WO2008053863A1 - Novel compound having 1,4-benzothiazin-3-one skeleton or 3,4-dihydroquinolin-2-one skeleton - Google Patents

Novel compound having 1,4-benzothiazin-3-one skeleton or 3,4-dihydroquinolin-2-one skeleton Download PDF

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WO2008053863A1
WO2008053863A1 PCT/JP2007/071071 JP2007071071W WO2008053863A1 WO 2008053863 A1 WO2008053863 A1 WO 2008053863A1 JP 2007071071 W JP2007071071 W JP 2007071071W WO 2008053863 A1 WO2008053863 A1 WO 2008053863A1
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group
methyl
oxo
ylidene
benzo
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PCT/JP2007/071071
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French (fr)
Japanese (ja)
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Takahiro Honda
Hisashi Tajima
Koushi Fujisawa
Masaaki Murai
Hiroyuki Aono
Masakazu Ban
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Santen Pharmaceutical Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D417/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to a novel compound having a 1,4-monobenzothiazin-3-one skeleton or a 3,4-dihydric quinolin-2-one skeleton, or a salt thereof, which is useful as a medicine.
  • These compounds are therapeutic agents for diseases involving angiogenesis, especially cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetes It is useful as a therapeutic agent for macular edema, psoriasis vulgaris, atherosclerosis, etc.
  • Angiogenesis is a phenomenon in which a new blood vessel network is formed from existing blood vessels, and is mainly observed in small blood vessels.
  • Angiogenesis is inherently a physiological phenomenon and is essential for embryonic blood vessel formation, but in adults it is usually limited to limited areas such as the endometrium and follicles and the wound healing process. Only observed.
  • diseases such as cancer, rheumatoid arthritis, caro-aged macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis
  • Pathological angiogenesis has been observed and is closely related to the pathological progression of these diseases.
  • Angiogenesis is regulated by the balance between the promoting factor and the inhibitory factor, and it is considered that angiogenesis occurs when the balance is lost (see Non-Patent Document 1 and Non-Patent Document 2).
  • VEGF Vascular endothelial growth factor
  • Flt_l vascular endothelial growth factor
  • Flk-1 vascular endothelial growth factor
  • drugs used for such treatment include indoline-2-one derivatives (see Patent Document 1), phthalazine derivatives (see Patent Document 2), and quinazoline derivatives (see Patent Document 1).
  • Patent Document 3 anthranilic acid amide derivatives (see Patent Document 4), 2 aminonicotinic acid derivatives (see Patent Document 5), 4 pyridylalkylthio derivatives (see Patent Document 6), etc.
  • Patent Document 7 reports a cyclic compound having a 1,4 benzothiazin 3 -one skeleton. In Patent Document 7, these are reported as cell growth inhibitors by inhibiting tyrosine kinases! However, there is no detailed activity data in the patent document, and no attempt has been made to introduce a hydrophilic substituent which is a feature of the compound of the present invention.
  • Non-Patent Document 1 Molecular Medicine vol.35 Special issue “Symptoms: Molecular mechanism of pathology”, Nakayama Shoten, 73-74 (1998)
  • Non-Patent Document 2 Protein Nucleic acid Enzyme Extra number “Advanced Drug Discovery”, Kyoritsu Shuppan, 1182— 11 87 (2000)
  • Patent Document 1 International Publication WO98 / 50356 Pamphlet
  • Patent Document 2 International Publication W098 / 35958 Pamphlet
  • Patent Document 3 International Publication WO97 / 30035 Pamphlet
  • Patent Document 4 International Publication WO00 / 27819 Pamphlet
  • Patent Document 5 International Publication WO01 / 55114 Pamphlet
  • Patent Document 6 International Publication WO04 / 078723 Pamphlet
  • Patent Document 7 International Publication WO00 / 75139 Pamphlet
  • the present invention relates to a compound represented by the general formula [I] or a salt thereof (hereinafter referred to as “the compound of the present invention” unless otherwise specified) and a pharmaceutical composition containing the compound of the present invention.
  • the pharmaceutical use of the compound of the present invention will be described in more detail.
  • the present invention relates to a therapeutic agent for diseases involving vascular neoplasia, which comprises the compound of the present invention as an active ingredient.
  • the present invention relates to therapeutic agents for retinopathy of prematurity, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis and the like.
  • ring A represents an aryl group or an aromatic heterocyclic ring
  • R represents a hydrogen atom, a halogen atom, an alkyl group or a halogenoalkyl group
  • X represents S or CH
  • Y represents a hydroxyl group, an alkoxy group or NR R;
  • R and R are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group,
  • R and R may join together to form a non-aromatic heterocycle;
  • Each of the above alkyl groups is selected from a hydroxyl group, an amino group, a carboxyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylamino group, an aryl group, an aromatic heterocyclic group and a non-aromatic heterocyclic group 1 or
  • Each aryl group described above may be a halogen atom, an amino group, a nitro group, an alkyl group, a halogenoalkynole group, an alkoxy group, a hydroxyalkyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkyl group.
  • each aromatic heterocyclic group described above is a halogen atom, Amino group, alkyl group, halogenoalkyl group, hydroxyalkyl group, alkyloxycarbonyl group, alkyl
  • substituents selected from a mino group and an alkylcarbonylamino group each non-aromatic heterocyclic group described above is a halogen atom, an amino group, an alkyl group, a halogenoalkynole group, a hydroxy group; It may have one or more substituents selected from an alkyl group, an alkyloxycarbonyl group, an alkylamino group, an alkylcarbonylamino group, and a non-aromatic heterocyclic group.
  • the present invention provides a novel compound having a 1,4 monobenzothiazin-3-one skeleton or a 3,4 dihydrin quinolin-2-one skeleton, or a salt thereof, useful as a medicament.
  • the novel cyclic compound according to the present invention has an excellent angiogenesis-inhibiting action, and diseases involving angiogenesis, such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retina It is useful as a therapeutic agent for venous occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, and atherosclerosis.
  • Halogen atom means fluorine, chlorine, bromine or iodine.
  • Alkyl refers to a straight-chain or branched alkyl having 1 to 6 carbon atoms. Specific examples include methinole, ethinole, n-propinole, n-butinole, n-pentinole, n-hexinole, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and the like. [0016] "Cycloalkyl” refers to cycloalkyl having 3 to 8 carbon atoms. Specific examples include cyclopropinole, cyclobutinole, cyclopentinole, cyclohexinole, cycloheptinole, cyclooctyl and the like.
  • Aryl refers to a monocyclic aromatic hydrocarbon or bicyclic or tricyclic fused polycyclic aromatic hydrocarbon having 6 to 14 carbon atoms.
  • the condensed polycyclic hydrocarbons formed by condensation of these monocyclic aromatic hydrocarbons or bicyclic or tricyclic condensed polycyclic aromatic hydrocarbons and cycloalkane rings are also referred to as “ Included in "Areel”.
  • Specific examples of monocyclic aromatic hydrocarbons include phenyl.
  • Specific examples of condensed polycyclic aromatic hydrocarbons include naphthyl, anthryl and phenanthryl.
  • Specific examples of condensed polycyclic hydrocarbons include indanyl, tetrahydronaphthyl, Tetrahydroanthryl and the like can be mentioned.
  • Aromatic heterocycle means a monocyclic aromatic heterocycle having one or more hetero atoms (nitrogen atom, oxygen atom, sulfur atom) in the ring, or a bicyclic or tricyclic fused ring Polycyclic aromatic Heterocycle.
  • monocyclic aromatic heterocycles include aromatic heterocycles having one hetero atom in the ring, such as pyrrole, furan, thiophene, and pyridine; imidazole, oxazole, thiazole, pyrazole, and isoxazole.
  • Azole aromatic heterocycles such as isothiazole; aromatic heterocycles having two nitrogen atoms in the ring such as pyrazine and pyrimidine, etc.
  • condensed bicyclic or tricyclic condensed polycyclic aromatic heterocycles Specific examples of these include condensed aromatic heterocycles such as indole, isoindoinole, benzimidazole, benzoxazonole, benzothiazonole, quinoline, isoquinoline, naphthyridine, thianthrene, phenoxatine, and phenanthorin. Can be mentioned.
  • Non-aromatic heterocycle means a monocyclic non-aromatic heterocycle having one or more heteroatoms (nitrogen atom, oxygen atom, sulfur atom) in the ring, or bicyclic or tricyclic A fused polycyclic non-aromatic heterocycle of
  • monocyclic non-aromatic heterocycles include saturated non-aromatic rings having one hetero atom in the ring such as pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, azepan, tetrahydropyran, and homopiperazine.
  • Aromatic heterocycles imidazolidine, oxazolidine, thiazolidine, virazolidine, piperazine, morpholine, dimorpholine, homopiperidine, homomolybdine
  • a saturated non-aromatic heterocycle having two heteroatoms in the ring such as ruphorin; one helium in the ring such as pyrroline, dihydrophane furan, dihydrothiophene, tetrahydropyridine, dihydropyridine, dihydropyran, pyran, etc.
  • Unsaturated non-aromatic heterocyclic ring having a tera atom unsaturated non-aromatic heterocyclic ring having two hetero atoms such as imidazoline, oxazoline, thiazoline, pyrazoline, etc., condensed in a bicyclic or tricyclic form
  • Specific examples of the polycyclic non-aromatic heterocyclic ring include chroman, indoline, isoindoline, xanthine and the like.
  • Alkoxy refers to a straight or branched alkoxy having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, n propoxy, n butoxy, n pentoxy, n hexenoreoxy, isopropoxy, isobutoxy, sec butoxy, tert butoxy, isopentoxy and the like.
  • Alkylamino refers to monoalkylamino having 1 to 6 carbon atoms or dialkylamino having 2 to 12 carbon atoms. Specific examples of monoalkylamino include methylamino, ethylamino, hexylamino, etc. Specific examples of dialkylamino include ethylmethylamino, dimethylamino, jetylamino, dihexylamino and the like.
  • Alkylcarbonyl refers to a straight or branched alkylcarbonyl having 2 to 7 carbon atoms. Specific examples include methylcarbonyl, ethylcarbonyl, n-propylcarboninole, n-butinorecanoreponinore, n-pentinorecanoreponinore, n-hexinorecanoreponinore, isopropinorecanoreponinore, isobutinorecanoreponinore, sec butinorecanole pononole, tert butylcarbonyl, isopentylcarbonyl and the like.
  • Alkyloxycarbonyl refers to a straight chain or branched alkynoxycarbonyl having 2 to 7 carbon atoms. Specific examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycanoleponinore, n-butoxycanoleponinole, n-pentoxycanoleponinole, n-hexinolexinoreponinore, isopropoxynoreponinore, isobutoxynoreponinore, sec — Butoxycarbonyl, tert butoxycarbonyl, isopentoxycarbonyl and the like.
  • Alkylcarbonylamino refers to a monoalkylcarbonylamino having 2 to 7 carbon atoms or a dialkylcarbonylamino having 4 to 14 carbon atoms.
  • Specific examples of monoalkyl carbonylamino include methylcarbonylamino, ethylcarbonylamidohexyl
  • Specific examples of carbonylamino isotope S and dialkylcarbonylamino include ethylmethylcarbonylamino, dimethylcarbonylamino, jetylcarbonylamino, dihexylcarbonylamino and the like.
  • Haldroxyalkyl refers to an alkyl having one or more hydroxyl groups as substituents.
  • Halogenoalkyl refers to an alkyl having the same or different one or more halogen atoms as substituents.
  • halogenoaromatic heterocycle refers to an aromatic heterocycle having the same or different halogen atoms as substituents.
  • halogenoalkyl aromatic heterocycle refers to an aromatic heterocycle having one or more halogenoalkyl groups as substituents.
  • amino aromatic heterocycle refers to an aromatic complex ring having one or more amino groups as substituents.
  • the substituent may be protected with a protecting group.
  • the aromatic heterocyclic group or the non-aromatic heterocyclic ring has a free nitrogen atom, the nitrogen atom may be protected with a protecting group.
  • the "protecting group for a free hydroxy group” is a substituted or unsubstituted alkyl group such as a methyl group, a methoxymethyl group, a benzyl group, a 4 methoxyphenylmethyl group, an aryl group, or an unsubstituted alkenyl group; Substituted or unsubstituted non-aromatic heterocyclic groups such as 3-bromotetrahydrobiranyl group, tetrahydrobiranyl group and tetrahydrofuranyl group; substituted or unsubstituted groups such as acetyl group, trifluoroacetyl group, benzoyl group and 4-chlorobenzoyl group An alkylcarbonyl group, or a substituted or unsubstituted arylylcarbonyl group; a methoxycarbonyl group, an ethoxycarbonyl group, an isobutoxycarbonyl group, a tert
  • a substituted or unsubstituted aryloxycarbonyl group a substituted silyl group such as a trimethylsilyl group, a triethylsilinole group, a triisopropylpropylsilyl group, a tertbutyldimethylsilinole group, a tertbutyldiphenylsilyl group; It is used as a protective group for free hydroxy groups.
  • Protecting group means an unsubstituted alkenyl group such as an aryl group; a hydrocarbonyl group such as a formyl group; a substitution such as an acetyl group, a trichloroacetyl group, a trifluoroacetyl group, a benzoyl group, a 4-chlorobenzoyl group, and a picolinol group.
  • substituted alkyl group substituted non-aromatic heterocyclic group, substituted alkylcarbonyl group, substituted arylcarbonyl group, substituted alkyloxycarbonyl group, substituted aryloxy group sulfonyl group, substituted silyl group, substituted alkylsulfonyl group
  • the substituted arylsulfonyl group is an alkyl substituted with one or more groups selected from a halogen atom, an alkoxy group, an alkyl group, an aryl group, a halogenoaryl group, an alkoxyaryl group, and a nitro group, respectively.
  • the "plural groups" as used in the present invention may be the same or different, and preferably represent 2 or 3 groups, more preferably 2 groups.
  • the "group" in the present invention includes a hydrogen atom, a halogen atom and an oxo ligand.
  • the “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and may be an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Salt acetic acid, fumanoleic acid, maleic acid, konsuccinic acid, citrate, tartaric acid, adipic acid, gnoleconic acid, gnolecoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1, 2-Ethane disulfonic acid, isethionic acid, ratatobionic acid, oleic acid, pamoic acid, polygalatathuronic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, Salts with organic acids such as naphthalene sulfonic acid and sulfosalicylic acid, quaternary ammonium salts such as methyl bromide and methyl iodide, bromine ions, salt
  • the compound of the present invention takes the form of a hydrate or a solvate! /!
  • R and R together form a non-aromatic heterocycle means that R and R together
  • the non-aromatic heterocycle formed through the ring may be the one shown in the above specific examples, but typical examples are pyrrolidine ring, piperidine ring, azepane ring, etc.
  • the formed non-aromatic heterocyclic ring may be the one shown in the above-mentioned specific examples, but typical examples are morpholine ring, piperazine ring and the like.
  • Ring A represents a benzene ring or a thiophene ring; and / or
  • Ring A may be substituted with a halogen atom; and / or
  • R represents a hydrogen atom or a halogenoalkyl group
  • Y represents a hydroxyl group, an alkoxy group or NR R; and / or
  • R and R are the same or different and represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group,
  • R and R may combine to form a non-aromatic heterocycle; and / or
  • the alkyl group defined above may have one or more substituents selected from a hydroxyl group, an alkyloxycarbonyl group, an aryl group, and an aromatic heterocyclic group; and / or
  • the aryl group as defined above may have one or more substituents selected from a nitro group, an alkyl group, an alkoxy group, a hydroxyalkylyl group, an alkylcarbonyl group and an alkyloxycarbonyl group; And / or
  • the aromatic heterocyclic group defined above may have one or more substituents selected from an alkyl group and a halogenoalkyl group; and / or
  • the non-aromatic heterocyclic group defined above may have one or more substituents selected from an alkyl group, an alkylamino group, an alkenyloxycarbonyl group, and an aromatic heterocyclic group. .
  • Ring A represents a benzene ring or a thiophene ring
  • ring A is a benzene ring
  • the benzene ring may be substituted with a halogen atom; and / or
  • R represents a hydrogen atom or a halogenoalkyl group
  • Y represents a hydroxyl group, an alkoxy group or NR R; and / or
  • R and R are the same or different and are a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a
  • R or R is an alkyl group
  • the alkyl group is a hydroxyl group, an alkyloxy
  • R or R is a non-aromatic heterocyclic group
  • the non-aromatic heterocyclic group is an alkyloxy group
  • Ring A represents a benzene ring, a fluorobenzene ring or a thiophene ring; and / or
  • R represents a hydrogen atom or a trifluoromethyl group
  • Y is a hydroxyl group, tert butoxy group, hydroxyamino group, tert butoxyamino group, pyridin-2-ylmethylamino group, pyridine-3-ylmethylamino group, pyridine-4-ylmethylamino group, 2 trifluoromethylpyridine, 5-methylmethylamino group, benzylamino group 4-methoxybenzylamino group, n-pentylamino group, 3-methoxycarbonyl-propylamino group, N-ethyl-N-pyridine-3-ylmethylamino group, N-ethyl-N 2-hydroxyethylamino group, cyclopropylamino group, cyclopropylamino group Pentaneamino group, phenylamino group, 3-hydroxymethylphenylamino group, 4 propylphenylamino group, 4-methoxyphenylamino group, 4 methylcarbophenylphenyl
  • the compound of the present invention can be produced by the following method. Each specific manufacturing method will be described in detail in the following [Example of manufacturing example].
  • Hal used in the following synthesis route represents a halogen atom.
  • the compound of the present invention is produced by properly using conditions and the like according to the main synthetic route consisting of routes A to D shown below.
  • the compound (I) of the present invention can be produced according to synthesis route A. That is, the present invention Compound (II) and primary or secondary amine (III) in an organic solvent such as N, N dimethylformamide (hereinafter abbreviated as DMF), TFP resin (J. Comb. Chem., 2000, 2, 691— 697).
  • an organic solvent such as N, N dimethylformamide (hereinafter abbreviated as DMF), TFP resin (J. Comb. Chem., 2000, 2, 691— 697).
  • Azabenzotriazole-1-yl 1, 1, 3, 3, 3-water-soluble carpoiimide (WSC) such as tetramethyluronium hexafluorophosphate (HATU), and ⁇ , ⁇ diisopropyl Compound (I) can be obtained by reacting in the presence of a base such as ethylamine (hereinafter abbreviated as DIEA) at room temperature to 80 ° C for 1 to 24 hours.
  • a base such as ethylamine (hereinafter abbreviated as DIEA)
  • the compound ( ⁇ ) of the present invention can be produced according to synthetic route B. That is, the compound (IV) is obtained by reacting the compound (IV) of the present invention with hydrogen chloride in an organic solvent such as dioxane at room temperature for 1 to 24 hours.
  • the compound (IV) of the present invention can be produced according to synthetic route C. That is, the compound
  • Compound (V) can be produced according to synthetic route D. That is, compound (V) can be obtained by heating and refluxing compound (VII) and aldehyde (VIII) in an organic solvent such as methanol in the presence of a base such as sodium methoxide for 1 to 24 hours.
  • the compound of the present invention produced by the above synthetic route can be made into the above-mentioned salt, hydrate or solvate form by a widely used technique.
  • VEGF-induced HUVEC proliferation reaction evaluation system (HUVEC: normal human umbilical vein-derived vascular endothelial cells), which is a method for evaluating the angiogenesis inhibitory effect of a drug
  • a cell growth inhibitory effect test of the compound of the present invention was conducted to evaluate its angiogenesis inhibitory effect. The details thereof will be described in the following Examples [Pharmacological test section], and it was found that the compound of the present invention has an excellent cell growth inhibitory effect and an angiogenesis inhibitory effect.
  • angiogenesis is caused by cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, It has been reported to be closely related to diseases such as retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, and atherosclerosis. Therefore, the compound of the present invention is highly expected as a therapeutic agent for those diseases involving angiogenesis.
  • the compound of the present invention can be administered orally or parenterally.
  • the dosage form include tablets, capsules, granules, powders, injections, ointments, eye drops, eye ointments and the like, and they can be formulated using a widely used technique.
  • oral preparations such as tablets, capsules, granules, powders and the like are used for excipients such as lactose, mannitol, starch, crystalline cellulose, light anhydrous carboxylic acid, calcium carbonate, calcium hydrogen phosphate, and stearic acid.
  • Lubricants such as magnesium stearate and talc, binders such as starch and hin, carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, disintegrants such as calcium citrate, hydroxypropylmethylcellulose, macrogol, silicone resin
  • a coating agent such as paraethyl benzoate, stabilizers such as benzyl alcohol, and flavoring agents such as sweeteners, acidulants and fragrances as necessary.
  • parenterals such as injections and eye drops include isotonic agents such as sodium chloride, concentrated glycerin, propylene glycolone, polyethylene glycol, potassium chloride, sonolebithonole, mannitol, sodium phosphate, hydrogen phosphate Buffering agents such as sodium, sodium acetate, citrate, glacial acetic acid, trometamol, surfactants such as polyoxyethylene sorbitan monolate, polyoxystearate 40, polyoxyethylene hydrogenated castor oil, sodium citrate, edet Stabilizers such as sodium nitrate, benzalkonium chloride, paraben, benzotonium chloride, noroxybenzoic acid ester, sodium benzoate, preservatives such as chlorobutanol, hydrochloric acid, citrate, phosphoric acid, glacial acetic acid, hydroxylated Sodium, sodium carbonate, sodium bicarbonate, etc.
  • a pH adjuster a soothing agent such as benzaric acid, cit
  • the present invention also provides a method for treating a disease associated with angiogenesis, which comprises administering to a patient a therapeutically effective amount of a compound of the present invention or a salt thereof.
  • the dose of the compound of the present invention can be appropriately selected depending on symptoms, age, dosage form and the like. For example, for oral preparations, 0.01 to 1000 mg, preferably 1 to 100 mg per day can be administered in a single dose or divided into several doses. In addition, eye drops can be administered at a concentration of usually 0.0001% to 10% (w / v), preferably 0.001% to 5% (w / v) once or divided into several times. .
  • reference compounds 1 2 to 7 were obtained using a compound selected from commercially available compounds and known compounds according to the production method of reference compound 11.
  • compounds 0-2 to 7 were obtained according to the production method of compound 0-1, using compounds selected from reference compounds 12-7, commercially available compounds and known compounds.
  • Compound 1 2-7 was obtained according to the production method of Compound 1-1, using Compound 0-2-7, a commercially available compound and a compound selected from known compounds.
  • the resin was washed twice with 10 mL of DMF, tetrahydrofuran, and methylene chloride in order, and then dried.DMF (resin (lOOmg, theoretical 0.1 mmol) to lmU and 3-aminomethylpyridine (7. Omg) , 0.069 mmol) at room temperature and stirred for 24 hours After filtering the reaction solution, the resin was washed twice with 2 mL of methylene chloride, DMF, and methylene chloride in this order. The target compound 22 mg was obtained as a yellow solid (yield 54%).
  • Compound 2-244 was obtained according to the production method of Compound 2-1, using Compound 17 and a compound selected from commercially available compounds and known compounds.
