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WO2013031930A1 - Dérivé d'imine - Google Patents

Dérivé d'imine Download PDF

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Publication number
WO2013031930A1
WO2013031930A1 PCT/JP2012/072103 JP2012072103W WO2013031930A1 WO 2013031930 A1 WO2013031930 A1 WO 2013031930A1 JP 2012072103 W JP2012072103 W JP 2012072103W WO 2013031930 A1 WO2013031930 A1 WO 2013031930A1
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group
carbon atoms
mmol
compound
added
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English (en)
Japanese (ja)
Inventor
佳代 松本
忠清 中川
渉 宮永
真 室野井
正之 杉木
竜大 山田
美里 野口
洋一郎 島
谷口　真也
篤史 ▲高▼田
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to a novel imine derivative having activated blood coagulation factor X (hereinafter sometimes abbreviated as FXa) inhibitory activity, and an anti-blood for blood extracorporeal circuit such as hemodialysis, which contains the imine derivative.
  • FXa activated blood coagulation factor X
  • the present invention relates to a pharmaceutical composition that can be used as a coagulant.
  • Blood extracorporeal circulation is a circulation circuit that retransmits blood into a living body through a device (for example, an artificial cardiopulmonary device, a blood purification device, etc.) that performs a certain treatment using an artificial blood flow path from the inside of the living body to the outside of the body. Is done by. Extracorporeal blood treatment may be required during blood purification therapy such as hemodialysis, hemofiltration, hemodiafiltration, and plasma exchange, and during cardiopulmonary bypass during open heart surgery.
  • a typical example of the blood purification apparatus is a dialyzer.
  • Blood extracorporeal circuit consisting of artificial blood flow path and various devices during extracorporeal blood circulation is a foreign substance, and blood coagulates when it comes in contact with it, so it is necessary to take measures to prevent blood coagulation in extracorporeal blood circulation circuit by some method is there.
  • anti-blood coagulants such as unfractionated heparin and low molecular weight heparin have been used for the purpose of preventing blood coagulation in this extracorporeal circuit.
  • heparin since unfractionated heparin has thrombin inhibitory activity in addition to FXa inhibitory activity, there is a known risk of bleeding tendency and it cannot be used for patients with a high bleeding risk.
  • low molecular weight heparin is a drug that chemically treats heparin to more selectively inhibit FXa against thrombin and has no thrombin inhibitory activity, thus reducing the risk of bleeding tendency, Used for patients with a tendency.
  • low molecular weight heparin since low molecular weight heparin has a long elimination half-life, it is difficult to stop bleeding when bleeding symptoms are observed.
  • nafamostat mesylate is used during some extracorporeal circulation such as hemodialysis. Nafamostat mesylate is also used for patients who already have bleeding lesions because of its short elimination half-life in vivo. However, nafamostat mesylate does not have strong inhibitory activity against FXa or thrombin and has a weak anticoagulant effect.
  • a patient having an extracorporeal circuit has a blood coagulation problem only when the circuit is used, and is often different from a patient who must always prevent blood coagulation.
  • a selective small molecule FXa inhibitor with a short blood half-life can be safely and conveniently used as an anti- (blood) coagulation agent (agent) for preventing blood coagulation for the extracorporeal circuit, and hemostasis after the end of the extracorporeal circulation It is thought that there is clearly less treatment and attention.
  • An object of the present invention is to provide a novel compound having anticoagulant activity based on selective FXa inhibitory action.
  • the present invention is also aimed at providing a selective FXa inhibitor.
  • the present invention also aims to provide an anti- (blood) coagulant (agent) (especially for an extracorporeal circuit such as hemodialysis).
  • the present invention also aims to provide a pharmaceutical composition containing the novel compound.
  • A′-LB ′ (wherein one of A ′ and B ′, has an ester bond in the molecule. Is an organic group having an imino group structure, the other is isoquinoline having an amino group, or thiophene, and L is a linker having an ester bond], and has a superior selective FXa inhibitory activity, and blood
  • A′-LB ′ an organic group having an imino group structure
  • the other is isoquinoline having an amino group, or thiophene
  • L is a linker having an ester bond
  • Ar 1 represents an aromatic hydrocarbon ring or an aromatic heterocyclic ring
  • Ar 2 is
  • V is an alkyl group having 1 to 10 carbon atoms which may have a substituent, an amino group which may be mono- or disubstituted with an alkyl group having 1 to 10 carbon atoms which may have a substituent, Or a 3- to 10-membered cyclic amino group which may have a substituent;
  • 1 X is the same or different and each has a halogen atom, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, an optionally substituted alkyl group having 1 to 10 carbon atoms, or a substituent.
  • An optionally substituted alkoxy group having 1 to 10 carbon atoms, an optionally substituted alkylthio group having 1 to 10 carbon atoms, an optionally substituted amino group, or a substituent Represents an optionally substituted carbamoyl group; m Zs are the same or different and each have a halogen atom, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, an optionally substituted alkyl group having 1 to 10 carbon atoms, or a substituent.
  • An optionally substituted alkoxy group having 1 to 10 carbon atoms, an optionally substituted alkylthio group having 1 to 10 carbon atoms, an optionally substituted amino group, or a substituent An optionally substituted alkoxy group having 1 to 10 carbon atoms, an optionally substituted alkylthio group having 1 to 10 carbon atoms, an optionally substituted amino group, or a substituent.
  • Y 2 represents —O—, —S—, —NHC ( ⁇ O) — or —C ( ⁇ O) NH—;
  • l represents an integer of 0 to 2;
  • m represents an integer of 0 to 2;
  • n represents an integer of 1 to 3.
  • a pharmaceutically acceptable salt thereof hereinafter abbreviated as compound (I)).
  • Y 2 is —NHC ( ⁇ O) — or —C ( ⁇ O) NH—, or a salt thereof.
  • Ar 1 is benzene or a 5- or 6-membered aromatic heterocyclic ring.
  • n is 1.
  • V is a 5- or 6-membered cyclic amino group which may have a substituent.
  • Y 2 is —NHC ( ⁇ O) —; V is a 5-membered cyclic amino group; X is an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms; Z is a halogen atom; Y 1 is —C ( ⁇ O) O—; l is 0 or 1; m is 0 or 1; and n is 1.
  • An activated blood coagulation factor X inhibitor comprising the compound according to any one of [1] to [12] above or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of [1] to [12] above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition according to the above [15] which is an anticoagulant for hemodialysis.
  • aryl group refers to a monocyclic to tricyclic aromatic hydrocarbon ring group which may have a substituent.
  • Specific examples include a phenyl group, a naphthyl group, an acenaphthylenyl group, an anthryl group, a phenanthryl group, and the like, preferably those having 6 to 14 carbon atoms, more preferably those having 6 to 10 carbon atoms, Preferred are a phenyl group and a naphthyl group, and particularly preferred is a phenyl group.
  • the “aryl group” may be a phenyl group in which a 5- to 8-membered cycloalkane or cycloalkene (the cycloalkane or cycloalkene may be further condensed with a benzene ring) is condensed. .
  • Examples of the “5- to 8-membered cycloalkane or cycloalkene” fused with the phenyl group include cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene And cyclooctadiene.
  • Examples of such a condensed ring include an indanyl group, an indenyl group, a dihydronaphthyl group, a tetrahydronaphthyl group, and a fluorenyl group.
