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WO2004035579A1 - Derive imidazopyridine, procede de production de ce dernier et utilisation correspondante - Google Patents

Derive imidazopyridine, procede de production de ce dernier et utilisation correspondante Download PDF

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Publication number
WO2004035579A1
WO2004035579A1 PCT/JP2003/013122 JP0313122W WO2004035579A1 WO 2004035579 A1 WO2004035579 A1 WO 2004035579A1 JP 0313122 W JP0313122 W JP 0313122W WO 2004035579 A1 WO2004035579 A1 WO 2004035579A1
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Prior art keywords
group
pyridine
optionally substituted
compound
naphthyl
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PCT/JP2003/013122
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English (en)
Japanese (ja)
Inventor
Keiji Kubo
Tetsuji Kawamoto
Yasuhiro Imaeda
Masaki Kawamura
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Takeda Pharmaceutical Company Limited
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Priority to AU2003271185A priority Critical patent/AU2003271185A1/en
Publication of WO2004035579A1 publication Critical patent/WO2004035579A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention provides a novel imidazopyridine useful for the prevention and treatment of arterial and venous thromboembolic diseases, inflammation, cancer, etc., which have an anticoagulant effect and an antithrombotic effect by inhibiting activated blood coagulation factor X (FXa).
  • the present invention relates to a derivative, a production method and a use thereof.
  • thrombus inhibitors In order to prevent and treat myocardial infarction and cerebral infarction, it is important to suppress the formation of thrombus.
  • Antithrombin agents, platelet aggregation inhibitors, etc. are being conducted as thrombus inhibitors.
  • antithrombin agents suppress platelet aggregation together with their anticoagulant effect, so these agents show bleeding tendency as a side effect, and their safety is problematic.
  • FXa inhibitors are considered to be safe anticoagulants because they specifically inhibit only coagulation factors.
  • the present inventors have found that an imidazopyridine derivative having a high selectivity and a strong inhibitory effect on FXa can exert a sustained and sufficient effect by oral administration, and is effective in treating thromboembolic diseases of arteries and veins, inflammation and cancer. We have been conducting diligent research because it is useful for prevention and treatment.
  • a novel imidazopyridine derivative represented by the following formula (I) or a salt thereof (hereinafter, sometimes referred to as compound (I)) has a selective and potent FXa inhibitory action and is highly safe. They have found that oral administration exerts a sustained and sufficient effect, and have completed the present invention.
  • Ar represents an optionally substituted naphthyl group, an optionally substituted phenyl group, an optionally substituted indolyl group, or an optionally substituted benzothienyl group
  • X represents a divalent hydrocarbon group which may be substituted
  • Z is one CO-, one SO-, or a ⁇ 0 2 - shows the ring a may be optionally Pipera gin ring or substituted optionally be substituted
  • a ring B represents an optionally substituted imidazopyridine ring, and a represents 0, 1 or 2. Or a salt thereof;
  • ring B is selected from a halogen atom, an optionally substituted carbon dihydrogen group, an optionally substituted diamino group, a nitro group and an esterified or amidated olepoxyl group Imidazo optionally substituted with one or more substituents
  • Ring B is an optionally substituted ( ⁇ _ 4 may I be substituted by an alkyl group
  • the compound according to (1) which is a midazo [1, 2_a] pyridine ring;
  • Equation (I) is equivalent to equation ( ⁇ )
  • R 1 and R 2 each independently represent a hydrogen atom, a halogen atom, an optionally substituted carbon group, an optionally substituted amino group, a nitro group, or an esterified or amidated group. And the other symbols have the same meanings as described in the above (1).
  • R 1 and R 2 are each independently a hydrogen atom or a C 4 alkyl group which may be substituted;
  • Ar is a naphthyl group substituted with a halogen atom or an indolyl group substituted with a halogen atom
  • X is an 8- alkylene group
  • Z is -C ⁇
  • R 1 and R 2 are Each of which may be independently substituted with a hydrogen atom or a hydroxyl group — a compound according to the above (6), wherein the compound is a 4-alkyl group or an esterified hydroxyl group, and a is 2;
  • M 1 represents a hydrogen atom, an alkali metal, an alkaline earth metal, or a leaving group, and other symbols have the same meanings as described in the above (1). Or a salt thereof;
  • M 2 represents a hydrogen atom, an alkali metal, an alkaline earth metal or a leaving group, and other symbols have the same meanings as described in the above (1). Or a salt thereof;
  • M 3 represents a hydrogen atom, a hydroxyl group, an alkali metal, an alkaline earth metal or a leaving group, and other symbols have the same meanings as described in the above (1).
  • a salt thereof and a compound of the formula (VII)
  • X ′ represents an alkenyl group, an alkynyl group or an alkyl group having a leaving group, and other symbols have the same meanings as in the above (1).
  • the compound obtained by the above reaction is further hydrolyzed, esterified, amidated, alkylated, acylated, reduced, reduced or acidified. And / or and a method for producing the compound according to (1), wherein the compound is subjected to a deprotection reaction;
  • (21) A method for inhibiting blood coagulation in a mammal, which comprises administering to the mammal an effective amount of the compound according to (1) or a salt thereof, or a prodrug thereof;
  • (22) A method for inhibiting activated blood coagulation factor X in a mammal, which comprises administering to the mammal an effective amount of the compound according to the above (1), a salt thereof, or a prodrug thereof;
  • Ar represents an optionally substituted naphthyl group, an optionally substituted phenyl group, an optionally substituted indolyl group, or an optionally substituted benzophenyl group.
  • examples of the “naphthyl group” include 1-naphthyl and 21-naphthyl, and among them, 2-naphthyl is preferable.
  • examples of the “indolyl group” include 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indrill, 6-indolyl, 7-indolyl, and among them, 2-indolyl is preferable.
  • examples of the “benzobenzoyl group” include 2-benzozoenyl, 3-benzozoenyl, 4-benzozoenyl, 5-benzozoenyl, 6-benzophenyl, 7-benzozoenyl and the like. Are preferred.
  • a “naphthyl group which may be substituted” represented by Ar "an optionally substituted Examples of the substituent that each of the phenyl group, the optionally substituted indolyl group, and the optionally substituted benzothienyl group include, for example, an optionally substituted alkyl group.
  • aryl group in the “optionally substituted aryl group” examples include C 6 _ such as phenyl, naphthyl, anthryl, phenanthryl, and acenaphthylenyl.
  • the substituents that the aryl group may have include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) and a lower alkyl group (eg, methyl- 6, alkyl such as methyl, ethyl, propyl).
  • a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • a lower alkyl group eg, methyl- 6, alkyl such as methyl, ethyl, propyl
  • lower alkenyl groups e.g., pinyl, C 2 _ 6 alkenyl, etc.
  • Ariru e.g., lower alkynyl group (embodiments, X ethynyl, Puroparugi 'C 2, such as Le - 6 alkynyl, etc.)
  • Ariru group e.g., phenyl , 6 of naphthyl - like 1 4 Ariru
  • lower alkoxy group e.g., methoxy, Etoki sheet, ⁇ one 6 alkoxy such as propoxy, etc.
  • lower alkylthio group e.g., methyl Chio, Echiruchio one 6 alkylthio such propylthio Etc.
  • Amino group an optionally substituted hydroxyl group, a cyano group, a nitro group, a nitroso group, an optionally substituted amidino group, an optionally substituted imidoyl group
  • the aryl group in the optionally substituted aryl group as the substituent may be "optionally substituted amino group", “optionally substituted hydroxyl group", and “substituted”
  • amidino group which may be substituted include: an optionally substituted naphthyl group, an optionally substituted phenyl group, and an optionally substituted indolyl group represented by A described below.
  • optionally substituted benzochenyl group as an optionally substituted “optionally substituted amino group", “optionally substituted hydroxyl group”, and "substituted And the same groups as the “amidino group”.
  • the Shikuroa alkyl group in the "substituted optionally may shea 'black alkyl group" as a substituent, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl cyclo, C 3 _ 7 cycloalkyl, etc.
  • heptyl like cyclohexane is No.
  • examples of the substituent of the cycloalkyl group include the same number of the same groups as the substituents in the aforementioned “aryl group which may be substituted”, an oxo group, a thioxo group, and the like.
  • the cyclo alkenyl group in the "optionally substituted cycloalkenyl group” as the substituent for example Shikuropuro base sulfonyl, cyclobutenyl, Shikuropen thenyl, C 3 one 6 cycloalkenyl, etc. cyclohexenyl like cyclohexane and the like.
  • substituent of the optionally substituted cycloalkenyl group include the same number of the same groups as the substituents in the above-mentioned “optionally substituted aryl group”, and oxo and thioxo groups. Is mentioned.
  • alkyl group in the “optionally substituted alkyl group” as a substituent examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- (: _ 6 alkyl etc.
  • examples of the substituent of the alkyl group include the same number of the same groups as the substituents in the aforementioned “aryl group which may be substituted”, and an oxo group, a thioxo group, and the like.
  • alkenyl group in the “optionally substituted alkenyl group” as the substituent examples include vinyl, aryl, isoprobenyl, 2-methylaryl, 1-propyl, 2-methyl-1-propyl, Butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2 "methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 41 methyl-3-pentenyl, 1 one hexenyl, 2 into single hexenyl, 3 one-hexenyl, 4 one hexenyl, C 2 of cyclohexenyl, etc., to 5 - 6 alkenyl and the like cited et be.
  • substituent of the alkenyl group examples include the same number of the same groups as the substituents in the above-mentioned “optionally substituted aryl group
  • alkynyl group in the “optionally substituted alkynyl group” as the substituent examples include ethynyl, 1_propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, and 2-pentynyl , 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 41-hexyl To hexynyl, C 2 of hexynyl, etc., to 5 - 6 alkynyl and the like.
  • examples of the alkynyl substituent include the same number of the same groups as the substituents in the above-mentioned “optionally substituted aryl group”, an oxo group, a thioxo group and the like.
