WO1998042688A1 - Derives de 4-arylmethylene-1,4-dihydro-2h-azine - Google Patents

Derives de 4-arylmethylene-1,4-dihydro-2h-azine Download PDF

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Publication number
WO1998042688A1
WO1998042688A1 PCT/JP1998/001291 JP9801291W WO9842688A1 WO 1998042688 A1 WO1998042688 A1 WO 1998042688A1 JP 9801291 W JP9801291 W JP 9801291W WO 9842688 A1 WO9842688 A1 WO 9842688A1
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group
optionally substituted
substituted
atom
ring
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PCT/JP1998/001291
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English (en)
Japanese (ja)
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Masashi Nakatsuka
Shin-Ichiro Okada
Kazunori Shimano
Shoji Watanabe
Yu Suzuki
Fumio Nishikaku
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Sumitomo Pharmaceuticals Co., Ltd.
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Priority to AU64232/98A priority Critical patent/AU6423298A/en
Publication of WO1998042688A1 publication Critical patent/WO1998042688A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a 4-arylmethylene-11,4-dihydro-12H-azine derivative useful as an osteoclast differentiation induction inhibitor, an anti-inflammatory drug, a bone destruction inhibitor, an antirheumatic drug, and the like.
  • non-steroidal anti-inflammatory drugs have been used as anti-inflammatory drugs and anti-rheumatic drugs. It is said that these inhibitors inhibit cyclooxygenase and block the biosynthesis of prostaglandins, which contributes to the effect (Allergy Clin. Immunol., Vol. 58, 691 (1976)). Also, a number of new nonsteroidal anti-inflammatory drugs are being searched for those that inhibit cyclooxygenase.
  • conventional non-steroidal anti-inflammatory drugs have the effect of reducing swelling and pain of inflammation, but cannot prevent the progression of bone tissue destruction in arthritis.
  • side effects such as gastrointestinal tract disorders often pose a problem, especially in the case of long-term administration. Therefore, there is a need for a novel anti-inflammatory drug having an essential therapeutic effect for inhibiting tissue destruction and having no side effects.
  • An object of the present invention is to provide a compound useful as an osteoclast differentiation induction inhibitor, an anti-inflammatory drug, a bone destruction inhibitor, an antirheumatic drug, and the like.
  • the present inventors have solved the above problem by using an osteoclast differentiation-inducing system reported in the above-mentioned reference (Journal of Bone Metabolism, Vol. 12, 188 (1994)).
  • an osteoclast differentiation-inducing system reported in the above-mentioned reference (Journal of Bone Metabolism, Vol. 12, 188 (1994)).
  • 4-arylmethylene-1,4-dihydro-2H-azine derivatives have strong osteoclast differentiation-inducing activity. Issued.
  • the present derivatives strongly inhibit collagen-induced arthritis in mice, and have completed the present invention. That is, the present invention is as follows.
  • Ar represents an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group.
  • Ring Ar 1 is an optionally substituted aromatic hydrocarbon ring or an optionally substituted aromatic hydrocarbon ring. Represents a ring.
  • R 1 is a hydrogen atom, a hydroxyl group, an optionally substituted sulfamoyl group, an optionally substituted sulfamoyl group ', a sulfo group, one R 3 , -OR 3 , one CO 2 R 4 , one (CS) OR 5 , One (C 0) represents SR 5 or — CS 2 R 5 .
  • R 3 is an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted heterocyclic group, Represents an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group or an optionally substituted
  • R 4 is an optionally substituted alkyl group, an optionally substituted aryl group or a substituted
  • R 5 represents an optionally substituted alkenyl group, an optionally substituted alkynyl group or an optionally substituted heterocyclic group, and R 5 represents an optionally substituted alkyl group or an optionally substituted aryl group.
  • R 2 represents a hydrogen atom, an optionally substituted sorbamoyl group, an optionally substituted sulfamoyl group, a sulfo group, a halogen atom, a cyano group, a nitro group, a carboxyl group, an optionally substituted amino group, An optionally substituted hydroxylamino group, mercapto group, acyl group, acyloxy group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted alkoxy group, 1S ( 0) n R 6, represents an R 7 or a C0 2 R 7.
  • R 2 represents one C ⁇ CH 2 —, one C0NH—, one C00—, —CON (lower alkyl) one or —CH 2 CH 2 —, and is bonded to the ortho position of Ar at the other end.
  • R 6 is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted
  • R 7 represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group Represents a ring group.
  • E represents an oxygen atom, a sulfur atom or one N (R 8 ).
  • R 8 represents a hydrogen atom, a hydroxyl group, an optionally substituted rubamoyl group, an optionally substituted sulfamoyl group, a sulfo group, one R 9 , -OR 9 , one CO 2 R 10 , one ( CS) OR It represents a CS 2 R U - u, - (CO) SR 11 or.
  • R 9 represents an alkyl group which may be substituted, an aryl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a heterocyclic group which may be substituted
  • R 1Q represents an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted alkenyl group, or an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group or an optionally substituted cycloalkyl group.
  • R 11 represents an optionally substituted alkynyl group or an optionally substituted heterocyclic group
  • R 11 represents an optionally substituted alkyl group or an optionally substituted aryl group.
  • A represents an oxygen atom, a sulfur atom or one N (R 12 ).
  • R 12 is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl
  • Ar is phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, chenyl, pyrrolyl, furyl, benzocenyl, benzofuryl, indolyl, imidazolyl, isorazolyl, azozolyl, azozolyl.
  • a monocyclic heterocyclic carbonyl group an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkoxy group, an optionally substituted lower Substituted with one or more groups arbitrarily selected from the group consisting of an alkenyl group, an optionally substituted lower alkynyl group, a lower alkylthio group, a lower alkylcarbonyl group, a lower alkylsulfinyl group and a lower alkylsulfonyl group [ 4] -Arylmethylene-1,4, dihydro-2H-azine derivative or a geometric isomer thereof or a pharmaceutically acceptable salt thereof according to any one of [1] to [3]. Salt,
  • Ring Ar 1 is a benzene ring, a naphthalene ring, a pyridine ring, a pyrazine ring, a pyrimidin ring, a pyridazine ring, a quinoline ring, an isoquinoline ring, a quinazoline ring, a quinoxaline ring, a thiophene ring, a pyronyl ring, a furan ring , Benzothiophene, benzofuran, indole, imidazoyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, benzimidazolyl, benzothiazole A 4-benzoylmethylene-1,4-dihydro_2H-azine derivative or its isomer according to any one of [1] to [4], which is a benzoxazole ring or a substituted
  • the ring Ar 1 is a benzene ring, a naphthalene ring, a pyridine ring or a substituted ring thereof.
  • the 4-arylmethylene-1,1,4-dihydro-2H-azine derivative or the geometric isomer thereof The body or a pharmaceutically acceptable salt thereof,
  • the ring represented by ring Ar 1 is unsubstituted, or the ring represented by ring Ar 1 is halogen atom, nitro group, cyano group, hydroxyl group, carboxy group, sulfo group, or substituted Amino group, optionally substituted rubamoyl group, monocyclic heterocyclic group optionally substituted with lower alkyl group, monocyclic heterocyclic carbonyl group optionally substituted with lower alkyl group, A lower alkyl group which may be substituted, a lower alkoxy group which may be substituted, a lower alkoxycarbonyl group which may be substituted, a lower alkenyl group which may be substituted, a lower alkynyl group which may be substituted, a lower alkylthio group, Lower alkylcarbonyl group, lower ⁇ [1] 4-alkylmethylene-1, which is substituted with one or more groups arbitrarily selected from the group consisting of a alkylsulfinyl group and
  • R 1 is —R 3 or —OR 3 (R 3 is as defined above), and R 8 is —R 9 or one OR 9 (R 9 is as defined above).
  • R 1 is —R 3 or —OR 3 (R 3 is as defined above)
  • R 8 is —R 9 or one OR 9 (R 9 is as defined above).