  • the “aryl group having 6 to 14 carbon atoms” refers to the above aryl group having 6 to 14 carbon atoms
  • the “aryl group having 6 to 10 carbon atoms” refers to the aryl group described above. Among groups, those having 6 to 10 carbon atoms.
  • aromatic hydrocarbon ring means a monocyclic to tricyclic aromatic hydrocarbon ring.
  • aromatic hydrocarbon ring examples include benzene, naphthalene, acenaphthylene, anthracene, phenanthrene and the like, preferably those having 6 to 14 carbon atoms, more preferably those having 6 to 10 carbon atoms, and further preferably benzene and naphthalene. Particularly preferred is benzene.
  • the “aromatic hydrocarbon ring” is a benzene ring condensed with a 5- to 8-membered cycloalkane or cycloalkene (the cycloalkane or cycloalkene may be further condensed with a benzene ring). May be.
  • Examples of the “5- to 8-membered cycloalkane or cycloalkene” fused with the benzene ring include cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene And cyclooctadiene.
  • Examples of such a condensed ring include indane, indene, dihydronaphthalene, tetrahydronaphthalene, fluorene and the like.
  • heteroaryl group means a 5- to 10-membered monocyclic to bicyclic ring containing 1 to 6 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring atoms.
  • An aromatic heterocyclic group is an aromatic heterocyclic group.
  • pyridyl group pyridazinyl group, pyrimidinyl group, pyrazinyl group, furyl group, thiophenyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl Group, oxadiazolyl group, thiadiazolyl group, benzofuryl group, benzothiophenyl group, indolyl group, isoindolyl group, benzoxazolyl group, benzothiazolyl group, benzimidazolyl group, indazolyl group, etc.
  • 5- or 6-membered monocyclic heteroaryl Group benzisoxazolyl group, benzisothiazolyl group, benzofurazanyl group, benzothiadiazolyl group, purinyl group, quinolinyl group, isoquinolinyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quino Sariniru group, pteridinyl group, imidazo benzoxazolyl group, imidazothiazolyl group, and bicyclic heteroaryl groups such as imidazoimidazolyl group.
  • the “heteroaryl group having 1 to 10 carbon atoms” refers to the above-mentioned “heteroaryl group” having 1 to 10 carbon atoms
  • the “heteroaryl group having 1 to 9 carbon atoms” refers to the above Among teloaryl groups, those having 1 to 9 carbon atoms.
  • the “aromatic heterocycle” means a 5- to 10-membered monocyclic to bicyclic ring containing 1 to 6 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring atoms.
  • An aromatic heterocycle Specifically, for example, 5 or 6 members such as pyridine, pyridazine, pyrimidine, pyrazine, furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, etc.
  • a “nitrogen-containing aliphatic heterocyclic group” (that is, a nitrogen-containing non-aromatic heterocyclic group) has at least one nitrogen atom as a ring atom, and one oxygen atom or sulfur atom.
  • the term refers to a 4- to 10-membered monocyclic to bicyclic saturated or partially unsaturated aliphatic heterocyclic group which may have the above.
  • Examples include thiomorpholinyl group, homopiperidyl group, homopiperazinyl group, indolinyl group, isoindolinyl group, tetrahydroquinolinyl group, tetrahydroisoquinolinyl group, and the like, preferably pyrrolidinyl group, piperidyl group, piperazinyl group, tetrahydroquinolinyl group , A tetrahydroisoquinolinyl group.
  • the “nitrogen-containing aliphatic heterocyclic group having 1 to 9 carbon atoms” refers to those having 1 to 9 carbon atoms among the above-mentioned “nitrogen-containing aliphatic heterocyclic groups”.
  • the “nitrogen-containing aliphatic heterocyclic group having 2 to 8 carbon atoms” refers to those having 2 to 8 carbon atoms among the above “nitrogen-containing aliphatic heterocyclic groups”.
  • the “3- to 10-membered cyclic amino group” has at least one nitrogen atom as a ring atom, and may further have one or more oxygen atoms or sulfur atoms.
  • pyrrolidinyl group pyrazolidinyl group, imidazolidinyl group, pyrrolinyl group, pyrazolinyl group, imidazolyl group, thiazolidinyl group, piperidyl group, piperidino group, piperazinyl group, quinuclidinyl group, morpholino group, morpholinyl group, thiomorpholino group, A thiomorpholinyl group, a homopiperidyl group, a homopiperazinyl group, an indolinyl group, an isoindolinyl group, a tetrahydroquinolinyl group, a tetrahydroisoquinolinyl group, etc.
  • a 5- or 6-membered cyclic amino group preferably a 5- or 6-membered cyclic amino group, more preferably A pyrrolinyl group, a pyrrolidinyl group, a piperidyl group, and a piperazinyl group are preferable, and a pyrrolinyl group and a pyrrolidinyl group are particularly preferable.
  • cycloalkyl group refers to an aliphatic hydrocarbon ring group, which may contain a double bond in the ring.
  • the “cycloalkyl group” preferably has 3 to 10 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclohexenyl group, a cyclopentenyl group, and the like. Particularly preferred is a cyclohexyl group.
  • cycloalkyl group having 3 to 10 carbon atoms refers to the above “cycloalkyl group” having 3 to 10 carbon atoms.
  • cycloalkyl group having 3 to 8 carbon atoms refers to the above “cycloalkyl group” having 3 to 8 carbon atoms.
  • alkyl group or “alkyl group moiety” in “alkylthio group”, “alkylamino group”, “alkoxy group”, “alkoxycarbonyl group” and the like is linear, branched, cyclic Or a partially cyclic aliphatic hydrocarbon group.
  • One having 1 to 10 carbon atoms is preferable, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 3 carbon atoms.
  • Particularly preferred are methyl group, ethyl group, isopropyl group, isobutyl group and cyclopropyl group, and more preferred are methyl group, ethyl group, isopropyl group and cyclopropyl group.
  • alkyl group having 1 to 10 carbon atoms means that having 1 to 10 carbon atoms among the above “alkyl groups”, and the “alkyl group having 1 to 6 carbon atoms” Among the above “alkyl groups”, those having 1 to 6 carbon atoms are meant.
  • alkylthio group having 1 to 10 carbon atoms means that the alkyl group portion has 1 to 10 carbon atoms in the above “alkyl group portion”.
  • an alkylamino group having 1 to 10 carbon atoms refers to an amino group that is mono- or di-substituted with the above-mentioned “alkyl group moiety” having 1 to 10 carbon atoms.
  • Is for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, cyclopropylmethylamino group, pentylamino group, Isopentylamino group, neopentylamino group, hexylamino group, heptylamino group, octylamino group, nonylamino group, decylamino group, (1,1-dimethyl-propyl) amino group, cyclopropylamino group, cyclobutylamino group, Cyclopentylamino group, cyclohexylamino group, cycloheptylamino group, cyclooctylamino Mono (alkyl) amino groups such as dimethylamino group, diethy
  • alkoxy group having 1 to 10 carbon atoms means that the alkyl group portion has 1 to 10 carbon atoms in the above “alkyl group portion”.
  • Alkoxy group having 1 to 6 carbon atoms refers to an “alkoxy
  • alkoxycarbonyl group having 2 to 10 carbon atoms refers to an alkyl group portion having 1 to 9 carbon atoms in the above “alkyl group portion”.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a fluorine atom and a chlorine atom are preferable.