  • the heterocyclic group in the “optionally substituted heterocyclic group” as a substituent includes, as an atom (ring atom) constituting a ring system, a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like.
  • aromatic heterocyclic group examples include, for example, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3 oxadiazolyl, 1,2,4 oxadiazolyl, 1,3 1,4-oxaziazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 5- to 6-membered aromatic monocyclic heterocyclic groups such as tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and, for example, benzofurael, isobenzofuranyl, benzo [b] phenyl, indoly
  • non-aromatic heterocyclic group examples include 3- to 8-membered groups such as, for example, oxilael, azetidinyl, oxeynyl, cesinyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. (Preferably 5 to 6 members) saturated or unsaturated (preferably saturated) non-aromatic monocyclic heterocyclic group (aliphatic monocyclic heterocyclic group), 1,3-dihydroisoindolyl, etc.
  • Some or all of the above aromatic monocyclic heterocyclic groups or aromatic condensed heterocyclic groups such as 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, etc. Examples include a non-aromatic heterocyclic group having a saturated bond.
  • the substituent which the heterocyclic group which may be substituted in the ⁇ optionally substituted heterocyclic group '' may have is the same as the substituent in the ⁇ optionally substituted aryl group '' described above. And a large number of similar groups. '
  • halogenated _ 6 alkoxy groups for example, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trichloromethoxy, 2,2, 2-trichloro mouth ethoxy, etc.
  • Lower alkyl group optionally substituted with the selected substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl) d one 6 alkyl, etc.) and the like, Ashiru group (C 1 one 6 Arukanoiru (eg, e mill, Asechiru, propionyl, pivaloyl, etc.), Benzoiru, - 6 Al alkylsulfonyl group (e.g., methanesulfonyl etc.), benzenesulfonyl ) And may be halogenated.
  • substituent eg,
  • alkoxycarbonyl group eg, methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trichloromethoxycarbonyl, etc.
  • 6 alkoxycarbonyl group e.g.
  • heterocyclic group in the above For example Hajime Tamaki (the “optionally substituted heterocyclic group” And the like, but the “amino group” in the “optionally substituted amino group” as a substituent is an optionally substituted imidoyl group (for example, _
  • 6- alkylimidoyl eg, formyl imidoyl, acetylimidoyl, etc.
  • cyclic amino group include, for example, 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl, and a lower alkyl group at the 4-position (e.g., methyl, ethyl, propyl). , isopropyl, heptyl, ter t-heptyl, etc. d one 6 alkyl group hexyl etc.
  • Ararukiru group e.g., benzyl, C 7 such as phenethyl - like 1 0 Ararukiru group
  • ⁇ Li Ichiru group Eg, phenyl, C 6 _!
  • Aryl group such as 1-naphthyl, 2-naphthyl, etc.
  • 3 to 8 members such as 1-piperazinyl, 1-pyrrolyl, 1-imidazolyl, etc. ( Preferred Or a 5- or 6-membered) amino group.
  • the “carboxyl which may be esterified or amidated” as a substituent includes free carboxyl, esterified carboxyl, and amidated carbonyl.
  • estersified carboxyl for example, a lower alkoxycarbonyl group, an aryloxycarbonyl group, a 7-lalkyloxycarbonyl group and the like can be mentioned.
  • Examples of the “lower alkoxycarbonyl group” include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and Examples include 16- alkoxycarbonyl such as sopentyloxycarbonyl, neopentyloxycarbonyl and the like, and among them, C_3 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl is preferable.
  • the " ⁇ Li one Ruo carboxymethyl local Poni Le group" for example, phenoxy force Ruponiru, 1 - naphthoquinone deer Lupo sulfonyl, 2-naphthoquinone deer C 7 such as Lupolen nil - 2 aryloxycarbonyl is preferred.
  • aryloxycarbonyl group and “aralkyloxycarbonyl group” may have a substituent, and the substituent may be the above-mentioned N-monosubstituted carbamoyl group.
  • substituents of the aralkyl group include the same groups as the aryl group and the groups similar to the groups exemplified as the substituents of the aralkyl group.
  • “Amidated carpoxyl” includes unsubstituted rubamoyl as well as N-monosubstituted rubamoyl and N, N-disubstituted rubamoyl.
  • N-monosubstituted rubamoyl examples include a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Pentyl one 6 alkyl, etc.), lower alkenyl groups (examples of hexyl, etc., to, vinyl, Ariru, isopropenyl, propenyl, butenyl, pentenyl, to such cyclohexenyl
  • C 2 - 6 alkenyl, etc. a cycloalkyl group (e.g., cyclopropyl, Shikuropuchi Le, cyclopentyl, C 3 of cyclohexyl etc. cyclohexane - 6 cycloalkyl, etc.), Ari Le group (e.g., phenyl, 1-naphthyl, 2 _ C 6 of naphthyl -. Ariru etc.), Ararukiru group (e.g., benzyl, C 7 such as phenethyl -. 1 0 Ararukiru, preferably phenylene Lou _ 4 alkyl and the like), ⁇ reel alkenyl group (e.g., cinnamyl, etc.
  • a cycloalkyl group e.g., cyclopropyl, Shikuropuchi Le, cyclopentyl, C 3 of cyclohexyl etc. cycl
  • the lower alkyl group, lower alkenyl group, cycloalkyl group, aryl group, aralkyl group, aryl alkenyl group, and heterocyclic group may have a substituent, and examples of the substituent include a hydroxyl group and a substituted an amino group [wherein amino groups also can include, for example, a lower alkyl group (e.g., methyl, Echiru, propyl, isopropyl, butyl, isobutyl, ter t-heptyl, pentyl, the hexyl, etc.
  • a lower alkyl group e.g., methyl, Echiru, propyl, isopropyl, butyl, isobutyl, ter t-heptyl, pentyl, the hexyl, etc.
  • E - 6 alkyl, etc.) E - 6 alkyl, etc.
  • Ashiru group eg, formyl, Asechiru, propionyl, d one 6 Arukanoiru such pivaloyl, Benzoi Le etc.
  • Karupokishiru, C have one or two such one 6 one alkoxy force Ruponiru group as location substituent Good.
  • a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • a nitro group e.g., a cyano group
  • a lower alkyl group which may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
  • a lower alkoxy group which may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
  • Examples of the lower alkyl group include d- 16 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. Particularly, methyl, ethyl and the like are preferable.
  • Examples of the lower alkoxy group include 16 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. Preferred are xy, ethoxy and the like. It is preferable that these substituents are the same or different and are substituted with 1 or 2 to 3 (preferably 1 or 2).
  • N, N-disubstituted rubamoyl group means a carpamoyl group having two substituents on a nitrogen atom, and one example of the substituent is an “N-monosubstituted carbamoyl group” described above. And the other are, for example, lower alkyl groups (eg, d- 16 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.).
  • d- 16 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.
  • C 3 _ 6 a cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. cyclohexylene), C 7 _ J 0 Ararukiru group (e.g., benzyl, phenethyl, etc., preferably phenylene Lou _ 4 alkyl, such as ) And the like.
  • two substituents may be combined with a nitrogen atom to form a cyclic amino.
  • the cyclic aminocarbamoyl group include 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, Piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl (sulfur atom may be oxidized), 1-pipergelcarbonyl, and a lower alkyl group at the 4-position (eg, methyl, ethyl, propyl, isopropyl, Petit Le, tert- heptyl, pentyl, a hexyl, etc., to - 6 alkyl, etc.), Ararukiru group (e.g., benzyl, C 7 such as phenethyl - 0 Ararukiru etc.), 7 aryl group (e.g., phenyl, 1 one-naphthyl
  • Examples of the substituent of the “optionally substituted thiocarbamoyl group” and the “optionally substituted sulfamoyl group” include the same substituents as those of the aforementioned “optionally substituted carbamoyl group” Is mentioned.
  • Examples of the “acyl group” as a substituent include a carboxylic acid-derived acyl group, a sulfonic acid-derived acyl group, and a sulfinic acid-derived acyl group.
  • a hydrogen atom or a substituent having one of the above “N-monosubstituent rubamoyl groups” on the nitrogen atom is bonded to carbonyl.
  • formyl, Asechiru, propionyl, d _ 6 Arukanoiru such Pibaroiru, Benzoiru and the like.
  • sulfonic acid-derived acyl group examples include those in which the above-mentioned “N-monosubstituted carbamoyl group” has one substituent on a nitrogen atom bonded to a sulfonyl, and the like.
  • methanesulfonyl, _ 6 alkylsulphonyl such as ethanesulfonyl, benzenesulfonyl and toluene sulfonyl.
  • sulfinic acid-derived acyl examples include those in which the above-mentioned “N-monosubstituted carpamyl” has a substituent having one on the nitrogen atom bonded to sulfinyl, and preferably methanesulfinyl And Ci- 6 alkylsulfonyl such as ethanesulfinyl and the like.
  • a r a halogen atom, _ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 Arukini Le, optionally substituted Amino, nitro, ⁇ ⁇ Bruno, optionally substituted amidino and esterification
  • Amido reduction by one or more, also selected from a good force Rupokishiru have good naphthyl optionally substituted with a substituent; or a halogen atom, alkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, optionally substituted Indolyl, which may be substituted with one or more substituents selected from amino, nitro, cyano, amidino which may be substituted and carboxyl which may be esterified or amidated, is preferred.
  • Ar is preferably naphthyl which may be substituted, and among them, naphthyl (preferably 2-naphthyl and the like) which may be substituted by a halogen atom is preferable.
  • Na is preferably naphthyl substituted with a halogen atom.
  • X represents a divalent hydrogen group which may be substituted.
  • Examples of the “optionally substituted divalent hydrocarbon group” represented by X include “an optionally substituted divalent chain hydrocarbon group” and “optionally substituted bivalent hydrocarbon group”. Or a divalent cyclic hydrocarbon group ”.
  • chain Sumyi ⁇ containing groups for example methylene, ethylene, trimethylene, tetramethylene, etc.