  • R ⁇ R 8 and R 12 are lower alkyl group which may be substituted, respectively, is being a lower alkyl group or a substituted be an optionally substituted phenyl group [8], wherein the 4 one ⁇ Li one Lmethylene-1,4-dihydro-2H-azine derivative or its geometric isomer or a pharmaceutically acceptable salt thereof,
  • R 2 is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, or an optionally substituted
  • a 4-cycloalkylenyl group or an optionally substituted aryl group [1] 4-arylmethylene-11,4-dihydro-12H-azine derivative or a derivative thereof according to any one of [9] to [9].
  • E is an oxygen atom or a sulfur atom.
  • [1 3] 4-arylmethylene 1-1 according to any one of [1] to [ 12 ], wherein A is an oxygen atom or —N (R 12 ) — (R 12 is as defined above). , 4-Dihydro-1 2 H-azine derivatives or geometric isomers thereof or pharmaceutically acceptable salts thereof,
  • Ar 2 is a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 3 carbon atoms which may be substituted by a hydroxyl group, an alkenyl group having 1 to 3 carbon atoms which may be substituted by a hydroxyl group, a hydroxyl group Substituted with an alkynyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an alkylthio group having 1 to 3 carbon atoms, an alkylsulfinyl group having 1 to 3 carbon atoms, and a lower alkyl group.
  • 2-naphthyl group which may be substituted with a group selected from the group consisting of a jyl group, a fluorine atom, a chlorine atom and a bromine atom, or a group selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom Represents a 2-quinolyl group.
  • E 1 represents an oxygen atom or a sulfur atom.
  • Q represents C (R 25 ) or a nitrogen atom.
  • R 24 and R 25 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an alkyl group having 1 to 3 carbon atoms which may be substituted by a hydroxyl group.
  • R 22 and R 23 is (1) or (2) Notoori below.
  • R 22 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-imidazolyl, 2-imidazolyl, a carbamoyl group or a lower alkoxycarbonyl group in which a nitrogen atom may be substituted by a lower alkyl group Represents an alkyl group having 1 to 3 carbon atoms.
  • R 23 is — (CH 2 ) nl —R 26 (nl represents 0, 1, 2 or 3.
  • R 2 6 represents a carboxy group, a sulfo group, an amino group which may be substituted with a lower alkyl group, pyrrolidino, piperidino, morpholino, 4-methylpiperazinyl, 1-imidazolyl, 2-imidazolyl or tetrazolyl.
  • R 26 is as defined above.), 10 CH 2 COOH, 1 CH—CHCOOH, or —CH ( CH 3 ) represents COOH.
  • R 22 is-(CH 2 ) n 2 -R 27 (n 2 represents 2 or 3.
  • R 27 is an amino group optionally substituted with a hydroxyl group or a lower alkyl group, pyrrolidino, piperi Represents dino, 1-imidazolyl or 2-imidazolyl.) Or — (CH 2 ) n 3 —COOH (n 3 represents 1, 2 or 3).
  • R 23 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, fluorine atom, chlorine atom, bromine atom, an alkoxy group having 1 to carbon atoms 3, an alkylthio group having 1 to 3 carbon atoms, alkyl of 1 to 3 carbon atoms A sulfinyl group, an alkanoyloxy group having 1 to 3 carbon atoms, a hydroxyl group, a rubamoyloxy group in which a nitrogen atom may be substituted with a lower alkyl group, and a sulfamoyl in which a nitrogen atom may be substituted with a lower alkyl group Oxy, cyano, cyanomethoxy, mono (CH 2 ) nl —R 26 (n 1 and R 26 are as defined above), —0— (CH 2 ) n 2 -R 26 (n 2 And R 26 are as defined above.), Represents one OCt COOH, one CH-CHCOOH or one
  • Ar 3 is a carbon atom which may be substituted with a fluorine atom, a chlorine atom, a bromine atom, and a hydroxyl group.
  • An alkyl group having 1 to 3 carbon atoms, an alkenyl group having 1 to 3 carbon atoms which may be substituted with a hydroxyl group, an alkynyl group having 1 to 3 carbon atoms which may be substituted with a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, carbon At least one or more groups selected from the group consisting of alkylthio groups of formulas 1-3, alkylsulfinyl groups of 1-3 carbon atoms, amino groups optionally substituted by lower alkyl groups, pyrrolidino, piperidino and nitro groups
  • Q 1 represents a methine or nitrogen atom.
  • R 28 and R 29 are as described in (1) or (2) below.
  • R 28 represents an alkyl group having 1 or 2 carbon atoms which may be substituted with a phenyl or lower alkoxycarbonyl group.
  • R 29 is — (CH 2 ) nl -R 30 (n 1 is as defined above.
  • R 28 is-(CH 2 ) n 2 -R 31 (n 2 is as defined above.
  • R 31 represents an amino group optionally substituted with a lower alkyl group, pyrrolidino or piperidino ) Or — (CH 2 ) n 3 —COOH (n 3 is as defined above).
  • R 29 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, an alkoxy group having 1 to 3 carbon atoms, an alkylthio group having 1 to 3 carbon atoms, acetoxy, or a nitrogen atom having a lower rank.
  • Ar 3 is 4-bromophenyl or 3,4-dichlorophenyl, Q 1 is methine, and R 28 and R 29 are U) or (2) below.
  • R 28 is methyl, and R 29 is — (CH 2 ) nl —COOH (n 1 is as defined above) or one CH (CH 3 ) COOH.
  • R 28 is - (CH 2) n 3 - CO OH (. N 3 has the same meaning as defined above) and, R 2 9 represents a hydrogen atom, methyl, fluorine atom, chlorine atom or bromine atom.
  • R 28 is methyl
  • R 29 is carboxy group
  • aryl groups include groups having 6 to 14 carbon atoms, and specific examples include phenyl, 1-naphthyl, 2-naphthyl, phenanthryl, and anthryl. Preferable are phenyl, 1-naphthyl and 2-naphthyl.
  • aromatic hydrocarbon ring examples include rings having 6 to 14 carbon atoms, and specific examples include a benzene ring, a naphthalene ring, a phenanthrene ring, and an anthracene ring. Preferable are a benzene ring and a naphthalene ring.
  • heterocyclic group examples include a monocyclic or bicyclic saturated or unsaturated heterocyclic group containing 1 to 6 nitrogen, oxygen and or sulfur atoms.
  • a saturated heterocyclic group examples include a monocyclic or bicyclic 5-membered saturated heterocyclic group such as tetrahydrofuryl, pyrrolidinyl and pyrazolidinyl, and a monocyclic or bicyclic monocyclic or bicyclic ring such as piperidyl, morpholinyl and piperazinyl.
  • examples thereof include a 6-membered saturated heterocyclic group and a monocyclic or bicyclic 1-membered saturated heterocyclic group such as hexamethyleneimino.
  • unsaturated heterocyclic groups include furyl, phenyl, indolyl, isothiazolyl, benzocenyl, isobenzofuranyl, pyrrolyl, benzofuryl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, and benzyl.
  • Monocyclic or bicyclic 5-membered unsaturated heterocyclic groups such as imidazolyl, benzothiazolyl, and benzoxazolyl, and pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, And monocyclic or bicyclic 6-membered unsaturated heterocyclic groups such as romenyl and the like.
  • the aromatic heterocyclic group refers to the above heterocyclic group that is aromatic.
  • Preferred examples of the aromatic complex ring group for Ar include, for example, pyridyl, pyrimidinyl, quinolyl, and phenyl. And the like.
  • the aromatic heterocyclic ring refers to, for example, a ring in which a hydrogen atom is bonded to the above aromatic heterocyclic group.
  • Preferred examples of the aromatic heterocyclic ring in the ring Ar 1 include, for example, a pyridine ring and the like.