  • the tablet with the above formulation is coated with 2 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the desired coated tablet.
  • a coating agent for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.
  • Desired tablets can be obtained by appropriately changing the type and amount of the compound of the present invention and additives.
  • a desired capsule can be obtained by appropriately changing the mixing ratio of the compound of the present invention and lactose.
  • the desired eye drop IJ can be obtained with the power s.
  • UVEC proliferation response evaluation system is Cancer Res., 59, 9
  • test compound was dissolved in dimethyl sulfoxide (hereinafter DMSO), and the resulting solution was diluted with a commercially available phosphate buffer solution (hereinafter PBS) to prepare a test compound solution of SO ⁇ g / mL.
  • DMSO dimethyl sulfoxide
  • PBS phosphate buffer solution
  • HUVEC was suspended in F12K medium containing 0.5% urine fetal serum (hereinafter FBS) to prepare a HUVEC suspension of 2 ⁇ 104 cells / mL.
  • FBS urine fetal serum
  • a 400 ng / mL VEGF solution was prepared by diluting with S-containing F12K medium.
  • test compound suspension absorbance of each well suspension (hereinafter referred to as test compound suspension) at 450 nm was measured.
  • the cell growth inhibition rate (%) which is an index of the angiogenesis inhibitory effect, was calculated from the formula shown below.
  • Table 1 shows the cell growth inhibition rates (%) of the test compounds (Compound 2-10, Compound 2-12, and Compound 2-26).
  • the compound of the present invention showed an excellent cell growth inhibitory action. Therefore
  • the compound of the present invention has an excellent angiogenesis inhibitory effect.

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Abstract

The object is to synthesize a novel compound having a 1,4-benzothiazin-3-one skeleton or a 3,4-dihydroquinolin-2-one skeleton and find a pharmacological activity of the compound. Specifically provided is a compound represented by the formula [I] or a salt thereof [wherein the ring A represents an aryl group, an aromatic heterocyclic group, or the like; R1 represents a hydrogen atom, a halogen atom, an alkyl group, a halogenoalkyl group, or the like; X represents S, CH2, or the like; Y represents a hydroxy group, an alkoxy group, NR2R3, or the like; and R2 and R3 independently represent ahydrogen atom, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, or the like.

Description

明 細 書  Specification
1 , 4一べンゾチアジンー3—オン骨格又は 3， 4ージヒドロキノリンー2—ォ ン骨格を有する新規化合物  1,4 1-benzothiazin-3-one skeleton or 3,4-dihydroquinolin-2-one skeleton
技術分野  Technical field
[0001] 本発明は医薬として有用な 1 , 4一べンゾチアジンー3—オン骨格又は 3, 4—ジヒド 口キノリンー2—オン骨格を有する新規化合物又はそれらの塩に関する。それらの化 合物は血管新生が関与する疾患の治療剤、特に癌、関節リウマチ、加齢性黄斑変性 、糖尿病網膜症、未熟児網膜症、網膜静脈閉塞症、ポリープ状脈絡膜血管症、糖尿 病黄斑浮腫、尋常性乾癬、粥状動脈硬化等の治療剤として有用である。  [0001] The present invention relates to a novel compound having a 1,4-monobenzothiazin-3-one skeleton or a 3,4-dihydric quinolin-2-one skeleton, or a salt thereof, which is useful as a medicine. These compounds are therapeutic agents for diseases involving angiogenesis, especially cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetes It is useful as a therapeutic agent for macular edema, psoriasis vulgaris, atherosclerosis, etc.
背景技術  Background art
[0002] 血管新生とは既存の血管から新しい血管ネットワークが形成される現象であり、おも に細小血管で観察される。血管新生は本来生理的な現象であり、胎生期の血管形 成にとって必須であるが、成人では通常、子宮内膜、卵胞等の限られた部位や創傷 治癒の過程等の限られた時期にしか観察されない。ところ力 癌、関節リウマチ、カロ 齢性黄斑変性、糖尿病網膜症、未熟児網膜症、網膜静脈閉塞症、ポリープ状脈絡 膜血管症、糖尿病黄斑浮腫、尋常性乾癬、粥状動脈硬化等の疾患において病的な 血管新生が観察され、それらの疾患の病態進展と密接に関係している。血管新生は その促進因子と抑制因子のバランスにより調節されており、それらのバランスが崩れ ることにより血管新生が発生すると考えられている（非特許文献 1、非特許文献 2参照 )。  Angiogenesis is a phenomenon in which a new blood vessel network is formed from existing blood vessels, and is mainly observed in small blood vessels. Angiogenesis is inherently a physiological phenomenon and is essential for embryonic blood vessel formation, but in adults it is usually limited to limited areas such as the endometrium and follicles and the wound healing process. Only observed. However, in diseases such as cancer, rheumatoid arthritis, caro-aged macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis Pathological angiogenesis has been observed and is closely related to the pathological progression of these diseases. Angiogenesis is regulated by the balance between the promoting factor and the inhibitory factor, and it is considered that angiogenesis occurs when the balance is lost (see Non-Patent Document 1 and Non-Patent Document 2).
[0003] 血管内皮細胞増殖因子（以下、『VEGF』とする）は、血管内皮細胞表面に存在する 受容体 (Flt_l、 KDR/Flk-1等）に特異的に作用して、血管内皮細胞の増殖、遊走、 管腔形成による毛細血管ネットワークの構築を促進する因子であり、血管新生の発 生において非常に重要な役割を担っている。そのため、この VEGFを阻害して、血管 新生の発生を制御することにより、血管新生が関与する疾患を治療する試みが数多 く報告されている。このような治療に用いる薬物として、例えば、インドリンー2—オン 誘導体 (特許文献 1参照）、フタラジン誘導体 (特許文献 2参照）、キナゾリン誘導体（ 特許文献 3参照）、アントラニル酸アミド誘導体 (特許文献 4参照）、 2 ァミノニコチン 酸誘導体 (特許文献 5参照）、 4 ピリジルアルキルチオ誘導体 (特許文献 6参照）等 を挙げること力 Sでさる。 [0003] Vascular endothelial growth factor (hereinafter referred to as "VEGF") acts specifically on receptors (Flt_l, KDR / Flk-1, etc.) present on the surface of vascular endothelial cells to It is a factor that promotes the construction of capillary networks through proliferation, migration, and lumen formation, and plays a very important role in the development of angiogenesis. Therefore, many attempts have been reported to treat diseases involving angiogenesis by inhibiting the VEGF and controlling the occurrence of angiogenesis. Examples of drugs used for such treatment include indoline-2-one derivatives (see Patent Document 1), phthalazine derivatives (see Patent Document 2), and quinazoline derivatives (see Patent Document 1). For example, Patent Document 3), anthranilic acid amide derivatives (see Patent Document 4), 2 aminonicotinic acid derivatives (see Patent Document 5), 4 pyridylalkylthio derivatives (see Patent Document 6), etc.
[0004] し力、し、これらの特許文献には、 1 , 4一べンゾチアジン 3—オン骨格又は 3, 4— ジヒドロキノリン— 2—オン骨格を有する環式化合物に関する記載はなされていない。  However, these patent documents do not describe a cyclic compound having a 1,4-monobenzothiazin 3-one skeleton or a 3,4-dihydroquinolin-2-one skeleton.
[0005] 一方、 1 , 4一べンゾチアジン 3 オン骨格を有する環式化合物が、特許文献 7に 報告されている。特許文献 7では、これらはチロシンキナーゼ阻害による細胞増殖抑 制剤として報告されて!/、る。し力もながらその特許文献には活性の詳細なデータが記 載されておらず、かつ、本発明化合物の特徴である親水性の置換基の導入も試みら れていない。  [0005] On the other hand, Patent Document 7 reports a cyclic compound having a 1,4 benzothiazin 3 -one skeleton. In Patent Document 7, these are reported as cell growth inhibitors by inhibiting tyrosine kinases! However, there is no detailed activity data in the patent document, and no attempt has been made to introduce a hydrophilic substituent which is a feature of the compound of the present invention.
非特許文献 1： Molecular Medicine vol.35臨時増刊号 「症候'病態の分子メカニズ ム」、中山書店、 73- 74 (1998)  Non-Patent Document 1: Molecular Medicine vol.35 Special issue “Symptoms: Molecular mechanism of pathology”, Nakayama Shoten, 73-74 (1998)
非特許文献 2 :蛋白質 核酸 酵素 増刊 「最先端創薬」、共立出版、 1182— 11 87 (2000)  Non-Patent Document 2: Protein Nucleic acid Enzyme Extra number “Advanced Drug Discovery”, Kyoritsu Shuppan, 1182— 11 87 (2000)
特許文献 1：国際公開 WO98/50356号パンフレット  Patent Document 1: International Publication WO98 / 50356 Pamphlet
特許文献 2：国際公開 W098/35958号パンフレット  Patent Document 2: International Publication W098 / 35958 Pamphlet
特許文献 3：国際公開 WO97/30035号パンフレット  Patent Document 3: International Publication WO97 / 30035 Pamphlet
特許文献 4：国際公開 WO00/27819号パンフレット  Patent Document 4: International Publication WO00 / 27819 Pamphlet
特許文献 5 :国際公開 WO01/55114号パンフレット  Patent Document 5: International Publication WO01 / 55114 Pamphlet
特許文献 6：国際公開 WO04/078723号パンフレット  Patent Document 6: International Publication WO04 / 078723 Pamphlet
特許文献 7：国際公開 WO00/75139号パンフレット  Patent Document 7: International Publication WO00 / 75139 Pamphlet
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0006] 1 , 4一べンゾチアジンー3 オン骨格又は 3, 4 ジヒドロキノリンー2 オン骨格を有 する新規化合物の合成研究及びそれらの化合物の薬理作用を見出すことは非常に 興味深い課題である。 [0006] Synthetic studies on novel compounds having a 1,4 monobenzothiazin-3-one skeleton or a 3,4 dihydroquinolin-2-one skeleton and finding the pharmacological action of these compounds are very interesting issues.
課題を解決するための手段  Means for solving the problem
[0007] 本発明者等は 1 , 4一べンゾチアジン 3—オン骨格又は 3, 4—ジヒドロキノリン 2 オン骨格を有する化合物の合成研究を行い、数多くの新規化合物を創製すること に成功した。 [0007] The present inventors have described 1,4-monobenzothiazin 3-one skeleton or 3,4-dihydroquinoline 2 We have conducted research on the synthesis of compounds with an on-skeleton and succeeded in creating many new compounds.
[0008] さらに、それらの化合物の薬理作用を種々研究したところ、それらの化合物は血管 新生阻害作用を有し、血管新生が関与する疾患の治療剤、特に癌、関節リウマチ、 加齢性黄斑変性、糖尿病網膜症、未熟児網膜症、網膜静脈閉塞症、ポリープ状脈 絡膜血管症、糖尿病黄斑浮腫、尋常性乾癬、粥状動脈硬化等の治療剤として有用 であることを見出し、本発明を完成させた。  [0008] Further, various studies on the pharmacological action of these compounds revealed that these compounds have angiogenesis-inhibiting action and are therapeutic agents for diseases involving angiogenesis, particularly cancer, rheumatoid arthritis, age-related macular degeneration. The present invention has been found to be useful as a therapeutic agent for diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis, etc. Completed.
[0009] すなわち、本発明は一般式 [I]で表される化合物又はその塩 (以下、特記なき限り『 本発明化合物』とする)及び本発明化合物を含有する医薬組成物に関する。本発明 化合物の医薬用途をより詳しく説明すると、本発明化合物を有効成分とする血管新 生が関与する疾患の治療剤に関するものであり、例えば、癌、関節リウマチ、加齢黄 斑変性、糖尿病網膜症、未熟児網膜症、網膜静脈閉塞症、ポリープ状脈絡膜血管 症、糖尿病黄斑浮腫、尋常性乾癬、粥状動脈硬化等の治療剤に関するものである。  That is, the present invention relates to a compound represented by the general formula [I] or a salt thereof (hereinafter referred to as “the compound of the present invention” unless otherwise specified) and a pharmaceutical composition containing the compound of the present invention. The pharmaceutical use of the compound of the present invention will be described in more detail. The present invention relates to a therapeutic agent for diseases involving vascular neoplasia, which comprises the compound of the present invention as an active ingredient. For example, cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retina The present invention relates to therapeutic agents for retinopathy of prematurity, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis and the like.
[0010] 下記一般式 [I]で表される化合物又はその塩。  [0010] A compound represented by the following general formula [I] or a salt thereof.
Figure imgf000005_0001
Figure imgf000005_0001
[0011] [式中、環 Aはァリール基又は芳香族複素環を示し； [Wherein ring A represents an aryl group or an aromatic heterocyclic ring;
Rは水素原子、ハロゲン原子、アルキル基又はハロゲノアルキル基を示し；  R represents a hydrogen atom, a halogen atom, an alkyl group or a halogenoalkyl group;
Xは S又は CHを示し；  X represents S or CH;
2  2
Yは水酸基、アルコキシ基又は NR Rを示し；  Y represents a hydroxyl group, an alkoxy group or NR R;
2 3  twenty three
Rと Rは同一又は異なって水素原子、水酸基、アルキル基、アルコキシ基、シクロア R and R are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group,
2 3 twenty three
ルキル基、ァリール基、芳香族複素環基又は非芳香族複素環基を示し；  An alkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group;
Rと Rが一緒になつて非芳香族複素環を形成してもよく； 上記した各アルキル基は水酸基、アミノ基、カルボキシル基、アルキルカルボニル基 、アルキルォキシカルボニル基、アルキルアミノ基、ァリール基、芳香族複素環基及 び非芳香族複素環基から選択される 1又は複数の置換基を有してもよく； 上記した各ァリール基はハロゲン原子、アミノ基、ニトロ基、アルキル基、ハロゲノアル キノレ基、アルコキシ基、ヒドロキシアルキル基、アルキルカルボニル基、アルキルォキ シカルボニル基、アルキルアミノ基、アルキルカルボニルァミノ基、芳香族複素環基 及び非芳香族複素環基から選択される 1又は複数の置換基を有してもよく； 上記した各芳香族複素環基はハロゲン原子、アミノ基、アルキル基、ハロゲノアルキ ル基、ヒドロキシアルキル基、アルキルォキシカルボニル基、アルキルアミノ基及びァ ルキルカルボニルァミノ基から選択される 1又は複数の置換基を有してもよく； 上記した各非芳香族複素環基はハロゲン原子、アミノ基、アルキル基、ハロゲノアル キノレ基、ヒドロキシアルキル基、アルキルォキシカルボニル基、アルキルアミノ基、ァ ルキルカルボニルァミノ基及び非芳香族複素環基から選択される 1又は複数の置換 基を有してもよい。 ] R and R may join together to form a non-aromatic heterocycle; Each of the above alkyl groups is selected from a hydroxyl group, an amino group, a carboxyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylamino group, an aryl group, an aromatic heterocyclic group and a non-aromatic heterocyclic group 1 or Each aryl group described above may be a halogen atom, an amino group, a nitro group, an alkyl group, a halogenoalkynole group, an alkoxy group, a hydroxyalkyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkyl group. One or more substituents selected from an amino group, an alkylcarbonylamino group, an aromatic heterocyclic group and a non-aromatic heterocyclic group may be present; each aromatic heterocyclic group described above is a halogen atom, Amino group, alkyl group, halogenoalkyl group, hydroxyalkyl group, alkyloxycarbonyl group, alkyl One or more substituents selected from a mino group and an alkylcarbonylamino group; each non-aromatic heterocyclic group described above is a halogen atom, an amino group, an alkyl group, a halogenoalkynole group, a hydroxy group; It may have one or more substituents selected from an alkyl group, an alkyloxycarbonyl group, an alkylamino group, an alkylcarbonylamino group, and a non-aromatic heterocyclic group. ]
発明の効果  The invention's effect
[0012] 本発明は医薬として有用な 1 , 4一べンゾチアジンー3 オン骨格又は 3, 4 ジヒド 口キノリン 2—オン骨格を有する新規化合物又はその塩を提供する。本発明に係る 新規環式化合物は、優れた血管新生阻害作用を有し、血管新生が関与する疾患、 例えば、癌、関節リウマチ、加齢性黄斑変性、糖尿病網膜症、未熟児網膜症、網膜 静脈閉塞症、ポリープ状脈絡膜血管症、糖尿病黄斑浮腫、尋常性乾癬、粥状動脈 硬化等の治療剤として有用である。  [0012] The present invention provides a novel compound having a 1,4 monobenzothiazin-3-one skeleton or a 3,4 dihydrin quinolin-2-one skeleton, or a salt thereof, useful as a medicament. The novel cyclic compound according to the present invention has an excellent angiogenesis-inhibiting action, and diseases involving angiogenesis, such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retina It is useful as a therapeutic agent for venous occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, and atherosclerosis.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0013] 特許請求の範囲及び明細書中で使用される各基は、特許請求の範囲及び明細書 全体を通して下記の意味を有するものとする。 [0013] Each group used in the claims and the specification shall have the following meanings throughout the claims and the specification.
[0014] 『ハロゲン原子』とはフッ素、塩素、臭素又はヨウ素を示す。 “Halogen atom” means fluorine, chlorine, bromine or iodine.
[0015] 『アルキル』とは炭素原子数 1〜6個の、直鎖又は分枝のアルキルを示す。具体例と してメチノレ、ェチノレ、 n プロピノレ、 n ブチノレ、 n ペンチノレ、 n へキシノレ、イソプロ ピル、イソブチル、 sec ブチル、 tert ブチル、イソペンチル等が挙げられる。 [0016] 『シクロアルキル』とは炭素原子数 3〜8個のシクロアルキルを示す。具体例としてシ クロプロピノレ、シクロブチノレ、シクロペンチノレ、シクロへキシノレ、シクロへプチノレ、シクロ ォクチル等が挙げられる。 “Alkyl” refers to a straight-chain or branched alkyl having 1 to 6 carbon atoms. Specific examples include methinole, ethinole, n-propinole, n-butinole, n-pentinole, n-hexinole, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and the like. [0016] "Cycloalkyl" refers to cycloalkyl having 3 to 8 carbon atoms. Specific examples include cyclopropinole, cyclobutinole, cyclopentinole, cyclohexinole, cycloheptinole, cyclooctyl and the like.
[0017] 『ァリール』とは炭素原子数 6〜； 14個の、単環式芳香族炭化水素又は 2環式若しく は 3環式の縮合多環式芳香族炭化水素を示す。また、それら単環式芳香族炭化水 素又は 2環式若しくは 3環式の縮合多環式芳香族炭化水素とシクロアルカン環の縮 合により形成される縮合多環式炭化水素も本願発明の『ァリール』に含まれる。単環 式芳香族炭化水素の具体例としてフエニルが、縮合多環式芳香族炭化水素の具体 例としてナフチル、アントリル、フエナントリル等力 縮合多環式炭化水素の具体例と してインダニル、テトラヒドロナフチル、テトラヒドロアントリル等が挙げられる。  “Aryl” refers to a monocyclic aromatic hydrocarbon or bicyclic or tricyclic fused polycyclic aromatic hydrocarbon having 6 to 14 carbon atoms. In addition, the condensed polycyclic hydrocarbons formed by condensation of these monocyclic aromatic hydrocarbons or bicyclic or tricyclic condensed polycyclic aromatic hydrocarbons and cycloalkane rings are also referred to as “ Included in "Areel". Specific examples of monocyclic aromatic hydrocarbons include phenyl. Specific examples of condensed polycyclic aromatic hydrocarbons include naphthyl, anthryl and phenanthryl. Specific examples of condensed polycyclic hydrocarbons include indanyl, tetrahydronaphthyl, Tetrahydroanthryl and the like can be mentioned.
[0018] 『芳香族複素環』とは 1又は複数のへテロ原子（窒素原子、酸素原子、硫黄原子）を 環内に有する単環式芳香族複素環又は 2環式若しくは 3環式の縮合多環式芳香族 複素環を示す。  [0018] "Aromatic heterocycle" means a monocyclic aromatic heterocycle having one or more hetero atoms (nitrogen atom, oxygen atom, sulfur atom) in the ring, or a bicyclic or tricyclic fused ring Polycyclic aromatic Heterocycle.
[0019] 単環式芳香族複素環の具体例として、ピロール、フラン、チォフェン、ピリジン等の 環内に 1個のへテロ原子を有する芳香族複素環;イミダゾール、ォキサゾール、チア ゾール、ピラゾール、イソォキサゾール、イソチアゾール等のァゾール系芳香族複素 環；ピラジン、ピリミジン等の環内に 2個の窒素原子を有する芳香族複素環等が、 2環 式若しくは 3環式の縮合多環式芳香族複素環の具体例として、インドール、イソインド 一ノレ、ベンゾイミダゾーノレ、ベンゾォキサゾーノレ、ベンゾチアゾーノレ、キノリン、イソキ ノリン、ナフチリジン、チアントレン、フエノキサチン、フエナント口リン等の縮合芳香族 複素環等が挙げられる。  [0019] Specific examples of monocyclic aromatic heterocycles include aromatic heterocycles having one hetero atom in the ring, such as pyrrole, furan, thiophene, and pyridine; imidazole, oxazole, thiazole, pyrazole, and isoxazole. Azole aromatic heterocycles such as isothiazole; aromatic heterocycles having two nitrogen atoms in the ring such as pyrazine and pyrimidine, etc. are condensed bicyclic or tricyclic condensed polycyclic aromatic heterocycles Specific examples of these include condensed aromatic heterocycles such as indole, isoindoinole, benzimidazole, benzoxazonole, benzothiazonole, quinoline, isoquinoline, naphthyridine, thianthrene, phenoxatine, and phenanthorin. Can be mentioned.
[0020] 『非芳香族複素環』とは 1又は複数のへテロ原子（窒素原子、酸素原子、硫黄原子） を環内に有する単環式非芳香族複素環又は 2環式若しくは 3環式の縮合多環式非 芳香族複素環を示す。  [0020] "Non-aromatic heterocycle" means a monocyclic non-aromatic heterocycle having one or more heteroatoms (nitrogen atom, oxygen atom, sulfur atom) in the ring, or bicyclic or tricyclic A fused polycyclic non-aromatic heterocycle of
[0021] 単環式非芳香族複素環の具体例として、ピロリジン、テトラヒドロフラン、テトラヒドロ チォフェン、ピぺリジン、ァゼパン、テトラヒドロピラン、ホモピぺラジン等の環内に 1個 のへテロ原子を有する飽和非芳香族複素環;イミダゾリジン、ォキサゾリジン、チアゾ リジン、ビラゾリジン、ピぺラジン、モルホリン、チ才モルホリン、ホモピぺリジン、ホモモ ルホリン等の環内に 2個のへテロ原子を有する飽和非芳香族複素環；ピロリン、ジヒド 口フラン、ジヒドロチォフェン、テトラヒドロピリジン、ジヒドロピリジン、ジヒドロピラン、ピ ラン等の環内に 1個のへテロ原子を有する不飽和非芳香族複素環;イミダゾリン、ォ キサゾリン、チアゾリン、ピラゾリン等の 2個のへテロ原子を有する不飽和非芳香族複 素環等が、 2環式若しくは 3環式の縮合多環式非芳香族複素環の具体例として、クロ マン、インドリン、イソインドリン、キサンチン等が挙げられる。 [0021] Specific examples of monocyclic non-aromatic heterocycles include saturated non-aromatic rings having one hetero atom in the ring such as pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, azepan, tetrahydropyran, and homopiperazine. Aromatic heterocycles: imidazolidine, oxazolidine, thiazolidine, virazolidine, piperazine, morpholine, dimorpholine, homopiperidine, homomolybdine A saturated non-aromatic heterocycle having two heteroatoms in the ring such as ruphorin; one helium in the ring such as pyrroline, dihydrophane furan, dihydrothiophene, tetrahydropyridine, dihydropyridine, dihydropyran, pyran, etc. Unsaturated non-aromatic heterocyclic ring having a tera atom; unsaturated non-aromatic heterocyclic ring having two hetero atoms such as imidazoline, oxazoline, thiazoline, pyrazoline, etc., condensed in a bicyclic or tricyclic form Specific examples of the polycyclic non-aromatic heterocyclic ring include chroman, indoline, isoindoline, xanthine and the like.