  • Arugiren for example vinylene, propylene, 1 - or 2 - butenylene, C 2 such blanking evening Jeniren - 8 Aruke two Ren, e.g. Echiniren, 1 - or 2 - propynylene, 1 - or 2 -. etc.
  • divalent cyclic hydrocarbon group in the “optionally substituted bivalent cyclic hydrocarbon group” represented by X include, for example, the aforementioned cycloalkyl group, cycloalkenyl group and aryl group And other groups formed by removing one hydrogen atom.
  • divalent aryl groups especially phenylene (1,2-phenylene, 1,3-phenylene) Len or 1,4-phenylene) is preferred.
  • an optionally substituted divalent chain hydrocarbon group is preferable, and among them, an optionally substituted C x _ s Alkylene groups are preferred.
  • the substituent which the “divalent hydrocarbon group” in the “optionally substituted divalent hydrocarbon group” represented by X may have, the above-mentioned Ar represented by Ar A naphthyl group, a phenyl group which may be substituted, an indolyl group which may be substituted, and a benzothienyl group which may be substituted.
  • Examples of the same substituent and oxo group as a good substituent include a lower alkyl group (eg, 16 alkyl such as methyl, ethyl and propyl), a lower alkenyl group (eg, vinyl, aryl).
  • C 2 such - 6 alkenyl, etc.
  • lower alkynyl group e.g., Echiniru, C 2 one 6 alkynyl etc. propargyl, etc.
  • an optionally substituted amino group an optionally substituted hydroxyl group
  • Shiano Group substituted Which may be an amidino group, a force Rupokishiru group, a lower alkoxy Cal Poni Le group (eg.
  • Methoxycarbonyl like one 6 Arukokishikaru Poniru such ethoxy Cal Poni Le
  • optionally substituted force Rubamoiru group e.g., _ 6 alkyl addition Ashiru is (eg, formyl, C 2 _ 6 Arukanoiru, Benzoiru, optionally halogenated C - 6 alkoxy force Ruponiru, good d _ 6 alkylsulfonyl which may be halogenated, benzenesulfonyl and the like) substituted with A carbamoyl group, etc.
  • an oxo group May be substituted 1 to 3 times.
  • the X - 6 alkylene group is preferable, and ethylene is particularly preferred.
  • Z represents one CO—, one SO— or —so 2 —.
  • Z is preferably one C O—.
  • ring A represents an optionally substituted piperazine ring or an optionally substituted homopidazine ring.
  • the substituents that may be possessed by the ⁇ optionally substituted piperazine ring '' and the ⁇ optionally substituted homopyrazine ring '' represented by ring A include those described above for A r
  • the same number of the same substituents as the substituents that the “optionally substituted aryl group” may have, as well as oxo and thioxo groups.
  • the ring A good piperidines Rajin ring are preferred which may be substituted, among others, water acid group or esterified or amidated unprotected force Rupokishiru optionally substituted _ 6 alkyl group group, And a piperazine ring which may be substituted with one or more substituents selected from a propyloxyl group which may be esterified or amidated.
  • a represents 0, 1 or 2 (preferably 2).
  • Ring B represents an optionally substituted imidazopyridine ring.
  • the mode of condensation of the imidazole ring and the pyridine ring in the imidazopyridine ring is not particularly limited, and is preferably, for example, imidazo [1,2_a] pyridine, imidazo [1,5-a] pyridine, and more preferably imidazo [1,2, pyridine] — A] Pyridine and the like are particularly preferred.
  • Examples of the substituent of the “optionally substituted imidazopyridine ring” represented by ring B include the aforementioned “optionally substituted naphthyl group” represented by Ar, Optionally substituted phenyl group '', ⁇ optionally substituted indolyl group '' and ⁇ optionally substituted benzothienyl group '', and the like.
  • substituents may be substituted at 1 to 5 (preferably 1 to 3) at substitutable positions. Further, the substituents are bonded to each other ring "but it may also be substituted imidazopyridine ring" for ring B (e.g., cyclopentane, cyclohexane, C 4 _ 8 cycloalkane ring such as cycloheptane, Benzene ring).
  • ring B e.g., cyclopentane, cyclohexane, C 4 _ 8 cycloalkane ring such as cycloheptane, Benzene ring.
  • a halogen atom an optionally substituted hydrocarbon group, an optionally substituted amino group, a nitro group, and an esterified or amidated olepoxyl group (preferably, Alkyl group which may be substituted, alkenyl group which may be substituted, alkynyl group which may be substituted, aryl group which may be substituted, carboxyl group which may be esterified, amidated Imidazo [1,2-a] pyridine ring, which may be substituted with one or more substituents selected from the group consisting of phenyloxyl group, and optionally substituted — may be substituted with a 4- alkyl group
  • An imidazo [1,2-a] pyridin ring is particularly preferred. Further, the nitrogen atom constituting the imidazopyridine ring may be oxidized.
  • the imidazo [1,2-a] pyridine ring as ring B may be bonded to ring A at any position that can be bonded, and the imidazo [1,2-a] pyridine ring at the 5-position, 6-position, It is preferably bonded to ring A at position 7 or 8.
  • the formula ( ⁇ ) is preferably bonded to ring A at position 7 or 8.
  • R 1 and R 2 each independently represent a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, or a nitro group.
  • a carboxyl group which may be esterified or amidated preferably, a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted
  • R 1 and R 2 are linked together to form a ring (for example, cyclopentene), a carboxyl group which may be esterified, a carboxyl group which may be esterified, or an amidated carboxyl group.
  • Tan shown hexane, C 4 8 cycloalkane ring such as cycloheptane, may form a benzene ring, etc.), and the other symbols are as defined above cyclohexylene. ] It is preferable that it is a compound represented by these.
  • hydrocarbon group as a substituent which may be present, and “optionally substituted hydrocarbon group” represented by R 1 and: 2
  • hydrocarbon group include, for example, a hydrogen atom at one bond of the “divalent hydrocarbon group” in the “optionally substituted divalent hydrocarbon group” represented by X And a hydrocarbon group formed by adding one of the above.
  • substituent that the hydrocarbon group may have include, And the same number of the same groups as the substituents that the “divalent hydrocarbon group” in “good divalent hydrocarbon group” may have.
  • Ring B optionally has a ⁇ optionally substituted hydroxyl group '' and a ⁇ optionally substituted hydroxyl group '' represented by R 1 and R 2
  • the optional substituent include the aforementioned “optionally substituted naphthyl group”, “optionally substituted phenyl group”, “optionally substituted indyl group” and “substituted” And the like.
  • the substituent which the benzothienyl group which may be optionally substituted may be the same as the substituent which may be possessed by the hydroxy group which may be substituted.
  • Examples of good substituents include “optionally substituted naphthyl group”, “optionally substituted phenyl group”, “optionally substituted indolyl group” and “substituted”
  • the benzozoenyl group which may be substituted '' may have the same number of similar groups as the substituents which the ⁇ optionally substituted amino group '' may have, and the like. No.
  • a ⁇ carboxyl group which may be esterified or amidated '', and a ⁇ carboxyl group which may be esterified or amidated '' represented by R 1 and R 2 Is replaced by Optionally substituted naphthyl group, optionally substituted phenyl group, optionally substituted indolyl group, and optionally substituted benzothienyl group
  • the group include the same groups as the “carboxyl group which may be esterified or amidated” ′.
  • the substituent of ring B, and R 1 and R 2 are each independently a hydrogen atom or may be substituted.
  • - 4 alkyl group preferably a hydroxyl group or an esterified or amidated power Rupokishiru may be substituted with group C, _ 4 alkyl group).
  • the formula (I) is the formula (1 ′) and Ar is a halogen atom in an indolyl group substituted with substituted naphthyl group or a halogen atom, X is C ⁇ - an 8 alkylene group, Z gar CO-, R 1 and R 2 pixels respectively independently A C 4 alkyl group which may be substituted with a hydrogen atom or a hydroxyl group, or an esterified ethoxy group, and a compound in which a is 2, such as 5- [4- [3-[(5- Kuguchiguchi-2-Indolyl) sulfonyl] propionyl] -Topiperazinyl] -2-methylimidazo [1,2-a] pyridine, 5- [4- [3-[(6- Kuguchiguchi-2-naphthyl) )
  • a prodrug of compound (I) is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, the compound (I) is enzymatically oxidized, reduced, hydrolyzed, or the like. ), Hydrolyzed by gastric acid, etc.
  • a compound that changes to compound (I) by causing The prodrug of the compound (1) may be a compound in which the amino group of the compound (I) is acylated, alkylated, or phosphorylated (for example, the amino group of the compound (I) may be eicosanoylated, alanylated, pentyryl).
  • Minocarboxylation (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylation
  • the hydroxyl group of compound (I) has been acylated, alkylated, phosphorylated or borated (for example, the hydroxyl group of compound '(I) has been acetylated, palmitoylated, propanoylated, vivaloylated, etc.).
  • the lipoxyl group of (I) is ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, Roxymethyl esterification, ethoxy carbonyloxylethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3,1-dioxolen-4-yl) methyl esterification, 1- (cyclohexyloxy) Carbonyloxy) ethyl esterification, methylamidation compound, etc.).
  • These compounds can be produced from compound (I) by a method known per se.
  • the prodrug of compound (I) can be prepared under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals”, Vol. 7, Molecular Design, pp. 163-198. It may change to the object (I).
  • salt of the compound (I) examples include pharmacologically acceptable salts, such as trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, cunic acid, dalconic acid, ascorbic acid, and benzoic acid.
  • Acid addition salts with acids such as acid, methanesulfonic acid, p-toluenesulfonic acid, caffeic acid, fumaric acid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfuric acid, etc.
  • Examples thereof include metal salts such as sodium, potassium, magnesium, and calcium, and organic salts such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine, and N-methylmorpholine.
  • metal salts such as sodium, potassium, magnesium, and calcium
  • organic salts such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine, and N-methylmorpholine.
  • Compound (I) may be labeled with an isotope (eg, 3 H, etc.) and the like.