  • halogen atom nitro group, cyano group, azide group, mercapto group, formyl group, imino group, hydroxyimino group, lower alkoxyimino group, hydroxyl group, protected hydroxyl group, optionally substituted amino Group, an optionally substituted hydroxyamino group, an optionally substituted lower alkoxyamino group, a carboxy group, an optionally substituted sorbamoyl group, an optionally substituted sorbamoyloxy group, a sulfo group, Good sulfamoyl group
  • R 13 represents a phenyl group or a monocyclic heterocyclic group.
  • the phenyl group or monocyclic heterocyclic group may be substituted, for example, by a halogen atom, a lower alkyl group, a lower haloalkyl group, a cyano group, a nitro group, an azide group, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, One or more arbitrarily selected from the group of amino group, optionally substituted rubamoyl group, carboxy group, lower alkylcarbonyl group, lower alkoxycarbonyl group, lower alkylthio group, lower alkylsulfinyl, lower alkylsulfonyl group, etc. May be substituted with a group.
  • a halogen atom a lower alkyl group, a lower haloalkyl group, a cyano group, a nitro group, an azide group, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group
  • alkyl group alkoxy group, alkoxycarbonyl group, alkoxy (thiocarbonyl) group, alkylthio group, (alkylthio) thiocarbonyl group, (alkylthio) carbonyl group, alkylcarbonyl group, alkylthioyl group, alkylsulfinyl Group, alkylsulfonyl group, alkylcarbonyloxy group, alkylthioyl Xyl group, alkylsulfonyloxy group
  • Each group in this group includes, for example, a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a formyl group, an amino group which may be substituted, a hydroxyl group, an acyl group, an acyloxy group, and a carboxy group.
  • a lower cycloalkyl group is, for example, a halogen atom, a lower alkyl group, a lower haloalkyl group, an amino group which may be substituted
  • a lower alkoxy group, a lower alkoxy group, a lower alkylthio group and a lower alkylthio group for example, a halogen atom, a lower cycloalkyl group, a monocyclic heterocyclic group, a phenyl group, a cyano group, and a nitro group; Group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, amino group which may be substituted, carbamoyl group which may be substituted, carboxy group, lower alkylcarbonyl group, lower alkoxycarbonyl group, lower alkylthio group, It may be substituted with one or more groups arbitrarily selected from the group consisting of lower alkylsulfinyl and lower alkylsulfonyl groups, etc.).
  • alkenyl group for example, a halogen atom, a lower cycloalkyl group, a monocyclic heterocyclic group, a phenyl group,
  • alkenyl groups include, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, formyl group, amino group which may be substituted, hydroxyl group, lower alkoxy group, lower haloalkoxy group, lower Alkoxycarbonyl group, lower alkylthio group, acyl group, acyloxy group, carboxy group, optionally substituted rubamoyl group, —R 13 , —OR 13 , —SR 13 , —OCH 2 R 13 and —S CH 2 R 13 (Wherein, R 13 has the same meaning as described above.) May be substituted with one or more groups arbitrarily selected from the group of ] e): alkynyl group
  • Alkynyl groups include, for example, halogen atoms, nitro groups, cyano groups, mercapto groups, S-group, thioxo group, formyl group, amino group which may be substituted, hydroxyl group, lower alkoxy group, lower haloalkoxy group, lower alkoxycarbonyl group, lower alkylthio group, acyl group, acyloxy group, carboxy group, R 14 , -OR 14 , —SR 14 , one OCH 2 R 14 and one SCH 2 R 14 (where R 14 represents a phenyl group.
  • the phenyl group is, for example, a halogen atom, Lower alkyl group, lower haloalkyl group, cyano group, nitro group, azide group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, optionally substituted amino group, optionally substituted rubamoyl group, carboxy group, lower alkyl Carbonyl group, lower alkoxycarbonyl group, lower alkylthio group, lower alkylsulfinyl and lower alkyl Sulfo alkenyl may be substituted with one or more groups selected arbitrarily from the group, such as a group.) May be substituted with 1 or more groups selected arbitrarily from the group of the like. ]
  • alkenyloxy group alkenyloxycarbonyl group, alkenylcarbonyl group, alkenylcarbonyloxy group, alkynyloxy group, alkynyloxycarbonyl group
  • Each group in this group includes, for example, a halogen atom, an oxo group, an amino group which may be substituted, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, an acyl group, an acyloxy group, a lower alkylthio group, a carboxy group, It may be substituted with one or more groups arbitrarily selected from the group consisting of a rubamoyl group, a lower alkoxycarbonyl group and a phenyl group.
  • Each group in this group includes, for example, a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a formyl group, a lower alkyl group, a lower haloalkyl group, a substituted or unsubstituted amino group, and a hydroxyl group.
  • Lower alkoxy group, lower haloalkoxy group, acyl group, ⁇ It may be substituted with one or more groups arbitrarily selected from the group consisting of a siloxy group, a lower alkylthio group, a carboxy group, an optionally substituted rubamoyl group and a lower alkoxycarbonyl group.
  • Preferred examples of the substituted aryl group and the substituted aromatic heterocyclic group for Ar and the substituent for the substituted aromatic hydrocarbon ring and the substituted aromatic heterocyclic ring for the ring Ar 1 include the following h)) And j) are included in any of the groups, and these groups may be arbitrarily substituted one or more times.
  • halogen atom nitro group, cyano group, hydroxyl group, carboxy group, sulfo group, optionally substituted amino group, optionally substituted rubamoyl group
  • R 15 represents a monocyclic heterocyclic group which may be substituted with a lower alkyl group.
  • each group in this group for example, a halogen atom, a nitro group, Shiano group, an optionally substituted ⁇ amino group, a carboxy group, a sulfo group, a hydroxyl group, may be substituted force Rubamoiru group, one R 15, - COR 15 (wherein, R 15 has the same meaning as described above.)
  • Lower alkoxy group, lower alkoxycarbonyl group, lower alkylthio group, lower alkylcarbonyl group, lower alkylthioyl group, lower alkylsulfinyl group, lower alkylsulfonyl group lower alkoxy group, lower alkoxycarbonyl group, lower alkylthio group, lower The alkylcarbonyl group, lower alkylthioyl group, lower alkylsulfinyl group and lower alkylsulfonyl group include, for example, halogen atom, cyano group, nitro group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, and optionally substituted amino group.
  • Examples of the monocyclic heterocyclic group represented by R 15 include a monocyclic 5- to 7-membered saturated nitrogen-containing heterocyclic group. Preferred examples thereof include 1-pyrrolidinyl, piperidino, morpholino, and 4-low , Quaternary alkyl-1-piperazinyl, hexamethylene imino and the like.
  • the preferred number of substituents is 1, 2 or 3 in the aryl group and the aromatic heterocyclic group in Ar, and 1 in the aromatic hydrocarbon ring and the aromatic heterocyclic ring in the ring Ar 1 Or 2. Further, these may be unsubstituted.
  • substituent of the substituted aryl group examples include methyl, hexyl, 2-methyl-2-propyl, 2-propyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2 , 2,2-Pentafluoroethyl, 6,6,6_Trifluhexyl, hydroxymethyl, methoxymethyl, hexoxymethyl, cyclopropylmethoxymethyl, acetoxymethyl, N, N-dimethylcarbamoyloxy Methyl, methanesulfonyloxymethyl, N, N-dimethylsulfamoyloxymethyl, 2- (1-pyrrolidinyl) ethoxymethyl, 2-methoxyethyl, carboxymethyl, methoxycarbonylmethyl, carbamoylmethyl, amidinomethyl, methylthio Methyl, cyanomethyl, aminomethyl, N-acetylaminomethyl, etheni , 2-propinyl, ethy
  • Preferred substituents include, specifically, methyl, hexyl, 2-methyl_2-propyl, 2-propyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2, 2,2-pentafluoroethyl, 6, 6, 6-trifluorohexyl, hydroxymethyl, methoxymethyl, hexyloxymethyl, cyclopropylmethoxymethyl, acetoxymethyl, N, N-dimethylcarbamoyloxymethyl, Methanesulfonyloxymethyl, N, N-dimethylsulfamoyloxymethyl, 2- (1-pyrrolidinyl) ethoxymethyl, 2-methoxethyl, carboxymethyl, methoxycarbylmethyl, carbamoylmethyl, amidinomethyl, methylthiomethyl, cyanomethyl , Aminomethyl, N-acetylaminomethyl, fluoro, Mouth, bromo, nitro, cyano, hydroxy,
  • One or more groups arbitrarily selected from the group consisting of these groups may be substituted.