[0022] 『アルコキシ』とは炭素原子数 1〜6個の、直鎖又は分枝のアルコキシを示す。具体 例としてメトキシ、エトキシ、 n プロポキシ、 n ブトキシ、 n ペントキシ、 n へキシ ノレォキシ、イソプロポキシ、イソブトキシ、 sec ブトキシ、 tert ブトキシ、イソペントキ シ等が挙げられる。 [0022] "Alkoxy" refers to a straight or branched alkoxy having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, n propoxy, n butoxy, n pentoxy, n hexenoreoxy, isopropoxy, isobutoxy, sec butoxy, tert butoxy, isopentoxy and the like.
[0023] 『アルキルァミノ』とは炭素原子数 1〜6個のモノアルキルアミノ又は炭素原子数 2〜 12個のジアルキルアミノを示す。モノアルキルァミノの具体例としてメチルァミノ、ェチ ルァミノ、へキシルァミノ等力 ジアルキルァミノの具体例としてェチルメチルァミノ、ジ メチルァミノ、ジェチルァミノ、ジへキシルァミノ等が挙げられる。  [0023] "Alkylamino" refers to monoalkylamino having 1 to 6 carbon atoms or dialkylamino having 2 to 12 carbon atoms. Specific examples of monoalkylamino include methylamino, ethylamino, hexylamino, etc. Specific examples of dialkylamino include ethylmethylamino, dimethylamino, jetylamino, dihexylamino and the like.
[0024] 『アルキルカルボニル』とは炭素原子数 2〜7個の、直鎖又は分枝のアルキルカル ボニルを示す。具体例としてメチルカルボニル、ェチルカルボニル、 n プロピルカル ボニノレ、 n ブチノレカノレポニノレ、 n ペンチノレカノレポニノレ、 n へキシノレカノレポニノレ、 イソプロピノレカノレポニノレ、イソブチノレカノレポニノレ、 sec ブチノレカノレポニノレ、 tert ブ チルカルボニル、イソペンチルカルボニル等が挙げられる。  “Alkylcarbonyl” refers to a straight or branched alkylcarbonyl having 2 to 7 carbon atoms. Specific examples include methylcarbonyl, ethylcarbonyl, n-propylcarboninole, n-butinorecanoreponinore, n-pentinorecanoreponinore, n-hexinorecanoreponinore, isopropinorecanoreponinore, isobutinorecanoreponinore, sec butinorecanole pononole, tert butylcarbonyl, isopentylcarbonyl and the like.
[0025] 『アルキルォキシカルボニル』とは炭素原子数 2〜7個の、直鎖又は分枝のアルキ ノレォキシカルボニルを示す。具体例としてメトキシカルボニル、エトキシカルボニル、 n プロポキシカノレポニノレ、 n ブトキシカノレポニノレ、 n ペントキシカノレポニノレ、 n へ キシノレォキシカノレポニノレ、イソプロポキシカノレポニノレ、イソブトキシカノレポニノレ、 sec— ブトキシカルボニル、 tert ブトキシカルボニル、イソペントキシカルボニル等が挙げ られる。  [0025] "Alkyloxycarbonyl" refers to a straight chain or branched alkynoxycarbonyl having 2 to 7 carbon atoms. Specific examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycanoleponinore, n-butoxycanoleponinole, n-pentoxycanoleponinole, n-hexinolexinoreponinore, isopropoxynoreponinore, isobutoxynoreponinore, sec — Butoxycarbonyl, tert butoxycarbonyl, isopentoxycarbonyl and the like.
[0026] 『アルキルカルボニルァミノ』とは炭素原子数 2〜7個のモノアルキルカルボニルアミ ノ又は炭素原子数 4〜 14のジアルキルカルボニルァミノを示す。モノアルキルカルボ ニルァミノの具体例としてメチルカルボニルァミノ、ェチルカルボニルアミ入へキシル カルボニルァミノ等力 S、ジアルキルカルボニルァミノの具体例としてェチルメチルカル ボニルァミノ、ジメチルカルボニルァミノ、ジェチルカルボニルァミノ、ジへキシルカル ボニルァミノ等が挙げられる。 [0026] "Alkylcarbonylamino" refers to a monoalkylcarbonylamino having 2 to 7 carbon atoms or a dialkylcarbonylamino having 4 to 14 carbon atoms. Specific examples of monoalkyl carbonylamino include methylcarbonylamino, ethylcarbonylamidohexyl Specific examples of carbonylamino isotope S and dialkylcarbonylamino include ethylmethylcarbonylamino, dimethylcarbonylamino, jetylcarbonylamino, dihexylcarbonylamino and the like.
[0027] 『ヒドロキシアルキル』とは、 1又は複数の水酸基を置換基として有するアルキルを示 す。 “Hydroxyalkyl” refers to an alkyl having one or more hydroxyl groups as substituents.
[0028] 『ハロゲノアルキル』とは、同一又は異なる 1又は複数のハロゲン原子を置換基とし て有するアルキルを示す。  “Halogenoalkyl” refers to an alkyl having the same or different one or more halogen atoms as substituents.
[0029] 『ハロゲノ芳香族複素環』とは、同一又は異なる 1又は複数のハロゲン原子を置換 基として有する芳香族複素環を示す。 [0029] The "halogenoaromatic heterocycle" refers to an aromatic heterocycle having the same or different halogen atoms as substituents.
[0030] 『ハロゲノアルキル芳香族複素環』とは、同一又は異なる 1又は複数のハロゲノアル キル基を置換基として有する芳香族複素環を示す。 [0030] The "halogenoalkyl aromatic heterocycle" refers to an aromatic heterocycle having one or more halogenoalkyl groups as substituents.
[0031] 『ァミノ芳香族複素環』とは、 1又は複数のアミノ基を置換基として有する芳香族複 素環を示す。 [0031] "Amino aromatic heterocycle" refers to an aromatic complex ring having one or more amino groups as substituents.
[0032] 本発明化合物が遊離の、ヒドロキシ基、アミノ基、アルキルアミノ基又はアルキル力 ルポニルァミノ基を置換基として有する場合、それらの置換基は保護基で保護されて いてもよい。また、芳香族複素環基又は非芳香族複素環が遊離の窒素原子を有する 場合も、該窒素原子は保護基で保護されていてもよい。  [0032] When the compound of the present invention has a free hydroxy group, amino group, alkylamino group or alkyl group sulfonylamino group as a substituent, the substituent may be protected with a protecting group. In addition, when the aromatic heterocyclic group or the non-aromatic heterocyclic ring has a free nitrogen atom, the nitrogen atom may be protected with a protecting group.
[0033] 『遊離のヒドロキシ基の保護基』とは、メチル基、メトキシメチル基、ベンジル基、 4 メトキシフエニルメチル基、ァリル基等の置換若しくは無置換アルキル基、又は無置 換アルケニル基； 3—ブロモテトラヒドロビラニル基、テトラヒドロビラニル基、テトラヒド ロフラニル基等の置換若しくは無置換非芳香族複素環基；ァセチル基、トリフルォロ ァセチル基、ベンゾィル基、 4 クロ口ベンゾィル基等の置換若しくは無置換アルキ ルカルポニル基、又は置換若しくは無置換ァリールカルボニル基;メトキシカルボ二 ノレ基、エトキシカルボニル基、イソブトキシカルボニル基、 tert ブトキシカルボニル 基、ベンジルォキシカルボニル基、 p メトキシベンジルォキシカルボニル基、 9ーフ ノレオレニルメトキシカルボニル基、ビュルォキシカルボニル基、ァリルォキシカルボ二 ノレ基、フエニルォキシカルボニル基、 p 二トロフエニルォキシカルボニル基等の置 換若しくは無置換アルキルォキシカルボニル基、無置換アルケニルォキシカルボ二 ル基、又は置換若しくは無置換ァリールォキシカルボニル基；トリメチルシリル基、トリ ェチルシリノレ基、トリイソプロビルシリル基、 tert ブチルジメチルシリノレ基、 tert ブ チルジフエニルシリル基等の置換シリル基；等の遊離のヒドロキシ基の保護基として 汎用されるものを示す。 [0033] The "protecting group for a free hydroxy group" is a substituted or unsubstituted alkyl group such as a methyl group, a methoxymethyl group, a benzyl group, a 4 methoxyphenylmethyl group, an aryl group, or an unsubstituted alkenyl group; Substituted or unsubstituted non-aromatic heterocyclic groups such as 3-bromotetrahydrobiranyl group, tetrahydrobiranyl group and tetrahydrofuranyl group; substituted or unsubstituted groups such as acetyl group, trifluoroacetyl group, benzoyl group and 4-chlorobenzoyl group An alkylcarbonyl group, or a substituted or unsubstituted arylylcarbonyl group; a methoxycarbonyl group, an ethoxycarbonyl group, an isobutoxycarbonyl group, a tertbutoxycarbonyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, 9- Phenylolenylmethoxycarbonyl group, buluo A substituted or unsubstituted alkyloxycarbonyl group or unsubstituted alkenyloxycarbonyl group such as a xoxycarbonyl group, an aryloxycarbonyl group, a phenyloxycarbonyl group, or a p-diphenyloxycarbonyl group. Or a substituted or unsubstituted aryloxycarbonyl group; a substituted silyl group such as a trimethylsilyl group, a triethylsilinole group, a triisopropylpropylsilyl group, a tertbutyldimethylsilinole group, a tertbutyldiphenylsilyl group; It is used as a protective group for free hydroxy groups.
[0034] 『遊離のアミノ基、遊離のアルキルアミノ基、遊離のアルキルカルボニルァミノ基、遊 離の窒素原子を有する芳香族複素環基又は遊離の窒素原子を有する非芳香族複 素環基の保護基』とは、ァリル基等の無置換アルケニル基；ホルミル基等のヒドロカル ボニル基；ァセチル基、トリクロロアセチル基、トリフルォロアセチル基、ベンゾィル基 、 4 クロ口ベンゾィル基、ピコリノィル基等の置換若しくは無置換アルキルカルボ二 ル基、置換若しくは無置換ァリールカルボニル基、又は無置換芳香族複素環カルボ ニル基；メトキシカルボニル基、イソブトキシカルボニル基、 tert ブトキシカルボニル 基、 2, 2, 2—トリクロ口エトキシカルボニル基、ベンジルォキシカルボニル基、ジフエ ニノレメトキシカノレポニノレ基、フエノキシカノレポニノレ基、 m—二トロフエノキシカノレポニノレ 基等の置換若しくは無置換アルキルォキシカルボニル、又は置換若しくは無置換ァ リールォキシカルボニル基；メチルスルホニル基、ベンジルスルホニル基、フエニルス ノレホニノレ基、 4 クロ口フエニルスルホニル基、トリノレスノレホニノレ基、 2, 4, 6 トリメチ ルフエニルスルホニル基等の置換若しくは無置換アルキルスルホニル基、又は置換 若しくは無置換ァリ一ルスルホニル基；等の遊離のアミノ基、遊離のアルキルアミノ基 、遊離のァリールアミノ基、遊離の窒素原子を有する芳香族複素環基又は遊離の窒 素原子を有する非芳香族複素環基の保護基として汎用されるものを示す。  [0034] “A free amino group, a free alkylamino group, a free alkylcarbonylamino group, an aromatic heterocyclic group having a free nitrogen atom, or a non-aromatic heterocyclic group having a free nitrogen atom. “Protecting group” means an unsubstituted alkenyl group such as an aryl group; a hydrocarbonyl group such as a formyl group; a substitution such as an acetyl group, a trichloroacetyl group, a trifluoroacetyl group, a benzoyl group, a 4-chlorobenzoyl group, and a picolinol group. Or an unsubstituted alkylcarbonyl group, a substituted or unsubstituted arylylcarbonyl group, or an unsubstituted aromatic heterocyclic carbonyl group; a methoxycarbonyl group, an isobutoxycarbonyl group, a tertbutoxycarbonyl group, 2, 2, 2-trichloro Oral ethoxycarbonyl group, benzyloxycarbonyl group, diphenylenomethoxymethoxyreponinole group, phenoxyca Substituted or unsubstituted alkyloxycarbonyl or substituted or unsubstituted aryloxycarbonyl group such as leponinore group, m-nitrophenoxycanoleponinole group; methylsulfonyl group, benzylsulfonyl group, phenylnonenoreno group, 4 A substituted or unsubstituted alkylsulfonyl group such as a phenylsulfonyl group, a trinolesnorephoninole group, a 2,4,6 trimethylphenylsulfonyl group, or a free or substituted amino group such as a substituted or unsubstituted arylsulfonyl group; , A free alkylamino group, a free arylamino group, an aromatic heterocyclic group having a free nitrogen atom or a non-aromatic heterocyclic group having a free nitrogen atom, which are widely used.
[0035] 前記の置換アルキル基、置換非芳香族複素環基、置換アルキルカルボニル基、置 換ァリールカルボニル基、置換アルキルォキシカルボニル基、置換ァリールォキシ力 ルポニル基、置換シリル基、置換アルキルスルホニル基又は置換ァリールスルホニル 基は、それぞれ、ハロゲン原子、アルコキシ基、アルキル基、ァリール基、ハロゲノアリ ール基、アルコキシァリール基及びニトロ基から選択される 1又は複数の基で置換さ れた、アルキル基、非芳香族複素環基、アルキルカルボニル基、ァリールカルボニル 基、アルキルォキシカルボニル基、ァリールォキシカルボニル基、シリノレ基、ァノレキル スルホ二ル基又はァリールスルホニル基を示す。 [0036] 本発明でいう『複数の基』は、それぞれの基が同一でも異なっていてもよぐ又、好 ましくは 2又は 3の基を、より好ましくは 2の基を示す。 [0035] The above substituted alkyl group, substituted non-aromatic heterocyclic group, substituted alkylcarbonyl group, substituted arylcarbonyl group, substituted alkyloxycarbonyl group, substituted aryloxy group sulfonyl group, substituted silyl group, substituted alkylsulfonyl group Alternatively, the substituted arylsulfonyl group is an alkyl substituted with one or more groups selected from a halogen atom, an alkoxy group, an alkyl group, an aryl group, a halogenoaryl group, an alkoxyaryl group, and a nitro group, respectively. A group, a non-aromatic heterocyclic group, an alkylcarbonyl group, an arylylcarbonyl group, an alkyloxycarbonyl group, an aryloxycarbonyl group, a silinore group, an aralkyl sulfonyl group, or an arylsulfonyl group. [0036] The "plural groups" as used in the present invention may be the same or different, and preferably represent 2 or 3 groups, more preferably 2 groups.
[0037] また、本発明でいう『基』には、水素原子、ハロゲン原子及びォキソ配位子も含まれ [0037] The "group" in the present invention includes a hydrogen atom, a halogen atom and an oxo ligand.
[0038] 本発明化合物における『塩』とは、医薬として許容される塩であれば特に制限はなく 、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等の無機酸との塩、酢酸、フ マノレ酸、マレイン酸、コノヽク酸、クェン酸、酒石酸、アジピン酸、グノレコン酸、グノレコへ プト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、乳酸、馬尿酸、 1 , 2—ェタン ジスルホン酸、イセチオン酸、ラタトビオン酸、ォレイン酸、パモ酸、ポリガラタツロン酸 、ステアリン酸、タンニン酸、トリフルォロメタンスルホン酸、ベンゼンスルホン酸、 p ト ルエンスルホン酸、硫酸ラウリルエステル、硫酸メチル、ナフタレンスルホン酸、スルホ サリチル酸等の有機酸との塩、臭化メチル、ヨウ化メチル等の四級アンモニゥム塩、 臭素イオン、塩素イオン、ヨウ素イオンなどのハロゲンイオンとの塩、リチウム、ナトリウ ム、カリウム等のアルカリ金属との塩、カルシウム、マグネシウム等のアルカリ土類金 属との塩、鉄、亜鉛等との金属塩、アンモニアとの塩、トリエチレンジァミン、 2—ァミノ エタノール、 2, 2—ィミノビス（エタノール）、 1ーデォキシ 1—(メチルァミノ） 2— D—ソルビトール、 2—アミノー 2—（ヒドロキシメチル） 1 , 3—プロパンジオール、プ ロカイン、 N, N ビス（フエ二ルメチル）一 1 , 2—エタンジァミン等の有機ァミンとの塩 等が挙げられる。 The “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and may be an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Salt, acetic acid, fumanoleic acid, maleic acid, konsuccinic acid, citrate, tartaric acid, adipic acid, gnoleconic acid, gnolecoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1, 2-Ethane disulfonic acid, isethionic acid, ratatobionic acid, oleic acid, pamoic acid, polygalatathuronic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, Salts with organic acids such as naphthalene sulfonic acid and sulfosalicylic acid, quaternary ammonium salts such as methyl bromide and methyl iodide, bromine ions, salts Salts with halogen ions such as ions and iodine ions, salts with alkali metals such as lithium, sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, metal salts with iron and zinc, ammonia Salt with, triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy 1- (methylamino) 2-D-sorbitol, 2-amino-2- (hydroxymethyl) 1, 3— Examples thereof include salts with organic amines such as propanediol, procaine, N, N bis (phenylmethyl) -1,2-ethanediamine.
[0039] 本発明化合物に幾何異性体又は光学異性体が存在する場合は、それらの異性体 も本発明の範囲に含まれる。  [0039] When a geometric isomer or optical isomer exists in the compound of the present invention, these isomers are also included in the scope of the present invention.
[0040] また、本発明化合物は水和物又は溶媒和物の形態をとつて!/、てもよ!/、。 [0040] Further, the compound of the present invention takes the form of a hydrate or a solvate! /!
[0041] さらに、本発明化合物にプロトン互変異性が存在する場合には、それらの互変異性 体も本発明の範囲に含まれる。 [0041] Furthermore, when proton tautomerism exists in the compound of the present invention, such tautomers are also included in the scope of the present invention.
[0042] 一般式 [I]中の波線は、その結合する二重結合の立体が E体もしくは Z体であること を表わす。 [0042] The wavy line in the general formula [I] indicates that the solid of the double bond to be bonded is E-form or Z-form.
[0043] 『Rと Rが一緒になつて非芳香族複素環を形成する』とは、 Rと Rが一緒になつて  [0043] "R and R together form a non-aromatic heterocycle" means that R and R together
2 3 2 3  2 3 2 3
単結合或いはへテロ原子を介して非芳香族複素環を形成することである。単結合を 介して形成された非芳香族複素環は上述の具体例に示したものであって良いが、代 表的な例はピロリジン環、ピぺリジン環、ァゼパン環などであり、ヘテロ原子を介して 形成された非芳香族複素環も上述の具体例に示したものであって良いが、代表的な 例はモルホリン環、ピぺラジン環などである。 The formation of a non-aromatic heterocycle via a single bond or a heteroatom. Single bond The non-aromatic heterocycle formed through the ring may be the one shown in the above specific examples, but typical examples are pyrrolidine ring, piperidine ring, azepane ring, etc. The formed non-aromatic heterocyclic ring may be the one shown in the above-mentioned specific examples, but typical examples are morpholine ring, piperazine ring and the like.
[0044] (a)本発明化合物における好ましい例として、一般式 [I]で示される化合物において 、各基が下記に示す基である化合物又はその塩が挙げられる。  [0044] (a) As a preferred example of the compound of the present invention, in the compound represented by the general formula [I], a compound in which each group is the group shown below or a salt thereof can be mentioned.
[0045] (al)環 Aはベンゼン環又はチォフェン環を示し；及び/又は  [0045] (al) Ring A represents a benzene ring or a thiophene ring; and / or
(a2)環 Aはハロゲン原子で置換されてもよく；及び/又は  (a2) Ring A may be substituted with a halogen atom; and / or
(a3) Rは水素原子又はハロゲノアルキル基を示し；及び/又は  (a3) R represents a hydrogen atom or a halogenoalkyl group; and / or
(a4) Xは S又は CHを示し；及び/又は  (a4) X represents S or CH; and / or
2  2
(a5) Yは水酸基、アルコキシ基又は NR Rを示し；及び/又は  (a5) Y represents a hydroxyl group, an alkoxy group or NR R; and / or
2 3  twenty three
(a6) Rと Rは同一又は異なって水素原子、水酸基、アルキル基、アルコキシ基、シ (a6) R and R are the same or different and represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group,
2 3 twenty three
クロアルキル基、ァリール基、芳香族複素環基又は非芳香族複素環基を示し;及び /又は  Represents a chloroalkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group; and / or
(a7) Rと Rが一緒になつて非芳香族複素環を形成してもよく；及び/又は  (a7) R and R may combine to form a non-aromatic heterocycle; and / or
2 3  twenty three
(a8)上記で規定したアルキル基は水酸基、アルキルォキシカルボニル基、ァリール 基及び芳香族複素環基から選択される 1又は複数の置換基を有してもよく；及び/ 又は  (a8) The alkyl group defined above may have one or more substituents selected from a hydroxyl group, an alkyloxycarbonyl group, an aryl group, and an aromatic heterocyclic group; and / or
(a9)上記で規定したァリール基はニトロ基、アルキル基、アルコキシ基、ヒドロキシァ ノレキル基、アルキルカルボニル基及びアルキルォキシカルボニル基から選択される 1 又は複数の置換基を有してもよく；及び/又は  (a9) the aryl group as defined above may have one or more substituents selected from a nitro group, an alkyl group, an alkoxy group, a hydroxyalkylyl group, an alkylcarbonyl group and an alkyloxycarbonyl group; And / or
(alO)上記で規定した芳香族複素環基はアルキル基及びハロゲノアルキル基から選 択される 1又は複数の置換基を有してもよく；及び/又は  (alO) The aromatic heterocyclic group defined above may have one or more substituents selected from an alkyl group and a halogenoalkyl group; and / or
(al l)上記で規定した非芳香族複素環基はアルキル基、アルキルアミノ基、アルキ ノレォキシカルボニル基及び芳香族複素環基から選択される 1又は複数の置換基を 有してもよい。  (all) The non-aromatic heterocyclic group defined above may have one or more substituents selected from an alkyl group, an alkylamino group, an alkenyloxycarbonyl group, and an aromatic heterocyclic group. .
