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WO2004056813A1 - Derive de benzodiazepine - Google Patents

Derive de benzodiazepine Download PDF

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Publication number
WO2004056813A1
WO2004056813A1 PCT/JP2003/016403 JP0316403W WO2004056813A1 WO 2004056813 A1 WO2004056813 A1 WO 2004056813A1 JP 0316403 W JP0316403 W JP 0316403W WO 2004056813 A1 WO2004056813 A1 WO 2004056813A1
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Prior art keywords
group
carbon atoms
ring
substituent
alkyl
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English (en)
Japanese (ja)
Inventor
Masaru Takayanagi
Kuniya Sakurai
Shunji Takehana
Kazumi Tashiro
Hiroshi Yamamoto
Masayuki Sugiki
Hidehiro Ichinose
Kayo Ootani
Haruko Hirashima
Yuki Saitou
Junko Matsushita
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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Priority to AU2003292595A priority Critical patent/AU2003292595A1/en
Publication of WO2004056813A1 publication Critical patent/WO2004056813A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to a novel benzodiazepine derivative which is useful as a medicament, particularly an activated blood coagulation factor X inhibitor, and which can be orally administered.
  • the present invention also relates to a pharmaceutical composition containing the benzodiazepine derivative as an active ingredient, which is a therapeutic agent for a disease caused by blood coagulation, thrombus, or embolus.
  • thromboembolic diseases such as myocardial infarction, cerebral thrombosis, and peripheral arterial thrombosis tend to increase year by year.
  • Anticoagulant therapy together with fibrinolytic therapy and antiplatelet therapy, plays a part in medical treatment in the treatment and prevention of thrombosis.
  • antithrombin drugs have been developed as thrombus formation inhibitors.Thrombin not only controls the activation of fibrinogen to fipurin, which is the final stage of the coagulation reaction, but also the activation of platelets and It was also known that inhibition was at risk of causing a bleeding tendency because it was also deeply involved in aggregation. In addition, its oral bioavailability is low, and no thrombin inhibitor that can be administered orally has been reported at present.
  • activated blood coagulation factor X is located at the confluence of the extrinsic and intrinsic coagulation cascade reactions and upstream of thrombin, so inhibition of this factor is more efficient than thrombin Pfl harm. And may have the potential to specifically inhibit the coagulation system [Tidwell et al., "THROMBOSIS RESEARC H", (USA), 1998, Vol. 19 , P. 3 9—3 4 9; “Progress in Medicine” by Hashid a Mitsuru
  • activated blood coagulation factor X is considered to be useful as a therapeutic agent for diseases caused by blood coagulation, thrombus, and embolism with a low risk of bleeding.
  • a number of activated blood coagulation factor X inhibitors have been studied so far, but at present no orally available inhibitors have been reported.
  • Benzodiazepine derivatives exhibiting activated blood coagulation factor X inhibitory activity include compounds represented by the following formula (X) in W002 / 26732.
  • R1 is a hydrogen atom, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, an alkyl group having 1 to 6 carbon atoms which may have a substituent, and the like,
  • the substituent may be a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a biperidyloxy group, an alkylpiberidyloxy group having 6 to 10 carbon atoms, or a 7 to 10 carbon atoms.
  • R4 and R5 are a hydrogen atom, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms And an alkoxyalkyl group having 1 to 1 carbon atoms, a methylenedioxy group and the like.
  • An object of the present invention is to provide a novel compound which can be orally administered and inhibits activated blood coagulation factor X in a favorable and selective manner and which has a low bleeding risk and is useful for the treatment of diseases caused by blood coagulation, thrombus and emboli. And to provide a medicament containing them.
  • the present inventors have conducted various studies on the substituents of these benzodiazepine derivatives.As a result, by introducing a specific substituent, particularly a highly hydrophilic substituent into ring A or ring C, particularly excellent activation was achieved. A compound having a blood coagulation factor X inhibitory activity and having an excellent anticoagulant effect was found.
  • the present invention provides a benzodiazepine derivative having a characteristic of R 1 and / or R 3 in the following general formula (1) or a pharmaceutically acceptable salt thereof. Further, the present invention provides a benzodiazepine derivative or a pharmaceutically acceptable salt thereof characterized by ring C in the following general formula (2) and substituents R 3 and R 5 thereof. Certain novel benzodiazepine derivatives having a hydroxyl group at the ring or an alkyl group substituted with a hydroxyl group at the ring have particularly excellent activity in inhibiting the activity of blood coagulation factor X and oral absorption.
  • the first embodiment of the present invention relates to a benzodiazene represented by the general formula (1).
  • a pin derivative or a pharmaceutically acceptable salt thereof (
  • Ring A represents any of an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms, and a cyclic alkyl group having 4 to 10 carbon atoms,
  • R 1 represents —R 7 —R 8, an alkoxyl group having 1 to 10 carbon atoms having a substituent, or an acylamino group having 1 to 6 carbon atoms having a substituent.
  • R 7 represents an alkyl group having 1 to 6 carbon atoms
  • R 8 represents an acylamino group having 1 to 10 carbon atoms which may have a substituent
  • 2 carbon atoms which may have a substituent
  • Diacylamino group of up to 10 (two acyl groups may be bonded to each other to form a ring), alkylpiperazinyl group of 5 to 10 carbon atoms, sulfonic acid group, hydrazine carbonyl group, carbon number of A mono-, di- or trialkylhydrazine carboxy group of 2 to 10, an alkylsulfonylamino group of 1 to 6 carbon atoms which may have a substituent, a carbon atom of 1 to 1 which may have a substituent 0 represents any of the acyloxy groups,
  • R 1 or R 8 has a substituent
  • substituents include an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, and trifluryl.
  • iminoalkylpyrrolidyloxy group methylenedioxy group, cyano group, iminoalkyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, phosphono group, dialkoxyphosphoryl group having 2 to 9 carbon atoms
  • Ring B and ring C may be the same or different, and each has 6 to 10 carbon atoms.
  • R 2 represents any one of a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxy group having 1 to 10 carbon atoms, a cyano group, and a nitro group.
  • R 3 is an alkoxy group having 1 to 11 carbon atoms, a hydroxyiminoalkyl group having 1 to 6 carbon atoms, an acyloxy alkyl group having 2 to 15 carbon atoms, and a diacyl group having 3 to 11 carbon atoms.
  • An aminoalkyl group two acyl groups may be bonded to each other to form a ring
  • R 3 when R 3 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, and a carbon atom having 1 carbon atom.
  • an alkylpiperazinyl group having 5 to 10 carbon atoms an alkyl homopiperazinyl group having 6 to 11 carbon atoms, a tetrahydroviranyl group, a tetrahydrothioviranyl group, a C1 to C6 Imidazolinyl group which may be substituted with an alkyl group, tetrahydropyrimidyl group which may be substituted with an alkyl group having 1 to 6 carbon atoms, thiazole group having a dihydric opening, dihydrooxazolyl group, 2-oxopyrrolidinyl group , Represents any of the isotizazolidinyl groups which may be oxidized,
  • R 4, R 5, and R 6 may be the same or different from each other, and include 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, and a carbon number.
  • a second aspect of the present invention is a compound represented by the following general formula (1):
  • R 3 represents a hydrogen atom, a halogeno group, a hydroxyl group, an alkoxy 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, C2 to C7 mono- or dialkyl rubamoyl group, methylenedioxy group, cyano group, C2 to C7 iminoalkyl group, C1 to C8 acyl group, piperidyloxy group, C6 to C10 Minoalkylpiperidyloxy group, alkylpiperidyloxy group having 5 to 10 carbon atoms, alkoxycarbonylbiperidyloxy group having 8 to 14 carbon atoms, pyrrolidyloxy group, iminoalkylpyrroli group having 5 to 9 carbon atoms Ziloxy group, alkylpyrrolidyloxy group
  • Alkyl group amidino group which may have a substituent, guanidino group which may have a substituent, piperidylalkyl group having 6 to 9 carbon atoms, iminoaluminylbiperidylalkyl group having 8 to 12 carbon atoms
  • the substituent is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, a carbon atom having 1 to 10 carbon atoms.
  • Hydroxyalkyl group alkoxyl group having 1 to 10 carbon atoms, alkoxyalkyl group having 1 to 10 carbon atoms, nitro group, formyl group, trifluoromethoxy group, trifluoromethyl group, carbamoyl group, thiolmoyl group Carbamoyl group, mono- or dialkyl carbamoyl group having 2 to 7 carbon atoms, amino group, mono- or dialkylamino group having 1 to 6 carbon atoms, aminoamino group having 1 to 9 carbon atoms, mono- or mono-alkyl having 2 to 9 carbon atoms Is a dialkylaminoalkyl group, an amidino group, a mono- or dialkylamidino group having 2 to 7 carbon atoms, a trialkylamidino group having 4 to 7 carbon atoms, a tetraalkylamidino group having 5 to 8 carbon atoms, a guanidino group, or a carbon atom having 3
  • dialkylguanidino groups 4 to 9 carbon atoms trialkylguanidino group, methylenedioxy group, cyano group, 2 to 7 carbon atoms iminoalkyl group, 1 to 8 carbon atoms, acyl group, piperidyloxy group, carbon atoms 6 to 10 alkylpiperidyloxy groups, 6 to 10 carbon atoms of iminoalkylbiperi Ziloxy group, alkoxycarbylbiperidyloxy group having 8 to 14 carbon atoms, lipidyloxy group, alkylpyrrolidyloxy group having 5 to 9 carbon atoms, iminoalkylpyrrolidyloxy group having 5 to 9 carbon atoms Group, alkoxycarbonyl having 7 to 13 carbon atoms, lipidyloxy group, lysine group, alkylpyrrolidine group having 5 to 9 carbon atoms, iminoalkylpyrrolidine group having 5 to 9 carbon atoms, piperidine group, carbon
  • a benzodiazepine derivative or a pharmaceutically acceptable salt thereof is provided.
  • a third aspect of the present invention is a compound represented by the following general formula (1):
  • R 1 represents a hydrogen atom, a halogeno group, a hydroxyl group, an alkoxy group having 1 to 10 carbon atoms, 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 carbamoyl group having 2 to 7 carbon atoms, cyano group, mono- or dialkylamino group having 1 to 6 carbon atoms, carboxy group, 2 to 7 carbon atoms
  • C1 -C6 alkyl substituted with a mono group
  • R 1 has a substituent
  • the substituent is an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group.
  • C1 to C6 mono- or dialkyl C1 to C6 mono- or dialkylamino group amidino group, C2 to C2 mono- or dialkylamino group
  • a benzodiazepine derivative or a pharmaceutically acceptable salt thereof is provided.
  • a fourth aspect of the present invention provides a benzodiazepine derivative represented by the general formula (2) or a pharmaceutically acceptable salt thereof.