  • alkylamino group or “amino group substituted with an alkyl group” (when the substituent in the “amino group optionally having substituents” is an alkyl group), “alkyl”
  • alkylamino moiety as a component such as “carbamoyl group substituted with a group” (when the substituent is an alkyl group in “optionally substituted carbamoyl group”) includes a monoalkylamino group A dialkylamino group is also included.
  • the two alkyl groups may be the same as or different from each other, and are bonded to each other to form a ring (for example, a nitrogen-containing heterocyclic ring corresponding to the above “nitrogen-containing heterocyclic group”, etc. (eg, pyrrolidine ring, pyrroline ring). )) May be formed.
  • a nitrogen-containing heterocyclic ring corresponding to the above “nitrogen-containing heterocyclic group”, etc. (eg, pyrrolidine ring, pyrroline ring). )
  • acyl group moiety as a component such as “acyloxy group” and “acylamino group” includes formyl group, alkylcarbonyl group having 2 to 10 carbon atoms (for example, acetyl group, ethylcarbonyl group, propyl group) Carbonyl group, isopropylcarbonyl group, butylcarbonyl group, isobutylcarbonyl group, sec-butylcarbonyl group, tert-butylcarbonyl group, cyclopropylmethylcarbonyl group, pentylcarbonyl group, isopentylcarbonyl group, neopentylcarbonyl group, hexylcarbonyl group , Heptylcarbonyl group, octylcarbonyl group, nonylcarbonyl group, (1,1-dimethyl-propyl) carbonyl group, cyclopropylcarbonyl group, cyclobutylcarbonyl group,
  • a substituent preferably (1) a halogen atom, (2) hydroxyl group, (3) an amino group, (4) an alkyl group having 1 to 6 carbon atoms, (5) an alkenyl group having 2 to 6 carbon atoms, (6) an alkynyl group having 2 to 6 carbon atoms, (7) an alkoxy group having 1 to 6 carbon atoms which may be substituted with phenyl, (8) an alkylamino group having 1 to 6 carbon atoms, (9) a cyano group, (10) a guanidino group, (11) a carboxyl group, (12) a carbamoyl group, (13) an acyloxy group having 1 to 6 carbon atoms, (14) an acylamino group having 1 to 6 carbon atoms, (15) a cycloalkyl group having 3 to 8 carbon atoms, (16) an alkylthio group having 1 to 6 carbon atoms, (17) an alkylsulfonamido group having 1 to 6 carbon carbon
  • compound (I) includes a mixture of various stereoisomers such as geometric isomers, tautomers, optical isomers, isolated isomers, stable isotopes, and radioisotopes.
  • Ar 1 represents an aromatic hydrocarbon ring or an aromatic heterocyclic ring.
  • Ar 1 is preferably an aromatic hydrocarbon ring having 6 to 10 carbon atoms or a 5- or 6-membered monocyclic aromatic heterocycle, more preferably benzene or a 5- or 6-membered monocyclic aromatic ring. It is a heterocyclic ring, more preferably benzene, pyridine or thiophene, and particularly preferably benzene.
  • V is mono- or di-substituted by an optionally substituted alkyl group having 1 to 10 carbon atoms and an optionally substituted alkyl group having 1 to 10 carbon atoms.
  • V is preferably a 3- to 10-membered cyclic amino group which may have a substituent, more preferably a 5- or 6-membered cyclic amino group which may have a substituent, and more preferably Is an optionally substituted 5-membered cyclic amino group, still more preferably a 5-membered cyclic amino group, and particularly preferably pyrrolinyl or pyrrolidinyl.
  • one X is the same or different and each is a halogen atom, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, or an alkyl group having 1 to 10 carbon atoms which may have a substituent.
  • 1 X is preferably the same or different and each is a halogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, or an optionally substituted carbon group having 1 to 10 carbon atoms.
  • m Zs are the same or different and each is a halogen atom, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, or an alkyl group having 1 to 10 carbon atoms which may have a substituent.
  • An alkoxy group having 1 to 10 carbon atoms which may have a substituent, an alkylthio group having 1 to 10 carbon atoms which may have a substituent, an amino group which may have a substituent, or The carbamoyl group which may have a substituent is shown.
  • the m Zs are preferably the same or different and each is a halogen atom, and more preferably the same or different and each is a chlorine atom.
  • the bonding position of Z may be a benzene ring or a pyridine ring.
  • Y 1 is preferably —C ( ⁇ O) O—, —OC ( ⁇ O) — or —C ( ⁇ O) S—, more preferably —C ( ⁇ O) O— or —C ( ⁇ O) S—, particularly preferably —C ( ⁇ O) O—.
  • Y 2 represents —O—, —S—, —NHC ( ⁇ O) — or —C ( ⁇ O) NH—.
  • Y 2 is preferably Ar 2
  • Y 2 is —O— or —S—, and Ar 2 is
  • Y 2 is —NHC ( ⁇ O) — or —C ( ⁇ O) NH—, and more preferably Ar 2 is
  • Y 2 is —NHC ( ⁇ O) —.
  • l represents an integer of 0-2.
  • l is preferably 0 or 1.
  • m represents an integer of 0-2.
  • m is preferably 0 or 1.
  • n represents an integer of 1 to 3. n is preferably 1.
  • Ar 1 is benzene or a 5- or 6-membered monocyclic aromatic heterocycle; Ar 2 is
  • Y 2 is —O— or —S—, or Ar 2 is
  • Y 2 is —NHC ( ⁇ O) — or —C ( ⁇ O) NH—;
  • V is an optionally substituted 5- or 6-membered cyclic amino group (preferably a 5- or 6-membered cyclic amino group);
  • X is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms;
  • Z is a halogen atom (preferably a chlorine atom);
  • Y 1 is —C ( ⁇ O) O—, —OC ( ⁇ O) — or —C ( ⁇ O) S—;
  • l is 0 or 1;
  • m is 0 or 1; and
  • n is 1.
  • Ar 1 is benzene, pyridine or thiophene; Ar 2 is
  • Y 2 is —NHC ( ⁇ O) —;
  • V is a 5-membered cyclic amino group (preferably pyrrolinyl or pyrrolidinyl);
  • X is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms;
  • Z is a halogen atom (preferably a chlorine atom);
  • Y 1 is —C ( ⁇ O) O—, —OC ( ⁇ O) — or —C ( ⁇ O) S—;
  • l is 0 or 1;
  • m is 0 or 1; and
  • n is 1.
  • Y 2 is —NHC ( ⁇ O) —;
  • V is a 5-membered cyclic amino group (preferably pyrrolinyl or pyrrolidinyl);
  • X is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms;
  • Z is a halogen atom (preferably a chlorine atom);
  • Y 1 is —C ( ⁇ O) O— or —C ( ⁇ O) S—;
  • l is 0 or 1;
  • m is 0 or 1; and
  • n is 1.
  • Y 2 is —NHC ( ⁇ O) —;
  • V is a 5-membered cyclic amino group (preferably pyrrolinyl or pyrrolidinyl);
  • X is an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms;
  • Z is a halogen atom (preferably a chlorine atom);
  • Y 1 is —C ( ⁇ O) O—; l is 0 or 1; m is 0 or 1; and n is 1.