  • Compound (I) or a salt thereof can be produced, for example, by the following methods A to D.
  • Each of the compounds described in the following reaction formulas may form a salt as long as it does not inhibit the reaction, and examples of such a salt include those similar to the salt of compound (I).
  • L 1 is a leaving group (eg, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) or a reactive derivative of sulfonic acid (eg, sulfonic acid ester, active sulfonic acid amide (eg, 1, 1, 2,4-triazolide, imidazolide, etc.), quaternary amine sulfonyl form
  • a leaving group eg, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) or a reactive derivative of sulfonic acid (eg, sulfonic acid ester, active sulfonic acid amide (eg, 1, 1, 2,4-triazolide, imidazolide, etc.), quaternary amine sulfonyl form
  • M 1 is a hydrogen atom, an alkali metal (eg, lithium, potassium, sodium, cesium, etc.), an alkaline earth metal (eg, calcium, magnesium, etc.) ) Or a leaving group (eg, a trimethylsilyl group), and other symbols have the same meanings as described above.
  • the compound (I) can be produced by reacting the compound (III) or a salt thereof represented by the following formula: Examples of the salt of the compound ( ⁇ ) or (III) include an acid addition salt of the compound (I) with an acid which forms an acid addition salt. This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected.
  • Such solvents include alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.), ethers (eg, dioxane, tetrahydrofuran, getylether, tei't-).
  • alcohols eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.
  • ethers eg, dioxane, tetrahydrofuran, getylether, tei't-).
  • This reaction may be carried out in the presence of a base, if necessary.
  • a base include lithium hydroxide, hydroxide hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate,
  • Inorganic bases such as potassium bicarbonate; for example, alkali metal salts of C Hi lower fatty acids such as sodium formate, sodium acetate, and potassium acetate; for example, triethylamine, tri (n-propyl) amine, tri (n-butyl) amine; Tertiary amines such as diisopropylethylamine, cyclohexyl dimethylamine, pyridine, lutidine, acollidine, ⁇ , ⁇ -dimethylaniline, ⁇ -methylpiperidine, ⁇ -methylpyrrolidine, and ⁇ -methylmorpholine are used.
  • the compound (II) is preferably used in an amount of 0.5 to 5 equivalents based on the compound (III). Or 0.8 to 2 equivalents.
  • the reaction temperature is 120 to 200 ° (:, preferably 0 to; L 70 ° C.
  • the reaction time varies depending on the type of the compound (II) or (III), the type of the solvent, the reaction temperature and the like, but is usually about 1 minute to about 12 hours, preferably about 15 minutes to about 24 hours.
  • L 2 is a leaving group (for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) or an alkylsulfonyloxy group (eg, , Methanesulfonyloxy, benzenesulfonyloxy, trifluoromethanesulfonyloxy, etc.), and optionally substituted arylsulfonyloxy group (eg, benzenesulfonyloxy, P-toluenesulfonyloxy) Carboxylic acid, its salt (inorganic salt, organic salt, etc.) or its reactive derivative (eg, acid halide, ester, acid azide, acid anhydride) , A mixed acid anhydride, an active amide, an active ester, an active thioester, etc.), and other symbols are as defined above. (In particular, a compound in which L 2 is a hydroxyl group is referred to give a
  • M 2 represents a hydrogen atom, an alkali metal (eg, lithium, potassium, sodium, cesium, etc.), an alkaline earth metal (eg, calcium, magnesium, etc.) or a leaving group. It has the same significance as described in Item 1.
  • the compound (I) can be produced by reacting the compound (V) represented by the formula: This method comprises the steps of reacting compound (V) or its salt with free acid (IV) or its salt (inorganic salt, organic salt, etc.) or its reactive derivative (for example, acid halide, ester, acid azide, acid anhydride, mixed acid, Anhydride, active amide, active ester, active thioester, etc.) This is done by responding.
  • the salt of the compound (V) include an acid addition salt of the above-mentioned compound (I) with those described as the acid forming the acid addition salt.
  • Inorganic salts used for compound (IV) include alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, etc.), and organic salts such as trimethylamine salt, triethylamine salt Tert-butyldimethyaniline salt, pyridine salt, quinoline salt and the like are used.
  • alkali metal salts eg, sodium salt, potassium salt, etc.
  • alkaline earth metal salts eg, calcium salt, etc.
  • organic salts such as trimethylamine salt, triethylamine salt Tert-butyldimethyaniline salt, pyridine salt, quinoline salt and the like are used.
  • Examples of the acid octylide include acid chloride, acid bromide and the like, examples of the ester include lower alkyl esters such as methylethyl, and examples of the mixed acid anhydride include monoalkyl carbonate mixed acid anhydride (eg, free acid (IV ) And monomethylcarbonate, monoethylcarbonate, monoisopropylcarbonate, monoisobutylcarbonate, monotert-butylcarbonate, monobenzylcarbonate, mono (p-nitrobenzyl) carbonate, monoallylcarbonate, etc.), ( ⁇ _ 6 aliphatic carboxylic acid mixed acid anhydride (e.g., the free acid (IV ') acetic acid, Shiano acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, Torifuruoro acetic, trichloroacetic port acetate, Aseto acetate Mixed anhydr
  • ring I ⁇ comprises ( ⁇ _ 6 alkyl (eg if methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec- butyl Le, tert- butyl, etc.), alkoxy (e.g., main Bok carboxymethyl, ethoxy, Provo alkoxy, Isopurobokishi , butoxy, tert- butoxy, etc.), a halogen atom (e.g. fluorine, chlorine, bromine, etc.), Okiso, Chiokiso, C - 6 alkylthio (e.g. methylcarbamoyl Thio, Echiruchio, propylthio, may be substituted with Puchiruchio etc.) etc.) and the like.
  • alkoxy e.g., main Bok carboxymethyl, ethoxy, Provo alkoxy, Isopurobokishi , butoxy, tert- butoxy,
  • the active ester examples include an organic phosphate (eg, ethoxyphosphate, diphenoxyphosphate, etc.), p-ditrophenyl ester, 2,4-diphenyl phenyl ester, cyanomethyl ester, pen-chloro! ⁇ phenyl ester, N-hydroxysuccinimide ester, N-hydroxyphenylimide ester, 1-hydroxybenzotriazole ester, 6-chloro- Examples include 11-hydroxybenzotriazole ester, 1-hydroxy-1H-2-pyridone ester and the like.
  • organic phosphate eg, ethoxyphosphate, diphenoxyphosphate, etc.
  • p-ditrophenyl ester 2,4-diphenyl phenyl ester, cyanomethyl ester
  • pen-chloro! ⁇ phenyl ester N-hydroxysuccinimide ester, N-hydroxyphenylimide ester
  • 1-hydroxybenzotriazole ester 6-chloro-
  • active thioester examples include aromatic heterocyclic thiol compounds [these heterocyclic rings are alkyl (eg, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, sec_butyl, tert-butyl, etc.)].
  • Alkoxy for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.
  • halogen atom for example, fluorine, chlorine, bromine, etc.
  • alkylthio for example, methylthio, ethylthio, propylthio, butylthio, etc.
  • 2-pyridylthiol ester, 2-benzothiazolylthiol ester and the like.
  • This reaction is generally carried out in a solvent, and if necessary, a base or a condensing agent (eg, carpoimides (DCC, WSC, DIC, etc.), a phosphoric acid derivative (eg, getyl cyanophosphate, DPPA, B0P-C1, etc.), 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) chloride-4-methylmorph orinium chloride (DMTMM: Kunishima et al., Tetrahedron, 1999, 55, 1315) 9) etc.
  • a base or a condensing agent eg, carpoimides (DCC, WSC, DIC, etc.)
  • a phosphoric acid derivative eg, getyl cyanophosphate, DPPA, B0P-C1, etc.
  • 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) chloride-4-methylmorph orinium chloride eg
  • compound (V) is used in 0.5 to 5 equivalents, preferably 0.8 to 2 equivalents, relative to compound (IV).
  • the reaction temperature is from 150 to 150 ° C, preferably from 120 to 100 ° C.
  • the reaction time varies depending on the type of compound (IV) or (V), the type of solvent and base, the reaction temperature, etc., but is usually about 1 minute to about 100 hours, preferably about 15 minutes to about 48 hours. It is.
  • oxidizing agents include oxygen, hydrogen peroxide, organic peracids such as perbenzoic acid, m-chloroperbenzoic acid, and peracetic acid, for example, lithium perchlorate, silver perchlorate, and tetraperchlorate.
  • Perchlorates such as butylammonium, for example periodates such as sodium periodate, periodate, manganese dioxide, lead tetraacetate, permanganates such as potassium permanganate, such as iodine , Bromine, halogen such as chlorine, N-bromosuccinimide, N-chlorosuccinimide, sulfuryl chloride, chloramine T and the like.
  • This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected.
  • solvents include, for example, alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol), ethers (eg, dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ester).
  • Tyl ether diisopropyl ether, ethylene glycol dimethyl ether, etc., esters (eg, ethyl formate, ethyl acetate, n-butyl oxalate, etc.), carboxylic acids (eg, formic acid, acetic acid, propionic acid, etc.), halogen Hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-dichloroethane, cyclobenzene, etc.), hydrocarbons (eg, n-hexane, benzene, toluene, etc.) ), Amides (eg, formamide, ⁇ , ⁇ -dimethylphos) Lumiamide, ⁇ , ⁇ -dimethylacetamide, etc.), ketones (eg, acetone, methylethylketone, methylisobutylketone, etc.), nitriles (
  • This reaction can also be performed in the presence of a base.
  • bases include, for example, alkali metal hydroxides such as lithium hydroxide, sodium heptaoxide and potassium hydroxide, alkaline earth metals such as magnesium hydroxide and calcium hydroxide, sodium carbonate and potassium carbonate.
  • Inorganic bases such as alkali metal carbonates such as sodium bicarbonate and alkaline metal bicarbonate such as hydrogen carbonate lime are used.