  • Ring A represents an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms, or a cyclic alkyl group having 4 to 10 carbon atoms,
  • R 1 is a hydrogen atom, a halogeno group, a hydroxyl group, an alkoxy group having 1 to 10 carbon atoms, a nitro group, a formyl group, a trifluoromethyl group, a trifluoromethoxy group, a trifluoromethyl sulfonyloxy group, Methylenedioxy group, carbamoyl group, thiocarbamoyl group, mono- or dialkyl carbamoyl group having 2 to 7 carbon atoms, cyano group, mono- or dialkylamino group having 1 to 6 carbon atoms, carboxy group, 2 to 7 carbon atoms An alkoxycarbonyl group having 3 to 7 carbon atoms, a hydroxycarbonyl alkenyl group having 3 to 7 carbon atoms, an alkoxycarbonylalkenyl group having 4 to 8 carbon atoms, a phosphono group, a dialkoxyphosphoryl group having 2 to 9 carbon atoms, and a
  • An alkyl group having 1 to 6 carbon atoms, which may be substituted, an alkyl group having 1 to 6 carbon atoms, which may be substituted and having 5 to 10 carbon atoms, May be an aryl group having 6 to 10 carbon atoms substituted with an alkyl group having 1 to 6 carbon atoms, or a carbon number substituted with an alkyl group having 1 to 6 carbon atoms which may have a substituent.
  • R 1 has a substituent
  • the substituent is an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a trifluoromethyl group, a trifluoromethyl group, Rubamoyl group, C2 to C7 mono- or dialkyl group Lubamoyl group, amino group, C1 to C7 aminoamino group, C1 to C6 mono or dialkylamino group, amidino group, C2 to C7 Mono- or dialkylamidino group, 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, and trialkylamidino group having 4 to 9 carbon atoms
  • iminoalkylpyrrolidyloxy group methylenedioxy group, cyano group, iminoalkyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, phosphono group, dialkoxyphosphoryl group having 2 to 9 carbon atoms
  • Ring B represents an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms,
  • R 2 represents any one of a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxy group having 1 to 10 carbon atoms, a cyano group, and a nitro group
  • R 4 represents a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms,
  • Ring C is a pyrrolidine, piberidine, homopiberidine, Radinium ring or homopiperazine
  • R 3 and R 5 may be the same or different, and may have a substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted cycloalkyl having 3 to 10 carbon atoms Group, an aryl group having 6 to 10 carbon atoms which may have a substituent, a heteroaryl group having 1 to 4 heteroatoms which may have a substituent, A non-aromatic heterocyclic group having 1 to 2 heteroatoms.
  • 13 and 115 may be bonded to each other to form a ring, wherein the ring may contain an unsaturated hydrogen bond, and the —CH 2 — group in the ring One may be replaced by 0, NH, or S,
  • R 3 or R 5 has a substituent
  • the substituent is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 1 to 6 carbon atoms, a cycloalkyl ring group having 3 to 10 carbon atoms, halogeno Group, oxo group, carbon number :!
  • R 4 and R 6 may be the same or different, and each represents 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, and a carbon atom having 1 to 1 carbon atoms.
  • a fifth aspect of the present invention provides a novel benzodiazepine derivative represented by the following general formula (3) or a pharmaceutically acceptable salt thereof.
  • Ring A represents any of a benzene ring, a pyridine ring and a thiophene ring,
  • R 1 is a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, an alkoxy group having 1 to 6 carbon atoms which may have a substituent, Good C2-C7 alkoxycarbonyl group, C3-C8 alkoxycarbonylalkyl group, C1-C6 alkylthio group, C1-C6 alkylsulfonyl A mono- or di-alkylamino group having 1 to 6 carbon atoms, or an alkyl group having 1 to 7 carbon atoms substituted by an amino group which may have a substituent;
  • R 1 has a substituent
  • the substituent is an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or di-alkyl rubamoyl group having 2 to 7 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, A non-aromatic hetero group having 1-2 carbon atoms which may be substituted with an alkyl group having 1-6 carbon atoms, and a hetero atom which may be substituted with an alkyl group having 1-6 carbon atoms.
  • Ring B represents any one of a benzene ring, a thiophene ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, and a biridazine ring;
  • R 2 represents a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxy group having 1 to 10 carbon atoms, a cyano group, or a nitro group,
  • R 4 represents any one of a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 10 carbon atoms;
  • Ring C represents any one of a benzene ring, a pyridine ring, a pyrrolidine ring, a piperidine ring, a homopiberidine ring, a piperazine ring, a homopiperazine, a cyclopentane ring, a cyclohexane ring, and a cycloheptane ring;
  • R 3 is an alkyl group having 1 to 6 carbon atoms which may have a substituent, a halogeno group, a cycloalkyl ring group having 3 to 10 carbon atoms which may have a substituent, 2 to 7 carbon atoms Mono or dialkylcarnomoyl group, an aryl group having 6 to 10 carbon atoms which may have a substituent, a heteroaryl group having 1 to 4 hetero atoms which may have a substituent, A hydroxyl group having a substituent, an amino group which may have a substituent, a non-aromatic heterocyclic group having 1 to 2 carbon atoms which may have a substituent, an alkyl group having 1 to 6 carbon atoms Substituted with a non-aromatic heterocyclic group having 1 to 2 heteroatoms which may be substituted Represents any of the carbonyl groups,
  • R 3 has a substituent
  • the substituent may be an alkyl group having 16 carbon atoms, a cycloalkyl ring group having 3 to 10 carbon atoms, a halogeno group, an oxo group, or an alkoxy group having 1 to 0 carbon atoms.
  • R 5 represents a hydrogen atom, a halogeno group, an alkyl group having 16 carbon atoms, an alkoxy group having 110 carbon atoms, a cyano group, or a nitro group,
  • n an integer from 0 to 2
  • P represents a hydroxyl group that has been prodrugged.
  • a sixth aspect of the present invention provides a novel benzodiazepine derivative represented by the following general formula (5) or a pharmaceutically acceptable salt thereof.
  • n an integer of 0 to 2
  • R 4 represents either a chloro group or a promo group
  • R 10 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl ring group having 3 to 6 carbon atoms, or a pyridyl group,
  • Y represents either a carbon atom or a nitrogen atom.
  • the present invention also relates to an activated blood coagulation factor X inhibitor and a pharmaceutical composition containing the above-mentioned benzodiazepine derivative or a pharmaceutically acceptable salt thereof, and particularly to the treatment of diseases caused by blood coagulation, thrombus or embolus. And a pharmaceutical composition for use.
  • FIG. 1 shows the time course of drug concentration in plasma after oral administration of rats with respect to the compounds of Examples 1, 2 and Reference Example 1.
  • the “aryl group” is preferably a mono- to di-aromatic hydrocarbon group having 6 to 10 carbon atoms. More preferably, it is a phenyl or naphthyl group.
  • the phenyl group may be condensed with a 5- to 8-membered cycloalkyl ring to form, for example, an indanyl or tetrahydronaphthyl group.
  • Heteroaryl group refers to a 5- to 8-membered monocyclic to heterocyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen as ring atoms. Is shown. Note that the sulfur atom or the nitrogen atom may be oxidized to form an oxide.
  • 5-membered ring group "furyl, phenyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl",-
  • a 5- to 6-membered monocyclic to bicyclic aromatic heterocyclic group containing 1 to 2 heteroatoms is more preferred, and a pyridyl and phenyl group are particularly preferred.
  • cycloalkyl (ring) group is preferably a monocyclic to bicyclic non-aromatic hydrocarbon group having 3 to 10 carbon atoms. More preferably, it is a cyclopentyl, cyclohexyl or cycloheptyl group.
  • Non-aromatic heterocyclic group means a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom as a ring atom:! And represents a 4- to 8-membered monocyclic to tricyclic non-aromatic heterocyclic group containing up to 2 members.
  • any carbon atom which is a ring atom may be substituted with an oxo group. Further, it may be condensed with a benzene ring.
  • non-aromatic hetero group in the present specification also includes a structure represented by the following formula (6).
  • bonding position to another group is not particularly limited.
  • non-aromatic heterocyclic group described in this specification
  • the “non-aromatic heterocyclic group” in the “substituted carbonyl group” and the like have the same meaning as the above “non-aromatic heterocyclic group”.
  • Non-containing non-aromatic heterocyclic group refers to a 4- to 8-membered mono- to bicyclic ring having at least one nitrogen atom as a ring atom and optionally having one oxygen atom or sulfur atom. And a non-aromatic heterocyclic group represented by the formula: In addition, any carbon atom which is a ring atom may be substituted with an oxo group.
  • 6-membered group “piperidinyl, biperazinyl, morpholinyl, thiomorpholinyl” 6- to 5-membered ring group: “indolinyl, isoindolinyl”
  • examples of the “nitrogen-containing non-aromatic heterocyclic group” in the present specification also include a structure represented by the following formula (8).
  • the bonding position to another group is not particularly limited.
  • Heteroatom means nitrogen, sulfur, oxygen
  • 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 black groups are particularly preferred.
  • halogeno in “halogenoalkyl group”, “halogenoalkoxy group” and the like described in the present specification has the same meaning as the above-mentioned halogeno.
  • Alkyl group refers to an alkyl group having 1 to 6 carbon atoms, which may be linear or branched. Of these, an alkyl group having 1 to 3 carbon atoms is preferred. Specifically, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, 360- and 7-ert monobutyl group, n-pentyl group, i-pentyl group, tert-pentyl Group, neopentyl group, 2-pentyl group, 3-pentyl group, n-hexyl group and 2-hexyl group. Of these, a methyl group, an ethyl group, an n-propyl group and an i-propyl group are preferred.
  • alkylsulfonyl group “alkylthio group”, and “alkyl group having 1 to 6 carbon atoms described in the present specification which may be substituted with 1 to 6 carbon atoms”
  • a non-aromatic heterocyclic group having 2 carbon atoms and a carbonyl group substituted with a non-aromatic heterocyclic group having 1 to 2 heteroatoms which may be substituted with an alkyl group having 1 to 6 carbon atoms ⁇ , ⁇ Alkylpiperazinyl group '', ⁇ alkylsulfonylamino group '', ⁇ mono-, di- or trialkylhydrazinecarbonyl group '', ⁇ hydroxyiminoalkyl group '', ⁇ acyloxyalkyl group '', ⁇ di.a ' “Alkyl” in “siloxyalkyl group” and the like is also the same as the above-mentioned alkyl.
  • Alkenyl group refers to an alkenyl group having 2 to 6 carbon atoms and having a straight or branched chain. Specific examples include a vinyl group, a propenyl group, and a 2-methyl-1-propenyl group.
  • alkoxycarbonyl described in this specification “Alkenyl” in “alkenyl group”, “mono- or di-alkyl rubamoylalkenyl group” and the like is also the same as the above-mentioned alkenyl.