[0046] すなわち、一般式 [I]で示される化合物において、上記（al)、 （a2)、 （a3)、 （a4)、  That is, in the compound represented by the general formula [I], the above (al), (a2), (a3), (a4),
(a5)、 （a6)、 （a7)、 （a8)、 （a9)、 （alO)及び（al l)から選択される 1又は 2以上の 各組合せからなる化合物またはその塩。 1 or 2 or more selected from (a5), (a6), (a7), (a8), (a9), (alO) and (al l) A compound comprising each combination or a salt thereof.
[0047] (b)本発明化合物におけるより好ましい例として、一般式 [I]で示される化合物におい て、各基が下記に示す基である化合物又はその塩が挙げられる。 [0047] (b) As a more preferred example of the compound of the present invention, in the compound represented by the general formula [I], a compound in which each group is a group shown below or a salt thereof is exemplified.
[0048] (bl)環 Aはベンゼン環又はチォフェン環を示し； [0048] (bl) Ring A represents a benzene ring or a thiophene ring;
環 Aがベンゼン環の場合、該ベンゼン環はハロゲン原子で置換されてもよく；及び/ 又は  When ring A is a benzene ring, the benzene ring may be substituted with a halogen atom; and / or
(b2) Rは水素原子又はハロゲノアルキル基を示し；及び/又は  (b2) R represents a hydrogen atom or a halogenoalkyl group; and / or
(b3) Xは S又は CHを示し；及び/又は  (b3) X represents S or CH; and / or
2  2
(b4)Yは水酸基、アルコキシ基又は NR Rを示し；及び/又は  (b4) Y represents a hydroxyl group, an alkoxy group or NR R; and / or
2 3  twenty three
(b5) Rと Rは同一又は異なって水素原子、水酸基、アルキル基、アルコキシ基、シ (b5) R and R are the same or different and are a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a
2 3 twenty three
クロアルキル基、ァリール基、芳香族複素環基又は非芳香族複素環基を示し;及び /又は  Represents a chloroalkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group; and / or
(b6) R又は Rがアルキル基の場合、該アルキル基は水酸基、アルキルォキシカル (b6) When R or R is an alkyl group, the alkyl group is a hydroxyl group, an alkyloxy
2 3 twenty three
ボニル基、ァリール基、アルコキシァリール基、芳香族複素環基及びハロゲノアルキ ル芳香族複素環基から選択される 1又は複数の置換基を有してもよく；及び/又は (b7) R又は Rがァリール基の場合、該ァリール基はニトロ基、アルキル基、アルコキ May have one or more substituents selected from a bonyl group, an aryl group, an alkoxyaryl group, an aromatic heterocyclic group and a halogenoalkyl aromatic heterocyclic group; and / or (b7) R or R Is an aryl group, the aryl group is a nitro group, an alkyl group, an alkoxy group.
2 3 twenty three
シ基、ヒドロキシアルキル基、アルキルカルボニル基及びアルキルォキシカルボニル 基から選択される 1又は複数の置換基を有してもよく；及び/又は  May have one or more substituents selected from a cis group, a hydroxyalkyl group, an alkylcarbonyl group and an alkyloxycarbonyl group; and / or
(b8) R又は Rが芳香族複素環基の場合、該芳香族複素環基はアルキル基で置換 (b8) When R or R is an aromatic heterocyclic group, the aromatic heterocyclic group is substituted with an alkyl group
2 3 twenty three
されてもよく；及び/又は  And / or
(b9) R又は Rが非芳香族複素環基の場合、該非芳香族複素環基はアルキルォキ (b9) When R or R is a non-aromatic heterocyclic group, the non-aromatic heterocyclic group is an alkyloxy group.
2 3 twenty three
シカルボニル基で置換されてもよく；及び/又は  May be substituted with a sicarbonyl group; and / or
(blO) Rと Rが一緒になつて非芳香族複素環を形成してもよく；及び/又は  (blO) R and R together may form a non-aromatic heterocycle; and / or
2 3  twenty three
(bl l) Rと Rが一緒になつて非芳香族複素環を形成する場合、該非芳香族複素環 (bl l) when R and R together form a non-aromatic heterocycle, the non-aromatic heterocycle
2 3 twenty three
はアルキル基、アルキルアミノ基、アルキルォキシカルボニル基及び芳香族複素環 基から選択される 1又は複数の置換基を有してもよい。  May have one or more substituents selected from an alkyl group, an alkylamino group, an alkyloxycarbonyl group, and an aromatic heterocyclic group.
[0049] すなわち、一般式 [I]で示される化合物において、上記 (bl)、（b2)、（b3)、（b4)、 [0049] That is, in the compound represented by the general formula [I], the above (bl), (b2), (b3), (b4),
(b5)、（b6)、（b7)、（b8)、（b9)、 (blO)及び（bl l)から選択される 1又は 2以上の 各組み合わせからなる化合物又はその塩。 1 or 2 or more selected from (b5), (b6), (b7), (b8), (b9), (blO) and (bl l) A compound comprising each combination or a salt thereof.
[0050] (c)本発明化合物における特に好ましい例として、一般式 [I]で示される化合物にお[0050] (c) As a particularly preferred example of the compound of the present invention, the compound represented by the general formula [I]
V、て、各基が下記に示す基である化合物又はその塩が挙げられる。 V, and compounds in which each group is a group shown below or a salt thereof.
[0051] (c l)環 Aはベンゼン環、フルォロベンゼン環又はチォフェン環を示し；及び/又は [0051] (cl) Ring A represents a benzene ring, a fluorobenzene ring or a thiophene ring; and / or
(c2) Rは水素原子又はトリフルォロメチル基を示し；及び/又は  (c2) R represents a hydrogen atom or a trifluoromethyl group; and / or
(c3) Xは S又は CHを示し；及び/又は  (c3) X represents S or CH; and / or
2  2
(c4) Yは水酸基、 tert ブトキシ基、ヒドロキシァミノ基、 tert ブトキシァミノ基、ピリ ジンー2 ィルメチルァミノ基、ピリジン 3 ィルメチルァミノ基、ピリジンー4ーィル メチルァミノ基、 2 トリフルォロメチルピリジン 5 ィルメチルァミノ基、ベンジルアミ ノ基、 4ーメトキシベンジルァミノ基、 n ペンチルァミノ基、 3—メトキシカルボニルプ 口ピルアミノ基、 N ェチルー N—ピリジンー3—ィルメチルァミノ基、 N ェチルー N 2—ヒドロキシェチルァミノ基、シクロプロピルアミノ基、シクロペンタンアミノ基、フエ ニルァミノ基、 3—ヒドロキシメチルフエニルァミノ基、 4 プロピルフエニルァミノ基、 4 ーメトキシフエニルァミノ基、 4 メチルカルボユルフェニルァミノ基、 4ーメトキシカル ボユルフェニルァミノ基、 4一二トロフエニルァミノ基、 3, 5—ジメトキシフエニルァミノ 基、ピリジン一 2 ィルァミノ基、ピリジン一 4 ィルァミノ基、 5 メチルピリジン一 2— ィルァミノ基、ピぺリジンー4 ィルァミノ基、 1—tert ブトキシカルボ二ルビペリジン 4 ィルァミノ基、 3—ジメチルァミノピロリジン 1ーィル基、ピぺリジン 1ーィル 基、ピぺラジン 1ーィル基、 4ーメチルビペラジン 1ーィル基、 4 ピリミジン 2— ィルピペラジン 1ーィル基、 4 tert ブトキシカルボニルピペラジン 1 ィル基 、モルフォリン— 4—ィル基、ァゼパン— 1—ィル基又は 1—ヒドロキシ— 3— (1H—ィ ンドール 3 ィル）プロパン 2 ィルァミノ基を示す。  (c4) Y is a hydroxyl group, tert butoxy group, hydroxyamino group, tert butoxyamino group, pyridin-2-ylmethylamino group, pyridine-3-ylmethylamino group, pyridine-4-ylmethylamino group, 2 trifluoromethylpyridine, 5-methylmethylamino group, benzylamino group 4-methoxybenzylamino group, n-pentylamino group, 3-methoxycarbonyl-propylamino group, N-ethyl-N-pyridine-3-ylmethylamino group, N-ethyl-N 2-hydroxyethylamino group, cyclopropylamino group, cyclopropylamino group Pentaneamino group, phenylamino group, 3-hydroxymethylphenylamino group, 4 propylphenylamino group, 4-methoxyphenylamino group, 4 methylcarbophenylphenylamino group, 4-methoxycarbophenylphenyla Mino group, 4-12 tropheni Amino group, 3,5-dimethoxyphenylamino group, pyridine-2-ylamino group, pyridine-4-ylamino group, 5-methylpyridine-1-2-aminoamino group, piperidine-4-ilamino group, 1-tert-butoxycarbonylbiperidine 4 Illamino group, 3-Dimethylaminopyrrolidine 1-yl group, Piperidine 1-yl group, Piperazine 1-yl group, 4-Methylbiperazine 1-yl group, 4 Pyrimidine 2-ylpiperazine 1-yl group, 4 tert Butoxycarbonyl It represents piperazine 1-yl group, morpholine-4-yl group, azepan-1-yl group or 1-hydroxy-3- (1H-indole 3-yl) propane 2-ilamino group.
[0052] すなわち、一般式 [I]で示される化合物において、上記（c l)、（c2)、（c3)及び (c4 )から選択される 1又は 2以上の各組み合わせからなる化合物又はその塩。  [0052] That is, in the compound represented by the general formula [I], a compound or a salt thereof comprising one or more combinations selected from the above (cl), (c2), (c3) and (c4).
[0053] (d)本発明化合物における特に好ましい具体例として、下記の化合物又はその塩が 挙げられる。  [0053] (d) Particularly preferred specific examples of the compound of the present invention include the following compounds or salts thereof.
[0054] . (2E)— tert ブチル 3—（4— ( (3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）フエニル）アタリレート、 •(2E)— tert ブチル 3— (3 フルォロ一 4— ( (3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）フエニル）アタリレート、 [0054]. (2E) — tertbutyl 3- (4— ((3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) talylate, • (2E) — tert butyl 3— (3 fluoro 1 4— ((3 oxo 3, 4 dihydro 1 2H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylate
•(2E)— tert ブチル 3— (4— ( (2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)— イリデン)メチル）フエニル）アタリレート、 • (2E) — tert butyl 3— (4— ((2 oxo 1, 2 dihydroquinoline 1 3 (4H) — ylidene) methyl) phenyl) atylate,
•(2E)— tert ブチル 3— (2— ( (2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)— イリデン)メチル）フエニル）アタリレート、  • (2E) — tert butyl 3— (2— ((2 oxo 1, 2 dihydroquinoline 1 3 (4H) — ylidene) methyl) phenyl) atylate,
•(2E)— tert ブチル 3—（5— ( (3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b] [ 1, 4]チアジン— 2 イリデン）メチル）チォフェン— 3 ィル）アタリレート、  • (2E) — tert butyl 3— (5— ((3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] thiazine-2 ylidene) methyl) thiophene-3 yl) atelate,
• (2E)—tert ブチル 3—（5— ( (3 ォキソー6 （トリフルォロメチル） 3, 4 ジ ヒドロー 2H べンゾ [b][l, 4]チアジンー2 イリデン）メチル）チォフェンー3 ィル )アタリレート、  • (2E) —tert butyl 3— (5— ((3 oxo 6 (trifluoromethyl) 3, 4 dihydro-2H benzo [b] [l, 4] thiazine-2 ylidene) methyl) thiophene 3 yl ) Atarirate,
•(2E)— tert ブチル 3— (5— ( (2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)— イリデン）メチル）チォフェンー3—ィル）アタリレート、  • (2E) — tert butyl 3— (5— ((2 oxo 1, 2 dihydroquinoline 1 3 (4H) — ylidene) methyl) thiophene 3 — yl) atelate
•(2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン 2—イリデン)メチル)フエニル）アクリル酸、  • (2E) — 3— (4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine 2-ylidene) methyl) phenyl) acrylic acid,
• (2E) -3- (3 フルォロ一 4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1 , 4]チアジン 2 イリデン)メチル）フエニル）アクリル酸、  • (2E) -3- (3 Fluoro 4 -— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylic acid,
. (2E) -3- (4— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル）アクリル酸、  (2E) -3- (4— ((2 oxo 1,2 dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) acrylic acid,
. (2E) -3- (2— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル）アクリル酸、  (2E) -3- (2 — ((2 oxo 1,2 dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) acrylic acid,
•(2E)— 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル）アクリル酸、  • (2E) — 3— (5— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) acrylic acid,
• (2E) -3- (5— ((3 ォキソ 6— (トリフルォロメチノレ) 3, 4 ジヒドロ一 2H— ベンゾ [b] [1, 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル）アクリル酸、 • (2E) -3- (5— ((3 oxo 6— (trifluoromethinole) 3, 4 dihydro- 1H— benzo [b] [1, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) Acrylic acid,
. (2E) -3- (5— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル） チォフェン 3—ィル）アクリル酸、 (2E) -3- (5— ((2—oxo 1,2-dihydroquinoline 1 3 (4H) -ylidene) methyl) thiophene 3-yl) acrylic acid,
•(2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン —2 イリデン)メチル）フエニル） N— (ピリジン— 3 ィルメチル）アクリルアミド、• (2E) — 3— (4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine —2 ylidene) methyl) phenyl) N— (pyridine-3-ylmethyl) acrylamide,
• 2—（4一（（E)— 3 ォキソー 3 （ピペリジン 1 ィル）プロペン 1 ィル）ベン ジリデン） 2H べンゾ [b] [1, 4]チアジン 3 (4H) オン、 • 2— (4 ((E) —3 oxoso 3 (piperidine 1 yl) propene 1 yl) benzylidene) 2H benzo [b] [1, 4] thiazine 3 (4H) ON,
•(2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン —2—イリデン）メチル）フエ二ル）一 N— (ピリジン一 2—ィル）アクリルアミド、  • (2E) — 3— (4— ((3 oxo 3, 4 dihydro-1 2H benzo [b] [l, 4] thiazine —2-ylidene) methyl) phenyl) 1 N— (pyridine 1 2— Le) acrylamide,
-メチル 4—((2E)—3—(4—((3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b] [1, 4 ]チァジン 2—イリデン)メチル）フエニル）アクリルアミド）ベンゾエート、 -Methyl 4 — ((2E) —3— (4 — ((3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] thiazine 2-ylidene) methyl) phenyl) acrylamide) benzoate,
• (2E)—N シクロペンチノレ一 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベン ゾ [b][l, 4]チアジンー2 イリデン）メチル）フエニル）アクリルアミド、  • (2E) —N Cyclopentinole 3— (4— ((3 oxo 3, 4 dihydro-1H benzo [b] [l, 4] thiazine-2-ylidene) methyl) phenyl) acrylamide,
•(2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン 2—イリデン）メチル）フエニル） N ペンチルアクリルアミド、  • (2E) — 3— (4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine 2-ylidene) methyl) phenyl) N pentylacrylamide,
• (2E) -N- (4 メトキシフエニル） 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [ 1 , 4]チアジン 2 イリデン)メチル）フエニル）アクリルアミド、  • (2E) -N- (4 methoxyphenyl) 3— (4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylamide,
. (2E) -N- (3 （ヒドロキシメチル）フエニル）ー3—（4— ((3 ォキソ 3, 4 ジヒ ドロー 2H ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）フエニル）アクリルアミド  (2E) -N- (3 (Hydroxymethyl) phenyl) -3- (4— ((3 oxo 3, 4 dihydro 2H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylamide
-メチル 4—((2E)—3—(4—((3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b] [1, 4]チアジン 2 イリデン)メチル)フエニル）アクリルアミド）酪酸、 -Methyl 4 — ((2E) —3— (4 — ((3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylamide) butyric acid,
• (2E) -3- (3 フルォロ一 4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1 ， 4]チアジン 2 イリデン）メチル）フエニル） N—(ピリジン 3 ィルメチル）ァク リルアミド、  • (2E) -3- (3 Fluoro 4-— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) N— (pyridine 3-ylmethyl) acrylamide ,
• (2E)—N シクロプロピノレー 3— (3 フノレオ口一 4— ((3 ォキソ 3, 4 ジヒドロ -2H-ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）フエニル）アタリノレアミド、 • (2E) —N Cyclopropinole 3— (3 Funoleo mouth 4— ((3 oxo 3, 4 dihydro-2H-benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) attalinoleamide ,
. (2E) -3- (4— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N— (ピリジンー3—ィルメチル）アクリルアミド、 (2E) -3- (4— ((2—Oxo 1,2-dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) N— (pyridine-3-ylmethyl) acrylamide,
• (2E)一 N シクロプロピノレー 3—（4一（（2 ォキソ一 1, 2 ジヒドロキノリン一 3 (4 H) イリデン)メチル）フエニル）アクリルアミド、  • (2E) -N-cyclopropynole 3- (4-(((2 oxo 1,2 dihydroquinoline 1 3 (4 H) ylidene) methyl) phenyl) acrylamide),
• 3—（4一（（E)— 3—（ァゼパン 1 ィル） 3—ォキソプロペン 1 ィル）ベンジ リデン） 3, 4 ジヒドロキノリン 2(1H)—オン、 • 3— (4 1 ((E) —3— (Azepan 1) 3—Oxopropene 1)) Redene) 3, 4 dihydroquinoline 2 (1H) -one,
•(2E)— N— (3, 5 ジメトキシフエ二ル）一 3— (4— ((2 ォキソ 1, 2 ジヒドロキ ノリンー 3 (4H)—イリデン)メチル）フエニル）アクリルアミド、  • (2E) —N— (3,5 dimethoxyphenyl) 1 3— (4 — ((2oxo1,2 dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
. (2E) -3- (4— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N— (ピリジン一 4—ィル）アクリルアミド、  (2E) -3- (4— ((2—oxo 1,2-dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) N— (pyridine 1-yl) acrylamide,
• (2E) -N- (4 ァセチルフエニル） 3— (4— ((2 ォキソ 1, 2 ジヒドロキノリ ン— 3 (4H)—イリデン)メチル）フエニル）アクリルアミド、  • (2E) -N- (4 acetylphenyl) 3— (4— ((2 oxo 1,2 dihydroquinolin— 3 (4H) —ylidene) methyl) phenyl) acrylamide,
. (2E) -3- (4— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N— (4—プロピルフエ二ノレ）アクリルアミド、  (2E) -3- (4— ((2—oxo 1,2-dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) N— (4-propylphenolinole) acrylamide,
• (2E)—N tert ブトキシー3—（4ー（（2 ォキソーl, 2 ジヒドロキノリンー3 (4 H) イリデン)メチル）フエニル）アクリルアミド、  • (2E) —N tertbutoxy 3— (4-((2 oxol, 2 dihydroquinoline-3 (4 H) ylidene) methyl) phenyl) acrylamide,
• (2E)—N ヒドロキシー3—（4— ((2 ォキソ 1, 2 ジヒドロキノリン 3(4H)— イリデン)メチル）フエニル）アクリルアミド、  • (2E) —N Hydroxy-3— (4 — ((2 oxo 1,2 dihydroquinoline 3 (4H) —ylidene) methyl) phenyl) acrylamide,
. (2E) -3- (2— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N— (ピリジンー3—ィルメチル）アクリルアミド、  (2E) -3- (2— ((2—Oxo 1, 2-dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) N— (pyridine-3-ylmethyl) acrylamide,
• (2E) N シクロプロピノレー 3—（2—（（2 ォキソ 1, 2 ジヒドロキノリン 3 (4 H) イリデン)メチル）フエニル）アクリルアミド、  • (2E) N cyclopropynole 3— (2 — ((2 oxo 1,2 dihydroquinoline 3 (4 H) ylidene) methyl) phenyl) acrylamide,
• (2E) -N- (5 メチルピリジン一 2 ィル） 3— (2— ((2 ォキソ 1, 2 ジヒド 口キノリン一 3 (4H)—イリデン)メチル）フエニル）アクリルアミド、  • (2E) -N- (5 Methylpyridine-2-yl) 3— (2— ((2 oxo-1,2 dihydrin quinoline 3 (4H) -ylidene) methyl) phenyl) acrylamide,
. (2E) -3- (2— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N フエニルアクリルアミド、  (2E) -3- (2— ((2—oxo 1,2-dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) N phenylacrylamide,
• (2E) -N- (4 ニトロフエニル） 3— (2— ((2 ォキソ 1, 2 ジヒドロキノリン - 3 (4H)—イリデン)メチル）フエニル）アクリルアミド、  • (2E) -N- (4 Nitrophenyl) 3— (2— ((2 oxo 1,2 dihydroquinoline-3 (4H) —ylidene) methyl) phenyl) acrylamide,
•(2E)— 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン — 2 イリデン）メチル）チォフェン 3 ィル） N (ピリジン一 3 ィルメチル）ァク リルアミド、  • (2E) — 3— (5— ((3 oxo 3, 4 dihydro-1 2H benzo [b] [l, 4] thiazine — 2 ylidene) methyl) thiophene 3 yl) N (pyridine 1 -3-methyl) Rilamide,
• (2E)—N ベンジノレ一 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル）アクリルアミド、 • (2E)— N ェチル N— (2 ヒドロキシェチル） 3— (5— ((3 ォキソ 3, 4— ジヒドロー 2H べンゾ [b][l, 4]チアジンー2 イリデン）メチル）チォフェンー3 ィ ル）アクリルアミド、 • (2E) —N Benzenore 3— (5— ((3 oxo 3, 4 dihydro 1H benzo [b] [1, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) acrylamide, • (2E) — N ethyl N— (2 hydroxyethyl) 3— (5— ((3 oxo 3, 4— dihydro-2H benzo [b] [l, 4] thiazine-2-ylidene) methyl) thiophene-3 Le) acrylamide,
• (2E) -N- (4 メトキシベンジル） 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [ 1 , 4]チアジン 2—イリデン）メチル）チォフェン 3—ィル）アクリルァ ミド、  • (2E) -N- (4 methoxybenzyl) 3— (5— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine 2-ylidene) methyl) thiophene 3-yl) acryla Mid,
• (2E)—N ェチノレ一 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1 , 4]チアジン— 2 イリデン)メチル）チォフェン— 3 ィル）—N— (ピリジン— 3 ィ ルメチル）アクリルアミド、  • (2E) —N ethynole 1— (5 — ((3 oxo 3,4 dihydro-1H benzo [b] [1,4] thiazine-2 ylidene) methyl) thiophene-3yl) —N— (pyridine — 3-methyl) acrylamide,
•(2E)— 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン  • (2E) — 3— (5— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine
•tert ブチノレ 4—((2E)—3—(5—((3 ォキソ 3, 4 ジヒドロー 2H—ベンゾ[ b][l, 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル）アクリルアミド）ピペリ ジン 1一力ノレボキシレート、 • tert butynole 4 — ((2E) —3— (5 — ((3 oxo 3, 4 dihydro-2H—benzo [b] [l, 4] thiazine 2 ylidene) methyl) thiophene 3yl) acrylamide) piperidine 1 Noreboxylate,
•(2E)— 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン — 2 イリデン）メチル）チォフェン 3 ィル） N (ピペリジン一 4 ィル）アクリル アミド 塩酸塩、  • (2E) — 3— (5— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine — 2 ylidene) methyl) thiophene 3 yl) N (piperidine -4- yl) acrylic Amide hydrochloride,
•tert ブチノレ 4—((2E)—3—(5—((3 ォキソ 3, 4 ジヒドロー 2H—ベンゾ[ b][l, 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル）アタリロイル）ピペラ ジン 1一力ノレボキシレート、  • tert butynole 4 — ((2E) —3— (5 — ((3 oxo 3, 4 dihydro-2H—benzo [b] [l, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) taliloyl) piperazine 1 Noreboxylate,
•2— ((4— ((E)— 3 ォキソ 3— (4— (ピリミジン一 2 ィル）ピぺラジン 1—ィル )プロペン 1ーィノレ）チォフェン 2—ィノレ）メチレン） 2H—べンゾ [b] [1 , 4]チア ジン 3 (4H)—オン、  • 2— ((4— ((E) — 3 oxo 3— (4— (pyrimidine 1 2 yl) piperazine 1 yl) propene 1 inore) thiophene 2 inore) methylene) 2H— benzo [b] [1, 4] thiazin 3 (4H) —one,
•(2E)— N— (3, 5 ジメトキシフエ二ル）一 3— (5— ((3 ォキソ 3, 4 ジヒドロ —2H べンゾ [b][l, 4]チアジンー2 イリデン）メチル）チォフェンー3 ィル）ァク リルアミド、  • (2E) — N— (3, 5 dimethoxyphenyl) 1 3— (5— ((3 oxo 3, 4 dihydro — 2H benzo [b] [l, 4] thiazine-2-ylidene) methyl) thiophene 3) acrylamide,
• (2E)— N— ((S)— 1—ヒドロキシ— 3— (1H—インドール— 3 ィル）プロパン— 2 ーィル）ー3—（5—（（3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b][l, 4]チアジン - 2 イリデン)メチル）チォフェン— 3 ィル）アクリルアミド、 • (2E) — N— ((S) — 1—Hydroxy— 3— (1H—Indole—3 yl) propane— 2 -Yl) -3- (5-((3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] thiazine-2 ylidene) methyl) thiophene-3 yl) acrylamide,
• (2E) -3- (5— ((3 ォキソ 6— (トリフルォロメチル） 3, 4 ジヒドロ一 2H— ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル） N—(ピリ  • (2E) -3- (5— ((3 oxo 6— (trifluoromethyl) 3, 4 dihydro- 1H— benzo [b] [1, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) N — (Piri
• (2E) -3- (5— ((3 ォキソ 6— (トリフルォロメチル） 3, 4 ジヒドロ一 2H— ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル） N—(ピリ • (2E) -3- (5— ((3 oxo 6— (trifluoromethyl) 3, 4 dihydro- 1H— benzo [b] [1, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) N — (Piri
•2— ((4— ((E)— 3— (4 メチルビペラジン 1—ィル） 3 ォキソプロペン 1 ィル）チォフェンー2 ィノレ）メチレン）ー6 （トリフルォロメチル） 2H べンゾ [b ][1, 4]チアジン 3 (4H)—オン、 • 2— ((4— ((E) — 3— (4 Methylbiperazine 1-yl) 3-oxopropene 1-yl) thiophene-2-inole) methylene) -6 (trifluoromethyl) 2H benzo [b] [ 1, 4] thiazine 3 (4H) —one,
•2- ((4- ((E)—3—モノレホリノ一 3—ォキソプロペン一 1—ィノレ）チォフェン一 2— ィル）メチレン）ー6 （トリフルォロメチル） 2H べンゾ [b] [1, 4]チアジン 3 (4 H) オン、  • 2- ((4- ((E) —3—Monolepholino 1-oxopropene 1-inole) thiophene 2-yl) methylene) -6 (Trifluoromethyl) 2H Benzo [b] [1 , 4] thiazine 3 (4 H) on,
• 2— ( (4— ( (E)— 3— (3 (ジメチノレアミノ）ピロリジン一 1—ィル） - 3 ォキソプロ ペン 1 ィル）チォフェンー2 ィノレ）メチレン）ー6 （トリフルォロメチル） 2H— ベンゾ [b][l, 4]チアジン 3 (4H)—オン、  • 2— ((4— ((E) — 3— (3 (Dimethinoreamino) pyrrolidine 1-yl)-3 -oxopropene 1 yl) thiophene-2 Inole) methylene) -6 (Trifluoromethyl) 2H— Benzo [b] [l, 4] thiazin 3 (4H) —one,
• 2— ( (4— ( (E)— 3 ォキソ 3 - (ピペラジン一 1—ィル）プロペン一 1—ィル）チォ フェンー2 ィル）メチレン） -6- (トリフルォロメチル） 2H べンゾ [b] [1, 4]チア ジン 3(4H)—オン 塩酸塩、及び  • 2— ((4— ((E) — 3 oxo 3-(piperazine 1-yl) propene 1-yl) thiophene 2 yl) methylene) -6- (trifluoromethyl) 2H Nzo [b] [1,4] thiazin 3 (4H) -one hydrochloride, and
. (2E) -3- (5— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル） チォフェン一 3—ィル） -N- (ピリジン一 3—ィルメチル）アクリルアミド。  (2E) -3- (5— ((2 oxo 1,2 dihydroquinoline 1 3 (4H) -ylidene) methyl) thiophen 1 yl) -N- (pyridine 1 -3-ylmethyl) acrylamide.
