, piperidyloxy group, alkylpiperidyloxy group having 6 to 10 carbon atoms, iminoalkylpiperidyloxy group having 6 to 10 carbon atoms, carbon number Alkoxy force of 8 to 14 L-propyl pyridyloxy group, pyrrolidyloxy group, alkylpiridyloxy group having 5 to 9 carbon atoms, iminoalkylpyrrolidyloxy group having 5 to 9 carbon atoms, 7 to 13 carbon atoms An alkoxycarbonylpyrrolidyloxy group, a pyrrolidine group, an alkylpyrrolidine group having 5 to 9 carbon atoms, an iminoalkylpyrrolidine group having 5 to 9 carbon atoms, a piperidine group, an alkylpyridine group having 6 to 10 carbon atoms, Iminoalkylpiperidine group having 6 to 10 carbon atoms, piperazine group, alkylpiperazine group having 5 to 13 carbon atoms, iminoalkylbiperazine group having 6 to 9 carbon atoms, carbon number An aryl group having 6 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, an arylsulfonyl group having 6 to 10 carbon atoms, a heteroarylsulfonyl group having 4 to 10 carbon atoms, 7 carbon atoms ~ 10 iminoalkylbiperazine carbonyl group, 6 ~ 10 carbon alkylpyrazinecarbonyl group, piperazine sulfonyl group, 5 ~ 9 carbon alkylpyrazine sulfonyl group, 6 ~ 9 carbon iminoalkylpyridinyl group Razine sulfonyl group, C1-8 alkylsulfonyl group, aminosulfonyl group, C2 A nonosulfonyl group, a piperidylalkyl group having 6 to 9 carbon atoms or an iminoaluminylpiperidylalkyl group having 8 to 12 carbon atoms, R3 represents a hydrogen atom, a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a nitro group, a formyl group, a trifluoromethyl group, a trifluoromethoxy group, a carbamoyl group, a thiocarbamoyl group, or a carbon atom. A mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, a methylenedioxy group, a cyano group, an iminoalkyl group having 2 to 7 carbon atoms, an acyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, a piperidyloxy group, Iminoalkylpiperidyloxy group having 6 to 10 carbon atoms, alkylpiperidyloxy group having 5 to 10 carbon atoms, alkoxycarbylpiperidyloxy group having 8 to 14 carbon atoms, pyrrolidyloxy group, 5 to 9 carbon atoms An iminoalkylpyrrolidyloxy group, an alkylpyrrolidyloxy group having 5 to 10 carbon atoms, an alkoxycal having 7 to 13 carbon atoms Bonylpyrrolidyloxy group, aryl-sulfonyl group having 6 to 10 carbon atoms, heteroarylsulfonyl group having 4 to 10 carbon atoms, carbon number? ~ 10 iminoalkylpiperazine carbonyl group, piperazine sulfonyl group, iminoalkylpiperazine sulfonyl group having 6 to 9 carbon atoms, alkyl group having 1 to 6 carbon atoms which may have a substituent, substituent A cyclic alkyl group having 3 to 8 carbon atoms which may have a mono- or dialkylamino group having 1 to 6 carbon atoms, an amino group which may have a substituent, and a carbon number which may have a substituent 1 to 9 aminoalkyl groups, a pyrrolidine group which may have a substituent, a piperidyl group which may have a substituent, a piperazine group which may have a substituent, and a group which may have a substituent An aryl group having 6 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms which may have a substituent, or a carbon substituted with an alkyl group having 1 to 6 carbon atoms which may have a substituent Aryl group having 6 to 10 carbon atoms which may have a substituent 1 to 6 A heteroaryl group having 5 to 10 carbon atoms substituted with an alkyl group; an alkyl group having 1 to 6 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms which may have a substituent; Substituted with 5- to 10-heteroaryl group which may be possessed Alkyl group having 1 to 6 carbon atoms, amidino group which may have a substituent, guanidino group which may have a substituent, piperidylalkyl group having 6 to 9 carbon atoms, or Represents any of iminoaluminylbiperidylalkyl groups, When R3 has a substituent, the substituent includes an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, a hydroxyalkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, and