  • alkylene group refers to an alkylene group having 1 to 6 carbon atoms, and examples thereof include a methylene group, an ethylene group, a propylene group, and a butylene group. Among them, a methylene group, an ethylene group and a propylene group are preferred, and a methylene group and an ethylene group are particularly preferred.
  • Alkoxy group refers to an alkoxyl group having 1 to 0 carbon atoms and having a linear or branched chain, an alkoxyl group having 4 to 5 carbon atoms and a cycloalkyl group, or may be condensed It shows an alkoxyl group having a cyclic carbon chain.
  • examples include a 3-phenylpropyloxy group, a 4-phenylbutoxy group, a cyclopropyloxy group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group.
  • a methoxy group, an ethoxy group and a cyclohexyloxy group are preferred.
  • alkoxy in “alkoxyalkyl group”, “alkoxyalkoxy group” and the like described in the present specification has the same meaning as the above-mentioned alkoxy.
  • alkoxycarbonyl group examples include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, a tert-butoxycarbonyl group, and the like. . Of these, a methoxycarbonyl group and an ethoxycarbonyl group are preferred.
  • alkoxycarbonyl alkyl group “alkoxycarbonylalkenyl group” and the like “alkoxy” “Carbonyl” has the same meaning as the above-mentioned alkoxycarbonyl.
  • acyl group examples include an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, a valeryl group, an isovaleryl group, a benzoyl group and a bivaloyl group.
  • acyloxyalkyl group “acylamino group”, “dicylamino group”, “acyloxy group”, “factory siloxyalkyl group”, “ “Acil” in “diasiloxyalkyl group” and the like are also the same as defined above.
  • the “mono- or di-alkyl rubamoyl group” includes a methylcarbamoyl group
  • Monoalkyl rubamoyl groups such as ethylcarbamoyl group, n-propyl rubamoyl group and i-propyl rubamoyl group, and dialkyl groups such as dimethylcarbamoyl group, acetyl carbamoyl group and di (n-propyl) rubamoyl group. And a carbamoyl group.
  • the chain length of the two alkyl groups of the dialkyl rubamoyl group may be the same or different.
  • the two alkyl groups of the dialkyl rubamoyl group may combine to form a ring, or may form a ring including an unsaturated hydrocarbon group.
  • one of the —CH 2 — groups may be substituted with 0, NH or S.
  • a 1-pyrrolidinecarbonyl group a 2,5-dihydro-11H-pyrroyl-1-ylcarbonyl group, a 1-piperidinecarbonyl group, a 1-piperazinecarbonyl group, a (morpholine-4-yl) carbonyl group And (thiomorpholine-4-yl) carbonyl group.
  • dimethylcarbamoyl group, 1-pyrrolidinecarbonyl group, (morpholin-1-yl) carbonyl group, 2,5-dihydro-1H-pyrroyl-1-ylcarbonyl group and (thiomorpholine-4-yl) A carbonyl group is preferred.
  • the “mono- or dialkylamino group” includes a monoalkylamino group such as a methylamino group, an ethylamino group, an n-propylamino group and an i-propylamino group, and a dimethylamino group, a getylamino group and a di (n-propyl) amino group. And the like.
  • the chain lengths of the two alkyl groups of the dialkylamino group may be the same or different.
  • two alkyl groups of the dialkylamino group may be bonded to each other to form a ring, or may include an unsaturated hydrocarbon group to form a ring.
  • one of the —CH 2 — groups may be substituted with ⁇ , NH or S.
  • Specific examples include a pyrrolidinyl group, a pyrrolyl group, a pyridinyl group, a morpholinyl group and a thiomorpholinyl group. Of these, a pyrrolidinyl group and a morpholinyl group are preferred.
  • “Mono- or dialkylaminoalkyl” includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylamino, n-propylaminomethyl and i-propylaminomethyl.
  • dialkylaminoalkyl groups such as aminomethyl group.
  • the chain lengths of the three alkyl groups of the dialkylaminoalkyl group may be the same or different.
  • two alkyl groups of a dialkylaminoalkyl group may be bonded to form a ring.
  • one of the —CH 2 — groups may be substituted with 0, NH or S.
  • a (pyrrolidine-11-yl) methyl group a (pyrrolidine-11-yl) ethyl group, a (pyrrolidine-11-yl) propyl group, a (piperidine-11-inole group) methyl group, a (morpholine- 4-yl) methyl group and (thiomorpholine-11-yl) methyl group.
  • the “prodruged hydroxyl group” is a group that forms a reversible prodrug derivative that is reconstituted at an appropriate site in a living body into a parent compound (original hydroxy compound).
  • Hashida Mitsuru Hashida Mitsuru
  • Nakao Hideo Nakao Hideo
  • Development of Pharmaceuticals Hirokawa Shoten
  • the “prodrugized hydroxyl group” is preferably a group represented by the general formula (4).
  • T represents a single bond, — ⁇ 112-0_ or (112-19) —, where R9 is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl having 2 to 10 carbon atoms.
  • R9 is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl having 2 to 10 carbon atoms.
  • Group, C1-C6 halogenoalkyl group, C2-C9 mono- or dialkylaminoalkyl group, Cyano group, Forminole group, C2-C7 alkoxyl group L-Polyl group, C3-C3 9 alkoxycarbonylalkyl groups, 4 to 8 carbon atoms Represents an alkoxycarbonylalkenyl group, an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 1 to 4 hetero atoms,
  • U is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and an alkoxyalkyl having 2 to 10 carbon atoms.
  • the substituent may be an alkyl group having 1 to 6 carbon atoms, a norlogeno group, an oxo group, or a carbon number:! Alkoxy group having 10 to 10 carbon atoms, alkoxyalkyl group having 2 to 10 carbon atoms, nitro group, trifluoromethyl group, trifluoromethyl group, mono- or dialkylamino group having 1 to 6 carbon atoms, methylenedioxy group, cyano group, carbon 1 to 8 carbon atoms, 6 to 10 carbon atoms, 1 to 4 heteroaryl groups, 1 to 8 carbon atoms, alkylsulfonyl group, 2 to 8 carbon atoms, mono- or dialkylaminosulfonyl Represents any of the groups.
  • Ring A is preferably a benzene ring, a pyridine ring, or a thiophene ring. Inside Also, a benzene ring is preferable.
  • R 7 represents an alkyl group having 1 to 6 carbon atoms
  • R 8 represents an acylamino group having 1 to 10 carbon atoms which may have a substituent
  • 2 carbon atoms which may have a substituent
  • a diacylamino group of up to 10 two acyl groups may be bonded to each other to form a ring
  • an alkylsulfonylamino group having 1 to 6 carbon atoms which may have a substituent and a substituent. It is preferable to represent any of the alkoxy groups having 1 to 10 carbon atoms which may be possessed.
  • R 1 has a hydrogen atom, a halogeno group, a hydroxyl group, an optionally substituted alkoxyl group having 1 to 6 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, and a substituent.
  • An alkyl group having 1 to 6 carbon atoms which may be used is preferable.
  • R 1 has a substituent
  • substituents include a hydroxyl group, a mono- or di-alkyl rubamoyl group having 2 to 7 carbon atoms, an amino group, a mono- or di-alkylamino group having 1 to 6 carbon atoms, and a carboxyl group.
  • Preferred are an alkoxycarbonyl group having 2 to 7 carbon atoms, an acyl group having 1 to 8 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, and a diacylamino group having 2 to 10 carbon atoms.
  • the diacylamino groups are bonded to each other to form a ring.
  • R 1 is a hydrogen atom, a fluoro group, a chloro group, a bromo group, a hydroxy group, a hydroxymethyl group, a methoxy group, a methylsulfonylalkyl group, a methylsulfonylmethyl group, a succinimidylalkyl group, a succinimidylmethyl And the ethoxycarbonylamino group is preferred.
  • Ring B is preferably a benzene ring, a thiophene ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, or a pyridazine. Among them, benzene ring and thiophene ring are more preferable. New
  • R 2 is preferably a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxyl group having 1 to 10 carbon atoms, a cyano group, or a nitro group.
  • a chloro group, a bromo group, a methyl group and a methoxy group are preferred.
  • Ring C is preferably a benzene ring, a pyridine ring, a pyrrolidine ring, a piperidine ring, a homopyridine ring, a piperazine ring, a homopirazine ring, a cyclopentane ring, a cyclohexane ring, or a cycloheptane ring.
  • benzene and peridine are preferred.
  • R 3 includes a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a mono- or di-alkyl rubamoyl group having 2 to 7 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, and a substituent.
  • a heteroaryl group having 1 to 10 carbon atoms and an alkoxy group having 1 to 11 carbon atoms which may be possessed are preferable.
  • R 3 has a substituent
  • substituents include an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a trifluoromethoxy group, and a trifluoromethyl group.
  • Methyl group, mono- or dialkyl alkyl group having 2 to 7 carbon atoms, mono- or dialkylamino group having 1 to 6 carbon atoms, aryl group having 1 to 10 carbon atoms, 1 to 10 carbon atoms Preference is given to a teraryl group, an alkoxy group having 1 to 11 carbon atoms, and a diacylamino group having 2 to 10 carbon atoms.
  • a fluoro group, a cyclo group, an alkyl group having 1 to 3 carbon atoms which may have a substituent, an alkoxyl group having 1 to 3 carbon atoms which may have a substituent, and 1 to 1 carbon atoms A 1-oxyl group and a di-amino group having 2 to 10 carbon atoms are preferred. At this time, it is more preferable that the diamino groups are bonded to each other to form a ring.
  • Ring D as R 3 may be substituted with an alkyl group having 1 to 6 carbon atoms
  • Preferred are an imidazolinyl ring, a tetrahydropyrimidinyl ring optionally substituted with an alkyl group having 1 to 6 carbon atoms, a dihydrothiazolyl ring, a dihydrooxazolyl ring, and a 2-oxopyrrolidinyl ring.
  • an imidazolinyl ring optionally substituted with an alkyl group having 1 to 6 carbon atoms and a tetrahydropyrimidinyl ring optionally substituted with an alkyl group having 1 to 6 carbon atoms are preferable.
  • An imidoylalkyl group, a succinimidoylmethyl group, an acetoxyl group, and an acetoxylmethyl group are preferred.
  • ⁇ D represents an imidazolidinyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms, a tetrahydropyrimidinyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms, or dihydrothiazol.
  • Groups, dihydrooxazolyl groups and 2-oxopyrrolidinyl groups are preferred.
  • R 4, R 5 R 6 include a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, and a carbon number; Preferred are an alkoxyl group having 1 to 10 carbon atoms, a methylenedioxy group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, and a heteroaryl group having 1 to 0 carbon atoms.
  • X is preferably an alkylene group having 1 to 3 carbon atoms. Among them, a methylene group and an ethylene group are preferred.
  • Ring A is preferably a benzene ring, a pyridine ring or a thiophene ring. Among them, a benzene ring is preferable.