  • the oxidizing agent is used in an amount of 0.1 to 20 equivalents, preferably about 0.1 equivalent to the compound (la). 4 to 10 equivalents, and 0.1 to 20 equivalents, preferably 0.4 to 10 equivalents, of the base are used.
  • This reaction may be performed in the presence of an acid, if necessary.
  • an acid examples include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and perchloric acid, methanesulfonic acid, and ethanesulfonic acid.
  • Sulfonic acids such as acid, benzenesulfonic acid, toluenesulfonic acid and camphorsulfonic acid, and organic acids such as formic acid, acetic acid, propionic acid and trifluoroacetic acid are used.
  • the amount of these acids to be used is 0.1 to 20 equivalents, preferably 0.5 to 0.5 equivalents, relative to compound (la).
  • the reaction temperature is from about 10 ° C to about 250 ° C, preferably from about 15 ° C to about 150 ° C.
  • the reaction time varies depending on the type of the compound (Ia), base or solvent, reaction temperature and the like, but is usually about 1 minute to about 50 hours, preferably about 5 minutes to about 24 hours.
  • ⁇ 3 is a hydrogen atom, a hydroxyl group, an alkali metal (eg, lithium, potassium, sodium, cesium, etc.), an alkaline earth metal (eg, calcium, magnesium, etc.) or a leaving group (eg, trimethylsilyl group, etc.) )
  • alkali metal eg, lithium, potassium, sodium, cesium, etc.
  • alkaline earth metal eg, calcium, magnesium, etc.
  • a leaving group eg, trimethylsilyl group, etc.
  • X ' is alkenyl or alkynyl (preferably, C 2 _ 8 alkenyl or C 2 _ 8 alkynyl), or a leaving group (eg a halogen atom (e.g., fluorine, chlorine, bromine, iodine), A 6- alkylsulfonyloxy group which may be substituted with 1 to 3 halogen atoms (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), which has a substituent Alkyl (preferably ( 8 alkyl)) having an aryl sulfonyloxy group (eg, benzenesulfonyloxy, P-toluenesulfonyloxy, p_bromobenzenesulfonyloxy, etc.) or a hydroxyl group; Other symbols are as defined above.
  • the compound (I) can be
  • This reaction is generally performed in a solvent, and if necessary, in the presence of a base.
  • a solvent and base used in this reaction the same solvents and bases as those described in the above-mentioned Method A can be used.
  • compound (VII) is used in 0.5 to 3 equivalents, preferably 0.8 to 2 equivalents, relative to compound (VI).
  • the reaction temperature is from 150 to 150 ° C, preferably from 120 to 120 ° C.
  • the reaction time varies depending on the type of compound (VI) or (VII), the type of solvent and base, the reaction temperature and the like, but is usually about 1 minute to about 100 hours, preferably about 15 minutes to about 24 hours.
  • the starting compounds (111), (V) and (VII) used in each of the above reactions can be synthesized, for example, by the following methods.
  • M 4 represents a hydrogen atom, an alkali metal (for example, Lithium, potassium, sodium, cesium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.) or leaving groups (eg, trimethylsilyl group, etc.), and other symbols are as defined above.
  • an alkali metal for example, Lithium, potassium, sodium, cesium, etc.
  • alkaline earth metals eg, calcium, magnesium, etc.
  • leaving groups eg, trimethylsilyl group, etc.
  • This reaction is carried out according to the reaction conditions, reaction solvent, reaction time, and the like described for the reaction of compound (II) with compound (II) in Method A, or a method analogous thereto.
  • Examples of the protecting group for amino include, but are not limited to, a substituent — 6-alkyl group ponyl (eg, formyl, acetyl, ethylcarbonyl, etc.), phenylca Luponyl, 6-alkyl mono-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), C6 ⁇ .
  • Aryloxycarbonyl eg, phenoxycarbonyl, etc.
  • C 7 —.
  • aralkyloxy-l-ponyl for example, benzyloxycarbonyl and the like
  • trityl phthaloyl and the like are used.
  • protecting groups may be substituted by 1 to 4 or so halogen atoms (e.g., Furuoro, black hole, promo, etc. Yodo), C ⁇ - 6 alkyl Ichiriki Ruponiru (e.g., Asechiru, E Ji Rukaruponiru, Buchirukaruponiru etc. ) May be substituted by nitro and the like.
  • Methods for removing protecting groups for amino groups are described in, for example, T. Double Green et al., "Protective Groups in Organic Synthesis", 1991, Piri-and-Sands, Inc., New York (TW Green et al. "Protective Groups in Organic Synthesis”). , John Wiley & Sons, Inc. New York), etc., or a method analogous thereto, for example, a method using an acid, a base, reduction, ultraviolet light, palladium acetate, or the like is used. .
  • the leaving group represented by L 3 such as those similar to the leaving group represented as L 2 is used.
  • reaction conditions, reaction solvent, reaction time and the like in this reaction are carried out under the same reaction conditions and the like as described for the reaction of compound (IV) with compound (V) in Method B, or a method analogous thereto.
  • This reaction is carried out under the same reaction conditions, reaction solvents, reaction times, and the like as described for the reaction of compound (IV) with compound (V) in Method I, or a method analogous thereto.
  • M 5 is a hydrogen atom, an alkali metal '(eg, lithium, potassium, sodium, cesium, etc.), an alkaline earth metal (eg, calcium, magnesium, etc.) or a leaving group (eg, trimethylsilyl group And other symbols have the same meanings as above. Or a salt thereof.
  • the reaction conditions, reaction solvent, reaction time and the like in this reaction are carried out according to the reaction conditions and the like described for the deprotection reaction of compound (XI I) in Method F or a method analogous thereto.
  • reaction conditions, reaction solvent, reaction time and the like in this reaction are carried out according to the reaction conditions and the like described for the reaction of compound (II) with compound (II) in Method A, or a method analogous thereto.
  • reaction conditions, reaction solvent, reaction time, etc. in this reaction are determined by the reaction conditions described in the reaction of compound (IV) with compound (V) in Method B, or a method analogous thereto. Is
  • reaction conditions, reaction solvent, reaction time and the like in this reaction are carried out according to the reaction conditions, reaction solvents and the like described for the reaction of compound (VI) with compound (VI I) in Method D, or a method analogous thereto.
  • the reaction conditions, reaction solvent, reaction time, and the like in the oxidation reaction of the zeo atom are performed by the oxidizing agent, reaction conditions, reaction solvent, and the like described in the oxidation reaction of compound (la) in Method C, or a method analogous thereto.
  • reaction conditions, reaction solvent, reaction time and the like in this reaction are carried out according to the reaction conditions and the like described for the deprotection reaction of compound (XI I) in Method F or a method analogous thereto.
  • Raw material conjugates (II) used in the above-mentioned production methods A to M are described in, for example, Japanese Patent Application Laid-Open No. Hei 5-051383, Japanese Patent Laid-Open No. Hei 5-039392, European Patent Patent Application Publication No. 4 7 1 2 3 6
  • the other starting compounds (IV), (VI), (XI) and (XVI) can be prepared by a method known per se (for example, the method described in WO 02/062334 pamphlet or the like) or It can be manufactured by a similar method.
  • a compound When a compound is obtained in a free state by each reaction of the present invention, it may be converted to a salt according to a conventional method, and when obtained as a salt, it may be converted to a free form or another salt according to a conventional method. It can also be converted.
  • 3- (5-halogeno-2-indolyl), sulfonylpropionic acid, its ester or amide, or a salt thereof [preferably, 3- (5-chloro- 2-indolyl) sulfonylpropionic acid, its ester or its amide, or a salt thereof), and 3- (1-tert-butoxycarbonyl-5-halogeno-2-indolyl) sulfonylpropionic acid, its ester or
  • the amide or a salt thereof is a novel one.
  • any salt may be used as long as it does not hinder the reaction, and examples thereof include those similar to the salt used in compound (I).
  • any ester any ester may be used as long as it does not hinder the reaction.
  • ester examples include, for example, (1) lower alkyl- 6 esters such as methyl, ethyl and tert-butyl; (2) Organophosphates (eg, jetoxyphosphate, diphenoxyphosphate, etc.), (3) p-nitrophenylester, (4) 2,4-dinitrophenylester, (5) cyanomethylester, (6) Pentachlorophenyl ester, (7) N-hydroxysuccinimide ester, (8) N-hydroxyphthalimide ester, (9) 1-hydroxybenzotriazole ester, (10) 6-chloro-1-hydroxybenzotriazole ester, ( 1 1) 1-Hydroxy-1H-2-pyridone ester, (12) Thioester [for example, aromatic Heterocyclic thiol compounds [these heterocyclic rings - 6 alkyl (e.g.
  • any amide may be used as long as it does not hinder the reaction.
  • an amide with a nitrogen-containing heterocyclic compound for example, an acid amide with pyrazole, imidazole, benzotriazole, etc.
  • nitrogen-containing heterocyclic I ⁇ was _ 6 alkyl (e.g. methyl, Echiru, propyl, isopropyl, heptyl, Isopuchi Le, sec- heptyl, ter t-butyl, etc.), - 6 alkoxy (e.g.
  • 3- (5-halogeno-2-indolyl) sulfonylpropionic acid, its ester, amide or salt thereof, and 3- (1-tert-butoxycarbonyl-5-halogeno-2-indolyl) sulfonylpropionic acid, Esters, amides or salts thereof may be used in reactions for synthesizing compound (I) after being derivatized to acid halides, mixed acid anhydrides, etc., and examples of acid halides include acid chlorides and acids.
  • mixed acid anhydride include mono-_ 4 alkyl carbonate mixed acid anhydride (e.g., motor Nomechiru carbonate, Monoechiru carbonate, monoisopropyl carbonate, monoisobutyl carbonate, mono-tert- heptyl carbonate, Monobe Njiru carbonate, mono ( p-Nitrobenzyl) Mixed acid anhydride with carbonic acid, monoallyl carbonic acid, etc.),-Mixed aliphatic anhydride of 6 aliphatic carboxylic acids (eg acetic acid) , Shiano acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, Isokichi Kusasan, pivalic acid, Torifuruoro acetic, trichloroacetic port acetate, mixed acid anhydride with Aseto acetate), C 7 _!