  • the anti- (blood) coagulant (agent) for an extracorporeal blood circuit containing an FXa inhibitor as an active ingredient according to the present invention is preferably one that disappears rapidly from the blood.
  • “the disappearance from the blood is rapid” means that the half-life in the stability test in whole blood shown in Test Example 4 described later is 10 minutes or less, preferably 5 minutes or less. More preferably, in the stability test (test example 5) in the liver S9 fraction showing disappearance in the body (liver), the residual rate after 30 minutes of the FXa inhibitor is preferably 80% or less.
  • the FXa inhibitor is preferably FXa selective, and more specifically, the difference between pIC 50 (FXa) and pIC 50 (FIIa) in the inhibitory activity evaluation system shown in Test Examples 1 and 2 described later. A large is preferable.
  • Blood extracorporeal circulation is an artificial blood circulation that passes through a blood circuit constructed outside the living body.
  • the “blood extracorporeal circuit” is a blood circuit in extracorporeal blood circulation, for example, a blood circuit formed by connecting a living body and an artificial organ when using the artificial organ. More specifically, for example, those used at the time of cardiopulmonary bypass and hemodialysis are mentioned, and in the present invention, a blood extracorporeal circuit is particularly preferred at the time of hemodialysis.
  • an alcohol derivative (1) as an intermediate is obtained by the method shown below. be able to. That is, by reacting 7-hydroxyisoquinoline with ethylene carbonate in a solvent such as N, N-dimethylformamide (hereinafter DMF) in the presence of a base such as potassium carbonate, the alcohol derivative (2) can be obtained. .
  • DMF N, N-dimethylformamide
  • a hydroxyl protecting group is introduced into this by using, for example, benzyl bromide or tert-butyldimethylchlorosilane in the presence of a suitable solvent and a base, and then, for example, oxidation of m-chloroperbenzoic acid or the like in a solvent such as dichloromethane.
  • An oxidant (3) can be obtained using an agent.
  • An aminoisoquinoline derivative (4) can be obtained by forming a leaving group using paratoluenesulfonyl chloride or the like in a pyridine solvent and treating with aminoethanol.
  • Y 1 is —C ( ⁇ O) O—
  • Y 2 is —O—
  • n is 1, an alcohol derivative (1) which is an intermediate can be obtained.
  • Y 1 is —C ( ⁇ O) O— or —C ( ⁇ O) S—
  • Y 2 is —NHC ( ⁇ O) —
  • n is 1,
  • the thiophene derivative (5) as an intermediate can be obtained by the method. That is, a thiophenecarboxylic acid derivative is formed in an acid chloride using a solvent such as dichloromethane, for example, oxalyl chloride or thionyl chloride, and treated with an amino alcohol or aminothiol in the general formula (I).
  • Ar 2 is
  • Y 3 represents an oxygen atom or a sulfur atom, and other symbols are as defined above.
  • V is an amino group which may be mono- or di-substituted with an alkyl group having 1 to 10 carbon atoms which may have a substituent, or 3 to 3 which may have a substituent.
  • Y 1 is —C ( ⁇ O) O— or —C ( ⁇ O) S—
  • the carboxylic acid derivative (6) as an intermediate is obtained by the following method. Obtainable.
  • a cyanoarylcarboxylic acid or cyanoheteroarylcarboxylic acid such as 4-cyanobenzoic acid in an alcohol such as methanol or ethanol: R 1 OH as a solvent and blowing hydrogen chloride gas as an acid, for example.
  • the imidate derivative (7) can be obtained.
  • a primary or secondary amine R 2 R 3 NH in a solvent such as an alcohol such as methanol or ethanol, in the general formula (I)
  • V may have a substituent.
  • An amino group which may be mono- or di-substituted by a good alkyl group having 1 to 10 carbon atoms, or a 3- to 10-membered cyclic amino group which may have a substituent, and Y 1 is —C ( The intermediate carboxylic acid derivative (6) in the case of O) O— or —C ( ⁇ O) S— can be obtained.
  • a cyanoaryl ester or cyanoheteroaryl ester such as ethyl 4-cyanobenzoate
  • the ester bond is hydrolyzed under acidic conditions after imidate formation and alkylamidation in the same manner.
  • V may have an amino group which may be mono- or di-substituted by an alkyl group having 1 to 10 carbon atoms which may have a substituent, or a substituent. It is possible to obtain a carboxylic acid derivative (6) which is an intermediate when it is a 3- to 10-membered cyclic amino group and Y 1 is —C ( ⁇ O) O— or —C ( ⁇ O) S—. it can.
  • R 1 represents an alkyl group having 1 to 6 carbon atoms
  • R 2 and R 3 are the same or different and each represents a hydrogen atom or an optionally substituted alkyl having 1 to 10 carbon atoms.
  • R 2 and R 3 together with the nitrogen atom to which they are attached may form a cyclic amino group having 3 to 10 carbon atoms which may have a substituent.
  • R 4 represents an alkyl group having 1 to 6 carbon atoms, and other symbols are as defined above.
  • V is an amino group which may be mono- or di-substituted by an alkyl group having 1 to 10 carbon atoms which may have a substituent, or 3 to 3 which may have a substituent.
  • alkyl group having 1 to 10 carbon atoms which may have a substituent or 3 to 3 which may have a substituent.
  • Y 1 is —C ( ⁇ O) O— or —C ( ⁇ O) S—
  • compound (Ia) can be obtained by the following method.
  • V has a substituent by allowing a condensing agent such as DCC (hereinafter DCC) or a catalytic amount of 4-dimethylaminopyridine (hereinafter DMAP) to act as necessary.
  • DCC condensing agent
  • DMAP catalytic amount of 4-dimethylaminopyridine
  • the salt may be pharmaceutically acceptable, for example, an acidic group in the case where an acidic group such as a carboxyl group is present in the formula
  • ammonium salts salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; aluminum salts; zinc salts; triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine
  • salts with organic amines such as arginine and salts with basic amino acids such as lysine.
  • a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid; acetic acid, trifluoroacetic acid, citric acid, benzoic acid
  • Organic carboxylic acids such as acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hybenzic acid, pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, malic acid
  • organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • compound (I) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is carried out from other salt forms. It can also be obtained by doing.
  • the compound of the present invention also includes solvates of compound (I), such as hydrates and alcohol adducts.
  • the compound of the present invention can be converted into a prodrug.
  • the prodrug in the present invention refers to a compound that is converted in the body to produce the compound of the present invention.
  • the active main body contains a carboxyl group or a phosphate group
  • their esters and amides can be mentioned.
  • the active main body contains an amino group, its amide, carbamate and the like can be mentioned.
  • the active main body contains a hydroxyl group, its ester, carbonate, carbamate and the like can be mentioned.
  • the compound of the present invention is converted into a prodrug, it may be bound to an amino acid or a saccharide.
  • the compound (I) which is the compound of the present invention or a pharmaceutically acceptable salt thereof can be produced and administered as it is, or as a pharmaceutical composition according to a conventional method using an ordinary formulation aid.
  • a pharmaceutical composition examples include tablets, powders, injections, lyophilized injections, or pills, granules, capsules, suppositories, solutions, dragees, devoted drugs, syrups, Suspensions, emulsions, lozenges, sublinguals, patches, buccal disintegrants (tablets), inhalants, enemas, ointments, patches, tapes, eye drops and the like.