[0055] 本発明化合物は、以下の方法により製造することができる。尚、個々の具体的な製造 方法については、後述の実施例 [製造例の項]で詳細に説明する。また、下記の合 成経路中で使用されている Halはハロゲン原子を示す。 [0055] The compound of the present invention can be produced by the following method. Each specific manufacturing method will be described in detail in the following [Example of manufacturing example]. In addition, Hal used in the following synthesis route represents a halogen atom.
[0056] 本発明化合物は以下に示す経路 A〜Dからなる主合成経路により、適宜条件などを 使い分けて製造される。 [0056] The compound of the present invention is produced by properly using conditions and the like according to the main synthetic route consisting of routes A to D shown below.
[0057] 本発明化合物（I)は、合成経路 Aに従い製造することができる。すなわち、本発明化 合物（II)と一級又は二級のァミン（III)を N, N ジメチルホルムアミド（以下 DMFと略 す）等の有機溶媒中、 TFPレジン (J. Comb. Chem. , 2000, 2, 691— 697)、。 一（7 ァザべンゾトリァゾールー 1ーィル） 1 , 1 , 3, 3—テトラメチルゥロニゥム へ キサフルオロフォスフェート（HATU)等の水溶性カルポジイイミド（WSC)、及び Ν, Ν ジイソプロピルェチルァミン（以下 DIEAと略す）等の塩基存在下、室温から 80 °Cで、 1時間から 24時間反応させることで化合物 (I)を得ることが出来る。 The compound (I) of the present invention can be produced according to synthesis route A. That is, the present invention Compound (II) and primary or secondary amine (III) in an organic solvent such as N, N dimethylformamide (hereinafter abbreviated as DMF), TFP resin (J. Comb. Chem., 2000, 2, 691— 697). 1 (7 Azabenzotriazole-1-yl) 1, 1, 3, 3, 3-water-soluble carpoiimide (WSC) such as tetramethyluronium hexafluorophosphate (HATU), and Ν, Ν diisopropyl Compound (I) can be obtained by reacting in the presence of a base such as ethylamine (hereinafter abbreviated as DIEA) at room temperature to 80 ° C for 1 to 24 hours.
[0058] 合成経路 A [0058] Synthesis route A
[化 2]  [Chemical 2]
Figure imgf000020_0001
Figure imgf000020_0001
[0059] 本発明化合物（Π)は、合成経路 Bに従い製造することができる。すなわち、本発明 化合物（IV)をジォキサン等の有機溶媒中室温で、塩化水素と 1時間から 24時間反 応させることで化合物（Π)が得られる。 [0059] The compound (Π) of the present invention can be produced according to synthetic route B. That is, the compound (IV) is obtained by reacting the compound (IV) of the present invention with hydrogen chloride in an organic solvent such as dioxane at room temperature for 1 to 24 hours.
[0060] 合成経路 B  [0060] Synthesis route B
[化 3]  [Chemical 3]
Figure imgf000020_0002
Figure imgf000020_0002
[0061] 本発明化合物（IV)は、合成経路 Cに従い製造することができる。すなわち、化合物 [0061] The compound (IV) of the present invention can be produced according to synthetic route C. That is, the compound
(V)と化合物 (VI) (例えば、アクリル酸 t ブチルエステル）を DMF等の有機溶媒中 、触媒量の酢酸パラジウムとトリフエニルホスフィンなどの配位子、及び DIEA等の塩 基存在下、室温から 100°Cで、 1時間から 24時間反応させることで本発明化合物（IV )を得ること力 S出来る。 (V) and compound (VI) (for example, t-butyl acrylate) in an organic solvent such as DMF in the presence of a catalytic amount of a ligand such as palladium acetate and triphenylphosphine, and a base such as DIEA at room temperature To 100 ° C for 1 to 24 hours to react with the compound of the present invention (IV ) Power S can be obtained.
[0062] 合成経路 C [0062] Synthesis route C
[化 4]  [Chemical 4]
Figure imgf000021_0001
Figure imgf000021_0001
[0063] 化合物 (V)は、合成経路 Dに従い製造することができる。すなわち、化合物 (VII)と アルデヒド (VIII)をメタノール等の有機溶媒中、ナトリウムメトキシド等の塩基存在下、 1時間から 24時間加熱還流させることで化合物 (V)を得ることが出来る。 [0063] Compound (V) can be produced according to synthetic route D. That is, compound (V) can be obtained by heating and refluxing compound (VII) and aldehyde (VIII) in an organic solvent such as methanol in the presence of a base such as sodium methoxide for 1 to 24 hours.
[0064] 合成経路 D  [0064] Synthesis route D
[化 5]  [Chemical 5]
Figure imgf000021_0002
Figure imgf000021_0002
[0065] 前記の合成経路により製造した本発明化合物は、汎用されている技術により、前述 した塩、水和物又は溶媒和物の形態とすることもできる。 [0065] The compound of the present invention produced by the above synthetic route can be made into the above-mentioned salt, hydrate or solvate form by a widely used technique.
[0066] 本発明化合物の有用性を見出すため、薬物の血管新生阻害効果を評価する方法 である VEGF誘発 HUVEC増殖反応評価系（HUVEC：正常ヒトさい帯静脈由来血 管内皮細胞）を使用して、本発明化合物の細胞増殖阻害効果試験を実施し、その血 管新生阻害効果を評価した。その詳細については、後述の実施例 [薬理試験の項] で説明するが、本発明化合物は優れた細胞増殖阻害作用を示し、血管新生阻害効 果を有することを見出した。  [0066] In order to find the usefulness of the compound of the present invention, a VEGF-induced HUVEC proliferation reaction evaluation system (HUVEC: normal human umbilical vein-derived vascular endothelial cells), which is a method for evaluating the angiogenesis inhibitory effect of a drug, A cell growth inhibitory effect test of the compound of the present invention was conducted to evaluate its angiogenesis inhibitory effect. The details thereof will be described in the following Examples [Pharmacological test section], and it was found that the compound of the present invention has an excellent cell growth inhibitory effect and an angiogenesis inhibitory effect.
[0067] 前述したように血管新生は癌、関節リウマチ、加齢性黄斑変性、糖尿病網膜症、未 熟児網膜症、網膜静脈閉塞症、ポリープ状脈絡膜血管症、糖尿病黄斑浮腫、尋常 性乾癬、粥状動脈硬化等の疾患と深く関係していることが報告されている。したがつ て、本発明化合物は、血管新生が関与するそれら疾患の治療剤として非常に期待さ れるものである。 [0067] As described above, angiogenesis is caused by cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, It has been reported to be closely related to diseases such as retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, and atherosclerosis. Therefore, the compound of the present invention is highly expected as a therapeutic agent for those diseases involving angiogenesis.
[0068] 本発明化合物は経口でも、非経口でも投与すること力 Sできる。投与剤型として、錠 剤、カプセル剤、顆粒剤、散剤、注射剤、軟膏、点眼剤、眼軟膏等が挙げられ、それ らは汎用される技術を使用して製剤化することができる。  [0068] The compound of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, granules, powders, injections, ointments, eye drops, eye ointments and the like, and they can be formulated using a widely used technique.
[0069] 例えば、錠剤、カプセル剤、顆粒剤、散剤等の経口剤は、乳糖、マンニトール、デ ンプン、結晶セルロース、軽質無水ケィ酸、炭酸カルシウム、リン酸水素カルシウム等 の賦形剤、ステアリン酸、ステアリン酸マグネシウム、タルク等の滑沢剤、デンプン、ヒ ン等の結合剤、カルボキシメチルセルロース、低置換度ヒドロキシプロピルメチルセル ロース、クェン酸カルシウム等の崩壊剤、ヒドロキシプロピルメチルセルロース、マクロ ゴール、シリコーン樹脂等のコーティング剤、パラォキシ安息香酸ェチル、ベンジル アルコール等の安定化剤、甘味料、酸味料、香料等の矯味矯臭剤等を必要に応じ て使用して、調製すること力できる。  [0069] For example, oral preparations such as tablets, capsules, granules, powders and the like are used for excipients such as lactose, mannitol, starch, crystalline cellulose, light anhydrous carboxylic acid, calcium carbonate, calcium hydrogen phosphate, and stearic acid. , Lubricants such as magnesium stearate and talc, binders such as starch and hin, carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, disintegrants such as calcium citrate, hydroxypropylmethylcellulose, macrogol, silicone resin Can be prepared by using a coating agent such as paraethyl benzoate, stabilizers such as benzyl alcohol, and flavoring agents such as sweeteners, acidulants and fragrances as necessary.
[0070] また、注射剤、点眼剤等の非経口剤は、塩化ナトリウム、濃グリセリン、プロピレング リコーノレ、ポリエチレングリコール、塩化カリウム、ソノレビトーノレ、マンニトール等の等張 化剤、リン酸ナトリウム、リン酸水素ナトリウム、酢酸ナトリウム、クェン酸，氷酢酸、トロ メタモール等の緩衝化剤、ポリオキシエチレンソルビタンモノォレート、ステアリン酸ポ リオキシ 40、ポリオキシエチレン硬化ヒマシ油等の界面活性剤、クェン酸ナトリウム、 ェデト酸ナトリウム等の安定化剤、塩化ベンザルコニゥム、パラベン、塩化べンゾトニ ゥム、ノ ラオキシ安息香酸エステル、安息香酸ナトリウム、クロロブタノール等の防腐 剤等、塩酸、クェン酸、リン酸、氷酢酸、水酸化ナトリウム、炭酸ナトリウム、炭酸水素 ナトリウム等の pH調整剤、ベンジルアルコール等の無痛化剤等を必要に応じて使用 し、調製すること力 Sでさる。 [0070] Also, parenterals such as injections and eye drops include isotonic agents such as sodium chloride, concentrated glycerin, propylene glycolone, polyethylene glycol, potassium chloride, sonolebithonole, mannitol, sodium phosphate, hydrogen phosphate Buffering agents such as sodium, sodium acetate, citrate, glacial acetic acid, trometamol, surfactants such as polyoxyethylene sorbitan monolate, polyoxystearate 40, polyoxyethylene hydrogenated castor oil, sodium citrate, edet Stabilizers such as sodium nitrate, benzalkonium chloride, paraben, benzotonium chloride, noroxybenzoic acid ester, sodium benzoate, preservatives such as chlorobutanol, hydrochloric acid, citrate, phosphoric acid, glacial acetic acid, hydroxylated Sodium, sodium carbonate, sodium bicarbonate, etc. Use a pH adjuster, a soothing agent such as benzyl alcohol, etc., as necessary, and prepare with S.
[0071] 本発明は、本発明化合物又はその塩の治療上有効な量を患者に投与することから なる血管新生が関与する疾患の治療方法も提供する。 [0072] 本発明化合物の投与量は、症状、年齢、剤型等により適宜選択して使用することが できる。例えば、経口剤では通常 1日当たり 0.01〜； 1000mg、好ましくは 1〜； 100m gを 1回又は数回に分けて投与することができる。また、点眼剤は通常 0.0001%〜1 0%(w/v)、好ましくは 0· 01%〜5%(w/v)の濃度のものを 1回又は数回に分け て投与することができる。 [0071] The present invention also provides a method for treating a disease associated with angiogenesis, which comprises administering to a patient a therapeutically effective amount of a compound of the present invention or a salt thereof. [0072] The dose of the compound of the present invention can be appropriately selected depending on symptoms, age, dosage form and the like. For example, for oral preparations, 0.01 to 1000 mg, preferably 1 to 100 mg per day can be administered in a single dose or divided into several doses. In addition, eye drops can be administered at a concentration of usually 0.0001% to 10% (w / v), preferably 0.001% to 5% (w / v) once or divided into several times. .
[0073] [製造例]  [0073] [Production Example]
参考例 1  Reference example 1
2- (4 ブロモベンジリデン） 2H べンゾ [b] [1, 4]チアジン 3 (4H) オン（参 考化合物 1 1)  2- (4 Bromobenzylidene) 2H Benzo [b] [1, 4] thiazine 3 (4H) ON (reference compound 1 1)
[化 06]  [Chemical 06]
Figure imgf000023_0001
Figure imgf000023_0001
[0074] 2H べンゾ [b][l, 4]チアジン 3(4H)—オン（3· 0g、 18mmol)と p ブロモベ ンズァノレデヒド（5.0g、 27mmol)のメタノール溶液（10mUにナトリウムメトキシド（2 8%メタノール溶液、 18mL)を加えた。反応液をー晚還流させた。反応液を室温まで 冷却し析出した固体をろ取した。減圧下乾燥させ標記参考化合物 4. lgを無色固体 として得た（収率 67%)。 [0074] 2H Benzo [b] [l, 4] thiazin 3 (4H) -one (3.0 g, 18 mmol) and p-bromobenzaldehyde (5.0 g, 27 mmol) in methanol (10 mU in sodium methoxide (2 8% methanol solution (18 mL) was added, and the reaction solution was refluxed.The reaction solution was cooled to room temperature and the precipitated solid was collected by filtration and dried under reduced pressure to give 4. lg of the title reference compound as a colorless solid. (Yield 67%).