a carbon number. Alkoxyalkyl group, nitro group, formyl group, trifluoromethoxy group, trifluoromethyl group, 1- to 10-carbon group, mono- or di-alkyl mono- or di-alkyl group having 2 to 7 carbon atoms, amino group A mono- or dialkylamino group having 1 to 6 carbon atoms, an aminoalkyl group having 1 to 9 carbon atoms, a mono- or dialkylaminoalkyl group having 2 to 9 carbon atoms, an amidino group, a mono- or dialkylamidino group having 2 to 7 carbon atoms C4-7 trialkylamidino group, C5-8 tetraalkylamidino group, guanidino group, C3-8 dialkyi Guanidino group, trialkyl guanidino group having 4 to 9 carbon atoms, methylenedioxy group, cyano group, iminoalkyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, piperidyloxy group, having 6 to 10 carbon atoms Alkylpiberidioxy group, iminoalkylpiperidyloxy group having 6 to 10 carbon atoms, alkoxycarbonylbiperidyloxy group having 8 to 14 carbon atoms, pyrrolidyloxy group, alkylpyrrolidyloxy group having 5 to 9 carbon atoms, Iminoalkylpyrrolidyloxy group having 5 to 9 carbon atoms, alkoxycarbonylpyrrolidyloxy group having 7 to 13 carbon atoms, pyrrolidine group, alkylpiperidine group having 5 to 9 carbon atoms, 5 to 9 carbon atoms Iminoalkylpiperidine group, piperidine group, alkylpiperidine group having 6 to 10 carbon atoms, iminoalkylpiperidine group having 6 to 10 carbon atoms, piperazine Alkenyl piperazine group having 5 to 13 carbon atoms, iminoalkylpiperazine group having 6 to 9 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, 6 carbon atoms ~ 10 arylsulfonyl groups, 4 to 10 heteroarylsulfonyl groups, 7 to 7 carbon atoms 10 iminoalkylpyrazine carbonyl group, 6 to 10 carbon alkylpyrazine carbonyl group, piperazine sulfonyl group, 5 to 9 carbon atom alkylpiperazine sulfonyl group, 6 to 9 carbon atom iminoalkylpyrazine sulfonyl group Represents a C1-8 alkylsulfonyl group, an aminosulfonyl group or a C2-8 mono or dialkylaminosulfonyl group,  114, 115, & 6, 117, 118 and 119 may be the same or different, respectively, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, an oxo group, a hydroxyl group, a hydroxyalkyl group having 1 to 10 carbon atoms A C1-C10 alkoxyl group, a C1-C10 alkoxyalkyl group, a nitro group, a trifluoromethoxy group, a trifluoromethyl group, an amino group, a C1-C6 mono- or Dialkylamino group, C1-C9 aminoalkyl group, C2-C9 mono- or dialkylaminoalkyl group, methylenedioxy group, cyano group, formyl group, carboxyl group, C2-C7 alkoxycarbonyl group, carbon An alkoxycarbonylalkyl group having 3 to 9 carbon atoms, a hydroxycarbonylalkyl group having 3 to 9 carbon atoms, a hydroxycarbonylalkenyl group having 3 to 7 carbon atoms C4 to C8 alkoxycarbonylalkenyl, phosphono, C2 to C9 dialkoxyphosphoryl, C1 to C4 monoalkoxyhydroxyphosphoryl, C1 to C6 alkylthio, carbon An alkylsulfonyl group of 1 to 6, an arylthio group of 6 to 10 carbon atoms which may have a substituent, a heteroarylthio group of 4 to 10 carbon atoms which may have a substituent A C1-C9 phosphorylalkyl group, a C3-C9 dialkoxyphosphorylalkyl group, a C2-C9 monoalkoxyhydroxyphosphoryl group, a 2-carboxy-2-oxoethyl group or a C1-C10 Represents any of the heteroaryl groups,  X is an alkylene group having 1 to 6 carbon atoms (in the chain, -H-, -C (= 0)-, -NHC (= 0)-, -C (= 0) NH-, -NHC (2 0 ) NH-may be included). Z1 and may be the same or different, and each represents a hydrogen atom, a halogeno group, Alkyl group, hydroxy group, hydroxyalkyl group having 1 to 6 carbon atoms, alkoxyalkyl group having 2 to 6 carbon atoms, thioalkyl group having 1 to 6 carbon atoms, alkylthioalkyl group having 2 to 8 carbon atoms, carbon number 1 to 6 carbon atoms substituted with an alkyl group having 6 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, and 6 to 10 carbon atoms substituted with an alkyl group having 1 to 6 carbon atoms. An aryl group having 1 to 6 carbon atoms, a heteroaryl group having 4 to 10 carbon atoms, an