  • the compound or pharmaceutical composition of the present invention is administered into a blood extracorporeal circuit or to a patient.
  • Preferred administration methods include direct administration into the blood extracorporeal circuit, intravenous administration, intramuscular administration, subcutaneous administration, and in some cases oral administration, rectal administration, intranasal administration, sublingual administration Is also possible.
  • direct administration into the blood extracorporeal circuit it is preferable to administer the blood at a site as close to the body as possible of the circuit for circulating blood outside the body. Is available.
  • the administration target is not particularly limited, and examples thereof include mammals (eg, mouse, rat, hamster, rabbit, cat, dog, pig, cow, sheep, horse, monkey, human, etc.).
  • mammals eg, mouse, rat, hamster, rabbit, cat, dog, pig, cow, sheep, horse, monkey, human, etc.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing them is provided as an anti- (blood) coagulant (agent) for hemodialysis, and dissolved or dispersed in a dialysate at the time of use.
  • the FXa inhibitor composition used in the dialyzer can be provided not only as it is, but also in the form of a dialysate or dialysate concentrate containing the FXa inhibitor.
  • the dialysate concentrate include a powder formulation for an artificial kidney, and can be prepared, for example, by concentrating a dialysate containing an FXa inhibitor by lyophilization or the like.
  • the dialysate concentrate can be diluted with an appropriate method before use, for example, with purified water to obtain a dialysate.
  • the compound of the present invention or the pharmaceutical composition is administered once or continuously in one blood extracorporeal circulation once, or divided into several times as necessary.
  • the dose of the compound of the present invention or the pharmaceutical composition is 0.01 mg to 10 g, preferably 1 mg to 1,000 mg as the amount of the compound that is an active ingredient per blood circulation or active ingredient per day.
  • the dose can be increased or decreased as appropriate according to the age, weight, symptoms, etc. of the patient / subject.
  • the appropriate concentration of the active ingredient compound in the dialysate depends on the compound used, the severity of the disease being treated and the characteristics of the patient being treated, but usually at the appropriate equilibrium of the compounds that can be used.
  • the average plasma concentration is in the range of 0.0001 to 1000 ⁇ mol / L, preferably 0.005 to 20 ⁇ mol / L.
  • TFA trifluoroacetic acid
  • Step 3 Synthesis of Intermediate 1 2-[(1-Aminoisoquinolin-7-yl) oxy] ethanol trifluoroacetate (4 g, 12.5 mmol) was dissolved in water (100 mL), and 1N hydrochloric acid (30 mL) was added. The solvent was distilled off under reduced pressure. After performing this operation three times, the title compound was obtained by washing with acetonitrile.
  • Example 1 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid 2-[(1-Aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid Acid (52.9 mg, 0.21 mmol) and intermediate 1 (50.0 mg, 0.21 mmol) were dissolved in pyridine (1.0 mL) at room temperature. N, N′-dicyclohexylcarbodiimide (hereinafter DCC) (51.4 mg, 0.25 mmol) was added to the solution, and the mixture was stirred at 50 ° C. for 1.5 hours.
  • DCC N′-dicyclohexylcarbodiimide
  • Example 2 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] benzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate step 1 4- [2 , 5-Dihydro-1H-pyrrol-1-yl (imino) methyl] benzoic acid hydrochloride Synthesis of 4-cyanobenzoic acid (1.50 g, 10.20 mmol) in ethanol (1.5 mL) with 4N hydrochloric acid / 1 , 4-Dioxane solution (50.0 mL) was added at room temperature and stirred overnight under sealing.
  • Example 2 Compound 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] benzoic acid hydrochloride (52.5 mg, 0.21 mmol) and intermediate 1 (50 mg, 0 .21 mmol) was dissolved in pyridine (1.0 mL) at room temperature. DCC (51.4 mg, 0.25 mmol) was added to the solution and stirred at 50 ° C. for 1.5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
  • Example 3 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2-fluorobenzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate step 1 Synthesis of 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-fluorobenzoic acid hydrochloride Dry ethanol of 2-fluoro-4-cyanobenzoic acid (720 mg, 4.35 mmol) A 4N hydrochloric acid / 1,4-dioxane solution (40 mL) was added to the solution (10 mL), and the mixture was stirred at room temperature for 2 days under sealed conditions.
  • Example 3 Compound 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-fluorobenzoic acid hydrochloride (113 mg, 0.323 mmol), intermediate 1 ( Pyridine (2.0 mL) was added to 66.0 mg, 0.323 mmol) and DCC (133 mg, 0.646 mmol), and the mixture was stirred at 40 ° C. for 1.5 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
  • Example 4 4- [imino (pyrrolidin-1-yl) methyl] -2-methylbenzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate step 1 4-cyano-2-methylbenzoic acid Synthesis of ethyl acid Ethanol (0.870 mL), diisopropylethylamine (1.74 mL, 10.0 mmol) and tetrakis (triphenyl) in a DMF solution (10 mL) of 4-bromo-2-methylbenzonitrile (980 mg, 5.00 mmol) Phosphine) palladium (289 mg, 0.250 mmol) was added, and the mixture was stirred overnight at 70 ° C.
  • 4-bromo-2-methylbenzonitrile 980 mg, 5.00 mmol
  • Phosphine palladium
  • Step 2 Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] -2-methylbenzoic acid hydrochloride 4-ethyl-2-cyano-2-methylbenzoate (1.98 g, 10.5 mmol) in ethanol (8.0 mL) 4N hydrochloric acid / 1,4-dioxane solution (39.0 mL) was added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated, diluted with ethanol (40.0 mL) and concentrated, pyrrolidine (1.7 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 4.5 hr.
  • reaction solution was concentrated, 1N aqueous hydrochloric acid solution (100 mL) was added, and the mixture was stirred at 70 ° C. overnight and concentrated three times.
  • the obtained residue was crystallized from ethanol / ethyl acetate, and the precipitate was collected by filtration and dried in vacuo at 50 ° C. overnight to give the title compound.
  • Example 4 Compound 4- [Imino (pyrrolidin-1-yl) methyl] -2-methylbenzoic acid hydrochloride (28.0 mg, 0.104 mmol), Intermediate 1 (25.0 mg, 0.104 mmol) ) And DCC (22.0 mg, 0.104 mmol) were added with pyridine (3.0 mL), and the mixture was stirred at room temperature for 5 and a half hours. DCC (22.0 mg, 0.104 mmol) and NMP (1.0 mL) were added to the reaction solution, and the mixture was stirred at 30 ° C. overnight. The reaction solution was treated by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
  • Example 5 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate step 1 Synthesis of ethyl 4-cyano-2-hydroxybenzoate 3-hydroxy-4-iodobenzonitrile (21.6 g, 88.1 mmol) was added to DMF (200 mL), ethanol (10.2 mL, 175 mmol), triethylamine (24.6 mL). , 175 mmol) and palladium acetate (catalytic amount) were added, and the mixture was stirred at 70 ° C.
  • Example 5 Compound 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzoic acid hydrochloride (70.0 mg, 0.248 mmol), Intermediate 1 Pyridine (2.0 mL) and NMP (0.5 mL) were added to (60.0 mg, 0.248 mmol) and DCC (51.0 mg, 0.248 mmol), and the mixture was stirred at 30 ° C. for 3.5 hours. DCC (26.0 mg, 0.126 mmol) was added to the reaction solution, and the mixture was stirred at 40 ° C.