  • R 1 is a hydrogen atom, a halogeno group, a hydroxyl group, an optionally substituted alkoxyl group having 1 to 6 carbon atoms, a carboxyl group, an alcohol having 2 to 7 carbon atoms.
  • a xycarbonyl group and an alkyl group having 1 to 6 carbon atoms which may have a substituent are preferable.
  • R 1 has a substituent
  • substituents include a hydroxyl group, a carbamoyl group, a mono- or di-alkyl group having 2 to 7 carbon atoms, an amino group, an amino group having 1 to 7 carbon atoms, and a carbon atom.
  • An aminosulfonyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, and a diacylamino group having 2 to 10 carbon atoms are preferred. At this time, it is more preferable that the diacylamino groups are bonded to each other to form ⁇ .
  • R 1 is a hydrogen atom, a fluoro group, a chloro group, a bromo group, a hydroxy group, a hydroxymethyl group, a methoxy group, a methylsulfonylalkyl group, a methylsulfonylmethyl group, a succinimidylalkyl group, a succinimidylmethyl And ethoxycarbonylamino groups are preferred.
  • Ring B is preferably a benzene ring, a thiophene ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, or a pyridazine ring. Of these, benzene and thiophene rings are more preferred.
  • R 2 is preferably a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxyl group having 1 to 10 carbon atoms, a cyano group, or a nitro group.
  • a chloro group, a bromo group, a methyl group and a methoxy group are preferred.
  • a pyrrolidinium ring, a piberidinium ring, a homopiberidinium ring, a piperazinium ring, and a homopiperazinium ring are all preferable.
  • a piperidinium ring is more preferred.
  • R 3 and R 5 an alkyl group having 1 to 6 carbon atoms which may have a substituent and a cycloalkyl group having 3 to 10 carbon atoms which may have a substituent are preferable. In this case, it is more preferable that R 3 and R 5 are bonded to each other to form a ring.
  • R 3 or R 5 has a substituent
  • the substituent is preferably an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 1 to 6 carbon atoms.
  • R 4 and R 6 a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, a methylenedioxy group, and a heteroaryl group having 1 to 10 carbon atoms are preferable.
  • X is preferably an alkylene group having 1 to 3 carbon atoms. Among them, a methylene group and an ethylene group are preferred.
  • Ring A is preferably a benzene ring, a pyridine ring or a thiophene ring. Among them, a benzene ring is more preferable.
  • R 1 represents a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, an alkoxy group having 1 to 6 carbon atoms which may have a substituent, This may be an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono or dialkylamino group having 1 to 6 carbon atoms or an alkyl group having 1 to 7 carbon atoms substituted by an amino group which may have a substituent. Good.
  • R 1 has a substituent
  • substituents include an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or di-alkyl rubamoyl group having 2 to 7 carbon atoms, and a mono- or di-alkyl group having 1 to 6 carbon atoms. May be substituted with an amino group, an alkyl group having 1 to 6 carbon atoms, and may be substituted with a non-aromatic heterocyclic group having 1 to 2 carbon atoms or an alkyl group having 1 to 6 carbon atoms.
  • a carbonyl group substituted with a non-aromatic heterocyclic group having 1 to 2 heteroatoms, an acyl group having 1 to 6 carbon atoms, and an alkylsulfonyl group having 1 to 6 carbon atoms are preferred.
  • an ethoxycarbonyl group, a dimethylamino group, a 1-pyrrolidylcarbonyl group, a 1-morpholinecarbonyl group, an acetyl group, and a methanesulfonyl group are more preferred.
  • Ring B is preferably a benzene ring, a thiophene ring, a pyridine group, a pyrazine ring, a pyrimidine ring, or a pyridazine ring. Among them, a benzene ring and a thiophene ring are more preferable.
  • a halogeno group an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, a C 1 to 1 carbon atom; an alkoxy group having L 0, a cyano group, and a nitro group are preferable.
  • a chloro group, a bromo group, a methyl group and a methoxy group are more preferred.
  • Ring C is preferably a benzene ring, a pyridine ring, a pyrrolidine ring, a piperidine ring, a homopiperidine ring, a piperazine ring, a homopiperazine ring, a cyclopentane ring, a cyclohexane ring, or a cycloheptane ring.
  • a piperidine ring, a homopiridin ring, a piperazine, and a homopirazine ring are more preferable.
  • an alkyl group having 1 to 6 carbon atoms which may have a substituent, a halogeno group, a cycloalkyl group having 3 to 10 carbon atoms which may have a substituent, 2 to 7 carbon atoms A mono- or di-alkyl rubamoyl group, an aryl group having 6 to 10 carbon atoms which may have a substituent, a heteroaryl having 1 to 4 carbon atoms which may have a substituent Group, hydroxyl group having a substituent, amino group which may have a substituent, non-aromatic heterocyclic group having 1 to 2 heteroatoms which may have a substituent, 1 to 6 carbon atoms
  • Number of heteroatoms optionally substituted with an alkyl group of: Preferred are carbonyl groups substituted with 2 to 2 non-aromatic heterocyclic groups. Among them, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclo
  • R 3 when R 3 has a substituent, the substituent includes an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 3 carbon atoms, a halogeno group, an oxo group, and a carbon number; Alkoxy group, trifluoromethoxy group, trifluoromethyl group, mono- or dialkyl group having 2 to 7 carbon atoms, rubamoyl group having 1 to 6 carbon atoms, mono- or dialkylamino group having 1 to 6 carbon atoms, 2 to 9 carbon atoms
  • Preferred is a heteroaryl group having 1 to 4 heteroatoms.
  • R 4; R 5 include a hydrogen atom, a halogeno group, and the number of carbon atoms; Preferred are alkyl groups having 6 to 6, and alkoxy groups having 1 to 10 carbon atoms. Among them, a hydrogen atom is more preferable.
  • X is preferably an alkylene group having 1 to 3 carbon atoms. Among them, an ethylene group is more preferred.
  • n is preferably an integer of 0 or 1.
  • P is preferably a group represented by the general formula (4).
  • T is preferably a single bond or one CH 2-0 —.
  • U is methyl, ethyl, ⁇ -propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, tert-pentyl Group, neopentyl group, 2-pentyl group, 3-pentyl group, n-hexyl group, 2-hexyl group, cyclopentyl group, cyclohexyl group, methoxy group, ethoxy group, isopropyloxy group, t-butyloxy group , Cyclopentyloxy group, cyclohexyloxy group, 1-propenyl group, 2-methyl-11-propenyl group, methoxymethyl group, 2-methoxy-2-propyl group, methylamino group, dibutylamino group, pyrrolidyl group, morpholyl Group, thiomorpholyl group, dimethylamin
  • i-propyl, tert-butyl, neopentyl, 3-pentyl, ethoxy, t-butyloxy, 2-methyl-1-propenyl, phenyl and pyridyl are more preferred.
  • Ring A represents any of a benzene ring, a pyridine ring and a thiophene ring,
  • Diacylamino group (two may be bonded to each other to form a ring), an optionally substituted alkylsulfonylamino group having 1 to 6 carbon atoms, substituent Represents any one of an alkoxy group having 1 to 10 carbon atoms which may have
  • R 1 or R 8 has a substituent
  • the substituent includes a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a carbamoyl group, a mono- or mono-alkyl group having 2 to 7 carbon atoms.
  • Dialkyl rubamoyl group amino group, aminoalkyl group having 1 to 7 carbon atoms, mono- or dialkylamino group having 1 to 6 carbon atoms, arylsulfonyl group having 6 to 10 carbon atoms, 4 to 10 carbon atoms Heteroarylsulfonyl group, carboxyl group, alkoxycarbonyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, phosphono group, aminosulfonyl group, dialkylaminosulfonyl group having 2 to 8 carbon atoms, carbon An alkylaminosulfonyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an acylamino group having 1 to 6 carbon atoms, a diacylamino group having 2 to 10 carbon atoms (the two Ring B represents any may form a ring) represents a benzene ring, Chiofen
  • Ring C represents any one of a benzene ring, a pyridine ring, a pyrrolidine ring, a piperidine ring, a homopiperidine ring, a piperazine ring, a homobiradizine, a cyclopentane ring, a cyclohexane ring, and a cycloheptane ring,
  • R3 is an alkoxy group having 1 to 11 carbon atoms, an acyloxyalkyl group having 2 to 15 carbon atoms, a diacylaminoalkyl group having 3 to 11 carbon atoms (the two acyl groups are bonded to each other) May form a ring), represents any of ring D,
  • ring D is an imidazolinyl group which may be substituted with an alkyl group having 1 to 6 carbon atoms, or a tetrahydropyrimidinyl group which may be substituted with an alkyl group having 1 to 6 carbon atoms.
  • Ring A represents any of a benzene ring, a pyridine ring and a thiophene ring,
  • R1 represents _R7-R8, an alkoxyl group having 1 to 10 carbon atoms having a substituent, or an acylamino group having 1 to 6 carbon atoms having a substituent, wherein R 7 represents an alkyl group having 1 to 6 carbon atoms; R 8 represents an acylamino group having 1 to 10 carbon atoms which may have a substituent; and 2 to 8 carbon atoms which may have a substituent.
  • a diacylamino group of 10 (two aryl groups may be bonded to each other to form a ring), an alkylsulfonylamino group having 1 to 6 carbon atoms which may have a substituent, and a substituent Represents any one of an alkoxy group having 1 to 10 carbon atoms,
  • R 1 or R 8 has a substituent
  • substituents include a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a carbamoyl group, a mono- or mono-alkyl group having 2 to 7 carbon atoms.
  • Dialkyl rubamoyl group amino group, aminoalkyl group having 1 to 7 carbon atoms, mono- or dialkylamino group having 1 to 6 carbon atoms, arylsulfonyl group having 6 to 10 carbon atoms, 4 to 10 carbon atoms Heteroarylsulfonyl group, carboxyl group, alkoxycarbonyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, phosphono group, aminosulfonyl group, dialkylaminosulfonyl group having 2 to 8 carbon atoms, carbon An alkylaminosulfonyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an acylamino group having 1 to 6 carbon atoms, a diacylamino group having 2 to 10 carbon atoms (the two acyl groups are bonded to each other)
  • Ring B represents any may form a ring)
  • R 2 represents any one of a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxy group having 1 to 10 carbon atoms, a cyano group, and a nitro group; Derivatives or pharmaceutically acceptable salts thereof are preferred.
  • Ring A represents any of a benzene ring, a pyridine ring and a thiophene ring,
  • R 1 represents one of R 7 —R 8, an alkoxyl group having 1 to 10 carbon atoms having a substituent, and an acylamino group having 1 to 6 carbon atoms having a substituent.
  • R 7 represents an alkyl group having 1 to 6 carbon atoms
  • R 8 represents an acylamino group having 1 to 10 carbon atoms which may have a substituent
  • 2 carbon atoms which may have a substituent a substituent.