aminoalkyl group having 1 to 6 carbon atoms, a carboxyl group, an alkoxy group having 2 to 6 carbon atoms. A carbonyl group, a C2-8 hydroxycarbonylalkyl group, a C3-8 alkoxycarbonylalkyl group, a C1-6 aminoamino group or a C2-C1 mono- or dialkylaminoalkyl group having L'0 Table Z1 and Z2 may combine to form a ring, and in this case, one Z1-Z2- represents an ethylene group, a trimethylene group or a tetramethylene group. ]  2. In the general formula (1), Ring A is a C6-C6 aryl group, a C3-C3 heteroaryl group or a C5- or C6-cyclic alkyl group,  R1 is a hydrogen atom, a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a trifluoromethyl group, a trifluoromethyl sulfonyloxy group, a canolebamoyl group, a mono- or dialkyl group having 2 to 7 carbon atoms Carbamoyl group, cyano group, nitro group, mono- or dialkylamino group having 1 to 6 carbon atoms, carboxysole group, alkoxycarbonyl group having 2 to 7 carbon atoms, 1 to 6 carbon atoms which may have a substituent An alkyl group, an alkylthio group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminoamino group having 2 to 7 carbon atoms which may have a substituent, and a piperazine which may have a substituent. Represents either a carbonyl group or an amidino group which may have a substituent, When R1 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, a mono- or dialkylamino group having 1 to 6 carbon atoms, or a heteroatom having 1 to 10 carbon atoms. Aryl group, carboxyl group, alkoxycarbonyl group having 2 to 7 carbon atoms, substituted with an alkyl group having 1 to 6 carbon atoms including at least one heteroatom selected from nitrogen, oxygen and sulfur. A carbon atom which may be substituted with an alkyl group having 1 to 6 carbon atoms, which contains one or more heteroatoms selected from the group consisting of carbocycles having 1 to 6 carbon atoms, nitrogen, oxygen and sulfur A carbonyl group, a phosphono group, a C2-C9 dialkoxyphosphoryl group, a C1-C4 monoalkoxyhydroxyphosphoryl group, a C1-C6 alkylsulfonyl group substituted with a C1-6 carbon ring The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the benzodiazepine derivative represents a group, a dialkylamidino group having 1 to 6 carbon atoms, or an acyl group having 1 to 8 carbon atoms. 3. In the general formula (1), ring A represents a phenyl group,  R1 is a hydrogen atom, a fluoro group, a chloro group, a bromo group, an oxa group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, a hydroxyl group, a carbon atom having 1 to 1 carbon atoms 10 alkoxyl group, alkyl group having 1 to 6 carbon atoms which may have a substituent, alkylthio group having 1 to 6 carbon atoms which may have a substituent or carbon atom which may have a substituent Represents an alkylsulfonyl group of the formulas 1 to 6, Has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, a phosphono group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, or a mono- or dialkyl group having 2 to 7 carbon atoms. Substituted with a C1-6 alkyl group containing at least one heteroatom selected from a rubamoyl group, a C1-6 mono- or dialkylamino group, nitrogen, oxygen and sulfur. 1 to 6 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms, including one or more heteroatoms selected from nitrogen, oxygen and sulfur A carbonyl group substituted with 1 to 6 carbon rings or an alkylsulfonyl group having 1 to 6 carbon atoms, an acyl group having 1 to 8 carbon atoms, and M and R 5 may be the same or different, and include a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxyl group having 1 to 6 carbon atoms, a trifluoromethoxy group, 2. The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is any one of a hydroxyl group, an alkylthio group having 1 to 6 carbon atoms, and an alkylsulfonyl group having 1 to 6 carbon atoms.  