  • Example 6 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methylbenzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate step 1 Synthesis of 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methylbenzoic acid hydrochloride 4-cyano-2-methylbenzoate (0.990 g, 5.23 mmol) 4N hydrochloric acid / 1,4-dioxane solution (19.5 mL) was added to an ethanol (4.0 mL) solution, and the mixture was stirred at room temperature to 30 ° C. for 2 days.
  • Example 6 Compound 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methylbenzoic acid hydrochloride (30.1 mg, 0.113 mmol) and intermediate 1 Pyridine (1.0 mL) and NMP (0.5 mL) were added to (27.2 mg, 0.113 mmol) and DCC (23.3 mg, 0.113 mmol), and the mixture was stirred at 30 ° C. for 1.5 hours. DCC (23.3 mg, 0.113 mmol) was added to the reaction mixture, and the mixture was stirred overnight at 30 ° C., and the post-reaction treatment was performed by reversed-phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound. Obtained.
  • Example 7 4- [imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate step 1 4-bromo-2- Synthesis of ethyl (methylthio) benzoate 4-Bromo-2-fluorobenzoic acid (2.50 g, 11.4 mmol) was dissolved in a mixed solvent of dichloromethane / ethanol (43 mL / 2.5 mL) at room temperature.
  • the ester was dissolved in THF (45 mL), sodium thiomethoxide (1.0 g, 14.3 mmol) was added, and the mixture was stirred at 80 ° C. for 20 hr. Ethyl acetate was added to the solution, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the title compound was obtained without purification.
  • Step 2 Synthesis of 4-cyano-2- (methylthio) benzoic acid
  • Ethyl 4-bromo-2- (methylthio) benzoate (2.85 g, 10.4 mmol) was dissolved in DMF (25 mL) and copper cyanide (1 .39 g, 15.5 mmol) was added and the mixture was stirred at 150 ° C. for 15 hours.
  • the solution was cooled to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added and stirred for a while, and the precipitated insoluble material was filtered through celite. The filtrate was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • a cyano compound as a crude product was obtained.
  • the cyano compound was suspended in a mixed solution of THF / methanol (20 mL / 20 mL). 2N aqueous sodium hydroxide solution (25 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours.
  • the solvent was removed under reduced pressure, neutralized with 1N hydrochloric acid, ethyl acetate was added, washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the title compound was obtained without purification by removing the solvent under reduced pressure.
  • Step 3 Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzoic acid 4-Cyano-2- (methylthio) benzoic acid (1.50 g, 7.76 mmol) was added to 4N hydrochloric acid / 1. , 4-Dioxane solution (14 mL) was suspended, dry ethanol (1.4 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the precipitate was filtered using 1,4-dioxane and petroleum ether.
  • Example 8 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate
  • Step 1 Synthesis of 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzoic acid 4-cyano-2- (methylthio) benzoic acid (800 mg, 4.14 mmol) ) was suspended in 4N hydrochloric acid / 1,4-dioxane (14 mL), ethanol (1.4 mL, 25 mmol) was added, and the mixture was stirred at room temperature for 24 hours.
  • Example 8 Compound 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzoic acid (57.7 mg, 0.220 mmol) was treated with NMP (0 5 mL), thionyl chloride (0.0176 mL, 0.242 mmol) was added at 8 ° C., and the mixture was stirred at 8 ° C. for 40 minutes. Thionyl chloride (0.0080 mL, 0.110 mmol) was added and stirred at 8 ° C. for 40 minutes, and then thionyl chloride (0.010 mL, 0.138 mmol) was further added and stirred at 8 ° C. for 1.5 hours.
  • Example 9 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid 2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl trifluoroacetate Intermediate 2 (50 mg, 0.24 mmol) was converted to NMP ( 250 ⁇ L) and pyridine (250 ⁇ L) and cooled at 0 ° C. under argon. 4- [Imino (pyrrolidin-1-yl) methyl] benzoyl chloride (66.1 mg, 0.24 mmol) was added and stirred at 0 ° C. for 2 hours.
  • Example 10 4- [Imino (pyrrolidin-1-yl) methyl] benzenecarbothioic acid S- (2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl) trifluoroacetate salt 5-chlorothiophene-2- Carboxylic acid (3.25 g, 20 mmol) and thionyl chloride (20 mL) were stirred at 65 ° C. and concentrated under reduced pressure. The residue was diluted with dichloromethane, and a solution of 2-aminoethanethiol (40 mmol) in dichloromethane was added dropwise to the two portions and stirred at room temperature.
  • Example 11 4- [Imino (pyrrolidin-1-yl) methyl] phenyl N-[(5-chloro-2-thienyl) carbonyl] - ⁇ -alaninate Trifluoroacetate
  • Step 2 Synthesis of Example 12 Compound 5-Chlorothiophene-2-carboxylic acid (3.25 g, 20 mmol) and thionyl chloride (20 mL) were stirred at 65 ° C. and concentrated under reduced pressure. The residue was diluted with dichloromethane, and a solution of 2-aminoethanol (40 mmol) in dichloromethane was added dropwise to the two portions and stirred at room temperature. The reaction solution was washed with water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example 13 4- [Imino (pyrrolidin-1-yl) methyl] -2-methoxyphenyl N-[(5-chloro-2-thienyl) carbonyl] - ⁇ -alaninate Trifluoroacetate step 1 4- [Imino (pyrrolidine-1 -Yl) methyl] -2-methoxyphenol Synthesis of hydrochloride To a dry ethanol solution (10 mL) of 4-hydroxy-3-methoxybenzonitrile (5.00 g, 33.2 mmol), 4N hydrochloric acid / 1,4-dioxane solution (40 mL) was added, and the mixture was stirred at room temperature for 2 days under sealed conditions.
  • Example 13 Compound 4- [Imino (pyrrolidin-1-yl) methyl] -2-methoxyphenol hydrochloride (95.0 mg, 0.370 mmol) and 3- ⁇ [(5-chloro-2-thienyl) ) Carbonyl] amino ⁇ propionic acid (100.0 mg, 0.428 mmol) was dissolved in pyridine (2.5 mL) at room temperature. DCC (114.6 mg, 0.56 mmol) was added to the solution, and DCC (114.6 mg, 0.56 mmol) was added at 50 ° C. for 2 hours, followed by stirring at room temperature for 15.5 hours.
  • Example 14 [imino (pyrrolidin-1-yl) methyl] nicotinic acid 2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl trifluoroacetate step 1 6- [imino (pyrrolidin-1-yl) Synthesis of methyl] nicotinic acid hydrochloride Methanol (20 mL) was added to 6-cyanonicotinic acid (1.59 g, 10.7 mmol), pyrrolidine (2.74 mL) and L-acetylcysteine (1.78 g) at 62 ° C. Stir for 2 hours.