  • a substituent of the substituted Ariru group and substituted heterocyclic group in RR ⁇ R 8 and R 12 for example, a halogen atom, a lower alkyl group, lower haloalkyl group, Shiano group, a nitro port group, azide group, a hydroxyl group, a lower alkoxy group A lower haloalkoxy group, an optionally substituted amino group, an optionally substituted rubamoyl group, a carboxy group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkylthio group, a lower alkylsulfinyl group, and a lower alkyl group And a sulfonyl group.
  • alkyl group include a straight-chain or branched alkyl group having 1 to 10 carbon atoms. Specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl Methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-methylbutyl, 3-methylbutyl, hexyl, 2-methylpentyl, 3,3-dimethylbutyl, heptyl, Examples include 1-ethylpentyl, 5-methylhexyl, octyl, 1,5-dimethylhexyl, 2-ethylhexyl, nonyl, and decyl.
  • Examples of the lower alkyl group include an alkyl group having 1 to 6 carbon atoms.
  • Examples of the substituent in the substituted alkyl group include, for example, any group included in each of the following groups a) to d). These groups may be arbitrarily substituted one or more times.
  • [Lower cycloalkyl group and lower cycloalkenyl group include, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, formyl group, optionally substituted amino group, hydroxyl group, lower alkoxy, lower haloalkoxy.
  • Carboxy group substitution It may be substituted with a rubamoyl group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a phenyl group, a monocyclic heterocycle, or the like.
  • lower alkoxy group, lower alkoxycarbonyl group, lower alkylthio group include, for example, halogen atom, lower cycloalkyl group, substituted amino group, hydroxyl group, It may be substituted with a lower alkoxy group, a lower haloalkoxy group, a carboxy group, an optionally substituted rubamoyl group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a phenyl group, a monocyclic heterocycle, or the like.
  • substituted alkyl group examples include: Include trifluoromethyl, 2-nitroethyl, 2-cyanopropyl, 4-mercaptobutyl, 3-oxobutyl, 2-piberidinoethyl, 2-hydroxyethyl, 3-methoxypropyl, ethoxycarbonylmethyl, cyclopropylmethyl, and cyclopropylmethyl.
  • lower haloalkyl group means a lower alkyl group substituted with 1 to 5 halogen atoms.
  • An alkoxy group refers to an oxy group to which an alkyl group is bonded. Specific examples include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, 1,1-dimethylethoxy, pentoxy, hexoxy and the like. Examples of the substituent of the substituted alkoxy group include the same as the substituent of the substituted alkyl group. Specific examples of the substituted alkoxy group include cyclopropylmethoxy, trifluoromethoxy, 2-pyrrolidinoethoxy, and benzyloxy. Xy, 2-pyridylmethoxy and the like.
  • the haloalkoxy group refers to an alkoxy group substituted with 1 to 5 halogen atoms.
  • alkoxycarbonyl group refers to a carbonyl group to which an alkoxy group is bonded. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl and the like.
  • the substituent in the substituted alkoxy group is the same as the substituent in the substituted alkyl group.
  • alkenyl group include a linear or branched alkenyl group having 2 to 10 carbon atoms and having 1 to 3 double bonds.
  • ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-12-propenyl, 1-pentenyl, 2 —Pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, 1,3-octactenyl, 2-Nonenyl, 1,3-nonagenyl, 2-decenyl and the like can be mentioned.
  • Preferred alkenyl groups include, for example, ethenyl, 1-propenyl, 1-butenyl and the like.
  • the lower alkenyl group includes an alkenyl group having 2 to 6 carbon atoms.
  • Examples of the substituent of the substituted alkenyl group include a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a formyl group, a substituted amino group, a hydroxyl group, a lower alkoxy group and a lower haloalkoxy.
  • an alkenyl group refers to an oxy group to which an alkenyl group is bonded.
  • the alkynyl group include a linear or branched alkynyl group having 2 to 10 carbon atoms and having 1 to 3 triple bonds. Specifically, ethinyl, 1-propynyl, 2-p Examples thereof include vinyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 4-pentynyl, 1-octynyl, 6-methyl-1-heptinyl, and 2-decynyl.
  • Preferred alkynyl groups include, for example, 1-propynyl, 11-butynyl group and the like.
  • the lower alkynyl group includes an alkynyl group having 2 to 6 carbon atoms.
  • Examples of the substituent of the substituted alkynyl group include a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a formyl group, a substituted amino group, a hydroxyl group, a lower alkoxy group, and a lower haloalkoxy group.
  • an alkynyloxy group refers to an oxy group to which an alkynyl group is bonded.
  • the cycloalkyl group include a cycloalkyl group having 3 to 10 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • the lower cycloalkyl group a cycloalkyl group having 3 to 6 carbon atoms can be mentioned.
  • a cycloalkyloxy group refers to an oxy group to which a cycloalkyl group is bonded.
  • Examples of the cycloalkenyl group include those having 5 to 10 carbon atoms, and specific examples include a cyclohexenyl group.
  • Examples of the lower cycloalkenyl group include a cycloalkenyl group having 3 to 6 carbon atoms.
  • a cycloalkenyloxy group refers to an oxy group to which a cycloalkenyl group is bonded.
  • Examples of the substituent of the substituted cycloalkyl group and the substituted cycloalkenyl group include a nitrogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a formyl group, a lower alkyl group, a lower haloalkyl group, Diamino group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, acyl group, acyloxy group, lower alkylthio group, carboxy group, optionally substituted rubamoyl group, lower alkoxycarbonyl group And the like.
  • acyl group examples include, for example, a compound represented by the formula —Z—R 16 (wherein Z represents one CO—, one CS—, —S 0— or —SO 2 —, and R 16 represents an alkyl group which may be substituted, And represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group.
  • acyl group examples include formyl, acetyl, propanoyl, 2-propanol, vivaloyl, trifluoroacetyl, benzoyl, nicotinyl, methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl and the like.
  • Preferred acetyl groups include acetyl groups.
  • an acyloxy group refers to an oxy group to which an acyl group is bonded.
  • substituent in the lubamoyl group examples include an alkyl group which may be substituted with an aryl group or a heterocyclic group, an aryl group, a heterocyclic group, and the like. May be replaced.
  • substituted rubamoyl group examples include ethylcarbamoyl, dimethylcarbamoyl, phenylcarbamoyl, 2-pyridylcarbamoyl, benzylcarbamoyl, and (3-pyridylmethyl) carbamoyl.
  • Examples of the substituent in the substituted sulfamoyl group include an alkyl group, an aryl group, a heterocyclic group and the like, and a plurality of the same or different substituents may be independently substituted.
  • Specific examples of the substituted sulfamoyl group include ethylsulfamoyl, dimethylsulfamoyl, phenylsulfamoyl, 2-pyridylsulfamoyl and the like.
  • Examples of the substituent in the substituted amino group include an acyl group and an alkyl group, and the same or different plural groups may be independently substituted.
  • Specific examples of the substituted amino group include acetoamide, propionamide, butylamide, 2-butylamide, methylamino, 2-methylpropylamino, and getylamino.
  • the substituent in the substituted hydroxyamino group may be substituted by any of a nitrogen atom and an oxygen atom, and examples of the substituent include the same substituents as those in the substituted amino group.
  • the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • the present invention includes 4-arylmethylene-11,4-dihydro-2H-azine derivatives represented by the formula 1 and geometric isomers based on double bonds thereof, as well as mixtures thereof. Particularly, the (Z) -isomer is preferred.