[0075] 1H-NMR(400MHz, DMSO— d ) [0075] 1 H-NMR (400 MHz, DMSO— d)
6  6
δ 7.03(ddd, J = 7.8, 7.8, 1.2 Hz, 1H), 7.08 (dd, J = 7.8, 1.2 Hz, 1H), 7.20 (dd, J = 7.8, 1.2, 1.2 Hz, 1H), 7.33(ddd, J = 7.8 , 7.8, 1.2 Hz, 1H), 7.63(d, J = 8.5 Hz, 2H) , 7.71 (d, J = 8.5 Hz, 2H), 7.76(s, 1H), 11. ll(s, 1H)  δ 7.03 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H), 7.08 (dd, J = 7.8, 1.2 Hz, 1H), 7.20 (dd, J = 7.8, 1.2, 1.2 Hz, 1H), 7.33 (ddd , J = 7.8, 7.8, 1.2 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.76 (s, 1H), 11.ll (s, 1H)
以下、市販化合物及び既知化合物から選択される化合物を用いて、参考化合物 1 1の製造方法に準じ、参考化合物 1 2〜7を得た。 [0076] 2—（4ーブロモー2—フルォロべンジリデン）ー2^1—べンゾ[13][1, 4]チアジンー3( 4H) オン (参考化合物 1 2) Hereinafter, reference compounds 1 2 to 7 were obtained using a compound selected from commercially available compounds and known compounds according to the production method of reference compound 11. [0076] 2— (4-Bromo-2-Fluorobenzylidene) -2 ^ 1—Benzo [1 3 ] [1, 4] thiazine-3 (4H) ON (Reference compound 1 2)
[化 07]  [Chemical 07]
Figure imgf000024_0001
Figure imgf000024_0001
[0077] H— NMR(400MHz, DMSO— d ) [0077] H—NMR (400MHz, DMSO—d)
6  6
δ 7.01 (m, IH), 7.06 (d, J = 7.9 Hz, IH), 7.19(m, IH), 7.27— 7 .33 (m, 3H), 7.54 (d, J = 7.9 Hz, IH), 7.85(s, IH), 11.03(s, IH) 3—（4 ブロモベンジリデン） 3, 4 ジヒドロキノリン 2 (1H)—オン（参考化合物 1-3)  δ 7.01 (m, IH), 7.06 (d, J = 7.9 Hz, IH), 7.19 (m, IH), 7.27—7.33 (m, 3H), 7.54 (d, J = 7.9 Hz, IH), 7.85 (s, IH), 11.03 (s, IH) 3— (4 Bromobenzylidene) 3, 4 Dihydroquinolin 2 (1H) —one (Reference compound 1-3)
[化 08]  [Chemical 08]
Figure imgf000024_0002
Figure imgf000024_0002
[0078] H— NMR(500MHz, DMSO— d ) [0078] H—NMR (500 MHz, DMSO— d)
6  6
δ 3.81 (s, 2Η), 7.14(brt, J = 8.0 Hz, IH), 7.26 (d, J = 8.5 Hz , 2H), 7.28(brd, J = 7.8 Hz, IH), 7.45(brt, J = 7.8 Hz, IH), 7. 48 (d, J = 8.5 Hz, 2H), 7.60(brd, J = 8.0 Hz, IH), 7.71 (s, IH), 11.81(brs, IH)  δ 3.81 (s, 2Η), 7.14 (brt, J = 8.0 Hz, IH), 7.26 (d, J = 8.5 Hz, 2H), 7.28 (brd, J = 7.8 Hz, IH), 7.45 (brt, J = 7.8 Hz, IH), 7.48 (d, J = 8.5 Hz, 2H), 7.60 (brd, J = 8.0 Hz, IH), 7.71 (s, IH), 11.81 (brs, IH)
3—（2 ブロモベンジリデン） 3, 4 ジヒドロキノリン 2 (1H)—オン（参考化合物 1-4)  3— (2 Bromobenzylidene) 3, 4 Dihydroquinolin 2 (1H) —one (Reference compound 1-4)
[化 09] [Chemical 09]
Figure imgf000025_0001
Figure imgf000025_0001
[0079] H— NMR(500MHz, DMSO— d ) [0079] H—NMR (500MHz, DMSO—d)
6  6
δ 3.84(s, 2H), 7.16(brt, J = 8.0 Hz, IH), 7.25— 7.34 (m, 3H) , 7 .40 (brd, J = 8.0 Hz, IH), 7.46(brt, J = 8.0 Hz, IH), 7.51 (s, 1 H), 7.60 (brd, J = 8.0 Hz, IH), 7.77(s, IH), 11.81 (s, IH)  δ 3.84 (s, 2H), 7.16 (brt, J = 8.0 Hz, IH), 7.25—7.34 (m, 3H), 7.40 (brd, J = 8.0 Hz, IH), 7.46 (brt, J = 8.0 Hz, IH), 7.51 (s, 1 H), 7.60 (brd, J = 8.0 Hz, IH), 7.77 (s, IH), 11.81 (s, IH)
2— ((4 ブロモチォフェンー2 ィノレ）メチレン） 2H べンゾ [b][l, 4]チアジン 3 (4H)—オン (参考化合物 1 5)  2— ((4 Bromothiophene-2-inole) methylene) 2H Benzo [b] [l, 4] thiazin 3 (4H) —one (Reference compound 1 5)
[化 10]  [Chemical 10]
Figure imgf000025_0002
Figure imgf000025_0002
[0080] H— NMR(500MHz, DMSO— d ) [0080] H— NMR (500 MHz, DMSO— d)
6  6
δ 7.04-7.10 (m, IH), 7.23 (m, IH), 7.40 (brd, J = 8.0 Hz, IH), 7.46 (brt, J = 8.0 Hz, IH), 7.51 (s, IH), 7.60 (brd, J = 8.0 Hz, IH), 7.77(s, IH), 11.81(s, IH)  δ 7.04-7.10 (m, IH), 7.23 (m, IH), 7.40 (brd, J = 8.0 Hz, IH), 7.46 (brt, J = 8.0 Hz, IH), 7.51 (s, IH), 7.60 ( brd, J = 8.0 Hz, IH), 7.77 (s, IH), 11.81 (s, IH)
2— ((4 ブロモチォフェンー2 ィル）メチレン） -6- (トリフルォロメチル） 2H— ベンゾ [b] [ 1 , 4]チアジン 3 (4H)—オン (参考化合物 1 6)  2— ((4 Bromothiophene-2-yl) methylene) -6- (Trifluoromethyl) 2H— Benzo [b] [1, 4] thiazin 3 (4H) —one (Reference compound 1 6)
[化 11]  [Chemical 11]
Figure imgf000025_0003
[0081] H-NMR(500MHz, DMSO— d )
Figure imgf000025_0003
[0081] H-NMR (500 MHz, DMSO— d)
6  6
δ 7. 35-7. 40 (m, 2H) , 7. 66— 7. 68 (m, 2H) , 8. 03(s, IH), 8. 04 (t, J δ 7. 35-7. 40 (m, 2H), 7. 66— 7.68 (m, 2H), 8. 03 (s, IH), 8. 04 (t, J
= 0. 6 Hz, IH), 11. 30(s, IH) = 0. 6 Hz, IH), 11. 30 (s, IH)
3— ((4 ブロモチォフェンー2 ィル）メチレン）一3, 4 ジヒドロキノリン 2(1H) オン (参考化合物 1 7)  3 -— ((4 Bromothiophene-2yl) methylene) 1,3,4 Dihydroquinoline 2 (1H) ON (Reference Compound 1 7)
[化 12]  [Chemical 12]
Figure imgf000026_0001
Figure imgf000026_0001
[0082] H-NMR(400MHz, DMSO— d ) [0082] H-NMR (400 MHz, DMSO— d)
6  6
δ 4. 02(s, 2H), 6. 97(d, J = 1. 5 Hz, IH), 7. 17(ddd, J = 8. 3， 8. 3, 1. 2 Hz, IH), 7. 30 (d, J = 8. 3 Hz, IH) , 7. 46 (d, J = 1. 5 Hz, ] H), 7. 47(ddd, J = 8. 3, 7. 8, 1. 2 Hz, IH), 7. 63 (dd, J = 7. 8， 1. 2 Hz, IH), 7. 84(s， IH), 11. 88 (s, IH)  δ 4.02 (s, 2H), 6.97 (d, J = 1.5 Hz, IH), 7.17 (ddd, J = 8. 3, 8. 3, 1.2 Hz, IH), 7. 30 (d, J = 8.3 Hz, IH), 7. 46 (d, J = 1.5 Hz,] H), 7. 47 (ddd, J = 8. 3, 7. 8, 1 2 Hz, IH), 7. 63 (dd, J = 7.8, 1.2 Hz, IH), 7. 84 (s, IH), 11. 88 (s, IH)
実施例 0  Example 0
(2E)— tert ブチル 3— (4— ( (3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1 , 4]チアジンー2 イリデン)メチル)フエニル）アタリレート（化合物 0— 1)  (2E) — tert butyl 3— (4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine-2 ylidene) methyl) phenyl) talate (compound 0— 1)
[化 13]  [Chemical 13]
Figure imgf000026_0002
Figure imgf000026_0002
[0083] 2—（4 ブロモベンジリデン） 2H べンゾ [b] [l, 4]チアジン 3 (4H) オン（ 3. lg、9. 3mmol、参考化合物 1 1)、酢酸パラジウム（210mg、 0. 93mmol)とト リ（0-トリル）ホスフィン（570mg、 1.8mmol)の入った反応容器を窒素ガスで置換し た。反応容器に DMF(50mU、 DIEA(3.3mL、 19mmol)、アクリル酸 tert ブチ ル（6.8mL、 46mmol)をカロえ、 60°Cでー晚加熱撹拌した。反応液を室温まで冷却 しクロ口ホルム（lOOmL)を用いてセライトろ過した。ろ液をクロ口ホルム（lOOmL)で 希釈し、飽和食塩水（200mL)で 2回洗浄し、硫酸マグネシウムで乾燥し、減圧下濃 縮した。残渣を水でろ取し、エタノールで洗浄し、減圧下乾燥して標記参考化合物 3 .4gを黄色固体として得た（収率 96%)。 [0083] 2- (4 bromobenzylidene) 2H benzo [b] [l, 4] thiazine 3 (4H) on (3. lg, 9.3 mmol, reference compound 1 1), palladium acetate (210 mg, 0. 93 mmol) and The reaction vessel containing li (0-tolyl) phosphine (570 mg, 1.8 mmol) was replaced with nitrogen gas. DMF (50 mU, DIEA (3.3 mL, 19 mmol), tert-butyl acrylate (6.8 mL, 46 mmol) was placed in a reaction vessel and stirred with heating at 60 ° C. The reaction solution was cooled to room temperature and cooled. The filtrate was diluted with black mouth form (lOOmL), washed twice with saturated brine (200 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The product was collected by filtration, washed with ethanol, and dried under reduced pressure to give 3.4 g of the title reference compound as a yellow solid (yield 96%).
[0084] 1H-NMR(400MHz, DMSO— d ) [0084] 1 H-NMR (400 MHz, DMSO— d)
6  6
δ 1.48(s, 9H), 6.61(d, J = 15.9 Hz, 1H) , 7.04 (ddd, J = 8.5, 7 . 1, 1.2 Hz, 1H), 7.06 (dd, J = 7.1, 1.2 Hz, 1H), 7.21 (ddd, J = 8.5, 7.1, 1.2 Hz, 1H), 7.36 (dd, J = 7.1, 1.2 Hz, 1H), 7.59(d, J δ 1.48 (s, 9H), 6.61 (d, J = 15.9 Hz, 1H), 7.04 (ddd, J = 8.5, 7.1, 1.2 Hz, 1H), 7.06 (dd, J = 7.1, 1.2 Hz, 1H ), 7.21 (ddd, J = 8.5, 7.1, 1.2 Hz, 1H), 7.36 (dd, J = 7.1, 1.2 Hz, 1H), 7.59 (d, J
= 15.9 Hz, 1H), 7.72(d, J = 8.5 Hz, 2H) , 7.81(s, 1H), 7.83(d , J = 8.5 Hz, 2H), 11.10(s, 1H) = 15.9 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.81 (s, 1H), 7.83 (d, J = 8.5 Hz, 2H), 11.10 (s, 1H)
以下、参考化合物 1 2〜7、市販化合物及び既知化合物から選択される化合物を 用いて、化合物 0— 1の製造方法に準じ、化合物 0— 2〜7を得た。  Hereinafter, compounds 0-2 to 7 were obtained according to the production method of compound 0-1, using compounds selected from reference compounds 12-7, commercially available compounds and known compounds.
[0085] (2E)— tert ブチル 3— (3 フルオロー 4— ( (3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）フエニル）アタリレート（化合物 0 2) [0085] (2E) — tert butyl 3— (3 fluoro-4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) talate (compound 0 2)
[化 14]  [Chemical 14]
Figure imgf000027_0001
Figure imgf000027_0001
[0086] H— NMR(500MHz, DMSO— d ) [0086] H—NMR (500MHz, DMSO—d)
6  6
δ 1.49(s, 9Η), 6.69(d, J = 15.9 Hz, 1H), 7.01 (m, 1H), 7.06 (dd , J = 7.9, 1.2 Hz, 1H), 7. 19(m, 1H), 7.31 (d, J = 7.3 Hz, 1H), 7.39 (dd, J = 7.9, 1.2 Hz, IH), 7.45(d, J = 1.2 Hz, IH), 7.57( d, J = 15.9 Hz, IH), 7.65(d, J = 7.9 Hz, IH), 7.96(s, IH), 11. 04 (s, IH) δ 1.49 (s, 9Η), 6.69 (d, J = 15.9 Hz, 1H), 7.01 (m, 1H), 7.06 (dd, J = 7.9, 1.2 Hz, 1H), 7. 19 (m, 1H), 7.31 (d, J = 7.3 Hz, 1H), 7.39 (dd, J = 7.9, 1.2 Hz, IH), 7.45 (d, J = 1.2 Hz, IH), 7.57 (d, J = 15.9 Hz, IH), 7.65 (d, J = 7.9 Hz, IH), 7.96 (s, IH), 11. 04 (s, IH)
(2E)— tert ブチル 3—（4— ( (2 ォキソ 1, 2 ジヒドロキノリンー3 (4H)—ィ リデン)メチル)フエニル）アタリレート（化合物 0— 3)  (2E) — tert butyl 3— (4— ((2 oxo 1, 2 dihydroquinoline-3 (4H) —ylidene) methyl) phenyl) talate (compound 0-3)
[化 15]  [Chemical 15]
Figure imgf000028_0001
Figure imgf000028_0001
H— NMR(400MHz, DMSO— d ) H—NMR (400MHz, DMSO—d)
6  6
δ 1.48 (s, 9Η), 3.86(s, 2H) , 6.46 (d, J = 15.9 Hz, IH), 7. 14 (t, J = 8.3 Hz, IH), 7.29(d, J = 8.3 Hz, IH), 7.33(d, J = 8.1 Hz , 2H), 7.44 (t, J = 8.3 Hz, IH), 7.52(d, J = 15.9 Hz, IH), 7.59 (d, J = 8.3 Hz, IH), 7.61 (d, J = 8.1 Hz, 2H) , 7.61(s, IH), 11. 80 (s, IH) δ 1.48 (s, 9Η), 3.86 (s, 2H), 6.46 (d, J = 15.9 Hz, IH), 7.14 (t, J = 8.3 Hz, IH), 7.29 (d, J = 8.3 Hz, IH), 7.33 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 8.3 Hz, IH), 7.52 (d, J = 15.9 Hz, IH), 7.59 (d, J = 8.3 Hz, IH) , 7.61 (d, J = 8.1 Hz, 2H), 7.61 (s, IH), 11. 80 (s, IH)
(2E)— tert ブチル 3—（2— ( (2 ォキソ 1, 2 ジヒドロキノリンー3 (4H)—ィ リデン)メチル）フエニル）アタリレート（化合物 0— 4)  (2E) — tert butyl 3— (2— ((2 oxo 1,2 dihydroquinoline-3 (4H) —ylidene) methyl) phenyl) talate (compound 0—4)
[化 16] [Chemical 16]
Figure imgf000028_0002
H— NMR(400MHz, DMSO— d )
Figure imgf000028_0002
H—NMR (400MHz, DMSO—d)
6  6
δ 1.42(s, 9Η), 3.96(s, 2H) , 6.38 (d, J = 15.9 Hz, IH), 7. 11 (m: )()()(p∞I 6Ip∞I rz LHHS卜卜 LHzosζ2ΖHsNι - . - · · δ 1.42 (s, 9Η), 3.96 (s, 2H), 6.38 (d, J = 15.9 Hz, IH), 7. 11 (m : ) () () (p∞I 6Ip∞I rz LHHS 卜卜 LHzosζ2ΖHsNι-.-
()(I6∞I∞HHHζsN · () (I6∞I∞HHHζsN
S6∞0 S6∞0
Figure imgf000029_0001
()c)Γ^，ίεヽ5sλoヽ ίιii 3 ィル）アタリレート（化合物 0— 7)
Figure imgf000029_0001
() c) Γ ^, ίε ヽ 5sλo ヽ ίιii 3 yl) Atarylate (Compound 0-7)
[化 19]  [Chemical 19]
Figure imgf000030_0001
Figure imgf000030_0001
H-NMR(500MHz, DMSO— d ) H-NMR (500MHz, DMSO—d)
6  6
δ 1.46 (s, 9H), 4.01 (s, 2H) , 6.25(d, J = 15.9 Hz, 1H), 7. 16(m, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.34(s, 1H), 7.45 (d, J = 15.9 H z, 1H), 7.62(d, J = 7.6 Hz, 1H), 7.74 (s, 1H), 7.75(s, 1H), 7.81( s, 1H), 11.87(s, 1H)  δ 1.46 (s, 9H), 4.01 (s, 2H), 6.25 (d, J = 15.9 Hz, 1H), 7.16 (m, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.34 ( s, 1H), 7.45 (d, J = 15.9 H z, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.74 (s, 1H), 7.75 (s, 1H), 7.81 (s, 1H) , 11.87 (s, 1H)
実施例 1  Example 1
(2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン一 2—イリデン)メチル)フエニル）アクリル酸 (化合物 1 1)  (2E) — 3— (4— ((3 oxo 3, 4 dihydro-1 2H benzo [b] [l, 4] thiazine-2-ylidene) methyl) phenyl) acrylic acid (compound 1 1)
[化 20]  [Chemical 20]
Figure imgf000030_0002
Figure imgf000030_0002
[0092] (2E)—tert ブチル 3—（4— ( (3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b] [ 1, 4]チアジンー2 イリデン）メチル）フエニル）アタリレート（3· 5g、 9.2mmol、化 合物 0— 1)のジォキサン懸濁液（25mUに 4M塩化水素ジォキサン溶液（25mL、 1 OOmmol)と DMF(lOmL)を加えた。反応溶液を室温にてー晚攪拌し、析出した固 体をろ取した。減圧下乾燥すると標的化合物が無色粉末で 2.7g得られた (収率 93 %)。 [0092] (2E) —tert butyl 3— (4— ((3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] thiazin-2-ylidene) methyl) phenyl) atarylate (3.5 g, 9.2 mmol, compound 0-1) in dioxane (25 mU, 4M hydrogen chloride dioxane solution (25 mL, 1 OOmmol) and DMF (lOmL) were added. The reaction solution was stirred at room temperature to precipitate. The solid was collected by filtration and dried under reduced pressure to obtain 2.7 g of the target compound as a colorless powder (yield 93%).
[0093] ifi— NMR(500MHz, DMSO— d ) δ 6. 63(d, J = 15. 9 Hz, IH), 7.04(brt, J = 8. 5 Hz, IH), 7. 07 ( brd, J = 8. 5 Hz, IH), 7. 21(brt, J = 8. 5 Hz, IH), 7. 36(brd, J =[0093] ifi— NMR (500 MHz, DMSO— d) δ 6. 63 (d, J = 15. 9 Hz, IH), 7.04 (brt, J = 8.5 Hz, IH), 7. 07 (brd, J = 8.5 Hz, IH), 7. 21 (brt, J = 8.5 Hz, IH), 7.36 (brd, J =
7. 1 Hz, IH), 7. 63(d, J = 15. 9 Hz, IH), 7. 73(d, J = 8. 6 Hz, 2 H), 7. 81 (s, IH), 7. 82(d, J = 8. 5 Hz, 2H) , 11.09 (s, IH), 12.47(s , IH) 7.1 Hz, IH), 7.63 (d, J = 15.9 Hz, IH), 7.73 (d, J = 8.6 Hz, 2 H), 7. 81 (s, IH), 7. 82 (d, J = 8.5 Hz, 2H), 11.09 (s, IH), 12.47 (s, IH)
以下、化合物 0— 2〜7、市販化合物及び既知化合物から選択される化合物を用い て、化合物 1—1の製造方法に準じ、化合物 1 2〜7を得た。  Compound 1 2-7 was obtained according to the production method of Compound 1-1, using Compound 0-2-7, a commercially available compound and a compound selected from known compounds.
(2E) -3- (3 フルォロ一 4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1 , 4]チアジン 2 イリデン)メチル)フエニル）アクリル酸 (化合物 1 2) (2E) -3- (3 Fluoro 1- ((3 oxo 3, 4 dihydro 1 2H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylic acid (compound 1 2)
[化 21] [Chemical 21]
Figure imgf000031_0001
Figure imgf000031_0001
H— NMR(500MHz, DMSO d )  H—NMR (500MHz, DMSO d)
6  6
δ 6. 69(d, J = 15. 9 Hz, IH), 7.01 (m, IH), 7.06(dd, J = 8. 2, 1 . 2 Hz, IH), 7. 18(m, IH), 7. 30 (dd, J = 8. 2, 1. 2 Hz, IH), 7.40 (d , J = 7. 9 Hz, IH), 7.45(d, J = 0. 9 Hz, IH), 7. 62(d, J = 15. 9 Hz, IH), 7. 66 (d, J = 7. 9 Hz, IH), 7. 96(s, IH), 11. 04 (s, IH), 12 .49(brs, IH) δ 6.69 (d, J = 15.9 Hz, IH), 7.01 (m, IH), 7.06 (dd, J = 8.2, 1.2 Hz, IH), 7.18 (m, IH) , 7.30 (dd, J = 8. 2, 1.2 Hz, IH), 7.40 (d, J = 7.9 Hz, IH), 7.45 (d, J = 0.9 Hz, IH), 7 62 (d, J = 15. 9 Hz, IH), 7. 66 (d, J = 7.9 Hz, IH), 7. 96 (s, IH), 11. 04 (s, IH), 12 .49 (brs, IH)
(2E) -3- (4— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル）アクリル酸 (化合物 1 3)  (2E) -3- (4— ((2 oxo 1,2 dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) acrylic acid (compound 1 3)
[化 22] [Chemical 22]
Figure imgf000032_0001
Figure imgf000032_0001
H— NMR(400MHz, DMSO— d ) H—NMR (400MHz, DMSO—d)
6  6
δ 3.86 (s, 2H), 6.48 (d, J = 15.9 Hz, IH) , 7.14 (t, J = 8.3 Hz, IH), 7.29(d, J = 8.3 Hz, IH), 7.34 (d, J = 8.1 Hz, 2H) , 7.44 (t , J = 8.3 Hz, IH), 7.56 (d, J = 15.9 Hz, IH), 7.59 (d, J = 8.3 Hz, IH), 7.61 (d, J = 8. 1 Hz, 2H) , 7.72(s, IH), 11.81 (s, IH), 12 .34 (s, IH) δ 3.86 (s, 2H), 6.48 (d, J = 15.9 Hz, IH), 7.14 (t, J = 8.3 Hz, IH), 7.29 (d, J = 8.3 Hz, IH), 7.34 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 8.3 Hz, IH), 7.56 (d, J = 15.9 Hz, IH), 7.59 (d, J = 8.3 Hz, IH), 7.61 (d, J = 8. 1 Hz, 2H), 7.72 (s, IH), 11.81 (s, IH), 12.34 (s, IH)
(2E) -3- (2— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル）アクリル酸 (化合物 1 4)  (2E) -3- (2— ((2 oxo 1,2 dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) acrylic acid (compound 1 4)
[化 23] [Chemical 23]
Figure imgf000032_0002
H— NMR(500MHz, DMSO— d )
Figure imgf000032_0002
H—NMR (500MHz, DMSO—d)
6  6
δ 3.96 (s, 2Η), 5.60(brs, IH), 6.41 (d, J = 15.9 Hz, IH), 7. ll(m , IH), 7.27-7.38 (m, 4H) , 7.41 (dd, J = 9.8, 1.2 Hz, IH), 7.43( m, IH), 7.50 (d, J = 8.1 Hz, IH), 7.78 (d, J = 8.5 Hz, IH), 7.8 l(d, J = 15.9 Hz, IH), 11.89(s, IH) δ 3.96 (s, 2Η), 5.60 (brs, IH), 6.41 (d, J = 15.9 Hz, IH), 7.ll (m, IH), 7.27-7.38 (m, 4H), 7.41 (dd, J = 9.8, 1.2 Hz, IH), 7.43 (m, IH), 7.50 (d, J = 8.1 Hz, IH), 7.78 (d, J = 8.5 Hz, IH), 7.8 l (d, J = 15.9 Hz, IH), 11.89 (s, IH)
(2E)— 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン一 2 イリデン）メチル）チォフェン 3 ィル）アクリル酸（化合物 1 5) SA15239 (2E) — 3— (5— ((3 oxo 3, 4 dihydro-1 2H benzo [b] [l, 4] thiazine-2-ylidene) methyl) thiophene 3 yl) acrylic acid (compound 1 5) SA15239
[化 24]
Figure imgf000033_0001
[Chemical 24]
Figure imgf000033_0001
[0098] H— NMR(400MHz, DMSO— d )  [0098] H—NMR (400MHz, DMSO—d)
6  6
δ 6.42(d, J = 15.9 Hz, IH), 7.03— 7. ll(m, 2H) , 7.23 (m, IH), 7.41 (d, J = 7.8 Hz, IH), 7.59(d, J = 15.9 Hz, IH), 7.95(s, IH ), 8.00(s, IH), 8.25(s, IH), 11.06(s, IH), 12.40(s, IH)  δ 6.42 (d, J = 15.9 Hz, IH), 7.03— 7. ll (m, 2H), 7.23 (m, IH), 7.41 (d, J = 7.8 Hz, IH), 7.59 (d, J = 15.9 Hz, IH), 7.95 (s, IH), 8.00 (s, IH), 8.25 (s, IH), 11.06 (s, IH), 12.40 (s, IH)
(2E) -3- (5— ((3 ォキソ 6— (トリフルォロメチノレ) 3, 4 ジヒドロ一 2H ベ ンゾ [b] [1, 4]チアジン 2 イリデン)メチル）チォフェン 3 ィル）アクリル酸（化 合物 1 6)  (2E) -3- (5— ((3 oxo 6— (trifluoromethinole) 3, 4 dihydro-2H benzo [b] [1, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) Acrylic acid (compound 1 6)
[化 25] [Chemical 25]
Figure imgf000033_0002
Figure imgf000033_0002
[0099] H— NMR(500MHz, DMSO— d ) [0099] H—NMR (500 MHz, DMSO— d)
6  6
δ 6.43(d, J = 15.9 Hz, IH) , 7.37— 7.39(m, 2H) , 7.59(d, J = 1 δ 6.43 (d, J = 15.9 Hz, IH), 7.37— 7.39 (m, 2H), 7.59 (d, J = 1
5.9 Hz, IH), 7.67(d, J = 8.9 Hz, IH), 7.99(d, J = 0.6 Hz, IH)5.9 Hz, IH), 7.67 (d, J = 8.9 Hz, IH), 7.99 (d, J = 0.6 Hz, IH)
, 8.01 (s, IH), 8.28(s, IH), 11.26(s, IH), 12.42(s, IH) , 8.01 (s, IH), 8.28 (s, IH), 11.26 (s, IH), 12.42 (s, IH)
(2E) -3- (5— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル） チォフェン 3—ィル）アクリル酸 (化合物 1 7)  (2E) -3- (5— ((2 oxo 1,2 dihydroquinoline 1 3 (4H) -ylidene) methyl) thiophen 3 yl) acrylic acid (compound 1 7)
[化 26] [Chemical 26]
Figure imgf000033_0003
[0100] H— NMR(400MHz, DMSO— d )
Figure imgf000033_0003
[0100] H— NMR (400 MHz, DMSO— d)
6  6
δ 4.02(s, 2H), 6.26 (d, J = 15.9 Hz, 1H), 7.16(m, 1H), 7.31— 7 .34 (m, 2H) , 7.45 (m, 1H) , 7.49 (d, J = 15.9 Hz, 1H), 7.63(dd, J = 7.8, 1.2 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.81 (s, 1H), 9.7 0(brs, 1H), 11.88(s, 1H)  δ 4.02 (s, 2H), 6.26 (d, J = 15.9 Hz, 1H), 7.16 (m, 1H), 7.31—7.34 (m, 2H), 7.45 (m, 1H), 7.49 (d, J = 15.9 Hz, 1H), 7.63 (dd, J = 7.8, 1.2 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.81 (s, 1H), 9.7 0 (brs, 1H), 11.88 ( s, 1H)
実施例 2  Example 2
(2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン一 2 イリデン)メチル)フエュル） N— (ピリジン— 3 ィルメチル）アクリルアミド（化合 物 2 1)  (2E) — 3— (4— ((3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] thiazine-2-ylidene) methyl) fur) N— (pyridine-3-ylmethyl) acrylamide (compound 2 1)
[化 27]  [Chemical 27]
Figure imgf000034_0001
Figure imgf000034_0001
[0101] (2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1, 4]チアジン一 2 イリデン）メチル）フエニル）アクリル酸（320mg、 1. Ommol、化合物 1 1)の DM F溶液（10mUにジイソプロピルカルポジイミド（320 μ L, 2. Ommol)、ジメチルアミ ノビリジン（13mg、 0. lOmmol)と TFPレジン（500mg)をカロえ室温力、ら 80。Cにて 24 時間撹拌した。レジンを 10mLの DMF、テトラヒドロフラン、塩化メチレンで順に 2回 ずつ洗浄した後乾燥した。 DMF(lmUにレジン（lOOmg,理論値 0. lmmol)と 3 —アミノメチルビリジン（7. Omg, 0.069mmol)を室温にて加え 24時間撹拌した。 反応液をろ過した後、レジンを 2mLの塩化メチレン、 DMF、塩化メチレンで順に 2回 ずつ洗浄した。洗浄液とろ液を一緒にし減圧下濃縮すると標的化合物 22mgが黄色 固体として得られた (収率 54%)。 [0101] (2E) — 3— (4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine- 1 ylidene) methyl) phenyl) acrylic acid (320 mg, 1. Ommol, compound 1) 1) DMF solution (10mU in diisopropyl carpositimide (320 μL, 2. Ommol), dimethylaminoviridine (13 mg, 0.1 mmol) and TFP resin (500 mg). The resin was washed twice with 10 mL of DMF, tetrahydrofuran, and methylene chloride in order, and then dried.DMF (resin (lOOmg, theoretical 0.1 mmol) to lmU and 3-aminomethylpyridine (7. Omg) , 0.069 mmol) at room temperature and stirred for 24 hours After filtering the reaction solution, the resin was washed twice with 2 mL of methylene chloride, DMF, and methylene chloride in this order. The target compound 22 mg was obtained as a yellow solid (yield 54%).