  • a diacylamino group of 1 to 10 (two acyl groups may be bonded to each other to form a ring); an alkylsulfonylamino group having 1 to 6 carbon atoms which may have a substituent; Represents any one of an alkoxy group having 1 to 10 carbon atoms,
  • R 1 or R 8 has a substituent
  • substituents include a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a carbamoyl group, a mono- or dialkyl carbamoyl group having 2 to 7 carbon atoms.
  • Ring C represents any one of a benzene ring, a pyridine ring, a pyrrolidine ring, a piperidine ring, a homopiperidine ring, a piperazine ring, a homopiperazine ring, a cyclopentane ring, a cyclohexane ring, and a cycloheptane ring;
  • R 2 represents any of a chloro group, a bromo group, a methyl group, and a methoxy group
  • R 3 is an 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, or a substituent. Represents any of heteroaryl groups having 1 to 10 carbon atoms,
  • R 3 has a substituent
  • substituents include a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, an acyl group having 1 to 8 carbon atoms, and an alkyl group having 1 to 6 carbon atoms.
  • R4, R5, R6 are a hydrogen atom, a halogeno group, a hydroxyl group, a hydroxyalkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, a carboxyl group, an alkoxy having 2 to 7 carbon atoms
  • the benzodiazepine derivative or the pharmaceutically acceptable salt thereof according to the above [3], which represents any of carbonyl groups, is preferable.
  • Ring A represents any one of a benzene ring, a pyridine ring, and a thiophene ring
  • Ring B represents any one of a benzene ring, a thiophene ring, a pyridine ring, a pyrimidine ring, and a pyridazine ring;
  • Ring C is benzene, pyridine, pyrrolidine, piperidine, homopiperidine, piperazine, homopiperazine, cyclopentane, cyclohexane ⁇ ⁇ ⁇ or cycloheptan ⁇ ,
  • R 2 represents a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, a carbon atom having 1 to 1 carbon atoms; an alkoxy group having L 0, a cyano group, or a nitro group;
  • R 3 is an alkoxy group having 1 to 11 carbon atoms, an acyloxy group having 2 to 15 carbon atoms, a diacylaminoalkyl group having 3 to 11 carbon atoms (the two acyl groups are bonded to each other) May form a ring), represents any of ring D,
  • ⁇ D represents an imidazolinyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms, a tetrahydropyrimidinyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms,
  • ⁇ A represents any of benzene, pyridine ring, and thiophene
  • R 1 represents any one of a hydrogen atom, a halogeno group, a hydroxyl group, an alkoxy group having 1 to 10 carbon atoms, and an alkyl group having 1 to 6 carbon atoms which may have a substituent.
  • substituents include a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a carbamoyl group, a mono- or dialkyl rubamoyl group having 2 to 7 carbon atoms, and an amino group.
  • Ring B represents a benzene ring, a thiophene ring, a pyridine ring, a pyrimidine ring, or a pyridazine ring;
  • ⁇ C represents any one of a benzene ring, a pyridine ring, a pyrrolidine ring, a piperidine ring, a homopiperidine ring, a piperazine ring, a homopiperazine ring, a cyclopentane ring, a cyclohexane, and a cycloheptane ring;
  • R 2 represents any one of a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxy group having 1 to 10 carbon atoms, a cyano group, and a nitro group
  • R3 is an alkoxy group having 1 to 11 carbon atoms, an acyloxyalkyl group having 2 to 15 carbon atoms, a diacylaminoalkyl group having 3 to 11 carbon atoms (the two acyl groups are bonded to each other) May form ⁇ ), represents one of the rings D,
  • ring D is an imidazolinyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms, a tetrahydropyrimidinyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms,
  • A represents any one of a benzene ring, a pyridine ring, and a thiophene ring
  • ring B represents any one of a benzene ring, a thiophene ring, a pyridine ring, a pyrimidine ring, and a pyridazine ring;
  • R 3 and R 5 may be the same or different, and may have a substituent.
  • R 3 and R 5 may combine with each other to form a ring, wherein the ring may contain an unsaturated hydrocarbon bond
  • examples of the substituent include an alkenyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, and an alkoxycarbonyl group having 2 to 7 carbon atoms.
  • the benzodiazepine derivative according to the above [9] or a pharmaceutically acceptable salt thereof is preferable.
  • Ring A represents any one of a benzene ring, a pyridine ⁇ , and a thiophene ring,
  • R 1 represents a hydrogen atom, a halogeno group, a hydroxyl group, an optionally substituted alkoxyl group having 1 to 6 carbon atoms, a carboxyl group, an alkoxyl group having 2 to 7 carbon atoms, a substituent group, Represents an alkyl group having 1 to 6 carbon atoms which may be present,
  • R 1 has a substituent
  • substituents include a hydroxyl group, a carbamoyl group, a mono- or dialkyl carbamoyl group having 2 to 7 carbon atoms, an amino group, and a 1 to 7 carbon atom.
  • C1-C6 mono- or dialkylamino group carboxyl group, C2-C7 alkoxycarbonyl group, C1-C8 acyl group, phosphono group, aminosulfonyl group, C2-C8 Dialkylaminosulfonyl group, alkylaminosulfonyl group having 1 to 6 carbon atoms, alkylsulfonyl group having 1 to 6 carbon atoms, diacylamino group having 2 to 10 carbon atoms (two acyl groups are bonded to each other to form a ring May be formed), represents an alkylsulfonylamino group having 1 to 6 carbon atoms, and an acyloxy group having 1 to 6 carbon atoms,
  • Ring B represents any of benzene, thiophen ⁇ , pyridine, pyrimidine and pyridazine rings
  • R 3 and R 5 may be the same or different, and may have a substituted alkyl group having 1 to 6 carbon atoms, and an optionally substituted cycloalkyl having 3 to 10 carbon atoms. Represents one of the groups
  • 1 ⁇ 3 and 115 may be bonded to each other to form a ring, wherein the ring may contain an unsaturated hydrocarbon bond,
  • R 3 or R 5 has a substituent
  • substituents include an alkenyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, and an alkoxy group having 2 to 7 carbon atoms.
  • Ring A is a benzene ring
  • R 1 is a hydrogen atom, a fluoro group, a chloro group, a promo group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, and 3 to 3 carbon atoms 8, alkoxycarbonylethyl group, methylthio group, methylsulfonyl group, morpholinemethyl group, pyrrolidinemethyl group, piperidinemethyl group, alkylpyrazinemethyl group having 1 to 6 carbon atoms, morpholineprovyl group, pyrrolidinepropyl group, Peridine propyl group, alkyl piperazine propyl group having 1 to 6 carbon atoms, morpholine carbonyl ethyl group, pyrrolidine carbonyl ethyl group, piperidine carbonyl ethyl group, alkyl piperazine carbonyl ethyl group having 1 to 6 carbon atom
  • R 2 is any of a chloro group, a promo group, a methyl group, and a methoxy group
  • R 4 and R 5 are both hydrogen atoms
  • T is a single bond, C H 2—0—,
  • U is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, tert-pentyl, neopentyl , 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropyloxy, t-butyloxy, cyclopentyloxy , Cyclohexyloxy, 1-propenyl, 2-methyl-1-propenyl, methoxymethyl, 2-methoxy-12-propyl, getylamino, dibutylamino, pyrrolidyl, morpholyl, thiomorpholyl Group, dimethylaminoamino group, 2-dimethylamino-2-propyl group, ace
  • Ring A is a benzene ring
  • R 1 is a hydrogen atom, a fluoro group, a chloro group, a promo group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, or a carbon atom having 3 to 3 carbon atoms.
  • Ring B is any one of a benzene ring, a thiophene ring, a pyridine ⁇ , a pyrazine ring, a pyrimidine ring, and a pyridazine ⁇ ,
  • R 2 is any of a chloro group, a bromo group, a methyl group, and a methoxy group
  • ring C is a benzene group, a pyridine ring, a pyrrolidine ring, a piperidine ring, a homopiberidine ring, a piperazine group, or a homopyridine group.
  • R 3 represents a carbon atom which may have a substituent: an alkyl group having 6 to 6 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms which may have a substituent, and a monoalkyl group having 2 to 7 carbon atoms.
  • a dialkyl molybmoyl group an aryl group having 6 to 10 carbon atoms which may have a substituent, a heteroaryl group having 1 to 4 hetero atoms which may have a substituent, A hydroxyl group having an amino group which may have a substituent; a non-aromatic heterocyclic group having 1 to 8 carbon atoms which may have a substituent; and carbon number optionally having a substituent. Any one of 1 to 8 carbonyl groups substituted with a non-aromatic heterocyclic group,
  • R 3 has a substituent
  • the substituent is a methyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a fluoro group, a cyclo group, a bromo group, a methoxy group, a trifluoromethyl group, or a trifluoromethyl group.
  • R 4 and R 5 are both hydrogen atoms
  • X is an alkylene group having 1 to 3 carbon atoms
  • T is a single bond, —C H 2— 0—,
  • U is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, tert-pentyl, neopentyl , 2-pentyl, 3-pentyl, n-hexyl, 2_hexyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropyloxy, t-butyloxy, cyclopentyloxy , Cyclohexyloxy group, 1-propenyl group, 2-methyl-1-propenyl group, methoxymethyl group, 2-methoxy-12-propyl group, getylamino group, dibutylamino group, pyrrolidyl group, morpholyl group, thiomorpholyl group, Dimethylaminomethyl group, 2-dimethylamino-2
  • n an integer from 0 to 2
  • the benzodiazepine derivative or the pharmaceutically acceptable salt thereof according to the above [13] is preferable.
  • the prodrugized hydroxyl group is an aromatic group selected from the group consisting of a benzene ring, a pyrididine ring and a thiophene ring. It is preferred that the ring is present in the aromatic ring A, wherein the ring; B is the above-mentioned specific aromatic ring, particularly a heteroaryl ring, and ⁇ C is a non-aromatic ring.
  • ring B is a thiophene ring and ring C is a non-aromatic hetero ring, for example, a piperidine ring.
  • the compounds described in Examples 1 to 10 below are particularly preferred.
  • the benzodiazepine compound represented by the general formula (5) is preferable as the active substance which is a conjugate of the above-mentioned prodrug conjugate.
  • n an integer of 0 to 2
  • R 4 represents a chloro group or a bromo group
  • R 10 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl ring group having 3 to 6 carbon atoms, or a pyridyl group;
  • Y represents either a carbon atom or a nitrogen atom.
  • the active substance compound represented by the general formula (5) shows almost no thrombin inhibitory activity, and thus is preferable because of a low risk of bleeding.
  • the compound (1) of the present invention can be obtained according to a typical synthesis method described in WO 02/26732 already disclosed.
  • the compound (2) of the present invention can be produced as follows.