  • Example 14 Compound 6- [Imino (pyrrolidin-1-yl) methyl] nicotinic acid hydrochloride (108.0 mg, 0.422 mmol) and intermediate 2 (100.0 mg, 0.486 mmol) were converted to pyridine ( 2.5 mL) at room temperature. DCC (152.0 mg, 0.737 mmol) was added to the solution and stirred at 50 ° C. for 36.5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
  • Example 15 4- [imino (pyrrolidin-1-yl) methyl] -2-methylbenzoic acid 2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl trifluoroacetate 4- [imino (pyrrolidin-1- Yl) methyl] -2-methylbenzoic acid hydrochloride (152 mg, 0.564 mmol) and intermediate 2 (100.0 mg, 0.486 mmol) were dissolved in pyridine (2.5 mL) at room temperature. DCC (151.6 mg, 0.735 mmol) was added to the solution and stirred at 50 ° C. for 3.5 hours.
  • Example 16 4- [Imino (pyrrolidin-1-yl) methyl] -2-methoxybenzoic acid 2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl trifluoroacetate step 1 4-cyano-2-methoxy Synthesis of Benzoic Acid Ethyl 4-cyano-2-methoxybenzoate (1.14 g, 5.51 mmol) was dissolved in a mixed solvent of ethanol (8 mL) and tetrahydrofuran (hereinafter THF) (8 mL), and 2N water was added under ice cooling. An aqueous sodium oxide solution (5.5 mL) was added dropwise.
  • THF tetrahydrofuran
  • Step 2 Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] -2-methoxybenzoic acid hydrochloride 4-Cyano-2-methoxybenzoic acid (945 mg, 5.33 mmol) was converted into 4N hydrochloric acid / 1,4-dioxane. It melt
  • Example 16 Compound 4- [Imino (pyrrolidin-1-yl) methyl] -2-methoxybenzoic acid hydrochloride (100.0 mg, 0.351 mmol) and intermediate 2 (72.0 mg, 0.350 mmol) ) was dissolved in pyridine (2.5 mL) at room temperature. DCC (108.3 mg, 0.525 mmol) was added to the solution and added at 50 ° C. for 3.5 hours, followed by addition of DCC (108.3 mg, 0.525 mmol) at 50 ° C. for 5 hours and 12. Stir for 5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
  • DCC 108.3 mg, 0.525 mmol
  • Example 17 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-fluorobenzoic acid 2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl trifluoroacetate intermediate Form 2 (100 mg, 0.49 mmol), 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-fluorobenzoic acid hydrochloride (123 mg, 0.49 mmol), DMC (103 mg , 0.61 mmol) was added dehydrated pyridine (1 mL) and stirred overnight.
  • Example 19 4- [Imino (pyrrolidin-1-yl) methyl] -2-methylbenzenecarbothioic acid S- (2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl) trifluoroacetate salt
  • Example 18 In the same manner as in 2-fluoro-4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride, instead of 4- [imino (pyrrolidin-1-yl) methyl] -2-methylbenzoic acid hydrochloride Performed with salt to give the title compound. Yield: 25 mg (0.045 mmol) Yield: 10% MS (ESI, m / z) 436 [M + H] +
  • Example 20 5- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] thiophene-2-carboxylic acid 2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl trifluoroacetate step 1 Synthesis of 5-[(2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] thiophene-2-carboxylic acid hydrochloride 5-formyl-2-thiophenecarboxylic acid (2.3 g, 16.9 mmol) ) Acetic acid (20 mL), sodium acetate (5.5 g, 67.6 mmol) and hydroxylamine hydrochloride (1.75 g, 25.4 mmol) were added, and the mixture was stirred at 60 ° C.
  • Example 21 5- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] thiophene-2-carbothioic acid S- (2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl) tri Fluoroacetate
  • 5-[(2,5-dihydro-1H-pyrrole-) was used instead of 2-fluoro-4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride.
  • 1-yl (imino) methyl] thiophene-2-carboxylic acid hydrochloride was used to give the title compound. Yield: 37 mg (0.069 mmol) Yield: 15% MS (ESI, m / z) 426 [M + H] +
  • Example 22 5- [Imino (pyrrolidin-1-yl) methyl] thiophene-2-carbothioic acid S- (2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl) trifluoroacetate step 1 5- [ Synthesis of imino (pyrrolidin-1-yl) methyl] thiophene-2-carboxylic acid hydrochloride 5-formyl-2-thiophenecarboxylic acid (2.3 g, 16.9 mmol) in acetic acid (20 mL) was added to sodium acetate (5. 5 g, 67.6 mmol) and hydroxylamine hydrochloride (1.75 g, 25.4 mmol) were added.
  • Step 2 Synthesis of Example 22 Compound 5- [imino (pyrrolidin-1-yl) methyl] thiophene-2-carboxylic acid hydrochloride (65.2 mg, 0.250 mmol) and intermediate 3 (55.4 mg, 0.250 mmol) ), Pyridine (2.0 mL) was added to DCC (51.5 mg, 0.250 mmol), and the mixture was stirred at room temperature for 1.5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
  • Example 23 4- [imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzoic acid 2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl trifluoroacetate 4- [imino (pyrrolidine- 1-yl) methyl] -2- (methylthio) benzoic acid (500 mg, 1.67 mmol) was dissolved in NMP (4.0 mL), and thionyl chloride (0.159 mL, 2.18 mmol) was added at 5 ° C. After stirring at 90 ° C.
  • Example 24 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzoic acid 2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl trifluoroacetate intermediate Form 2 (47 mg, 0.23 mmol), 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzoic acid hydrochloride (65 mg, 0.23 mmol), and DMC ( 42 mg, 0.23 mmol) was added dehydrated pyridine (1 mL), and the mixture was stirred overnight.
  • Example 25 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzenecarbothioic acid S- ⁇ 2-[(5-chloro-thiophen-2-carbonyl) -amino]- Ethyl ⁇ ester trifluoroacetate salt
  • the title compound was obtained in the same manner as the Example 24, using the intermediate 3 instead of the intermediate 2. Yield: 12 mg (0.021 mmol) Yield: 9% MS (ESI, m / z) 450 [M + H] +
  • Example 26 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methylbenzenecarbothioic acid S- (2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl ) Trifluoroacetic acid salt 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methylbenzoic acid hydrochloride (32.4 mg, 0.122 mmol) and intermediate 3 (27. 1 mg, 0.122 mmol) was dissolved in pyridine (1.5 mL) at room temperature. DCC (50.4 mg, 0.244 mmol) was added to the solution and stirred at room temperature for 17 hours.
  • Example 27 4- [Imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzenecarbothioic acid S- (2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl) trifluoroacetate step 1 4- [Imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzoic acid Synthesis of trifluoroacetate 4-Cyano-2- (methylthio) benzoic acid (100 mg, 0.518 mmol) was suspended in a 4N hydrochloric acid / 1,4-dioxane solution (1.5 mL), and dry ethanol (0.15 mL) was added at room temperature.
  • Example 27 Compound 4- [Imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzoic acid trifluoroacetate (67.7 mg, 0.225 mmol) and Intermediate 3 (50.0 mg , 0.225 mmol) was dissolved in pyridine (2.0 mL) at room temperature. DCC (92.3 mg, 0.450 mmol) was added to the solution and stirred at room temperature for 24 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
  • Example 28 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzoic acid 2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ ethyl trifluoroacetic acid Salt
  • 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzoic acid 63.0 mg, 0.240 mmol) was dissolved in NMP (0.5 mL), Thionyl chloride (0.0192 mL, 0.264 mmol) was added at 8 ° C., and the mixture was stirred at 8 ° C. for 40 minutes.