[0102] 1H-NMR(400MHz, DMSO— d ) [0102] 1 H-NMR (400 MHz, DMSO— d)
6  6
δ 4.44 (d, J = 5.9 Hz, 2H) , 6.75 (d, J = 15.9 Hz, 1H) , 7.01— 7 .09 (m, 2H), 7.21 (m, IH), 7.33— 7.40 (m, 2H) , 7.52 (d, J = 15.9 Hz, IH), 7.69-7.76 (m, 5H) , 7.80(s, IH), 8.48 (dd, J = 4.9, 1.7 Hz, IH), 8.55(d, J = 1.7 Hz, IH), 8.75(t, J = 5.6 Hz, IH), 11. 08 (s, IH) δ 4.44 (d, J = 5.9 Hz, 2H), 6.75 (d, J = 15.9 Hz, 1H), 7.01— 7 .09 (m, 2H), 7.21 (m, IH), 7.33— 7.40 (m, 2H), 7.52 (d, J = 15.9 Hz, IH), 7.69-7.76 (m, 5H), 7.80 (s, IH ), 8.48 (dd, J = 4.9, 1.7 Hz, IH), 8.55 (d, J = 1.7 Hz, IH), 8.75 (t, J = 5.6 Hz, IH), 11. 08 (s, IH)
以下、化合物 1 7、市販化合物及び既知化合物から選択される化合物を用い て、化合物 2—1の製造方法に準じ、化合物 2— 2 44を得た。  Hereinafter, Compound 2-244 was obtained according to the production method of Compound 2-1, using Compound 17 and a compound selected from commercially available compounds and known compounds.
2— (4— ((E)— 3—ォキソ 3— (ピペリジン 1—ィル）プロペン一 1—ィル）ベンジ リデン） 2H ベンゾ [b] [ 1 , 4]チアジン 3 (4H) オン（化合物 2— 2) 2— (4— ((E) — 3—oxo 3— (piperidine 1-yl) propene 1-yl) benzylidene) 2H benzo [b] [1, 4] thiazine 3 (4H) ON (compound twenty two)
[化 28] [Chemical 28]
Figure imgf000035_0001
H— NMR(500MHz, DMSO d )
Figure imgf000035_0001
H—NMR (500MHz, DMSO d)
6  6
δ 1.45-1.60 (m, 6H) , 3.49— 3.57 (m, 2H) , 3.60— 3.69 (m, 2H) , 7 .03 (dd, J = 7.6, 7.6 Hz, IH), 7.08 (d, J = 7.1 Hz, IH), 7.20 ( ddd, J = 7.6, 7.1, 1.5 Hz, IH), 7.32— 7.36 (m, 2H) , 7.51 (d, J =δ 1.45-1.60 (m, 6H), 3.49— 3.57 (m, 2H), 3.60— 3.69 (m, 2H), 7.03 (dd, J = 7.6, 7.6 Hz, IH), 7.08 (d, J = 7.1 Hz, IH), 7.20 (ddd, J = 7.6, 7.1, 1.5 Hz, IH), 7.32— 7.36 (m, 2H), 7.51 (d, J =
15.4 Hz, IH), 7.71 (d, J = 8.3 Hz, 2H) , 7.81 (s, IH), 7.85 (d, J15.4 Hz, IH), 7.71 (d, J = 8.3 Hz, 2H), 7.81 (s, IH), 7.85 (d, J
= 8.3 Hz, 2H), 11.07(s, IH) = 8.3 Hz, 2H), 11.07 (s, IH)
(2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン一 2—イリデン)メチル)フエュル）—N— (ピリジン— 2—ィル）アクリルアミド（化合物 2— 3) (2E) — 3— (4— ((3 oxo 3, 4 dihydro-1 2H benzo [b] [l, 4] thiazine-2-ylidene) methyl) fur) —N— (pyridine-2-yl) acrylamide (Compound 2-3)
[化 29] [Chemical 29]
Figure imgf000036_0001
Figure imgf000036_0001
H— NMR(400MHz, DMSO— d )  H—NMR (400MHz, DMSO—d)
6  6
δ 7.00-7.15(m, 4H) , 7.21(ddd, J = 7.8, 7, 8, 1.4 Hz, IH), 7.3 5(d, J = 7.8 Hz, IH), 7.67(d, J = 15.9 Hz, IH), 7.72— 7.83 (m , 6H), 8.25(d, J = 8.3 Hz, IH), 8.36(ddd, J = 4.9, 1.7, 0.8 Hz , IH), 10.75(s, IH), 11.09(s, IH) δ 7.00-7.15 (m, 4H), 7.21 (ddd, J = 7.8, 7, 8, 1.4 Hz, IH), 7.3 5 (d, J = 7.8 Hz, IH), 7.67 (d, J = 15.9 Hz, IH), 7.72—7.83 (m, 6H), 8.25 (d, J = 8.3 Hz, IH), 8.36 (ddd, J = 4.9, 1.7, 0.8 Hz, IH), 10.75 (s, IH), 11.09 (s , IH)
メチル 4— ((2E)— 3—（4— ((3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b] [1, 4]チアジン 2 イリデン)メチル）フエニル）アクリルアミド）ベンゾエート（化合物 2— 4)  Methyl 4— ((2E) — 3— (4— ((3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylamide) benzoate (compound 2-4)
[化 30]  [Chemical 30]
Figure imgf000036_0002
Figure imgf000036_0002
H— NMR(500MHz, DMSO— d )  H—NMR (500MHz, DMSO—d)
6  6
δ 3.84(s, 3H), 6.92(d, J = 15.8 Hz, IH) , 7.04 (ddd, J = 8.2, 7 .6, 1.2 Hz, IH), 7.08 (dd, J = 8.2, 1.2 Hz, IH), 7.21 (ddd, J = 7.6, 7.6, 1.2 Hz, IH), 7.36 (d, J = 7.6 Hz, IH), 7.68 (d, J = 15 .8 Hz, IH), 7.78(s, 4H) , 7.82(s, IH), 7.85(d, J = 8.8 Hz, 2H) , 7.96 (d, J = 8.8 Hz, 2H) , 10.61(s, IH), 11.10(s, IH) δ 3.84 (s, 3H), 6.92 (d, J = 15.8 Hz, IH), 7.04 (ddd, J = 8.2, 7.6, 1.2 Hz, IH), 7.08 (dd, J = 8.2, 1.2 Hz, IH ), 7.21 (ddd, J = 7.6, 7.6, 1.2 Hz, IH), 7.36 (d, J = 7.6 Hz, IH), 7.68 (d, J = 15.8 Hz, IH), 7.78 (s, 4H) , 7.82 (s, IH), 7.85 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 10.61 (s, IH), 11.10 (s, IH)
(2E)—N シクロペンチノレ一 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ン (2E) —N Cyclopentinole 3— (4— ((3 Oxo 3, 4 Dihydro-2H
[b][l, 4]チアジン 2 イリデン)メチル）フエニル）アタリノレアミド（化合物 2— 5) [化 31] [b] [l, 4] thiazine 2 ylidene) methyl) phenyl) attalinoleamide (compound 2-5) [Chemical 31]
Figure imgf000037_0001
Figure imgf000037_0001
[0107] H— NMR(500MHz, DMSO— d ) [0107] H—NMR (500MHz, DMSO—d)
6  6
δ 1.38-1.44 (m, 2H) , 1.50— 1.58 (m, 2H) , 1.62— 1.70 (m, 2H) , 1 .80-1.88 (m, 2H), 4. ll(m, IH), 6.68 (d, J = 15.6 Hz, IH), 7.03 (dd, J = 7.7, 7.3 Hz, IH), 7.07 (dd, J = 8.2, 1.2 Hz, IH), 7.21 (ddd, J = 8.2, 7.3, 1.2 Hz, IH), 7.35(d, J = 7.7 Hz, IH), 7.44 (d, J = 15.6 Hz, IH), 7.67(d, J = 8.3 Hz, 2H) , 7.72 (d, J = 8. 3 Hz, 2H), 7.83(s, IH), 8.13(d, J = 7.4 Hz, IH), 11.08 (s, IH) (2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン一 2 イリデン）メチル）フエ二ル）— N ペンチルアクリルアミド（化合物 2— 6)  δ 1.38-1.44 (m, 2H), 1.50— 1.58 (m, 2H), 1.62— 1.70 (m, 2H), 1.80-1.88 (m, 2H), 4. ll (m, IH), 6.68 ( d, J = 15.6 Hz, IH), 7.03 (dd, J = 7.7, 7.3 Hz, IH), 7.07 (dd, J = 8.2, 1.2 Hz, IH), 7.21 (ddd, J = 8.2, 7.3, 1.2 Hz , IH), 7.35 (d, J = 7.7 Hz, IH), 7.44 (d, J = 15.6 Hz, IH), 7.67 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.3 Hz , 2H), 7.83 (s, IH), 8.13 (d, J = 7.4 Hz, IH), 11.08 (s, IH) (2E) — 3— (4— ((3 oxo 3, 4 dihydro- 1H benzo [ b] [l, 4] thiazine-2-ylidene) methyl) phenyl) —N pentylacrylamide (compound 2-6)
[化 32]  [Chemical 32]
Figure imgf000037_0002
Figure imgf000037_0002
[0108] H— NMR(500MHz, DMSO— d ) [0108] H—NMR (500MHz, DMSO—d)
6  6
δ 0.88 (t, J = 7.0 Hz, 3H), 1.42— 1.50 (m, 2H) , 1.90— 1.95 (m, 4H), 3.13-3.18 (m, 2H) , 6.68 (d, J = 15.9 Hz, IH), 7.03 (dd, J = 7.9, 7.3 Hz, IH), 7.07(d, J = 7.9 Hz, IH), 7.21 (dd, J = 7. 9, 7.3 Hz, IH), 7.35(d, J = 7.9 Hz, IH), 7.46 (d, J = 15.8 Hz, IH), 7.68 (d, J = 8.3 Hz, 2H) , 7.73(d, J = 8.3 Hz, 2H) , 7.80 (s , IH), 8.15(t, J = 5.6 Hz, IH), 11.08 (s, IH) δ 0.88 (t, J = 7.0 Hz, 3H), 1.42— 1.50 (m, 2H), 1.90— 1.95 (m, 4H), 3.13-3.18 (m, 2H), 6.68 (d, J = 15.9 Hz, IH ), 7.03 (dd, J = 7.9, 7.3 Hz, IH), 7.07 (d, J = 7.9 Hz, IH), 7.21 (dd, J = 7.9, 7.3 Hz, IH), 7.35 (d, J = 7.9 Hz, IH), 7.46 (d, J = 15.8 Hz, IH), 7.68 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.80 (s , IH), 8.15 (t, J = 5.6 Hz, IH), 11.08 (s, IH)
(2E)— N— (4 メトキシフエニル） 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H— ベンゾ [b] [ 1 , 4]チアジン 2 イリデン)メチル）フエニル）アタリノレアミド（化合物 2— 7)  (2E) — N— (4 Methoxyphenyl) 3— (4— ((3 Oxo 3, 4 Dihydro- 1H— Benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) attalinoleamide (compound 2—7)
[化 33]  [Chemical 33]
Figure imgf000038_0001
Figure imgf000038_0001
[0109] H— NMR(500MHz, DMSO— d )  [0109] H—NMR (500MHz, DMSO—d)
6  6
δ 3.74(s, 3H), 6.92(d, J = 15.8 Hz, IH), 6.93(d, J = 8.8 Hz , 2H), 7.04(ddd, J = 8.2, 7.6, 1.2 Hz, IH), 7.08 (dd, J = 8.2, 1 .2 Hz, IH), 7.21(ddd, J = 7.6, 7.6, 1.2 Hz, IH), 7.35(d, J = 7 .6 Hz, IH), 7.59(d, J = 15.8 Hz, IH), 7.63(d, J = 8.8 Hz, 2H) , 7.75(s, 4H), 7.82(s, IH), 10.19(s, IH), 11.10(s, IH)  δ 3.74 (s, 3H), 6.92 (d, J = 15.8 Hz, IH), 6.93 (d, J = 8.8 Hz, 2H), 7.04 (ddd, J = 8.2, 7.6, 1.2 Hz, IH), 7.08 ( dd, J = 8.2, 1.2 Hz, IH), 7.21 (ddd, J = 7.6, 7.6, 1.2 Hz, IH), 7.35 (d, J = 7.6 Hz, IH), 7.59 (d, J = 15.8 Hz, IH), 7.63 (d, J = 8.8 Hz, 2H), 7.75 (s, 4H), 7.82 (s, IH), 10.19 (s, IH), 11.10 (s, IH)
(2E) N— (3 （ヒドロキシメチル）フエニル）ー3—（4— ((3 ォキソ 3, 4 ジヒ ドロー 2H—ベンゾ [b] [ 1 , 4]チアジン 2—イリデン）メチル）フエニル）アクリルアミド (化合物 2— 8)  (2E) N— (3 (Hydroxymethyl) phenyl) -3- (4— ((3 oxo 3, 4 dihydro 2H—benzo [b] [1, 4] thiazine 2-ylidene) methyl) phenyl) acrylamide ( Compound 2-8)
[化 34]  [Chemical 34]
Figure imgf000038_0002
Figure imgf000038_0002
[0110] 'H-NMRCSOOMHz, DMSO— d ) [0110] 'H-NMRCSOOMHz, DMSO— d)
6  6
δ 4.50(d, J = 5.8 Hz, 2H) , 5.22 (t, J = 15.8 Hz, IH), 7.03 (dd, J = 7.9, 7.3 Hz, IH), 7.08 (dd, J = 8.2, 1.2 Hz, IH), 7.21 (dd, J = 7.9, 7.3 Hz, IH), 7.34— 7.41( m, 2H), 7.60-7.66 (m, 2H) , 7.72— 7.82 (m, 6H) , 8.58 (d, J = 6.8δ 4.50 (d, J = 5.8 Hz, 2H), 5.22 (t, J = 15.8 Hz, IH), 7.03 (dd, J = 7.9, 7.3 Hz, IH), 7.08 (dd, J = 8.2, 1.2 Hz, IH), 7.21 (dd, J = 7.9, 7.3 Hz, IH), 7.34 — 7.41 (m, 2H), 7.60-7.66 (m, 2H), 7.72— 7.82 (m, 6H), 8.58 (d, J = 6.8
, 1.5 Hz, IH), 10.19(s, IH), 11.10(s, IH) , 1.5 Hz, IH), 10.19 (s, IH), 11.10 (s, IH)
メチル 4— ((2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1, 4 ]チアジン 2 イリデン)メチル)フエニル）アクリルアミド）酪酸 (化合物 2— 9) Methyl 4— ((2E) — 3— (4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylamide) butyric acid (compound 2-9)
[化 35] [Chemical 35]
Figure imgf000039_0001
Figure imgf000039_0001
H-NMR(500MHz, DMSO d ) H-NMR (500MHz, DMSO d)
6  6
δ 1.69-1.73 (m, 2Η) , 2.33— 2.38 (m, 2Η) , 3. 18— 3.22 (m, 2Η) , 3 .60(s, 3Η), 6.68 (d, J = 15.8 Hz, IH), 7.04 (dd, J = 7.6, 7.3 H z, IH), 7.08 (d, J = 7.3 Hz, IH), 7.21 (dd, J = 7.6, 7.3 Hz, IH) , 7.36 (dd, J = 7.3 Hz, IH), 7.45(d, J = 15.8 Hz, IH), 7.73(d, J = 8.2 Hz, 2H), 7.81 (s, IH), 7.82(d, J = 8.2 Hz, 2H) , 8.20— 8 .21 (m, IH), 11.08(s, IH) δ 1.69-1.73 (m, 2Η), 2.33— 2.38 (m, 2Η), 3.18— 3.22 (m, 2Η), 3.60 (s, 3Η), 6.68 (d, J = 15.8 Hz, IH) , 7.04 (dd, J = 7.6, 7.3 H z, IH), 7.08 (d, J = 7.3 Hz, IH), 7.21 (dd, J = 7.6, 7.3 Hz, IH), 7.36 (dd, J = 7.3 Hz , IH), 7.45 (d, J = 15.8 Hz, IH), 7.73 (d, J = 8.2 Hz, 2H), 7.81 (s, IH), 7.82 (d, J = 8.2 Hz, 2H), 8.20— 8 .21 (m, IH), 11.08 (s, IH)
(2E) -3- (3 フルォロ一 4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1 ， 4]チアジン 2 イリデン）メチル）フエニル） N—(ピリジン 3 ィルメチル）ァク リルアミド（化合物 2— 10)  (2E) -3- (3 Fluoro 4-— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) N— (pyridine 3-ylmethyl) acrylamide ( Compound 2—10)
[化 36] [Chemical 36]
Figure imgf000040_0001
Figure imgf000040_0001
[0112] H— NMR(500MHz, DMSO— d ) [0112] H—NMR (500MHz, DMSO—d)
6  6
δ 4.44 (d, J = 5.8 Hz, 2H) , 6.78 (d, J = 15.9 Hz, IH), 7.01 (m , IH), 7.01 (dd, J = 7.9, 1.2 Hz, IH), 7. 19(m, IH), 7.29— 7.32( m, 2H), 7.38 (dd, J = 7.9, 4.3 Hz, IH), 7.51 (d, J = 15.9 Hz, 1 H), 7.68 (d, J = 8.2 Hz, IH), 7.74 (d, J = 7.9 Hz, 2H) , 7.96 (s, IH), 8.48 (dd, J = 4.6, 1.5 Hz, IH) , 8.54 (d, J = 1.5 Hz, IH), 8 .73 (t, J = 5.8 Hz, IH), 11.02(s, IH)  δ 4.44 (d, J = 5.8 Hz, 2H), 6.78 (d, J = 15.9 Hz, IH), 7.01 (m, IH), 7.01 (dd, J = 7.9, 1.2 Hz, IH), 7.19 ( m, IH), 7.29— 7.32 (m, 2H), 7.38 (dd, J = 7.9, 4.3 Hz, IH), 7.51 (d, J = 15.9 Hz, 1 H), 7.68 (d, J = 8.2 Hz, IH), 7.74 (d, J = 7.9 Hz, 2H), 7.96 (s, IH), 8.48 (dd, J = 4.6, 1.5 Hz, IH), 8.54 (d, J = 1.5 Hz, IH), 8. 73 (t, J = 5.8 Hz, IH), 11.02 (s, IH)
(2E)—N シクロプロピノレー 3— (3 フノレオ口一 4— ((3 ォキソ 3, 4 ジヒドロ -2H-ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）フエニル）アクリルアミド（化 合物 2 11)  (2E) —N Cyclopropynole 3— (3 Funoleo mouth 1 4 — ((3 oxo 3, 4 dihydro-2H-benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylamide (compound Thing 2 11)
[化 37]  [Chemical 37]
Figure imgf000040_0002
Figure imgf000040_0002
[0113] H— NMR(400MHz, DMSO— d )  [0113] H—NMR (400MHz, DMSO—d)
6  6
δ 0.45-0.50 (m, 2H) , 0.65— 0.70 (m, 2H) , 2.78 (m, IH), 6.63(d, J = 15.9 Hz, IH), 6.90-7.10 (m, 2H) , 7.15(m, IH), 7.27— 7.35 (m, 3H), 7.45(d, J = 15.9 Hz, IH), 7.67(d, J = 8.6 Hz, IH), 7 .95(s、 IH), 8.25(d, J = 4.6 Hz, IH), 11.03(s, IH) (2E) -3- (4— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル) フエニル） N—(ピリジンー3 ィルメチル）アクリルアミド（化合物 2— 12) δ 0.45-0.50 (m, 2H), 0.65— 0.70 (m, 2H), 2.78 (m, IH), 6.63 (d, J = 15.9 Hz, IH), 6.90-7.10 (m, 2H), 7.15 (m , IH), 7.27— 7.35 (m, 3H), 7.45 (d, J = 15.9 Hz, IH), 7.67 (d, J = 8.6 Hz, IH), 7.95 (s, IH), 8.25 (d, J = 4.6 Hz, IH), 11.03 (s, IH) (2E) -3- (4— ((2 oxo 1,2 dihydroquinoline 3 (4H) -ylidene) methyl) phenyl) N— (pyridine-3-ylmethyl) acrylamide (compound 2-12)
[化 38] [Chemical 38]
Figure imgf000041_0001
Figure imgf000041_0001
H— NMR(400MHz, DMSO— d ) H—NMR (400MHz, DMSO—d)
6  6
δ 3.85(s, 2Η), 4.41(d, J = 5.9 Hz, 2H) , 6.62 (d, J = 15.8 Hz, IH), 7.14 (t, J = 7.3 Hz, IH), 7.27— 7.51 (m, 8H) , 7.59(d, J = 7.5 Hz, IH), 7.69(d, J = 7.9 Hz, IH), 7.71 (s, IH), 8.46 (dd, J = 4.8, 1.7 Hz, IH), 8.52(d, J = 1.7 Hz, IH), 8.66 (t, J = 5.9δ 3.85 (s, 2Η), 4.41 (d, J = 5.9 Hz, 2H), 6.62 (d, J = 15.8 Hz, IH), 7.14 (t, J = 7.3 Hz, IH), 7.27— 7.51 (m, 8H), 7.59 (d, J = 7.5 Hz, IH), 7.69 (d, J = 7.9 Hz, IH), 7.71 (s, IH), 8.46 (dd, J = 4.8, 1.7 Hz, IH), 8.52 ( d, J = 1.7 Hz, IH), 8.66 (t, J = 5.9