  • a compound (9) obtained according to a typical synthesis method disclosed in WO 02/26732 is used as a starting material, and a solvent such as dichloromethane, for example, triacetoxyborohydride is used as a reducing agent.
  • a solvent such as dichloromethane, for example, triacetoxyborohydride
  • acetonitrile or dimethylformamide as a solvent, and react with an alkyl halide such as methyl iodide in the presence of a base such as potassium carbonate.
  • a base such as potassium carbonate.
  • R 5 R 3 in the formula (2)
  • acetate nitrile dimethylformamide is used as a solvent in the presence of a base such as carbonated lime, for example, an alkyl halide such as ethylpromide.
  • a base such as carbonated lime
  • an alkyl halide such as ethylpromide.
  • the compound (3) of the present invention can be produced as follows.
  • n 0 and T is a single bond
  • T a single bond
  • a base such as potassium carbonate.
  • carbonyl halides (11) such as acetyl chloride, pivaloyl chloride, etc.
  • Hal represents a hydrogen atom or a logen atom.
  • the salt of the benzodiazepine derivative represented by any of the general formulas (1), (2), (3) and (5) may be any pharmaceutically acceptable salt.
  • mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, lactic acid, salicylic acid, mandelic acid, citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid
  • Examples thereof include acid addition salts with organic acids such as tannic acid, malic acid, tosylic acid, methanesulfonic acid, and benzenesulfonic acid.
  • a salt with an alkali metal such as ammonium salt, sodium or potassium, or an alkaline earth such as calcium or magnesium
  • the compound represented by any one of the general formulas (1), (2), (3) and (5) of the present invention includes solvates thereof such as hydrates and alcohol adducts. I have.
  • the compound of the present invention may have tautomers and geometric isomers, and the present invention also includes a separated form of these isomers and a mixture thereof.
  • the compound of the present invention may have an asymmetric carbon atom, and may have an optical isomer based on the asymmetric carbon atom.
  • the present invention relates to a compound obtained by separating these optical isomers or a mixture thereof. Also included.
  • the compounds of the present invention also include pharmaceutically acceptable prodrugs.
  • a pharmaceutically acceptable prodrug has a group that can be converted into a carboxyl group, an amino group, an amidino group, a guanidino group, a hydroxyl group, or the like in a living body.
  • the groups that constitute these prodrugs include, for example, Mitsuru Hashida
  • Non-Patent Document 2 “Hashida Mitsuru”, “Progress in Medicine”, 1985, Vol. 5, No. 7, p.2157-2161 (Non-Patent Document 2) and Hideo Nakao (Nakao Hideo), Pharmaceutical Development (Hirokawa Shoten) ", 1990, Vol. 7, p.163-198 (Non-Patent Document 3).
  • the compound represented by any of formulas (1), (2), (3) and (5) or a salt thereof is administered as it is or as various pharmaceutical compositions.
  • Pharmaceutical compositions containing a compound represented by any of the general formulas (1), (2), (3) and (5) or a salt thereof as an active ingredient include a pharmaceutical carrier usually used in the art, It is adjusted using excipients in the usual manner.
  • the dosage form of such a pharmaceutical composition may be, for example, tablets, powders, pills, granules, capsules, suppositories, solutions, dragees and the like. Can be manufactured.
  • tablets may contain the active ingredient benzodiazepine derivative of the present invention in the form of a known auxiliary substance, for example, an excipient such as lactose, calcium carbonate or calcium phosphate, a binder such as acacia, corn starch or gelatin, alginic acid, corn starch or acetonitrile. It is obtained by mixing with a bulking agent such as gelatinized starch, a sweetening agent such as sucrose, lactose or saccharin, a flavoring agent such as peppermint or cherry, and a lubricant such as magnesium stearate, talc or carboxymethylcellulose. .
  • a known auxiliary substance for example, an excipient such as lactose, calcium carbonate or calcium phosphate, a binder such as acacia, corn starch or gelatin, alginic acid, corn starch or acetonitrile. It is obtained by mixing with a bulking agent such as gelatinized starch, a sweetening
  • the administration route is oral.
  • the dose may vary depending on the patient's age, body weight, condition, and administration method, but the daily dose to an adult is usually 0.01 in the case of oral administration.
  • the obtained residue is dissolved in ethanol 1.21, glycine ethyl ester hydrochloride 219.5 g (1.57mo1) and sodium hydrogen carbonate 132.1g (1.57mo1) are added, and the mixture is heated at 60 ° C. Stirred. The insolubles were filtered and the solvent was distilled off. After extraction with ethyl acetate and washing with water, the organic phase was extracted with 3 M hydrochloric acid. The aqueous phase was made alkaline with a 6 M aqueous sodium hydroxide solution, extracted with ethyl acetate, and washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off.
  • the obtained residue was dissolved in a mixed solvent of 100 ml of ethanol and 200 ml of tetrahydrofuran, and 16.8 g (40 Ommo 1) of lithium hydroxide monohydrate was dissolved in 20 Oml of water, followed by stirring at room temperature. After completion of the reaction, the solvent was distilled off, and azeotropic distillation with toluene was performed to remove water.
  • Step 3 4 [(5- (2-Chlorophenyl)) carbonyl] 1-6-Methoxy-1, 3,4,5-tetrahydro-1H-1.4H-benzodiazepin-12-one Success
  • the ethyl acetate phase is converted to 1M hydrochloric acid, 1M aqueous sodium hydroxide solution, After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting crystals were washed with ethyl acetate. The crystals were combined with the previous crystals and dried under reduced pressure to obtain the title compound.
  • Step 5 4 [(5-Clo (2-Chenyl)) carbonyl] — 6-Methoxy-11- (2-piperidine-14-ylethyl) -1,3,4,5-tetrahydro-2H— Synthesis of 1,4-Penzodiazepin-2-one hydrochloride
  • Step 6 4 [(5-Chloro (2-Chenyl)) carbonyl] -1- [2- (1-Isopropylpiperidin-1-yl) ethyl] -6-methoxy-1,3,4 Synthesis of 5 —Tetrahydro-2H-1,4-benzodiazepin-1-one
  • Step 7 4 [(5-Clo- (2-Chenyl)) carbonyl] —6-Hydroxy-1- [2- (1-Isopropylpyridine-1-41) ethyl] —1,3,4, Synthesis of 5-tetrahydro-2H-1,4-benzodiazepin-12-one
  • Examples 1 to Table 1 shows the structure and physicochemical data of the compound of L0. 9
  • ⁇ indicates the bonding position to the oxygen atom.
  • Example 11 4- (2- ⁇ 4-[(5-Clo-Chen-1-yl) carbonyl] -1 6-methoxy-2-oxo-1,2,3,4,5-tetrahydro-1H-1,4 -Benzo'dazepine 1-yl ⁇ ethyl) Synthesis of 1, 1-Jetyl biperidinium trifluoracetate
  • the solvent was distilled off, and the obtained crude product was subjected to reverse-phase high-performance liquid chromatography using octadecyl-dodecyl-bonded silica gel as a filler, containing 0.1% of trifluoroacetic acid (v / V), and eluted with a mixed solution of water and acetonitrile, and the desired fraction was lyophilized to give the title compound.
  • Example 14 8 (2— ⁇ 4- [5-Clo-open-1-yl] carbonyl ⁇ -6-methoxy-12-oxo-1,2,3,4,5-tetrahydro-1H—1, 4-Benzodazepine 1-yl) ethyl) 15-Azoniaspiro [4,5] decane trifluoroacetate synthesis
  • Example 14 The same operation as in Example 14 was performed using 1,5-dibromopentane to obtain the title compound.
  • Example 14 The same operation as in Example 14 was performed using (Z) -1,4-dichloro-1,2-butene to obtain the title compound.
  • Step 1 t-Butyl 4- (2- ⁇ 4-[(5-chloro-en-1-yl) carbonyl] -1-6-methoxy-2-oxo-1,2,3,4,5-tetrahydro-1H-1 4-Penzodiazepine-1-yl ⁇ ethyl) Synthesis of piperidine-11-carboxylate T-butyl 4 [(5- (2-cyclopentenyl)) carbonyl] —6-methoxy-1- 1,3,4,5-tetrahydro-2H—1,4-monobenzodiazepine obtained in Step 3 of Reference Example 1
  • the same operation as in Step 4 of Reference Example 1 was carried out using 12-one as a starting material and using t-butyl 4-chloroethylpyrazine-11-carboxylate to obtain the title compound.
  • Step 2 4 [(5-Chloro-2-yl) carbonyl] —6-methoxy-1- (2-pyrazine-1-ylethyl) -1,3,4,5-tetrahydro-1H — Synthesis of 1,4-benzo and diazevin-1-one
  • Example 18 4-[(5-Clo-guchi-1-2-yl) carbonyl] -1-6-methoxy 1- [4- (2-Methyl-5,6-dihydropyrimidine-1 (4H) -yl) benzyl] —1,3,4,5-tetrahydro-2H—1,4-1-benzodiazepine—2— Synthesis of on-trifluoroacetate
  • Step 2 (4-Aminobenzyl) 1-41 [(5-chloroacetone 12-yl) carbonyl] 1-6-methoxy-1,3,4,5-tetrahydro-2H—1,4-benzodiazepine 1— Synthesis of on-trifluoroacetate
  • Step 2 4 [(5—Chloro-1-yl) carbonyl] —6-Fluoro
  • Example 18 The same operation as in Example 18 was carried out except for using 4-[(5-cyclopent-2-yl) carbonyl] -6-methoxy-1,3,4,5-tetrahydro-1 2H-1,4-benzodiazepine. 4-([5-Crosin-Chain-1-yl) carboni] —6-Fluoro-1,3,4,5-tetrahydro-1H—1,4-Penzodiazepine-1— Use to afford the title compound. Yield 15.9mg (0.0255mmo 1) Yield 2.6% (4 steps) MS (ESI, m / z) 511 (MH +)
  • Step 6 8- (Aminomethyl) -14-[(5-chloro-en-1-yl) carbonyl] 1-1- [2- (1-Isopropylpyridin-1-4-yl) ethyl] 1, Synthesis of 3,4,5-tetrahydro- 1H- 1,4-benzodiazepin-12-one ditrifluoroacetate
  • Step 7 N- ( ⁇ 4- [(5-Clo-Chen-2-yl) carbonyl] — 1- 1 [2- (1-Isopropylpyridin-1- 4-ethyl) ethyl] —2-oxo-1 2 , 3,, 5-Tetrahydro-1H-1,4, -benzodiazepine-8-yl ⁇ methyl) methanesulfonamide trifluoroacetate
  • Process 1 2 Synthesis of 4-Methyl-1-6-tolutoluene Dissolve 5. g (29 mmo 1) of 2-chlorotoluene 6-nitrotoluene in 50 g of sulfuric acid, add 10.4 g (4 lmmo 1) of iodine, 1.25 g (5.8 mmo 1) of potassium periodate A solution of 50 g of sulfuric acid was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 500 g of crushed ice and stirred, and the supernatant was removed.