  • mono-_ 4 alkyl carbonate mixed acid anhydride e.g., motor
  • optical isomers can be present in compound U), both of these individual optical isomers and mixtures thereof are, of course, included in the scope of the present invention.
  • Optical resolution or individual production can also be performed according to a means known per se.
  • Cerebral infarction ischemic cerebrovascular disorder, cerebral embolism due to atrial fibrillation and heart failure, valvular disease, acute ischemic stroke, acute cerebral thrombosis, cerebral vasospasm after subarachnoid hemorrhage, Alheimer's disease, Transient cerebral ischemic attacks (TI, mixed dementia, cerebrovascular dementia, asymptomatic / multiple cerebral infarction, lacunar infarction, etc.)
  • TI Transient cerebral ischemic attacks
  • Treatment improvement of prognosis of cerebral infarction
  • Secondary onset prevention, extracranial and internal arteries Prevention and treatment of thrombosis after bypass surgery, combined use or supplementary use with thrombolytic agents for cerebral infarction (especially ischemic cerebrovascular disease), combined therapy with antiplatelet drugs such as aspirin in preventing cerebral infarction.
  • acute coronary artery disease such as acute myocardial infarction, myocardial infarction, ischemic coronary artery disease, unstable angina pectoris, cardiomyopathy, acute heart failure, congestive chronic heart failure, valvular disease, etc.
  • Pulmonary embolism Acute pulmonary embolism, economy class syndrome, Thrombocytopenia due to dialysis' Augmentation of blood coagulation system ⁇ Complement activation, Thrombocytopenia during major surgery, Thrombocytopenic purpura, Atherosclerosis progression ⁇ Metastasis ⁇ Systemic inflammatory response syndrome (SIRS) or inflammation ⁇ Cancer ⁇ Leukemia ⁇ Major surgery ⁇ Disseminated intravascular coagulation (DIC) that occurs in patients with sepsis, hepatic dysfunction due to ischemia or ischemia or blood stasis Prevention and treatment of various organ failures (eg, pulmonary failure, liver failure, renal failure, heart failure, etc.), systemic lupus erythematosus, collagen disease, hyperthyroidism, postpartum paralysis, etc.
  • organ failures eg, pulmonary failure, liver failure, renal failure, heart failure, etc.
  • systemic lupus erythematosus collagen disease, hypert
  • the compound ⁇ of the present invention or a salt thereof can be administered orally or parenterally as it is or in combination with a pharmacologically acceptable carrier.
  • the preparation of the present invention containing compound (I) or a salt thereof has a dosage form for oral administration.
  • dosage forms for oral administration include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), syrups, emulsions, and suspensions.
  • dosage forms for parenteral administration include injections, infusions, drops, suppositories and the like.
  • a suitable base material eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, a mixture of butyric acid polymer and dalicholic acid polymer, polyglycerol It is also effective to form a sustained-release preparation in combination with a fatty acid ester.
  • the content of compound (I) or a salt thereof in the preparation of the present invention varies depending on the form of the preparation, but is usually 2 to 85% by weight, preferably 5 to 70% by weight, based on the whole preparation. %. ⁇
  • a method for producing the compound (I) or a salt thereof in the above-mentioned dosage form a known production method generally used in the art can be applied.
  • excipients if necessary, excipients, binders, disintegrants, lubricants, sweeteners, and the like which are usually used in the field of formulation when producing the dosage form. It can be produced by appropriately adding an appropriate amount of a surfactant, a suspending agent, an emulsifier and the like.
  • binders include 5 to 10% by weight starch paste, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, glycerin And the like.
  • disintegrants include starch, calcium carbonate and the like.
  • lubricant examples include magnesium stearate, stearic acid, calcium stearate, purified talc and the like.
  • sweetening agents examples include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.
  • surfactant examples include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl stearate 40, and the like.
  • suspending agents include gum arabic, sodium alginate, sodium lipoxymethylcell monosodium, methylcellulose, bentonite and the like.
  • emulsifiers include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.
  • a coloring agent, a preservative, a fragrance, a flavoring agent, a stabilizer, a thickener, etc. which are generally used in the field of purification, may be used.
  • An appropriate amount can be added.
  • the preparation of the present invention containing compound (I) or a salt thereof is stable, has low toxicity, and can be used safely.
  • the daily dose varies depending on the patient's condition, body weight, compound type, administration route, etc.For example, in the case of oral administration to a patient with thrombosis, an adult
  • the daily dose is about 1 to 2000 mg, preferably about 3 to 100 mg, more preferably about 1 to 200 mg as the active ingredient (compound (I) or a salt thereof). 10 to 50 mg, which can be administered once or in two or three divided doses.
  • the compound (I) of the present invention or a salt thereof is administered parenterally, it is usually administered in the form of a liquid (eg, an injection).
  • a liquid eg, an injection
  • the single dose varies depending on the administration subject, target organ, symptoms, administration method, and the like, but, for example, in the form of an injection, usually about 0.0 lmg to about 100 mg / kg body weight, preferably about 100 mg / kg. It is convenient to administer about 0.01 to about 50 mg, more preferably about 0.01 to about 20 mg, by intravenous injection.
  • Injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intravenous injections, etc., and sustained-release preparations include iontophoresis transdermals Etc. are included.
  • Such injections are prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound (I) of the present invention or a salt thereof in a sterile aqueous or oily liquid.
  • Aqueous liquids for injection include physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium salt, sodium salt, etc.).
  • glucose and other adjuvants eg, D-sorbitol, D-mannitol, sodium salt, sodium salt, etc.
  • alcohols eg, ethanol
  • polyalcohols eg, propylene glycol, polyethylene glycol
  • nonionic surfactants eg, polysorbate 80, HCO-50
  • oily liquid examples include sesame oil and soybean oil, which may be used in combination with a solubilizing agent such as benzyl benzoate or benzyl alcohol.
  • a solubilizing agent such as benzyl benzoate or benzyl alcohol.
  • buffers eg, phosphate buffer, sodium acetate buffer
  • soothing agents eg, benzalkonium chloride, proforce hydrochloride, etc.
  • stabilizers eg, human serum albumin, polyethylene glycol, etc.
  • storage Agents eg, benzyl alcohol, phenol, etc.
  • the compound of the present invention may be suitably used for inhibiting HMG-CoA reductase such as thrombolytic agents (eg, TPA, perokinase, etc.), therapeutic agents for Alheimer (eg, carane, etc.), cholesterol (eg, simpastatin, pravastatin, etc.) Drugs), TG lowering drugs (eg, clofibrate, etc.), AII antagonists (eg, candesartan cilexetil, rosartan, etc.), antiplatelet drugs (eg, clopidogrel, abciximab, aspirin, etc.), Ca antagonists (eg, , Calslot, amlodipine, etc.), ACE inhibitors (eg, enalabril, captopril, etc.), j3 blockers (eg, metoprolol, carvedil, etc.), antiarrhythmic drugs (eg, procarinamide, etc.) (Hereinafter abbreviated
  • the concomitant drug may be a low molecular compound, a high molecular protein, a polypeptide, an antibody, or a vaccine.
  • the administration form of the compound of the present invention and the concomitant drug is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) separate preparation of the compound of the present invention and the concomitant drug.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the compound of the present invention.
  • the present invention is further described in the following Examples, Preparation Examples and Experimental Examples, which are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. It may be changed in a range.
  • Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography, thin layer chromatography).
  • TLC Thin Layer Chromatography, thin layer chromatography
  • a TLC plate was detected using Merck's 60F254 or Fuji Silica Chemical's NH, and the developing solvent used was the solvent used as the elution solvent in column chromatography. UV detector was adopted as the method.
  • silica gel for the column Kieselgel 60 (70 to 230 mesh) or Kieselgel 60 (230 to 400 mesh) also manufactured by Merck was used.
  • As the basic silica gel for the column basic silica NH-DM1020 (100 to 200 mesh) manufactured by Fuji Silicon Chemical Co., Ltd. was used.
  • NMR spectra were measured on a Varian Gemini 200 or 300 spectrometer using tetramethylsilane as internal or external standard, chemical shifts ⁇ 5 values, and coupling constants in Hz. Indicated. IR spectra were measured with a Shimadzu FTZR-8200 spectrometer. In the mixed solvents, the numerical values shown in parentheses are the volume mixing ratios of each solvent. The% in the solution represents the number of grams in 100 ml of the solution. The symbols in Reference Examples and Examples have the following meanings. s: Singlelet
  • 5-Icloimidazo [1,2-a] pyridine (4.58 g) and piperazine (25.8 g) were mixed and stirred at 125 ° C for 18 hours in an atmosphere of argon.
  • Water (200 mL) and chloroform (200 mL) were added to the obtained solid, and the organic layer was separated.
  • the organic layer was washed with brine (200 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in ethanol (100 mL), di-tert-butyl dicarbonate (6.55 g) was added dropwise at room temperature, and the reaction solution was stirred at room temperature for 1 hour.
  • reaction solution was poured into ice water (500 mL) and extracted with ethyl acetate (150 mL). The extract was washed with water (150 mL X 3) and saturated saline QOOL), dried over anhydrous magnesium sulfate, The solvent was distilled off under reduced pressure.
  • Example 5 5- [4- [3-C (1-1 ert-butoxycarbonyl-5-coguchi-2-indolyl) sulfonyl] propionyl] -1-piperazinyl] -2-methyl obtained in Example 5
  • 0.47 g (yield 73%) of the title compound was obtained as a white powder from imidazo [1,2-a] pyridin (0.72 g).