  • Example 29 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzenecarbothioic acid S- (2- ⁇ [(5-chloro-2-thienyl) carbonyl] amino ⁇ Ethyl) trifluoroacetate salt 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzoic acid (50.0 mg, 0.191 mmol) was added to NMP (1. 0 mL) and cooled to 5 ° C., thionyl chloride (0.0417 mL, 0.573 mmol) was added, and the mixture was stirred for 1 hour.
  • Table 1 and Table 2 show the structural formulas of the compounds described in the examples.
  • TFA represents trifluoroacetic acid.
  • Test Example 1 Measurement of Activation Factor X Activity Inhibitory Activity Using a 96-well plate (# 3396, Costar), 100 mM Tris-HCl buffer containing 0.02% Tween20, 0.1% PEG6000, 0.2M NaCl After 130 ⁇ L of 10 ⁇ L of 0.015 U / mL FXa and 10 ⁇ L of the test compound were mixed for 10 minutes, 50 ⁇ L of chromogenic substrate 0.2 mM S-2222 was added. Using a microplate reader Benchmark Plus (BIO-RAD), the reaction rate was measured from the change over time in absorbance at 405 nm. The control reaction rate was 100%, and the negative logarithm of the concentration at which the control reaction rate was suppressed by 50% was defined as the pIC 50 value. The results are shown in Table 3.
  • Test Example 2 Activation Factor II (FIIa, Thrombin) Inhibitory Activity Measurement Using a 96-well plate (# 3396, Costar), 100 mM Tris containing 0.02% Tween20, 0.1% PEG6000, 0.2M NaCl -10 ⁇ L of 0.125 U / mL activated factor IIA (thrombin) and 10 ⁇ L of the test compound were mixed in 130 ⁇ L of HCl buffer for 10 minutes, and then 50 ⁇ L of chromogenic substrate 0.1 mM S-2238 was added. Using a microplate reader Benchmark Plus (BIO-RAD), the reaction rate was measured from the change over time in absorbance at 405 nm. The control reaction rate was 100%, and the negative logarithm of the concentration at which the control reaction rate was suppressed by 50% was defined as the pIC 50 value. The results are shown in Table 3.
  • Test Example 3 Measurement of anticoagulant activity The measurement was performed in accordance with the aPTT measurement method using a fully automatic blood coagulation time measurement device Sysmex Cs-2000i. 8 ⁇ L of 10 mg / mL DDVP solution (DDVP standard product, Wako) and 40 ⁇ L of test compound solution are placed in a sample tube (MS-18, Nippon Medical Science) and human plasma (standard human plasma for blood coagulation test, GCH-100A). , Sysmex) 360 ⁇ L was used as a test sample. 50 ⁇ L of the test sample was incubated at 37 ° C.
  • Test Example 5 Stability evaluation in liver S9 fraction
  • Metabolic reaction mixture (0.1 mM EDTA-100 mM potassium phosphate buffer (pH 7.4), 2 mg / mL human liver S9 fraction, 0.5 mM nicotinamide adenine dinucleotide phosphorus Acid-oxidized 5 mM glucose-6-phosphate, 1 unit / mL glucose-6-phosphate dehydrogenase) was prewarmed at 37 ° C. for 5 minutes. After pre-warming, a DMSO solution of the substrate was added so that the final drug solution concentration was 2 ⁇ M, and metabolic reaction was started at 37 ° C.
  • compound (I) and pharmaceutically acceptable salts thereof have high FXa inhibitory activity and anti- (blood) clotting action, and as anti- (blood) clotting agents (agents),
  • Various diseases in which FXa-dependent coagulation processes are involved in the pathology such as thrombus formation during extracorporeal circulation, cerebral infarction, cerebral thrombus, cerebral embolism, transient ischemic attack (TIA), acute and chronic myocardial infarction Stable angina, pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial vascular surgery and valve replacement, reocclusion and restenosis after coronary artery bypass surgery, percutaneous It can be used as a therapeutic or prophylactic agent for re-occlusion and restenosis after vascular reconstruction such as mechanical transluminal coronary angioplasty (PTCA) or percutaneous coronary artery recanalization therapy (PTCA).
  • Compound (I) and pharmaceutically acceptable salts thereof are useful as anti- (blood) coagulants (agents) in blood extracorporeal circuits (for example, hemodialyzers, heart-lung machines, etc.).
  • Compound (I) and pharmaceutically acceptable salts thereof are rapidly eliminated from the blood, that is, have a short half-life in blood, so that it is easy to stop bleeding when bleeding symptoms are observed during administration. It is useful as an anti- (blood) coagulant (agent) that can be used safely.
  • compound (I) and pharmaceutically acceptable salts thereof have low thrombin inhibitory activity, are selective FXa inhibitors, and can be used safely in terms of bleeding risk (agents) ).

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Abstract

Nouveau dérivé d'imine ayant une activité inhibitrice sur le facteur de coagulation sanguine X activé ou sel pharmaceutiquement acceptable de celui-ci. Cette invention concerne un composé représenté par la formule (I) [chaque symbole dans la formule étant tel que défini dans la description] ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2012/072103 2011-08-31 2012-08-31 Dérivé d'imine Ceased WO2013031930A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018035185A (ja) * 2017-10-13 2018-03-08 株式会社ダイセル カリウム塩の製造方法、及びカリウム塩

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6054318A (ja) * 1983-09-05 1985-03-28 Otsuka Pharmaceut Co Ltd 血栓症予防及び治療剤、冠循環改善剤
WO1999047503A1 (fr) * 1998-03-19 1999-09-23 Ajinomoto Co., Inc. Derives d'aminoisoquinoleine
WO2000071508A2 (fr) * 1999-05-24 2000-11-30 Cor Therapeutics, Inc. Inhibiteurs du facteur xa
WO2004046138A1 (fr) * 2002-11-21 2004-06-03 Merck Patent Gmbh Carboxamides
WO2005095440A1 (fr) * 2004-03-03 2005-10-13 Sanofi-Aventis Deutschland Gmbh Derives beta-aminoacide en tant qu'inhibiteurs du facteur xa
WO2006083003A1 (fr) * 2005-02-02 2006-08-10 Ajinomoto Co., Inc. Nouveau dérivé de benzamidine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6054318A (ja) * 1983-09-05 1985-03-28 Otsuka Pharmaceut Co Ltd 血栓症予防及び治療剤、冠循環改善剤
WO1999047503A1 (fr) * 1998-03-19 1999-09-23 Ajinomoto Co., Inc. Derives d'aminoisoquinoleine
WO2000071508A2 (fr) * 1999-05-24 2000-11-30 Cor Therapeutics, Inc. Inhibiteurs du facteur xa
WO2004046138A1 (fr) * 2002-11-21 2004-06-03 Merck Patent Gmbh Carboxamides
WO2005095440A1 (fr) * 2004-03-03 2005-10-13 Sanofi-Aventis Deutschland Gmbh Derives beta-aminoacide en tant qu'inhibiteurs du facteur xa
WO2006083003A1 (fr) * 2005-02-02 2006-08-10 Ajinomoto Co., Inc. Nouveau dérivé de benzamidine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018035185A (ja) * 2017-10-13 2018-03-08 株式会社ダイセル カリウム塩の製造方法、及びカリウム塩

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