  • the solid residue was dissolved in ethyl acetate, washed sequentially with a 1M sodium hydroxide solution, a sodium thiosulfate solution, and a saturated saline solution, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the solvent was distilled off. The obtained crude product was purified by silica gel gel chromatography to obtain the title compound.
  • Methyl 1 ⁇ 2 -— [1- (t-butoxycarbonyl) piperidine-1-yl] ethyl ⁇ — 6—chloro mouth—41 — ((5-cyclo mouth chain—1-2—yl) carbonyl ] —2-oxo-1,2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-18-carboxylate as a starting material, the same operation as in step 4 of Example 21 Gave the title compound.
  • Step 8 t-butyl 4- (2- ⁇ 8- (promomethyl) -1-6-chloro-[[5-chloro-en-1-yl) carbonyl] —2-oxo-2,3,4,5 -Synthesis of tetrahydro-1H-1,4-benzodiazepine-1-yl) ethyl) piberidine-1-carboxylate
  • Step 1 4-[(5-chloro-1--2-yl) carbonyl] -8- (Hydroxymethyl) 1-1- [2- (1-Isopropylpiperidine-14-ethyl) ethyl]
  • Step 2 ⁇ 4-[(5-Crosin-1-2-yl) carbonyl] — 1- [2— (1-Isopropylpyridin-1-4-yl) ethyl] —2-Oxo-1,2,3 Synthesis of 4,5-tetrahydro-1H-1,4-benzodiazepine-18-yl ⁇ methylacetate trifluoroacetate
  • Step 2 Synthesis of t-butyl 4-[(methoxymethoxy) methyl] —4— ⁇ 2-[(methylsulfonyl) oxy] ethyl ⁇ piperidine—1-carboxylate
  • the t-butyl obtained in Step 1 Dissolve 0.22 g (0.83 mmol) of butyl 4-aryl-4- (hydroxymethyl) piperidine-1-carboxylate in 2 ml of methylene chloride, 0.30 ml of diisopropylethylamine and methoxymethyl chloride 0.1 ml was added, and the mixture was stirred with heating for 3 hours.
  • Step 4 4-[(5-chloro-2--2-enyl) carbonyl] -6-fluoro-11- ⁇ 2- [4- (hydroxymethyl) -11-pyridine-14-ylpiperidine-14-yl] ethyl ⁇ ⁇ Synthesis of 1,3,4,5-tetrahydro-1-H-2,4-benzodiazepin-2-one trifluoroacetate
  • the compound obtained in the step 3 was dissolved in 5 ml of a dioxane solution containing 4N-hydrogen chloride and stirred at room temperature for 2 hours, and then the solvent was distilled off. Then, 6 ml of ethanol, 0.38 ml (2.7 mmol) of triethylamine and 8 lmg (0.54 mmol) of 4-monopyridine pyridine hydrochloride were added thereto. The mixture was heated and stirred at C for 7 hours. After evaporating the solvent, the obtained crude product was purified by the same procedure as in Example 11 to obtain the title compound.
  • Example 26 1-[(4- ⁇ 2- [4 -— [(5-methyl-2--2-enyl) carbonyl] -18- (hydroxymethyl) -12-oxo-1,2,3,4,5-tetrahydrid Rho 1H—1,4-Penzodiazepine—11-yl] ethyl ⁇ —Synthesis of 1—pyridine—14-ylpiperidine—4-yl) methyl] pyrrolidine—1,5-dione trifluoroacetate
  • Example 21 4- (t-butoxycarbonyl) -2-oxo-1,2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-18-carboxylic acid obtained in Step 1 10.7 g (35 mmo l), and ⁇ the Toryechiruamin 5. 8 ml (42mmo 1) in tetrahydrofuran 350 ml, click every mouth formic Echiru 3. 7 ml 39 mmo 1) is stirred for 30 minutes was added at 0 a C. About 10 g of ice is added, followed by 2.7 g (7 lmmo 1) of sodium borohydride, and the mixture is stirred for 1 hour.
  • the solvent was distilled off, and the residue was diluted with ethyl acetate and worked up according to a conventional method to obtain 9.lg of a crude product.
  • the obtained crude product 9.lg, triethylamine 7.Oml (5 Ommol mmol) was dissolved in 40 Oml of tetrahydrofuran, 3.2 ml of acetyl chloride (45 mmo 1) was added at 0 ° C, and the mixture was stirred at room temperature for 1 hour.
  • the solvent is distilled off.
  • the residue was diluted with ethyl acetate and worked up according to a conventional method to obtain 10.1 g of a crude product.
  • Step 2 t-Butyl 4- (2- ⁇ 8-[(acetyloxy) methyl] -1-4-((5-chloro-1--2-enyl) carbonyl]]-2-oxo-1,2,3,4,5-tetrahydro 1 H—1,4-Penzodiazepine-1—yl ⁇ ethyl) 1-4 — [(Methoxymethoxy) methyl] piperidine-1-carboxylate
  • ⁇ 4 [(5—chloro) obtained in Step 1 Mouth—2—Chenyl) carbonyl] —2—yearly oxo-1,2,3,4,5-tetrahydro-1H—1,4-benzodiazepine-18-yl ⁇ methyl acetate
  • Example 25 obtained in Step 2 t-Butyl 4-[(methoxymethoxy) methyl] -4- ⁇ 2-[(methylsulfonyl) oxy] ethyl ⁇ piperidine-11-carboxylate This afforde
  • Step 31 1-[(4-I ⁇ 2- [4 -— [(5-Chloro-2-Chenyl) carbonyl] -8- (hydroxymethyl) -1-oxo-1,2,3,4,5-tetrahydro-1H—1, 4-benzodiazepine-1-yl] ethyl ⁇ — 1-pyridine-1-4-rubiperidine-1 4-yl) methyl] pyrrolidine-1, 5-diethylenetritrifluoro Synthesis of acetate
  • the residue was extracted with ethyl acetate, post-treated according to a conventional method, and purified by silica gel column chromatography (40 to 50% ethyl acetate Z hexane) to obtain 0.89 g of a compound. . Subsequently, the resultant was dissolved in 8 ml of a dioxane solution containing hydrogen chloride and stirred for 30 minutes, and the solvent was distilled off to obtain a crude product.
  • the obtained crude product was dissolved in 5 ml of methylene chloride salt, 0.22 ml (1.59 mmo 1) of triethylamine and 0.266 g (1.22 mmo 1) of t-butyl carbonate were added, and the mixture was added overnight. Stirred. After extraction using ethyl acetate, a post-treatment was carried out according to a conventional method to obtain a crude product.
  • the obtained crude product was dissolved in 5 ml of tetrahydrofuran, and 0.30 g (l.15 mmol) of triphenylphosphine and 0.113 g (l.15 mmo1) of succinimide were added.
  • Example 27 1- ⁇ [4— (2— ⁇ 4 — [(5-chloro-1-en-2-carbonyl) carbonyl] —6-hydroxy-2-oxo-1,2,3,4,5-tetrahydro-1H -1, 4-diazepine-1 -yl] "ethyl)-1-isopropylpiridin-4-yl] methyl ⁇ pyrrolidine-1,5-dione Trifluoroacetate Synthesis process 1 t-butyl 4-( 2— ⁇ 4— [(5-chloro-en-2-yl) carbonyl) —6-methoxy-12-oxo-1,2,3,4,5-tetrahydro-1H— 1,4-dazepine-1— Synthesis of 4-([methoxymethoxy) methyl] piperidine-11-carboxylate
  • Step 2 4 [(5-Crosin-1-yl) carbonyl] 1-1— ⁇ 2-—4-Hydroxymethyl) biperidine—41-yl] ethyl ⁇ 1-6-Methoxy-1, Synthesis of 3,4,5-tetrahydro-1H-2,4-benzodiazepin-12-one
  • the t-butyl 4- (2— ⁇ 4-[(5—black-mouth chain—2-—) obtained in Step 1 Le) carbonyl] — 6-methoxy-2-oxo-1,2,3,4,5-tetrahide 1H—1,4-dazepine-11-yl ⁇ ethyl) 1-4-1 [(methoxymethoxy) methyl] bi
  • the same operation as in step 5 of Reference Example 1 was performed using lysine-11-carboxylate as a starting material to obtain the title compound.
  • Step 4 t-butyl 4— (2— ⁇ 4— [(5—black mouth chain—2-yl) [Bonyl] -1-6-methoxy-2-oxo-1,2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-1-ethyl ⁇ ethyl 4-1-1 [(2,5-dioxopyridine-1-1-) 1) Synthesis of methyl] piperidine-11-carboxylate t-butyl 4- (2- ⁇ 4-[(5-chloro-en-2-yl) carbonyl] -1-6-methoxy obtained in step 3 1,2-oxo-1,2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-1-ethyl ⁇ ethyl (hydroxymethyl) piperidine-11-carboxylate 0.64 g (1.
  • Step 5 1— ⁇ [4— (2- ⁇ 4- [(5-Clo-Chen-2-yl) carbonyl] —6-Methoxy-1-2-oxo-1,2,3,4,5-tetrahydro-1 1 H—1,4-Benzodazepine-1-yl ⁇ ethyl) Pyridine-1-4-yl] methyl ⁇ bi-Lynth-1 Synthesis of 2,5-dione
  • Step 6 1- ⁇ [4- (2- ⁇ 4- [(5-chloro-en-1-yl) carbonyl]] — 6-methoxy-2-oxo-1,2,3,4,5-tetrahydro-1H — 1, 4, —Benzodazepine—1-yl ⁇ ethyl) Synthesis of 1-1,1-isopropylpyridin-1-4-yl] methyl ⁇ pyrrolidine-1,2,5-dione
  • Step 7 1— ⁇ [4- (2— ⁇ 4- [(5-Clo-Chen-1-yl) carbonyl] — 6-Hydroxy-2-oxo-1,2,3,4,5-tetrahydro-1 H-1,4-Diazepine-1-yl ⁇ ethyl) 1-Isopropylpiperidine-1-4-yl] methyl ⁇ pyrrolidine-1 2,5-dione
  • Step 2 1 ( ⁇ 4-[(5-Clo-Chen-1-yl) carbonyl] —2-—Kiso-1 2,3,4,5-Tetrahydro-1H—1,4—Penzodiazepine-1— ⁇ Synthesis of methylpyrrolidine-1, 5-dione
  • Example 29 1 [(4 — [(5-Clo-Chen-1-yl) carbonyl] —1 -— ⁇ 2- [4- (hydroxymethyl) -1-1-pyridine-14-piperidine-1-4— Yl] ethyl ⁇ —2-oxo-1,2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-18-yl) methyl] pyrrolidine-1,2,5-dione Trifluoroacetate
  • Step 2 1— ( ⁇ 4- [(5-Clo-Chen-2-yl) carbonyl] — 1 ⁇ ⁇ 2- [4- (Hydroxymethyl) pyridin-1-4-yl] ethyl ⁇ 1 2— Synthesis of oxo-1,2,3,4,5-tetrahydro-1H-1,4—besizodiazepine-8-yl ⁇ methyl ⁇ pyrrolidine-1,2,5-dione
  • Step 3 [(4-I [(5-Clo-Cou—2—yl) carbonyl] 1 1— ⁇
  • Example 30 4- ⁇ 2— [7-acetyl-4 — [(5-chlorothiophene-2-yl) carbonyl] -18-hydroxymethyl-12-oxo-1,2,3,4,5-tetrahydro-1 1H—1,4-benzodiazepine-1-yl] ethyl ⁇ — 1-pyridine-14-yl-piperidine-1-4-ylacetate trifluoroacetate Synthesis Step 14 4-hydroxy-14- (2-methanesulfonyloxy-1) Synthesis of 1-carboxyalkyl tert-butyl ester
  • Step 2 4 [(5-Chlorothiophene-2-yl) carbonyl] —8-Hydroxymethyl-1- 1- [2- (Hydroxy-1- 1-pyridine-14-ylbiperidine-14-yl) ethyl] — Synthesis of 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-1-one
  • the solvent was removed under reduced pressure, and the resulting residue was subjected to reversed-phase high-performance liquid chromatography using octa-dodecyl group chemically bonded silica gel as a filler, containing 0.1% of trifluoroacetic acid (v / v).