  • the present invention relates to all of them. Also included are isomers and mixtures thereof.
  • the 4-arylmethylene-1,4-dihydro-2H-azine derivative or its geometrical variant can be converted to a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include acid addition salts and base addition salts.
  • Acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, citrate, oxalate, acetate, formate, and the like.
  • Organic acid salts such as propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, and benzenesulfonate are listed.
  • base addition salts include sodium, potassium, Inorganic base salts such as calcium salt, magnesium salt, and ammonium salt; and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt.
  • the present invention also includes solvates such as hydrates of 4-arylmethylene-1,4-dihydro-2H-azine derivatives or geometric isomers thereof or pharmaceutically acceptable salts thereof.
  • the 4-arylmethylene-1,4-dihydro-12H-azine derivative represented by the formula 1 or its geometric isomer can be produced, for example, by the following four production methods.
  • Suitable solvents may be those which do not adversely affect the reaction, but preferably include tetrahydrofuran, dichloromethane and a mixed solvent thereof.
  • a solution of the compound of formula 2 and 1 to 6 equivalents of a base may be reacted by adding 1 to 6 equivalents of trichloroacetyl chloride, triphosgene, or thiophosgene at a temperature of, for example, 178 to 80 ° C. it can.
  • the newly formed double bond isomer when R 2 is a hydrogen atom, the (Z) —isomer is usually selectively obtained.
  • R 2 is other than a hydrogen atom, a mixture of the (E) -isomer and the (Z) -isomer is usually obtained.
  • the identification of geometric isomers can be performed using a general method such as a method for measuring nuclear Overhauser effect, X-ray crystal structure analysis in proton NMR measurement, and the like.
  • the isomers produced are subjected to a photoisomerization reaction using a high-pressure mercury lamp or the like to form a mixture of isomers, and a conventional method such as chromatography, recrystallization, etc.
  • a desired variant can be obtained.
  • Compounds of formula 1 in which E is a sulfur atom can also be prepared by reacting a compound of formula 1 in which E is an oxygen atom with a sulfurizing reagent such as Lawesson's reagent or diphosphorus pentasulfide. .
  • the solvent may be any one which does not adversely affect the reaction, and examples thereof include carbon disulfide, toluene, pyridine, 1,2-dichloroethane and a mixed solvent thereof.
  • the above sulfurating reagent for example, from room temperature to the solvent reflux temperature To react.
  • an appropriate protecting group such as a general method such as acetal in the case of a carbonyl group can be used.
  • a compound of Formula 1 wherein E is —N (R 8 ) — (R 8 is as defined above) is a compound of the formula: H 2 N—R 8 (R 8 ) wherein E is an oxygen atom or a sulfur atom.
  • the solvent may be any one which does not adversely affect the reaction, and examples thereof include water, lower alcohols such as methanol and ethanol, tetrahydrofuran, toluene, pyridine and a mixed solvent thereof.
  • a solution of the compound represented by the formula 1 and a compound represented by the formula: H 2 N—R 8 (where R 8 has the same meaning as described above) can be reacted, for example, at room temperature to solvent reflux temperature.
  • R 8 has the same meaning as described above
  • a general method can be used.
  • an appropriate protecting group such as acetal can be used.
  • a compound of formula 2 has a carboxyl group in RR 2 , Ar or ring Ar 1
  • the carboxyl group is converted to an acid anhydride or an acid halide when treated with trichloroacetyl chloride, triphosgene, thiophosgene, or the like.
  • trichloroacetyl chloride triphosgene, thiophosgene, or the like.
  • these may be treated with various alcohols such as water, methanol, ethanol, and phenol, or various amines such as ammonia, methylamine, dimethylamine, aniline, and benzylamine to form carboxylic acid, It can lead to compounds of formula 1 having an ester or amide group.
  • the compound of the formula 2 has a group that can react with trichloroacetyl chloride, triphosgene, thiophosgene, etc. (for example, a hydroxy, amino, mercapto group, etc.), these substituents should be protected by an appropriate protecting group.
  • trichloroacetyl chloride, triphosgene, thiophosgene, etc. for example, a hydroxy, amino, mercapto group, etc.
  • these substituents should be protected by an appropriate protecting group.
  • a hydroxy group an acetyl group, a methoxymethyl group, a t-butyldimethylsilyl group, etc.
  • an amino group an acetyl group, a benzyloxycarbonyl group, etc.
  • a mercapto group an acetyl group, And a methyl group.
  • the compound of Formula 1 has a group that may react, protection, deprotection, or conversion of the protecting group can be performed as desired.
  • This protection, deprotection, or conversion of protecting groups can be accomplished by conventional methods, for example, Protective Groups in Organic Synthes is 2nd Edition, TW Greene and PGM Wuts, John Wiley and Sons, Inc. 1991).
  • the substituents of the compound of formula 1 may be optionally or optionally, for example, oxidized, for example, if they have a sulfide as a substituent, conversion to a sulfoxide or sulfone derivative , Reduction, for example, conversion to an alcohol derivative when it has a formyl group as a substituent, solvolysis, for example, conversion to an alcohol or acid derivative by hydrolysis when it has an ester, or nitrile as a substituent
  • conversion reaction such as conversion into a carboxylic acid derivative, addition, elimination, condensation, alkylation, side chain elongation such as acylation, and substitution reaction can also be performed.
  • Compounds of formula 2 are known or can be prepared by known methods. For example, the following methods are mentioned.
  • R 17 represents a hydrogen atom, a lower alkyl group, an aryl group or an arylalkyl group.
  • the amide ketone of the formula 4 can be produced.
  • This oxidative cleavage reaction can be performed by a general method, for example, a method using ozone as an oxidizing agent.
  • ozone is generated by passing oxygen through a commercially available ozone generator, and is usually a mixed gas with oxygen.
  • the reaction solvent is not limited as long as it does not adversely affect the reaction. For example, acetic acid, ethyl acetate, dichloromethane and a mixed solvent thereof are used.
  • Ozone is passed through the solution of the compound of formula 3 at a temperature of, for example, 178 to 80 ° C., and the reaction is completed. can get.
  • the production of the indole of formula 3 is carried out by a general method, such as the Fischer indole synthesis method using a substituted hydrazine and a substituted 4-phenyl-12-butanone.
  • a 3-position-substituted compound can be synthesized by introducing a 3-position-unsubstituted window to a magnesium amide and subsequently using an arylalkyl halide.
  • Comprehensive 'Heterocyclic' Chemistry Vol.4, Part 3 Comprehensive Heterocyclic Chemistry, Volume 4, Part 3, Pergamon Press 1984
  • Heterocyclic Compounds Vol.25 Heterocyclic Compounds, Volume 25, John Wiley and Sons, Inc. 1972
  • the method described in the literature cited therein are described in the literature cited therein.
  • an aminocarbonyl compound represented by the formula 2a can be produced.
  • This hydrolysis can be performed by a general method, for example, a method of treating with dilute hydrochloric acid in an ethanol solution.
  • the substituents of the compounds represented by Formula 3, Formula 4 and Formula 2a may be, if necessary or necessary. Protection, deprotection, or conversion of protecting groups by conventional methods, as appropriate.
  • RR 2 , Ar and ring Ar 1 are as defined above.
  • M is an alkali metal atom.
  • a reaction of an isocyanic anhydride of the formula 5 with an anion reagent of the formula 6 gives The aminocarbonyl compound can be produced as a suitable solvent, as long as it does not adversely affect the reaction, but preferably includes tetrahydrofuran, getyl ether, and a mixed solvent thereof. For example, it is desirable to add 1 to 3 equivalents of a solution of the anion reagent of the formula 6 at a temperature of ⁇ 78 to 80 ° C.
  • the preparation of the nonionic reagent can be carried out by a general method, for example, by reacting the corresponding halide with lithium metal or magnesium metal, 2-methylpyridine, 4-tol nitrile.