  • Example 9a The title was obtained in the same manner as in Example 7b) from tert-butyl 4- (imidazo [1,2-a] pyridin-5-yl) -2-pyrazinecarboxylate (0.65 g) obtained in Example 9a). 0.47 g (yield 38%) of the compound was obtained as a colorless powder. NMR (CDC1 3) (51.46 ( 9H, s), 2.75-5.19 (11H,), 6.29
  • Example 11 5- [4- (tert-Butoxycarbonyl) -3-methyl-1-piperadiel] imidazo [1,2-a] pyridine (8.54 g) obtained in a) was added to concentrated hydrochloric acid (22.2 mL). ) And stirred at room temperature for 20 minutes. Ethanol (85 mL) was added to the reaction solution, the resulting mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. Crystals are ethanol (10 mL) and getyl ether (10 mL) After drying under reduced pressure, 5.93 g (yield 76%) of the title compound was obtained as pale brown crystals.
  • Example 12c 5- [4- [3-[(6-Couguchi-2-naphthyl) sulfonyl] propionyl] -3-methyl-1-piperazinyl] -2-methylimidazo [1] obtained in Example 12c)
  • 0.51 g Yield 98%) of the title compound was obtained as a white powder from [, 2-a] pyridine (0.61 g).
  • Example 32 5- [4- [3-[(6-Chloro-2-naphthyl) sulfonyl] propioel] -3-carboxy-1-piperazinyl] -2-methylimidazo [1,2-a] pyridine obtained in Example 32
  • the title compound (0.22 g, yield 49%) was obtained as a colorless powder from (0.50 g) in the same manner as in Example 8.
  • Example 15 5- [4- (tert-Butoxycarbonyl) -1-piperazinyl] -3-nitroimidazo [1,2-a] pyridine (17.4 g) obtained in a) in methanol (300 mL) A 4N hydrogen chloride / ethyl acetate solution (80 mL) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from ethanol to give 3-nitro-5- (topiperazinyl) imidazo [1,2-a] pyridine • dihydrochloride as yellow crystals, 16.Og (quantitative determination). Target).
  • 3_Nitro-5- (1-piperazinyl) imidazo [1,2-a] pyridine'DBIK9.13 g) was added to a suspension of dihydrochloride (9.61 g) in acetonitrile (300 mL) and the mixture was added at room temperature for 10 minutes. Stirred. 3- (6-Chloro-2-naphthyl) sulfonylpropionic acid (8.96 g) and 0Bt (5.51 g) were added, and the mixture was cooled to 0 ° C. Triethylamine (6.07 g) and WSC (6.90 g) were added to the mixture, and the mixture was stirred at room temperature for 2 days.
  • the reaction solution was concentrated under reduced pressure, and the obtained residue was concentrated in 10% sodium carbonate. Diluted with aqueous solution of water and extracted with dichloromethane. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by a basic silica gel column (eluent: hexane Z: ethyl acetate 1: 3), and crystallized from ethyl acetate to give 9.95 g (yield 63%) of the title compound as pale yellow crystals. .
  • the obtained residue was diluted with a 10% aqueous solution of sodium carbonate and extracted with dichloromethane. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue obtained is purified with basic silica gel column (eluent; methanol Z ethyl acetate 1:20), dissolved in a mixture of ethyl acetate and ethanol, and 4N ethyl acetate hydrogen chloride solution (5 mL) And stirred under ice-cooling for 30 minutes. The precipitate was collected by filtration, washed with ethyl acetate, and dried to give the title compound (1.02 g, yield 11.4) as colorless crystals.
  • Example 32 5- [4- [3-[(6-Couguchi-2-naphthyl) sulfonyl] propionyl] -3-carpoxy-1-piperazinyl] -2-methylimidazo obtained in Example 32 a] Dissolve pyridine (0.40 g), WSC (0.20 g), and HOBt (0.16 g) in DMF (10 mL), add 40% aqueous methylamine solution (0.1 g), stir for 10 minutes, and then add triethylamine (0.42 g). ) And at room temperature
  • Example 24 From 5- [4- (tert-butoxycarpenyl) -1-piperazinyl] -2- (trihydroxyethyl) imidazo [1,2-a] pyridine (3.46 g) obtained in Example 24a) lb) to give 2.87 g (yield 90%) of the title compound.
  • the reaction solution was concentrated under reduced pressure, diluted with an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. After the extract was dried over sodium sulfate, the solvent was concentrated under reduced pressure.
  • the obtained residue was purified by basic silica gel ram (ethyl acetate to ethyl acetate Z methanol 20: 1) to obtain 0.11 g of an amide compound as a pale yellow powder.
  • the obtained amide form (0.11 g) was dissolved in concentrated hydrochloric acid (ImL) and stirred at room temperature for 1 hour.
  • a saturated aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was diluted with an aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column (chloroform / methanol 20: 1 ⁇ 10: 1) to give the title compound (60 rag, yield 24%) as a colorless powder.
  • Example lc from the 2- (N-acetylaminomethyl) -5- (topiperazinyl) imidazo [1,2-a] pyridine dihydrochloride (1.04 g) obtained in Example 29d). In the same manner as in the above, 1.25 g (yield 90%) of the title compound was obtained.
  • the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by a basic silica gel column (eluent; ethyl acetate / ethyl acetate / methanol 20: 1), and the resulting compound was dissolved in ethanol (2 mL). (0.5 mL) and concentrated under reduced pressure.
  • the residue was recrystallized from ethyl acetate to give the title compound (120 mg, yield 51%) as a white powder.
  • N-Chlorosuccinimide (0.76 g) was treated with 2- (N-acetylaminomethyl) -5- [4- (tert-butoxycarbonyl) -1-piperazinyl] imidazo [1,2-a] pyridine (1.6 g) )), And stirred at room temperature for 1 hour. Saturated hydrogen carbonate The extract was washed sequentially with an aqueous solution (20 mL) and saturated saline (20 mL), and dried over anhydrous magnesium sulfate.
  • Example 38a Performed from 5-6- [3- (methylcarbamoyl) methyl-4- (tert-butoxycarbonyl) -1-piperazinyl] -2-methylimidazo [1,2-a] pyridine (0.26 g) obtained in Example 38a). In the same manner as in Example 37d), 0.12 g (yield 38%) of the title compound was obtained as a colorless powder.
  • the imidazo [1,2-a] pyridine (0.18 g) was optically resolved by HPLC (CHIRALPAK AS 4.6 mm x 25 mm, eluent: hexane / ethanol 70:30) using a chiral stationary phase.
  • the title compound (80 mg, optical purity 99.9 or more) was obtained as a pale yellow powder as a pre-elution component.
  • Example 1c was obtained from 5- (1-piperazinyl) -2- (N-trifluoromethanesulfonylaminomethyl) imidazo [1,2-a] pyridine 'dihydrochloride (1.31 g) obtained in Example 43b).
  • Example 36b from 5- [4- (tert-butoxycarbonyl) -1-piperazinyl] -2- (ethoxycarbonylmethyl) imidazo [1,2-a] pyridine (1.5 g) obtained in Example 44b) )) And 5- [4- [3-[(6-Cupro-2-naphthyl) sulfonyl] propionyl] -1-pyrazinyl] -2-ethoxycarbonylmethylimidazo [1,2-a
  • the pyridine was obtained as a colorless oil.
  • Example 45b) obtained from 5- [4- (tert-butoxycarbonyl) -1-piperazinyl] -2- (2-hydroxyethyl) imidazo [1,2-a] pyridine (2.0 g) obtained in Example 45b) In the same manner as in 36b), 1.5 g (yield 62%) of the title compound was obtained as white crystals.
  • reaction solution was washed with an aqueous sodium hydrogen carbonate solution and concentrated under reduced pressure.
  • residue was purified by silica gel column (eluent; ethyl acetate-ethyl acetate methanol 20: 1) to give the title compound (0.65 g, yield 59%) as a brown oil.
  • the reaction solution was concentrated under reduced pressure, diluted with an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (eluent; ethyl acetate ⁇ ethyl acetate / methanol 5: 1) to give 0.42 g (yield 79%) of the title compound as a yellow oil.
  • 1.07 g (yield 81%) of the title compound was obtained as a white solid.
  • Example 3e The title was obtained in the same manner as in Example 3e) from the 2- (1-hide mouth quichetyl) -5 (topiperazinyl) imidazo [1,2-a] pyridine 'dihydrochloride (0.83 g) obtained in Example 24b). 0.89 g (yield 72%) of the compound was obtained as a pale yellow powder.
  • the reaction mixture was poured into an ice-cooled saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform (100 mL ⁇ 2). After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (ethyl acetate / ethanol 5: 1 ⁇ 2: 1) to obtain 3.45 g (yield 69%) of the title compound as a pale yellow solid.
  • Example 51 Performed from 5- [4- (tert-butoxycarbonyl) -1-piperazinyl] -2- (dimethylcarbamoyl) methylimidazo [1,2-a] pyridine (1.5 g) obtained in a). In the same manner as in Example 44, 1.5 g (yield 67%) of the title compound was obtained as a white solid.
  • Example 53 from 5- [4- (tert-butoxycarbonyl) -1-piperazinyl] -2-((pyrubamoyl) methylimidazo [1,2-a] pyridine (0.91 g) obtained in Example 53a). In the same manner as in 36b), 0.59 g (yield 62%) of the title compound was obtained as white crystals. NMR (CDC1 3) ⁇
  • Example 41 5- [4- (tert-butoxycarbonyl) -3- (2-hydroxyethyl) -1-piperazinyl] -2-methylimidazo [1,2-a] pyridine (0.50) obtained in a) To a solution of g) and triethylamine (0.28 g) in THF (5 mL) was added methanesulfonyl chloride (0.16 mL) while cooling to 0 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with an aqueous solution of sodium carbonate and extracted with ethyl acetate.
  • the reaction solution was diluted with an aqueous sodium hydrogen carbonate solution, and the organic layer was separated.
  • the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by basic silica gel column (eluent; ethyl acetate-ethyl acetate Zmethanol 20: 1) to obtain 210 mg (yield: 45) of the title compound as a colorless powder.
  • [1,2-a] pyridine dihydrochloride was obtained as a white solid.