  • the target compound was obtained by eluting with a mixed solution of water and acetonitrile and freeze-drying the desired fraction.
  • Step 3 4— ⁇ 2— [7-Acetyl_4 — [(5-Chlorothiophen-1-yl) carbonyl] —8-Hydroxymethyl-2-oxo-1,2,3,4,5-tetrahydrid 1 1H— 1, 4 Benzodiazepine 1 1 1 ⁇ f] ethyl ⁇ — Synthesis of 1—pyridine 1 4—ylupiperidine—4—yl acetate
  • Example 31 4- ⁇ 2-4-[(5-chlorothiophene-2-yl) carbonyl] -8-hydroxymethyl-12-oxo-1,2,3,4,5-tetrahydro-1H-1,4 —Benzodazepine— 1-yl ⁇ ethyl ⁇ 1—11—pyridine—4—Irupibe Synthesis of lysine-4-yl acetate trifluoroacetate
  • the obtained residue was dissolved in 1 Oml of methanol, 8 mg (0.51 ol) of potassium carbonate was added, and the mixture was stirred at room temperature overnight.
  • the methanol was removed under reduced pressure, and the obtained residue was subjected to reversed-phase high-performance liquid chromatography using a dodecyl group chemically bonded type silica gel as a packing material, containing 0.1% trifluoroacetic acid (v / v) and eluted with a mixed solution of water and acetate nitrile, and the desired fraction was lyophilized to give the title compound.
  • the compounds of the present invention are useful as active ingredients in pharmaceutical preparations.
  • it since it has an activated blood coagulation factor X inhibitory effect, it is a disease caused by blood coagulation, thrombus, or embolism involving activated blood coagulation factor X, and a disease in cerebrovascular disease (for example, Blood vessels in transient cerebral blood attack, cerebral thrombosis, cerebral infarction, cerebral embolism, stroke, subarachnoid hemorrhage Diseases in ischemic heart disease (eg, acute myocardial infarction, chronic myocardial infarction, unstable angina), diseases in pulmonary vascular disorders (eg, pulmonary infarction, pulmonary embolism, etc.), deep vein thrombosis Disease, generalized intravascular coagulation syndrome, reocclusion and restenosis after coronary artery bypass surgery, after percutaneous transluminal coronary angioplasty (PTCA) after coronary artery infusion and coronary thrombolysis (PTCR) It is useful as
  • SD (IGS) rats were fasted the day before and used for experiments.
  • the compound of Reference Example 1 and its prodrug compound, the compounds of Examples 1 and 2 were orally administered by gavage to SD (IGS) rats at 30 mg / kg.
  • 630 ul of blood was collected under ether anesthesia and mixed with 70 ul of 3.8% trisodium citrate.
  • the obtained blood was centrifuged at 4 ° C for 15 minutes at 3000 rpm to obtain plasma.
  • the obtained plasma was subjected to protein removal treatment, and then quantified as the compound concentration of Reference Example 1 using HPLC.
  • Figure 1 shows the changes in plasma concentration after oral administration.
  • the maximum plasma concentration was 0.24 g / m1 and the bioavailability was 13%.
  • the plasma concentration of the compound of Example 2 was increased, with maximum plasma concentrations of 0.81 ⁇ g / ml and 0.64 bar / 1111, respectively, with a bioavailability of 35% and 27 %.
  • Example 1 and Example 2 exhibited high oral absorbability and were rapidly converted to the active compound in the body.
  • Test example 2
  • Anticoagulant activity was determined using a prothrombin time (PT) assay.
  • PT measurement was performed as shown below. That is, a test tube containing the plasma 5 obtained in Test Example 1 was set on a Sysmex CA-3000 fully automatic blood coagulation analyzer (Toa Medical Electronics Co., Ltd.), and incubated at 37 ° C for 3 minutes. Medical Electronics Co., Ltd., and 100 ⁇ l of ⁇ Egret brain tissue and thromboplastin, 13.2 mM calcium chloride) were added. PT was measured automatically by the same device. The PT time of plasma obtained by blood collection before administration of the evaluation compound was used as a control, and the PT elongation rate with respect to the control was determined, and used as an index of anticoagulant activity.
  • PT prothrombin time
  • the compound of Reference Example 1 increased the prothrombin time by 112% compared to the control at the maximum plasma concentration, whereas the compounds of Examples 1 and 2 increased the prothrombin time by 129% and 123% of the control, respectively.
  • prothrombin time is correlated with anticoagulant, antithrombotic, and antiembolic effects, according to Hara et al., Thrombosis and Haemostasis, (Germany) ), 1995, Vol. 74, No. 2, p. 635-639 (see Non-Patent Document 4).
  • the prothrombin time of the compound described in the document was 18.6 seconds, and the prothrombin time of the vehicle was 17.8 seconds. Shows that prothrombin time is extended by 110%.
  • this compound significantly reduced the thrombus weight after oral administration of 7.8 mg to rats.
  • Example 1 and Example 2 significantly prolonged prothrombin time, which is an indicator of anticoagulant activity, and exhibited high anticoagulant activity. It can exert thrombotic and anti-embolic effects sufficiently.
  • N-benzoyl-L-iso-mouth isyl-L-glucamyl-glycyl-L-arginyl-P-nitroanilide hydrochloride (manufactured by Peptide Research Laboratories, Inc.) was added to a buffer solution of pH 8.4 with Tris-HCl buffer. Solution 5 adjusted to 8 mM was added, the absorbance was measured, and the initial reaction rate was determined. A control obtained by adding 10/1 of Tris-monohydrochloride buffer prepared at pH 8.4 instead of the solution of the evaluation mixture was used as a control.
  • the absorbance was measured using a MICROPLATE READER Model 3550-UV (BIO RAD) at a wavelength of 405 nm at intervals of 15 seconds for 16 minutes. Calculate the negative logarithmic value of the concentration of the test compound when inhibiting the activity (initial rate) of activated blood coagulation factor X without addition of the test compound by 50% (abbreviated as p IC 50). It was used as an index of factor X inhibitory activity.
  • Reference Example 1 The pIC50 value of the compound of Reference Example 1, which is the active form of the prodrug of the present invention, was 7.7, indicating a very high activated blood coagulation factor X inhibitory activity. Therefore, Reference Example 1 is useful as an active substance.
  • the negative logarithmic value of the concentration of the test compound when inhibiting the thrombin activity (initial velocity) by 50% when no test compound was added (abbreviated as PIC50) was used as an index of the thrombin inhibitory activity.
  • the pIC50 value of the compound of Reference Example 1, which is the active substance for the prodrug of the present invention, was 4.6, and it was confirmed that the compound exhibited almost no thrombin inhibitory activity. Therefore, the compound of Reference Example 1 is useful as an active substance of a compound having a low risk of bleeding.
  • Plasma Blood was collected from healthy individuals, and 1/10 volume of a 3.8% aqueous solution of trisodium citrate was added, and plasma was separated by centrifugation. DMS0 solution 5 ⁇ 1 containing the test compound was added to plasma 451, 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 Co., Ltd.), incubate at 37 ° C for 3 minutes, and transfer 100-1 thromboplastin C plus (Dade Behring). In addition, prothrombin time (PT) was measured by the same instrument.
  • PT prothrombin time
  • Table 2-1, Table 2-2 and Table 2-3 show the activated blood coagulation factor X inhibitory activity and the anticoagulant activity of the compounds of Examples 11 to 31 (the structure in the table is trifluoroacetic acid). Salt was omitted).
  • the benzodiazepine derivative of the present invention exhibits high permeability, is rapidly converted in the body, and has a specific high inhibitory activity on activated blood coagulation factor X. And high anticoagulant activity based on this was confirmed. Therefore, it is clear that the benzodiazepine derivative of the present invention is useful as a therapeutic agent for blood coagulation, thrombus, and embolism-related diseases associated with activated blood coagulation factor X.

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Abstract

L'invention concerne un dérivé de benzodiazépine, son analogue et des sels pharmaceutiquement acceptables de celui-ci, ainsi que des compositions médicinales contenant ces composés. Etant donné qu'il peut être administré oralement et qu'il inhibe bien et de façon sélective le facteur X de coagulation du sang activé, ce dérivé de benzodiazépine est utile dans le traitement de maladies causées par la coagulation du sang, thrombus et embole avec peu de risque d'hémorragie.
PCT/JP2003/016403 2002-12-19 2003-12-19 Derive de benzodiazepine Ceased WO2004056813A1 (fr)

Priority Applications (1)

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AU2003292595A AU2003292595A1 (en) 2002-12-19 2003-12-19 Benzodiazepine derivative

Applications Claiming Priority (2)

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JP2002367877A JP2006151807A (ja) 2002-12-19 2002-12-19 ベンゾジアゼピン誘導体
JP2002-367877 2002-12-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8227506B2 (en) 2005-02-02 2012-07-24 Ajinomoto., Inc. Benzamidine compound

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026732A1 (fr) * 2000-09-27 2002-04-04 Ajinomoto Co.,Inc. Derive de benzodiazepine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026732A1 (fr) * 2000-09-27 2002-04-04 Ajinomoto Co.,Inc. Derive de benzodiazepine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8227506B2 (en) 2005-02-02 2012-07-24 Ajinomoto., Inc. Benzamidine compound

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