  • RR 2 , Ar, ring Ar 1 and M are as defined above.
  • R 18 represents a protecting group for an amino group.
  • R 19 represents a lower alkyl group.
  • Y represents the activity of a carboxyl group.
  • the ketoester derivative of the formula 9 can be produced by reacting the compound of the formula 7 with the enolate anion compound of the formula 8.
  • Suitable solvents are those which do not adversely affect the reaction, and preferably include tetrahydrofuran and the like.
  • a solution of the compound of formula 7 is added, for example, to a solution of the enolatonion of formula 8 previously prepared at 178 to 50 ° C. and reacted.
  • the compound of the formula 7 is prepared by starting from the corresponding anthranilic acid derivative having a protected amino group as a starting material and then reacting with thionyl chloride or the like, or is generally not isolated from the reaction with isobutyl chlorocarbonate or the like. Used.
  • the enolate dione of formula 8 can be produced by reacting the corresponding aryl acetate with lithium diisopropylamide, sodium hydride or the like.
  • examples of the protecting group for the amino group include those commonly used, for example, Protective Groups in Organic Synthes is 2nd Edition, TW Greene and PGM Wuts, John Wiley and Sons, Inc. 1991) can be used.
  • examples of the activating group of the carboxyl group include a halogen atom such as a chlorine atom and a bromine atom, and a mixed acid anhydride with sulfonic acid or carboxylic acid.
  • Substituents on the compounds of Formula 7, Formula 8, Formula 9 and Formula 2a can be protected, deprotected, or converted into protecting groups, if desired or necessary, by common procedures.
  • the aminoaminocarbonyl compound of the formula 2a By reacting the 2-aminobenzonitrile derivative of the formula 10 with the anion reagent represented by the formula 6, the aminoaminocarbonyl compound of the formula 2a can be produced.
  • Suitable solvents include those which do not adversely affect the reaction, and preferably include tetrahydrofuran and the like. It is desirable to react with a solution of the compound of formula 10 by adding 1 to 3 equivalents of a solution of the anion reagent of formula 6 which is commercially available, for example, at -78 to 80 C, or prepared in advance.
  • the compound of the formula 6 can be produced, for example, from the corresponding 2-nitrobenzonitrile derivative by reducing the nitro group with metallic iron or the like, and then introducing a substituent to the amino group.
  • the preparation of the anion reagent of the formula 6 can be carried out by a general method, for example, the reaction of a corresponding halide with lithium metal or magnesium.
  • a corresponding anion reagent can be produced by reacting with methyllithium or butyllithium.
  • the substituents of the compounds of Formula 10 and Formula 2a can be protected, deprotected, or converted into protecting groups as desired, or as necessary, by common procedures.
  • RA r and ring A r 1 are as defined above.
  • X represents a nitrile group or a halogenated carbonyl group.
  • the aniline of the formula 2b is selected.
  • a minocarbonyl compound can be produced.
  • Aluminum chloride, zinc chloride, boron trichloride and the like are used as Lewis acids.
  • Suitable solvents are those which do not adversely affect the reaction, and preferably include dichloroethane, dichloromethane and a mixed solvent thereof.
  • Ar and ring Ar 1 are each an optionally substituted aryl group, an optionally substituted aryl group or an aromatic hydrocarbon ring.
  • R 2G may be substituted Carbamoyl group, sulfamoyl group which may be substituted, halogen atom, carboxyl group, acyl group, cycloalkyl group which may be substituted, cycloalkenyl group which may be substituted, alkyl group which may be substituted, substituted An optionally substituted alkenyl group, an optionally substituted alkynyl group or —CO 2 R 7 (where R 7 has the same meaning as described above.))
  • the compound of the formula 14 is added to the compound of the formula 13 under basic conditions.
  • the compound of the formula 15 can be produced.
  • the base include sodium hydride.
  • the reaction solvent may be any one which does not adversely affect the reaction, and examples thereof include tetrahydrofuran, dimethylformamide and a mixed solvent thereof.
  • the compound of the formula 14 can be added to a solution of the compound of the formula 13 and a base at ⁇ 20 to 100 ° C. and reacted.
  • R 20 is preferably an optionally substituted alkyl group, an optionally substituted arylalkyl group, an optionally substituted alkyloxycarbonyl group, or the like.
  • the protecting group of the amino group of the compound of the formula 15 is removed to produce the aminopulponyl compound of the formula 2c.
  • This deprotection can be performed by a general method. 6-2) Method of substituting an oxygen atom for A with a sulfur atom or —N (R 12 )-(R 12 is as defined above.)
  • the compounds of formulas 2a and 2b that can be produced by (1) to (5) are protected, deprotected, or converted to a protecting group, and, if necessary or necessary, have their substituents. , Reduction, solvolysis, addition, elimination, condensation, alkylation, acylation, etc.
  • a new derivative of Formula 2 can be produced by performing a substitution reaction or the like. For example, a compound of formula 2a or 2b is reacted with a sulfurizing reagent such as diphosphorus pentasulfide or Lawesson reagent to replace the oxygen atom of the carbonyl group with a sulfur atom, so that A is a sulfur atom. Certain aminothiocarbonyl compounds of formula 2 can be obtained. Similarly, a primary amine or a hydroxylamine derivative is allowed to act on the carbonyl group and a desired reaction is carried out, whereby A is one N (R 12 ) — (R 12 is as defined above. ) Can be obtained.
  • a compound of the formula 1 (compound of the formula 1a) wherein A is -N (R 12 ) 1 (R 12 is as defined above) can be produced by the following method.
  • the compound of formula 1a can be produced by reacting the anion reagent of formula 6 with the compound of formula 16.
  • Suitable solvents include those which do not adversely affect the reaction, and preferably include tetrahydrofuran.
  • the solution of the compound of formula 16 is added and reacted, for example, at 178-80 ° C.
  • the compound of the formula 17 may be isolated as an intermediate, but in this case, under a general condition, for example, an inert solvent such as toluene using a catalytic amount of Perform a dehydration reaction at a temperature of 0 to 120 ° C, (J. Chem. Soc. (C), 1055-1058 (1971)) 0 Production method: 3
  • the compound of formula 1 (an isomer of one double bond) is dissolved in a suitable solvent, for example, acetone, and the reaction temperature is not particularly limited, but is usually in the range of 178 to 50 ° C, such as a high-pressure mercury lamp.
  • a photoisomerization reaction can be carried out by irradiating with light for 1 to 3 hours to obtain a mixture of isomers. This mixture can be separated into each isomer by a usual method, for example, chromatography, recrystallization and the like. Manufacturing method: 4
  • a substituent or the like can be introduced or converted into the compound of the formula 1 produced by the above production method 1, 2 or 3.
  • the compound of the formula 1 having a phenolic hydroxyl group or the like can be obtained by subjecting the compound of the formula 1 having a corresponding alkoxy group to cleavage of the alkoxy group using a general method, for example, using boron tribromide or trimethylsilyl iodide. be able to.
  • the compound of the formula 1 having a carboxy group can be obtained by subjecting the compound of the formula 1 having a nitrile group to acid hydrolysis or the like.
  • acyl group can be introduced by carrying out a Friedet Crafts reaction and further deprotecting the protecting group of the amino group.
  • a compound of the formula 1 having a hydroxyl group is converted into a sulfonate ester according to a conventional method, and then subjected to a carbonylation reaction, a hydroformylation reaction or a cyanation reaction in the presence of a palladium complex catalyst, thereby obtaining an alkoxycarbonyl group, a carbamoyl group.
  • a compound of the formula 1 having a formyl group or a cyano group can be produced.
  • the compound of formula 1 having sulfoxide or sulfone can be produced by oxidizing the compound of formula 1 having sulfide according to a conventional method.
  • R 21 is an optionally substituted sulfamoyl group, an optionally substituted sulfamoyl group, or an optionally substituted sulfamoyl group.