4. In the general formula (1), ring A represents a vinyl group,  R1 represents a hydrogen atom, a fluoro group, a chloro group, a bromo group, a halide group, an amino group, a cyano group, a nitro group, a carboxyl group, an ethoxycarbonyl group, a carboxyethyl group, an ethoxycarbonylethyl group, Morpholine alkyl, hydroxyl, methyl, methoxy, methylthio, methylsulfonyl, phosphonoethyl, morpholinecarbonylethyl, piperazinecarbonylethyl, isopropyl piperazinecarbonylethyl, methyl 2. The benzodiazepine derivative according to claim 1, which is a sulfonylaminopropyl group, a hydroxymethyl group or a hydroxypropyl group, or a pharmaceutically acceptable salt thereof.  5. The benzodiazepine derivative or the pharmaceutically acceptable salt thereof according to claim 4, wherein in formula (1), at least one of R 4 and R 5 is a hydrogen atom. 6. In the general formula (1), ring B represents an aryl group having 6 to 10 carbon atoms or 4 to carbon atoms; a heteroaryl group having L 0,  The benzodiazepine derivative according to claim 1, wherein R2 is any one of a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, and an alkoxyl group having 1 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof. Possible salt.  7. In the general formula (1), 璟 B is an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,  R2 is a hydrogen atom, a chloro group, a promo group or a methyl group, and R6 and R7 may be the same or different, respectively, and include a hydrogen atom, a halogeno group, The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is any one of an orthomethyl group, a methoxy group and a hydroxyl group.  8. In the general formula (1), ring B is an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms;  R2 is a chloro group, a promo group or a methyl group,  2. The benzodiazepine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R 6 and R 7 are both hydrogen atoms.  9. The benzodiazepine derivative or the pharmaceutically acceptable salt thereof according to claim 8, wherein in formula (1), ring B is either a phenyl group or a thiophene group. 10. —In the general formula (1), the ring C is one heteroatom selected from oxygen and / or sulfur containing at least one nitrogen atom excluding a pyrrolidyl group, a piperidyl group or a piperazinyl group. A non-aromatic carbocyclic ring having 2 to 8 carbon atoms which may contain R3 is a halogeno group, a nitro group, an iminoalkyl group having 2 to 7 carbon atoms, a mono- or dialkyl-rubumoyl group having 2 to 7 carbon atoms, an acyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 27 carbon atoms, piperidyloxy Group, an iminoalkylpiperidyloxy group having 6 to 10 carbon atoms, an alkylpiperidyloxy group having 5 to 10 carbon atoms, an amino group which may have a substituent, and a Good C2-C9 aminoalkyl group, C1-C6 alkyl group which may have a substituent, C3-C8 cyclic alkyl group which may have a substituent, Substituent A pyrrolidine group which may have a substituent, a piperazine group which may have a substituent, a heteroaryl group having 1 to 10 carbon atoms which may have a substituent or a substituent. Any of the amidino groups that may be  When R3 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, / Group, mono- or di-C2-9 Alkylaminoalkyl group, mono- or dialkylamidino group having 2 to 7 carbon atoms, trialkylamidino group having 4 to 7 carbon atoms, pyrrolidine group, piperidine group or alkylsulfonyl group having 1 to 8 carbon atoms or pyridyl group 2. The benzodiazepine derivative according to claim 1, or a pharmaceutically acceptable salt thereof.  In the general formula (1), R3 is an alkyl group having 1 to 6 carbon atoms which may have a substituent or a cyclic alkyl group having 3 to 8 carbon atoms which may have a substituent. Item 10. The benzodazebine derivative or the pharmaceutically acceptable salt thereof according to Item 10. 12. The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 11, wherein in the general formula (1), ring C is any one of groups represented by the following general formula (2).