  • 3 _ [(1-tert-butoxycarbonyl-5-chloro-2-indolyl) sulfonyl] propionic acid (1.0 g) was suspended in acetonitrile (50 mL). HOBt ⁇ H 20 (0.66 g), WSC (0.75 g) was added sequentially, and the mixture was stirred at room temperature for 20 minutes. To this reaction mixture, add the previously obtained 5- (1-piperazinyl) -2- (2-hydroxyethyl) imidazo [1,2-a] pyridine 'dihydrochloride, DBU (936 mL) and triethylamine (1.1 mL).
  • Example 60 Performed on a solution of 3-[(6-chloro-2--2-naphthyl) sulfonyl] propanoic acid (0.45 g) obtained in Example 60a), WSC (0.43 g) and HOBt (0.35 g) in DMF (30 mL).
  • Example 60 5- [3- (Caprubamol) -1-piperazinyl] -2-ethoxycarponylimidazo [1,2-a] pyridin (0.48 g) obtained in a) was added and stirred at room temperature for 3 days. .
  • the reaction solution was concentrated under reduced pressure, diluted with an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate and THF.
  • Cyanuric chloride (0.50 g) was obtained in Example 53a) as 5- [4- (tert-butoxycarbonyl) -1-pidrazinyl] -2- (potumbamoyl) methylimidazo [1, 2-a].
  • Pyridine (1.95 g) was added to a dimethylformamide solution (6 mL), and the mixture was stirred at room temperature for 1 hour.
  • cyanuric chloride (0.5 g) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. Under ice-cooling, a saturated aqueous solution of hydrogencarbonate (50 mL) and ethyl acetate (50 mL) were added to the reaction solution.
  • Trimethyltin azide (0.43 g) was obtained from 5- [4- (tert-butoxycarbonyl) -1-piperazinyl cyanomethylimidazo [1,2-a] pyridine (0.47 g) obtained in Example 62a). The mixture was added to a toluene solution and refluxed for 12 hours under an argon atmosphere. After the toluene was distilled off under reduced pressure, the residue was dissolved in methanol and concentrated again under reduced pressure. To the residue was added ethyl ether, and the precipitate was collected by filtration to give the title compound (0.68 g, quantitative) as a pale-brown solid.
  • Example 51a A 5- [4_ (tert-butoxycarbonyl) -1-] obtained in Example 51a) was added to a suspension of cerium salt (5.72 g) in THF (30 mL) vigorously stirred at room temperature for 12 hours under a nitrogen atmosphere. Piperazinyl] -2- (dimethylcarbamoyl) methylimidazo [1,2-a] pyridine (3.0 g) was added, and the mixture was stirred for 1 hour. To this mixture was added dropwise a 1M methylmagnesium bromide solution in THF (124 mL) at 0 ° C, and the mixture was stirred at the same temperature for 1 hour.
  • the reaction mixture was poured into an ice-cooled 5% aqueous acetic acid solution, and extracted with ethyl acetate (50 mL ⁇ 3). The extract was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by a silica gel column (eluent: ethyl acetate-ethyl acetate / ethanol 2: 1) to give 1.9 g (yield 69%) of the title compound as a yellow oil.
  • Example 64b Performed from 5- [4- (tert-butoxycarbonyl) -1-piperazinyl] -2- (2-hydroxypropyl) imidazo [1,2-a] pyridine (0.88 g) obtained in Example 64b). In the same manner as in Example 36b), 0.72 g (yield 73%) of the title compound was obtained as white crystals.
  • the mixture was stirred at 125 ° C. for 18 hours under an argon atmosphere.
  • Water (200 mL) and chloroform (200 mL) were added to the obtained solid, the organic layer was separated, washed with saturated brine (200 mL), and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, the obtained residue was dissolved in ethanol (100 mL), di-tert-butyl dicarbonate (5.36 g) was added dropwise at room temperature, and the reaction solution was stirred at room temperature for 1 hour. .
  • the solvent was distilled off under reduced pressure, water (200 mL) was added to the residue, and the mixture was extracted with ethyl acetate (200 mL).
  • Example 65b 5- (2,3,5,6-tetrahydro-7H-1,4-diazepine-tolyl) obtained in Example 65b) 1.12 g (yield 90%) of the title compound was obtained as a colorless powder from imidazo [1,2-a] pyridine dihydrochloride (0.87 g) in the same manner as in Example lc).
  • the reaction solution was poured into ice water and stirred for 10 minutes. After adding concentrated hydrochloric acid to PH3, the mixture was stirred at 0 ° C for 1 hour.
  • the reaction solution was made alkaline by adding an aqueous solution of potassium carbonate, and then extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The brown oily residue was dissolved in concentrated hydrochloric acid (2 mL) and ethanol (2 mL) and stirred at room temperature for 1 hour.
  • 71c tert-butyl 4-imidazo [1,2-a] pyridine-6-yl-1-pyrazinecarboxylate 4- (6-amino-3-pyridinyl) -1 obtained in Example 71 b) -Piperazinecarponic acid tert-butyl (240 mg) and a 40% aqueous chloroacetaldehyde solution (338 mg) were dissolved in ethanol (20 mL) and refluxed for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with an aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate.

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Abstract

La présente invention concerne un dérivé imidazopyridine représenté par la formule (I) dans laquelle Ar représente naphtyle facultativement substitué, phényle facultativement substitué, indolyle facultativement substitué ou benzothiényle facultativement substitué; X représente un groupe hydrocarbure bivalent facultativement substitué; Z représente -CO-, -SO- ou -SO2-; l'anneau A représente un anneau pipérazine facultativement substitué ou un anneau homopipérazine facultativement substitué; l'anneau B représente un anneau imidazopyridine facultativement substitué; et a représente 0, 1 ou 2. Ce dérivé est utile en tant qu'agent thérapeutique destiné à la thrombose. Formule (I)
PCT/JP2003/013122 2002-10-15 2003-10-14 Derive imidazopyridine, procede de production de ce dernier et utilisation correspondante WO2004035579A1 (fr)

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US7745623B2 (en) 2004-05-21 2010-06-29 Takeda Pharmaceutical Company Limited Cyclic amide derivative, and its production and use
US8071614B2 (en) 2007-10-12 2011-12-06 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8076354B2 (en) 2007-10-12 2011-12-13 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8481531B2 (en) 2009-04-15 2013-07-09 Astex Therapeutics Ltd Bicyclic heterocyclyl derivatives as FGFR kinase inhibitors for therapeutic use
US8513276B2 (en) 2006-12-22 2013-08-20 Astex Therapeutics Limited Imidazo[1,2-a]pyridine compounds for use in treating cancer
US8716282B2 (en) 2009-10-30 2014-05-06 Janssen Pharmaceutica Nv Imidazo[1,2-b]pyridazine derivatives and their use as PDE10 inhibitors
US8722687B2 (en) 2009-04-15 2014-05-13 Astex Therapeutics Ltd Imidazo [1,2-A]pyridine derivatives as FGFR kinase inhibitors for use in therapy
US8796244B2 (en) 2008-06-13 2014-08-05 Astex Therapeutics Ltd Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
US8835441B2 (en) 2005-05-20 2014-09-16 Amgen Inc. Heterobicyclic metalloprotease inhibitors
US8859543B2 (en) 2010-03-09 2014-10-14 Janssen Pharmaceutica Nv Imidazo[1,2-a]pyrazine derivatives and their use for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases
US8895745B2 (en) 2006-12-22 2014-11-25 Astex Therapeutics Limited Bicyclic heterocyclic compounds as FGFR inhibitors
US9550784B2 (en) 2012-07-09 2017-01-24 Beerse Pharmaceutica NV Inhibitors of phosphodiesterase 10 enzyme
US9669035B2 (en) 2012-06-26 2017-06-06 Janssen Pharmaceutica Nv Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders
US10604523B2 (en) 2011-06-27 2020-03-31 Janssen Pharmaceutica Nv 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors

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US7745623B2 (en) 2004-05-21 2010-06-29 Takeda Pharmaceutical Company Limited Cyclic amide derivative, and its production and use
US8835441B2 (en) 2005-05-20 2014-09-16 Amgen Inc. Heterobicyclic metalloprotease inhibitors
US8895745B2 (en) 2006-12-22 2014-11-25 Astex Therapeutics Limited Bicyclic heterocyclic compounds as FGFR inhibitors
US8513276B2 (en) 2006-12-22 2013-08-20 Astex Therapeutics Limited Imidazo[1,2-a]pyridine compounds for use in treating cancer
US8859582B2 (en) 2007-10-12 2014-10-14 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8076354B2 (en) 2007-10-12 2011-12-13 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8859583B2 (en) 2007-10-12 2014-10-14 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8071614B2 (en) 2007-10-12 2011-12-06 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8796244B2 (en) 2008-06-13 2014-08-05 Astex Therapeutics Ltd Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
US8722687B2 (en) 2009-04-15 2014-05-13 Astex Therapeutics Ltd Imidazo [1,2-A]pyridine derivatives as FGFR kinase inhibitors for use in therapy
US8481531B2 (en) 2009-04-15 2013-07-09 Astex Therapeutics Ltd Bicyclic heterocyclyl derivatives as FGFR kinase inhibitors for therapeutic use
US8716282B2 (en) 2009-10-30 2014-05-06 Janssen Pharmaceutica Nv Imidazo[1,2-b]pyridazine derivatives and their use as PDE10 inhibitors
US8859543B2 (en) 2010-03-09 2014-10-14 Janssen Pharmaceutica Nv Imidazo[1,2-a]pyrazine derivatives and their use for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases
US10604523B2 (en) 2011-06-27 2020-03-31 Janssen Pharmaceutica Nv 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives
US9669035B2 (en) 2012-06-26 2017-06-06 Janssen Pharmaceutica Nv Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders
US9550784B2 (en) 2012-07-09 2017-01-24 Beerse Pharmaceutica NV Inhibitors of phosphodiesterase 10 enzyme
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation

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