  • the hydrogen of the 1-position nitrogen atom of the compound of the formula 1b is extracted with a suitable base (for example, sodium hydride), and the compound of the formula 18 is acted thereon, whereby the compound of the formula 1c can be produced.
  • suitable solvents are those that do not adversely affect the reaction, and preferably include tetrahydrofuran, dimethylformamide, and a mixed solvent thereof.
  • a solution of the compound of the formula 1b and 1 to 6 equivalents of a base can be reacted by adding 1 to 6 equivalents of the compound of the formula 18 at a temperature of ⁇ 78 to 80 ° C.
  • the above-mentioned production method exemplarily describes in detail the production steps of the 4-arylmethylene-11,4-dihydro-2H-azine derivative represented by the formula 1 or the geometric isomer thereof in the present invention. However, this does not limit the production method such as starting materials, production process, reaction conditions, or processing conditions.
  • the 4-arylmethylene-11,4-dihydro-2H-azine derivative represented by the formula 1 of the present invention or a geometric isomer thereof can be converted into a pharmaceutically acceptable salt thereof according to a conventional method. it can.
  • Osteoclast differentiation induction inhibitors are useful as anti-inflammatory drugs, bone destruction inhibitors, antirheumatic drugs, etc. Specifically, bone destruction due to osteoporosis, periodontal disease, bone metastasis cancer, hypercalcemia, It is useful for treating joint distortion associated with artificial joint replacement.
  • the 4-arylmethylene-1,4-dihydro-2H-azine derivative of the present invention or a geometric isomer thereof or a pharmaceutically acceptable salt thereof is used for therapy, it is orally or as a pharmaceutical composition.
  • compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, and the like.
  • compositions for parenteral administration include injections Aqueous preparations, oily preparations, ointments, creams, lotions, aerosols, suppositories, patches, and the like. These formulations are prepared using conventionally known techniques, and can contain nontoxic and inert carriers or excipients usually used in the field of formulation. The dose varies depending on the patient's condition such as age and body weight, symptoms, and the administration route.
  • the amount of the active ingredient of the compound of the present invention per adult is 0.05 to 5000 mg, preferably 0.5 to 5000 mg.
  • a daily dose of 500 mg can be administered once to three times daily, or can be administered intermittently or intermittently.
  • Preferred examples of the compound of the present invention are shown below.
  • CH 3 CH CHC0 2 HHH CH 3 1 -pyrrolidino HH CH 3 3-pyrrolidinopropyl HH CH 3 HH CH 2 NHCH 3 CH 3 H (CH 2 ) 3 N (CH 3 ) 2 H CH 3 HH C0N (CH 3 3)) 2 CH 3 H (CH 2 ) 2 C0N (CH 3 ) 2 H CH 3 HH (CH 2 ) 2 CN
  • Example 1 0
  • Example 1 1
  • Example 1 2
  • Example 1 4 Example 1 5
  • Example 17 Example 18 Example 1 9 Example 20
  • Example 2 1 Example 2 2 Example 2 3 Example 2 4
  • Example 2 5 Example 2 6 Example 2 7 Example 2 8
  • Example 2 9 Example 3 0 Example 3 1 Example 3 2
  • Example 4 1 Example 4 2 Example 4 3 Example 4 4
  • Toluethylamine (0.40 ml) was added to a solution of the compound produced in Reference Example 23 (270 mg ) in 1,4-dioxane (5 ml ) under ice-cooling under a nitrogen atmosphere, and the mixture was stirred for 10 minutes. To this solution was added triphosgene (103 mg). After stirring at room temperature for 1 hour, the mixture was extracted with black form (50m1 x 2), and the organic layer was dried over anhydrous sodium sulfate to reduce the solvent. The pressure was removed. The residue was purified by recrystallization from ethanol to obtain the desired product (26 Omg) as white crystals.
  • Example 56 Example 57
  • Example 58 Example 59
  • Example 60 Example 6 1 Example 62 Example 63
  • Example 68 Example 6 9
  • Example 70 Example 7 1
  • Example 72 Example 73
  • Example 74
  • Example 79 was obtained in a similar manner to that described in Example 77 using p-bromobenzylmagnesium bromide instead of amide. This was a 1: 1 mixture of E and Z forms.
  • Example 79
  • Example 80 Example 81
  • Example 8 2 Example 83
  • the spectrum data of the produced compound is shown below.
  • Example 84 All of these compounds were identified by 1 H-NMR spectrum, 13 C-NMR spectrum, spectrum data such as mass spectrum, IR spectrum, and UV spectrum, and elemental analysis. All of these compounds were in the (Z) form (as shown in the structural formula).
  • Example 84
  • Example 85 The spectrum data of the produced compound is shown below.
  • Example 87 All of these compounds were identified by 1 H-NMR spectrum, 13 C-NMR spectrum, spectrum data such as mass spectrum, IR spectrum, UV spectrum, melting point, and elemental analysis. All of these compounds were in the (Z) form (as shown in the structural formula).
  • Example 87 All of these compounds were identified by 1 H-NMR spectrum, 13 C-NMR spectrum, spectrum data such as mass spectrum, IR spectrum, UV spectrum, melting point, and elemental analysis. All of these compounds were in the (Z) form (as shown in the structural formula).
  • Example 87 All of these compounds were identified by 1 H-NMR spectrum, 13 C-NMR spectrum, spectrum data such as mass spectrum, IR spectrum, UV spectrum, melting point, and elemental analysis. All of these compounds were in the (Z) form (as shown in the structural formula).
  • Example 88 Example 89
  • Example 90 Example 91 1 The following shows the spectrum data of the produced compound.
  • Example 93 Example 93 Example 95 Example 5 The following shows the spectrum data of the produced compound.
  • Example 98 The spectrum data of the produced compound are shown below.
  • Example 100 All of these compounds were identified by 1 H-NMR spectrum, 13 C-NMR spectrum, mass spectrum, IR spectrum, UV spectrum, etc., melting point, and elemental analysis. All of these compounds were in the (Z) form (as shown in the structural formula).
  • Example 100 All of these compounds were identified by 1 H-NMR spectrum, 13 C-NMR spectrum, mass spectrum, IR spectrum, UV spectrum, etc., melting point, and elemental analysis. All of these compounds were in the (Z) form (as shown in the structural formula).
  • Example 101 Example 102
  • Example 103 Example 104
  • the spectrum data of the produced compound is shown below.
  • Example 1 0 5 Example 1 0 6
  • Example 1 0 7 Example 1 0 8
  • Example 1 0 9 Example 1 1 0 Example 1 1 1
  • Example 1 Example 1 2 Example 1 1 3 Example 1 1 4
  • Example 1 1 5 Example 1 1 6 The spectrum data of the produced compound are shown below.
  • Example 1 Example 1 7 Example 1 8 Example 1 1 9 Example 1 20
  • Example 1 Example 1 25 Example 1 26 Example 1 27 Example 1 28
  • Example 1 2 9 Example 1 3 0 Example 1 3 1 Example 1 3 2
  • Example 1 3 9 Example 1 4 0 Example 1 4 1 Example 1 4 3 Example 1 44
  • Example 1 50 All of these compounds were identified by 1 H-NMR spectrum, 13 C-NMR spectrum, mass spectrum, IR spectrum, UV spectrum, and other spectral data, as well as by melting point and elemental analysis. These compounds were (Z) -form or (E) -form (the structural formula).
  • Example 1 50 All of these compounds were identified by 1 H-NMR spectrum, 13 C-NMR spectrum, mass spectrum, IR spectrum, UV spectrum, and other spectral data, as well as by melting point and elemental analysis. These compounds were (Z) -form or (E) -form (the structural formula).
  • Example 1 50 All of these compounds were identified by 1 H-NMR spectrum, 13 C-NMR spectrum, mass spectrum, IR spectrum, UV spectrum, and other spectral data, as well as by melting point and elemental analysis. These compounds were (Z) -form or (E) -form (the structural formula).