(2) 13. The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 12, wherein in formula (1), R 8 and R 9 are both hydrogen atoms.  1. The benzodiazepine derivative or the pharmaceutically acceptable salt thereof according to claim 11, wherein X is an alkylene group having 1 to 6 carbon atoms.  1 5. —In the general formula (1), ring A represents a phenyl group, Represents a hydrogen atom, a fluoro group, a chloro group, a bromo group, a halide group, an amino group, a cyano group, a nitro group, a carboxyl group, an ethoxycarbonyl group, a carboxyethyl group, an ethoxycarbonylethyl group, and morpholine. Alkyl group, hydroxyl group, methyl group, methoxy group, methylthio group, methylsulfonyl group, phosphonoethyl group, morpholinecarbonylethyl group, piperazinecarbonylethyl group, isopropylpirazazinecarbonylethyl group, methanesulfonylamino Propyl group, hydroxy Represents a methyl or hydroxypropyl group,  Ring B represents either a phenyl group or a thiophene group,  R2 represents a hydrogen atom, a chloro group, a bromo group or a methyl group,  Ring C represents one of the groups represented by the general formula (2) according to claim 12,  R3 represents any one of a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a pyridyl group;  X is a methylene group, an ethylene group, or a propylene group (the chain may contain one C (= 0)-); and  2. The benzodiazepine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein both Z1 and Z2 are hydrogen atoms.  16. The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 15, wherein in general formula (1), R 5, R 6, R 7 and R 9 are hydrogen atoms.  17. In the general formula (1), ifA represents a phenyl group;  Is a hydrogen atom, a carboxyl group, an ethoxycarbonyl group, a carboxyethyl group, an ethoxycarbonylethyl group, a morpholinealkyl group, a morpholinecarboxyleethyl group, a piperazinecarbonylethyl group, or an isopropylpyrazinecarboxyleethyl group. Represents a hydroxymethyl group,  Ring B represents either a phenyl group or a phenyl group,  R2 represents a chloro group, a promo group or a methyl group,  Ring C represents one of the groups represented by the general formula (2) according to claim 12,  R3 represents any of a methyl group, an ethyl group, an isopropyl group, a cyclobutyl group, a cyclopentyl group, and a pyridyl group;  X is a methylene group or an ethylene group or a propylene group, R 4 is a hydrogen atom, a fluoro group, a chloro group, a methoxy group, a methyl group, R5, R6, R7 and: 9 are both hydrogen atoms, and  2. The benzodiazepine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein both Z1 and Z2 are hydrogen atoms.  18. A benzodiazepine derivative represented by the general formula (II) or a pharmaceutically acceptable salt thereof.

(In the general formula (Γ),  R1 ′ is a halogeno group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, an alkoxyl group having 1 to 10 carbon atoms or a hydroxyl group,  Here, when M ′ has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms or a hydroxyl group, Ring represents one of the following groups, and

R3 ⁵ is an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group or C of 3-8 carbon atoms These are heteroaryl groups of the numbers 1 to 10. )  19. An activated blood coagulation factor X inhibitor comprising, as an active ingredient, the benzodiazepine derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 18.  20. A pharmaceutical composition comprising the benzodiazepine derivative according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient.  21. An anticoagulant or a prophylactic or therapeutic agent for thrombosis or embolus, comprising the benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18 as an active ingredient.