  • Example 1 50 All of these compounds were identified by 1 H-NMR spectrum, 13 C-NMR spectrum, mass spectrum, IR
  • Example 107 The following compounds were produced from the compound of Example 107 in the same manner as in Example 79.
  • Example 1 5 1 (Z) -4- (1, -6-dimethyl-2-oxo-1, 4-dihydro-2H-3,1 benzoxazine-14-ylidenemethyl) monobenzaldehyde
  • Example 8 Under a nitrogen atmosphere, the compound prepared in Example 8 (1.03 g), sodium formate (31 Omg), bis (diphenylphosphine) palladium (II) chloride (5 Omg) in dimethylformamide (8 m l) The suspension was stirred at 110 ° C for 3 hours under a carbon monoxide atmosphere. After allowing to cool, saturated aqueous sodium hydrogen carbonate (50 ml) was added, and the mixture was extracted with black-mouthed form (20 mix 3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Isopropyl ether was added to the residue containing DMF, and the insolubles were collected by filtration to obtain the desired product (0.58 g) as yellow crystals. Mp 172.0-173.5 ° C.
  • Example 1 54 (Z) — 4 benzylidene — 6 — (3-hydroxy-1-propynyl) 1-methyl-1,4-dihydro-2H—3,1-benzobenzoxa: 1-2-one
  • Example 1 55 Example 1 56
  • Example 122 In the same manner as in Example 100, the following compound was produced from the compound of Example 122. Mp 2 14.0-2 15.0 ° C.
  • Example 1 Example 1 6 3
  • Example 109 The compound of Example 109 was added to a saturated aqueous solution of sodium bicarbonate, and the mixture was stirred vigorously. When the filtrate was allowed to stand, a white solid precipitated. The solid was collected by filtration, washed with a small amount of water, and dried to obtain the desired product.
  • Example 166 and 167 were obtained by reducing the compounds of Examples 151 and 152 with sodium borohydride in a mixed solvent of ethanol and Z-form. Also, using the compound of Example 151, a reductive amination was carried out by adding an ethanol solution of methylamine to the above system to obtain the compound of Example 168.
  • Example 16 6 Example 16 7
  • Example 1 6 9 Example 1 7 0
  • Example 1 7 2 Example 1 7 3
  • Example 1 7 5 Example 1 7 6 Example 1 7 7
  • Example 1 8 0 Example 1 8 1
  • 1,1-Carbonyldiimidazole was reacted with the compound of Example 173 in acetonitrile dichloroethane solvent to obtain an amide compound.
  • Reference example 1 0 Reference example 1 1 Reference example 1 2 Reference example 1 3
  • Example 56 Example 57 The spectrum data of the produced compound are shown below.
  • Reference example 80 Reference example 8 1 Reference example 82 Reference example 83 Reference example 84 Reference example 8 5 Reference example 8 6
  • the number of osteoclasts formed was stained after tartaric acid-resistant acid phosphatase staining, and cells with three or more nuclei stained were counted under a microscope.
  • the inhibition rate of each compound was determined by setting the inhibition rate of the vehicle to 0% and the inhibition rate when the number of osteoclasts was 0 to 100%. The results are shown in the table below. Thus, it was found that the compounds of the present invention strongly suppressed osteoclast differentiation induction.
  • test compound was suspended in a 0.5% methylcellulose solution (MC) and administered once a day from the day after the first sensitization once a day for 44 consecutive days in groups of 10 animals.
  • the dose was 50 mg / kg (per kg of mouse body weight), and the control group received only MC.
  • Administration was by oral gavage using a sonde for mice. Was.
  • the arthritis score was based on macroscopically observed joint swelling, the X-ray score was based on the radiographic destruction of the joint structure, and a biochemical serum test (serum amyloid P value) was performed.
  • Example 1 and Example 109 suppressed the arthritis score by 66% and 63%, respectively, as compared with the control group. This compound also suppressed the increase in X-ray score by 57% and 62%, respectively.
  • serum amyloid P levels were reduced, and serologic abnormalities due to arthritis were also improved. No abnormalities were observed in body weight, liver weight, or other appearance, etc., by administration of these compounds.
  • 4-arylmethylene-1,4-dihydro-12H-azine derivatives or their geometric shapes which are useful as osteoclast differentiation induction inhibitors, anti-inflammatory agents, bone destruction inhibitors, antirheumatic agents, etc.
  • An isomer or a pharmaceutically acceptable salt thereof can be provided.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention a trait à des dérivés de 4-arylméthylène-1,4-dihydro-2H-azine, représentés par la formule générale (1), à leurs isomères géométriques ou à leurs sels acceptables d'un point de vue pharmaceutique. Ces dérivés se révèlent utiles en tant qu'inhibiteurs d'une induction différentielle des ostéoclastes, anti-inflammatoires, inhibiteurs de l'ostéoclasie et antirhumatismaux, etc. Dans ladite formule, Ar représente un aryle éventuellement substitué ou un hétéroaryle éventuellement substitué, le noyau Ar1 représente un noyau hydrocarbure aromatique éventuellement substitué ou un hétéroaryle éventuellement substitué, R1 représente un hydrogène, un carbamoyle éventuellement substitué, un sulfamoyle éventuellement substitué, etc., R2 représente un hydrogène, un carbamoyle éventuellement substitué, un sulfamoyle éventuellement substitué, etc., E représente un oxygène, un soufre ou -N(R8)- et A représente un oxygène, un soufre ou -N(R12)-.
PCT/JP1998/001291 1997-03-26 1998-03-23 Derives de 4-arylmethylene-1,4-dihydro-2h-azine WO1998042688A1 (fr)

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Cited By (3)

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US7196087B2 (en) 2004-01-16 2007-03-27 Roche Palo Alto Llc Quinazolinone and benzoxazinone derivatives and uses thereof
CN102850375A (zh) * 2012-03-06 2013-01-02 江西师范大学 一类多取代吡啶并[4, 3-d]噁嗪化合物及制备方法
WO2013021363A1 (fr) 2011-08-11 2013-02-14 Actelion Pharmaceuticals Ltd Dérivés de quinazoline-2,4-dione

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JPS4821952B1 (fr) * 1970-10-02 1973-07-02
JPS5251379A (en) * 1975-10-24 1977-04-25 Sumitomo Chem Co Ltd Preparation 3,4-dihydro-2(1h)-quinazoline derivates

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JPS4821952B1 (fr) * 1970-10-02 1973-07-02
JPS5251379A (en) * 1975-10-24 1977-04-25 Sumitomo Chem Co Ltd Preparation 3,4-dihydro-2(1h)-quinazoline derivates

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MORGENSTERN O, ET AL.: "UNTERSUCHUNGEN ZUR DARSTELLUNG UND REAKTIVITET C-ANELLIERTER ABKOEMMLINGE DES 1,3,4-BENZOTRIAZEPINS UND ENTSPRECHENDER VORPRODUKTE N,N-VERKNUEPFTE HETEROBICYCLEN AUS CYCLISCHEN HYDRAZIN-DERIVATEN. 12. MITTEILUNG ", PHARMAZIE, vol. 51, 1 January 1996 (1996-01-01), pages 458 - 467, XP002917462, ISSN: 0031-7144 *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7365063B2 (en) 2003-11-25 2008-04-29 Roche Palo Alto Llc Quinazolinone and benzoxazinone derivatives and uses thereof
US7196087B2 (en) 2004-01-16 2007-03-27 Roche Palo Alto Llc Quinazolinone and benzoxazinone derivatives and uses thereof
WO2013021363A1 (fr) 2011-08-11 2013-02-14 Actelion Pharmaceuticals Ltd Dérivés de quinazoline-2,4-dione
US8916573B2 (en) 2011-08-11 2014-12-23 Actelion Pharmaceuticals Ltd. Quinazoline-2,4-dione derivatives
CN102850375A (zh) * 2012-03-06 2013-01-02 江西师范大学 一类多取代吡啶并[4, 3-d]噁嗪化合物及制备方法

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