Hz, IH), 11.81(s, IH) Hz, IH), 11.81 (s, IH)
(2E) N シクロプロピノレー 3—（4一（（2 ォキソ 1, 2 ジヒドロキノリン 3 (4H )—イリデン)メチル)フエニル）アクリルアミド（化合物 2— 13) (2E) N Cyclopropynole 3- (4 (((2oxo1,2 dihydroquinoline 3 (4H) -ylidene) methyl) phenyl) acrylamide (compound 2-13)
[化 39] [Chemical 39]
Figure imgf000041_0002
Figure imgf000041_0002
H— NMR(400MHz, DMSO— d )  H—NMR (400MHz, DMSO—d)
6  6
δ 0.42-0.46 (m, 2H) , 0.64— 0.69 (m, 2H) , 2.75 (m, IH), 3.84(s, 2H), 6.48 (d, J = 15.9 Hz, IH), 7.14 (m, IH), 7.28— 7.50 (m, 7H) , 7.58 (d, J = 7.6 Hz, IH), 7.72(s, IH), 8.16 (d, J = 4.6 Hz, IH ), 11.80(s, IH) δ 0.42-0.46 (m, 2H), 0.64— 0.69 (m, 2H), 2.75 (m, IH), 3.84 (s, 2H), 6.48 (d, J = 15.9 Hz, IH), 7.14 (m, IH ), 7.28—7.50 (m, 7H) , 7.58 (d, J = 7.6 Hz, IH), 7.72 (s, IH), 8.16 (d, J = 4.6 Hz, IH), 11.80 (s, IH)
3— (4—（（E)— 3—（ァゼパン 1 ィル） 3—ォキソプロペン 1 ィル）ベンジリ デン） 3, 4 ジヒドロキノリン一 2 (1H)—オン（化合物 2— 14)  3— (4 — ((E) — 3— (azepan 1 yl) 3—oxopropene 1 yl) benzylidene) 3, 4 dihydroquinolinone 2 (1H) —one (compound 2-14)
[化 40]  [Chemical 40]
Figure imgf000042_0001
Figure imgf000042_0001
[0116] H— NMR(400MHz, DMSO— d ) [0116] H—NMR (400MHz, DMSO—d)
6  6
δ 1.45-1.50(m, 4H) , 1.60-1.70(m, 4H) , 3.50(t, J = 6.3 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H) , 3.85 (s, 2H) , 7.09 (d, J = 15.6 H z, IH), 7.14 (m, IH), 7.29 (d, J = 8.1 Hz, IH), 7.33(d, J = 8. 1 Hz, 2H) , 7.45 (m, IH) , 7.46 (d, J = 15.6 Hz, IH) , 7.58 (d, J = 7. 8 Hz, IH), 7.62(d, J = 8.1 Hz, 2H) , 7.68(s, IH), 11.80(s, IH) (2E)-N-(3, 5—ジメトキシフエ二ル）一 3— (4— ((2—ォキソ 1, 2—ジヒドロキ ノリンー 3 (4H)—イリデン)メチル）フエニル）アタリノレアミド（化合物 2— 15)  δ 1.45-1.50 (m, 4H), 1.60-1.70 (m, 4H), 3.50 (t, J = 6.3 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H), 3.85 (s, 2H), 7.09 (d, J = 15.6 H z, IH), 7.14 (m, IH), 7.29 (d, J = 8.1 Hz, IH), 7.33 (d, J = 8.1 Hz, 2H), 7.45 (m, IH), 7.46 (d, J = 15.6 Hz, IH), 7.58 (d, J = 7.8 Hz, IH), 7.62 (d, J = 8.1 Hz, 2H), 7.68 (s, IH), 11.80 ( s, IH) (2E) -N- (3,5-Dimethoxyphenyl) 1 3— (4— ((2-Oxo 1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) attalinole Amides (compound 2-15)
[化 41]  [Chemical 41]
Figure imgf000042_0002
Figure imgf000042_0002
[0117] H— NMR(400MHz, DMSO— d ) δ 3.70(s, 6H), 3.86(s, 2H) , 6.22(s, IH), 6.77(d, J = 15.6 Hz, H), 6.94 (s, 2H), 7.13(s, IH), 7.25— 7.80 (m, 9H) , 10.13(s, IH), 1 1.80(s, IH) [0117] H—NMR (400MHz, DMSO—d) δ 3.70 (s, 6H), 3.86 (s, 2H), 6.22 (s, IH), 6.77 (d, J = 15.6 Hz, H), 6.94 (s, 2H), 7.13 (s, IH), 7.25— 7.80 (m, 9H), 10.13 (s, IH), 1 1.80 (s, IH)
(2E) -3- (4— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル) フエニル） N— (ピリジン— 4 ィル）アクリルアミド（化合物 2— 16)  (2E) -3- (4— ((2-Oxo 1, 2-dihydroquinoline 1 (4H) -ylidene) methyl) phenyl) N— (pyridine-4-yl) acrylamide (compound 2-16)
[化 42]  [Chemical 42]
Figure imgf000043_0001
Figure imgf000043_0001
[0118] H— NMR(400MHz, DMSO— d ) [0118] H—NMR (400MHz, DMSO—d)
6  6
δ 3.86(s, 2H), 6.22(s, IH), 6.78 (d, J = 15.6 Hz, IH), 7. 13(s, H), 7.25-7.80 (m, 12H), 10.92(s, IH), 11.80(s, IH)  δ 3.86 (s, 2H), 6.22 (s, IH), 6.78 (d, J = 15.6 Hz, IH), 7. 13 (s, H), 7.25-7.80 (m, 12H), 10.92 (s, IH ), 11.80 (s, IH)
(2E)— N— (4 ァセチルフエニル） 3— (4— ((2 ォキソ 1, 2 ジヒドロキノリ ン 3 (4H) イリデン)メチル）フエニル）アタリノレアミド（化合物 2— 17)  (2E) — N— (4 acetylphenyl) 3— (4— ((2 oxo 1,2 dihydroquinolin 3 (4H) ylidene) methyl) phenyl) attalinoleamide (compound 2-17)
[化 43]  [Chemical 43]
Figure imgf000043_0002
Figure imgf000043_0002
[0119] H— NMR(500MHz, DMSO— d ) δ 2.54 (s, 3H), 3.88(s, 2H) , 6.82(d, J = 15.9 Hz, IH), 7. 16(m,[0119] H—NMR (500MHz, DMSO—d) δ 2.54 (s, 3H), 3.88 (s, 2H), 6.82 (d, J = 15.9 Hz, IH), 7.16 (m,
IH), 7.30 (d, J = 8.2 Hz, IH), 7.38 (d, J = 8.2 Hz, 2H) , 7.45 (mIH), 7.30 (d, J = 8.2 Hz, IH), 7.38 (d, J = 8.2 Hz, 2H), 7.45 (m
, IH), 7.57-7.63 (m, 4H) , 7.75(s, IH), 7.83(d, J = 8.9 Hz, 2H), IH), 7.57-7.63 (m, 4H), 7.75 (s, IH), 7.83 (d, J = 8.9 Hz, 2H)
, 7.96 (d, J = 8.9 Hz, 2H) , 10.54(s, IH), 11.82(s, IH) , 7.96 (d, J = 8.9 Hz, 2H), 10.54 (s, IH), 11.82 (s, IH)
(2E) -3- (4— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N— (4 プロピルフエニル）アクリルアミド（化合物 2— 18)  (2E) -3- (4— ((2 oxo 1,2 dihydroquinoline 1 (4H) -ylidene) methyl) phenyl) N— (4 propylphenyl) acrylamide (compound 2-18)
[化 44]  [Chemical 44]
Figure imgf000044_0001
Figure imgf000044_0001
H-NMR(500MHz, DMSO d ) H-NMR (500MHz, DMSO d)
6  6
δ 0.88 (t, J = 7.3 Hz, 3H), 1.56 (t, J = 7.3 Hz, 2H) , 2.50-2. 55 (m, 2H), 3.87(s, 2H) , 6.78 (d, J = 15.9 Hz, IH), 7. 13(m, IH), 7. 14(d, J = 8.6 Hz, 2H), 7.29(d, J = 8.2 Hz, IH), 7.35— 7.48 ( m, 3H), 7.50-7.63 (m, 6H) , 7.74 (s, IH), 10. ll(s, IH), 11.81(s, 1 H) δ 0.88 (t, J = 7.3 Hz, 3H), 1.56 (t, J = 7.3 Hz, 2H), 2.50-2.55 (m, 2H), 3.87 (s, 2H), 6.78 (d, J = 15.9 Hz, IH), 7.13 (m, IH), 7.14 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.2 Hz, IH), 7.35—7.48 (m, 3H), 7.50 -7.63 (m, 6H), 7.74 (s, IH), 10. ll (s, IH), 11.81 (s, 1 H)
(2E)— N— tert ブトキシ 3—（4一（（2 ォキソ 1, 2 ジヒドロキノリン 3 (4H )—イリデン)メチル)フエニル）アクリルアミド（化合物 2— 19)  (2E) — N— tert Butoxy 3— (4 ((2 oxo 1,2 dihydroquinoline 3 (4H) -ylidene) methyl) phenyl) acrylamide (compound 2-19)
[化 45] [Chemical 45]
Figure imgf000045_0001
Figure imgf000045_0001
[0121] H— NMR(300MHz, DMSO— d ) [0121] H—NMR (300MHz, DMSO—d)
6  6
δ 1.18(s, 9H), 3.84(s, 2H) , 6.49(d, J = 15.6 Hz, IH), 7. 10 (m, δ 1.18 (s, 9H), 3.84 (s, 2H), 6.49 (d, J = 15.6 Hz, IH), 7.10 (m,
IH), 7.25-7.35 (m, 3H) , 7.40— 7.50 (m, 4H) , 7.57(d, J = 7.7 H z, IH), 7.70(s, IH), 10.54(brs, IH), 11.79(s, IH) IH), 7.25-7.35 (m, 3H), 7.40— 7.50 (m, 4H), 7.57 (d, J = 7.7 H z, IH), 7.70 (s, IH), 10.54 (brs, IH), 11.79 ( s, IH)
(2E)—N ヒドロキシー3—（4— ((2—ォキソ 1, 2—ジヒドロキノリン 3(4H)—ィ リデン)メチル)フエュル）アタリノレアミド（化合物 2— 20)  (2E) —N Hydroxy-3— (4 -— ((2-Oxo 1, 2-dihydroquinoline 3 (4H) —ylidene) methyl) fur) atalinoleamide (Compound 2-20)
[化 46]  [Chem 46]
Figure imgf000045_0002
Figure imgf000045_0002
[0122] H— NMR(300MHz, DMSO— d ) [0122] H—NMR (300MHz, DMSO—d)
6  6
δ 3.85(s, 2H), 6.58 (d, J = 16.2 Hz, IH), 7.13(m, IH), 7.27(d, J = 7.9 Hz, IH), 7.33(d, J = 7.9 Hz, 2H) , 7.43 (m, IH), 7.55— 7.65 (m, 4H), 7.71 (s, IH), 10.12(brs, IH), 11.79(s, IH)  δ 3.85 (s, 2H), 6.58 (d, J = 16.2 Hz, IH), 7.13 (m, IH), 7.27 (d, J = 7.9 Hz, IH), 7.33 (d, J = 7.9 Hz, 2H) , 7.43 (m, IH), 7.55— 7.65 (m, 4H), 7.71 (s, IH), 10.12 (brs, IH), 11.79 (s, IH)
(2E) -3- (2— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N—(ピリジンー3 ィルメチル）アクリルアミド（化合物 2— 21)  (2E) -3- (2— ((2 oxo 1,2 dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) N— (pyridine-3-ylmethyl) acrylamide (compound 2-21)
[化 47]
Figure imgf000046_0001
[Chemical 47]
Figure imgf000046_0001
H— NMR(500MHz, DMSO— d )  H—NMR (500MHz, DMSO—d)
6  6
δ 3.95(s, 2H), 4.39(d, J = 5.8 Hz, 2H) , 6.57 (d, J = 15.9 Hz, IH), 7.10(t, J = 7.9 Hz, IH), 7.25— 7.38 (m, 6H) , 7.42— 7.48 (m , 2H), 7.61-7.68 (m, 2H) , 7.70 (d, J = 15.9 Hz, IH), 8.46 (d, J = 4.9, 1.8 Hz, IH), 8.51 (d, J = 1.8 Hz, IH), 8.68 (t, J = 5.8δ 3.95 (s, 2H), 4.39 (d, J = 5.8 Hz, 2H), 6.57 (d, J = 15.9 Hz, IH), 7.10 (t, J = 7.9 Hz, IH), 7.25— 7.38 (m, 6H), 7.42— 7.48 (m, 2H), 7.61-7.68 (m, 2H), 7.70 (d, J = 15.9 Hz, IH), 8.46 (d, J = 4.9, 1.8 Hz, IH), 8.51 (d , J = 1.8 Hz, IH), 8.68 (t, J = 5.8
Hz, IH), 11.87(s, IH) Hz, IH), 11.87 (s, IH)
(2E)—N シクロプロピル一 3— (2— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H )一イリデン)メチル)フエニル）アタリノレアミド（化合物 2— 22) (2E) —N Cyclopropyl mono 3— (2— ((2 oxo 1,2 dihydroquinoline mono 3 (4H) monoylidene) methyl) phenyl) attalinoleamide (compound 2-22)
[化 48] [Chemical 48]
Figure imgf000046_0002
H— NMR(500MHz, DMSO— d )
Figure imgf000046_0002
H—NMR (500MHz, DMSO—d)
6  6
δ 0.40-0.46 (m, 2H) , 0.64— 0.69 (m, 2H) , 2.72 (m, IH), 3.94(s, 2H), 6.42(d, J = 15.9 Hz, IH), 7.10 (m, IH), 7.23(s, IH), 7.24 -7.37 (m, 4H), 7.40— 7.50 (m, 2H) , 7.59(d, J = 7.6 Hz, IH), 7. 61 (d, J = 15.9 Hz, IH), 8.19(d, J = 4.6 Hz, IH), 11.89(s, IH) (2E)— N— (5 メチルピリジン一 2 ィル） 3— (2— ((2 ォキソ 1, 2 ジヒドロ キノリン 3 (4H) イリデン)メチル）フエニル）アタリノレアミド（化合物 2— 23) δ 0.40-0.46 (m, 2H), 0.64— 0.69 (m, 2H), 2.72 (m, IH), 3.94 (s, 2H), 6.42 (d, J = 15.9 Hz, IH), 7.10 (m, IH ), 7.23 (s, IH), 7.24 -7.37 (m, 4H), 7.40—7.50 (m, 2H), 7.59 (d, J = 7.6 Hz, IH), 7.61 (d, J = 15.9 Hz, IH), 8.19 (d, J = 4.6 Hz, IH), 11.89 (s, IH) (2E) — N— (5 Methylpyridine-2-yl) 3— (2— ((2 Oxo 1, 2 Dihydroquinoline) 3 (4H) ylidene) methyl) phenyl) atalinoleamide (compound 2-23)
[化 49]
Figure imgf000047_0001
[Chemical 49]
Figure imgf000047_0001
H— NMR(500MHz, DMSO— d ) H—NMR (500MHz, DMSO—d)
6  6
δ 2.25(s, 3H), 3.98(s, 2H) , 6.93(d, J = 15.6 Hz, IH), 7. 10 (m, IH), 7.25-7.50 (m, 7H) , 7.60— 7.67 (m, 2H) , 7.82(d, J = 15.6 Hz, IH), 8.08 (d, J = 8.6 Hz, IH), 8.16(d, J = 2.1 Hz, IH), 10. 64 (s, IH), 11.89(s, IH) δ 2.25 (s, 3H), 3.98 (s, 2H), 6.93 (d, J = 15.6 Hz, IH), 7. 10 (m, IH), 7.25-7.50 (m, 7H), 7.60— 7.67 (m , 2H), 7.82 (d, J = 15.6 Hz, IH), 8.08 (d, J = 8.6 Hz, IH), 8.16 (d, J = 2.1 Hz, IH), 10. 64 (s, IH), 11.89 (s, IH)
(2E) -3- (2— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N—フエニルアクリルアミド（化合物 2— 24)  (2E) -3- (2— ((2 oxo 1,2 dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) N-phenylacrylamide (compound 2-24)
[化 50] [Chemical 50]
Figure imgf000047_0002
H— NMR(500MHz, DMSO— d )
Figure imgf000047_0002
H—NMR (500MHz, DMSO—d)
6  6
δ 4.00(s, 2H), 6.76 (d, J = 15.6 Hz, IH), 7.07 (m, IH), 7.30— 7 .46 (m, 7H), 7.50 (d, J = 7.6 Hz, IH), 7.69 (d, J = 9.2 Hz, IH) , 7.80(d, J = 15.6 Hz, IH), 7.91 (d, J = 9.2 Hz, 2H) , 8.24 (d, J = 9.2 Hz, 2H), 10.20(s, IH), 11.88(s, IH) δ 4.00 (s, 2H), 6.76 (d, J = 15.6 Hz, IH), 7.07 (m, IH), 7.30—7.46 (m, 7H), 7.50 (d, J = 7.6 Hz, IH), 7.69 (d, J = 9.2 Hz, IH), 7.80 (d, J = 15.6 Hz, IH), 7.91 (d, J = 9.2 Hz, 2H), 8.24 (d, J = 9.2 Hz, 2H), 10.20 ( s, IH), 11.88 (s, IH)
(2E)— N— (4 ニトロフエニル） 3— (2— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)—イリデン)メチル）フエニル）アタリノレアミド（化合物 2— 25)  (2E) — N— (4 Nitrophenyl) 3— (2— ((2 oxo 1, 2 dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) attalinoleamide (compound 2-25)
[化 51]
Figure imgf000048_0001
[Chemical 51]
Figure imgf000048_0001
H— NMR(500MHz, DMSO— d ) H—NMR (500MHz, DMSO—d)
6  6
δ 4.00(s, 2H), 6.77(d, J = 15.6 Hz, IH), 7.10(m, IH), 7.30— 7 .46 (m, 6H), 7.50 (d, J = 7.6 Hz, IH), 7.70 (d, J = 9.2 Hz, IH) , 7.90 (d, J = 15.6 Hz, IH), 7.91 (d, J = 9.2 Hz, 2H) , 8.24 (d, J = 9.2 Hz, 2H), 10.80(s, IH), 11.90(s, IH) δ 4.00 (s, 2H), 6.77 (d, J = 15.6 Hz, IH), 7.10 (m, IH), 7.30—7.46 (m, 6H), 7.50 (d, J = 7.6 Hz, IH), 7.70 (d, J = 9.2 Hz, IH), 7.90 (d, J = 15.6 Hz, IH), 7.91 (d, J = 9.2 Hz, 2H), 8.24 (d, J = 9.2 Hz, 2H), 10.80 ( s, IH), 11.90 (s, IH)
(2E)— 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン一 2 イリデン）メチル）チォフェン 3 ィル） N—(ピリジン 3 ィルメチル）アタリ ルアミド（化合物 2— 26)  (2E) — 3— (5— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine-2- ylidene) methyl) thiophene 3 yl) N— (pyridine 3 ylmethyl) acetylamide ( Compound 2-26)
[化 52]  [Chemical 52]
Figure imgf000048_0002
H— NMR(400MHz, DMSO— d )
Figure imgf000048_0002
H—NMR (400MHz, DMSO—d)
6  6
δ 4.43(d, J = 5.9 Hz, 2H) , 6.55 (d, J = 15.9 Hz, IH) , 7.03— 7 . 10 (m, 2H), 7.23 (t, J = 8.1 Hz, IH), 7.36— 7.41 (m, 2H) , 7.48 ( d, J = 15.9 Hz, IH), 7.72(d, J = 7.8 Hz, IH), 8.01 (s, IH), 8.1 3(s, IH), 8.48 (dd, J = 4.9, 1.7 Hz, IH), 8.54 (d, J = 1.7 Hz, 1 H), 8.73 (t, J = 5.8 Hz, IH), 11.07(s, IH) δ 4.43 (d, J = 5.9 Hz, 2H), 6.55 (d, J = 15.9 Hz, IH), 7.03— 7.10 (m, 2H), 7.23 (t, J = 8.1 Hz, IH), 7.36— 7.41 (m, 2H), 7.48 (d, J = 15.9 Hz, IH), 7.72 (d, J = 7.8 Hz, IH), 8.01 (s, IH), 8.1 3 (s, IH), 8.48 (dd, J = 4.9, 1.7 Hz, IH), 8.54 (d, J = 1.7 Hz, 1 H), 8.73 (t, J = 5.8 Hz, IH), 11.07 (s, IH)
(2E)—N ベンジノレ一 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1 , 4]チアジン 2 イリデン)メチル）チォフェン 3 ィル）アタリノレアミド（化合物 2—  (2E) —N Benzenoreol 3— (5— ((3 oxo 3, 4 dihydrol 2H benzo [b] [1, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) attalinoleamide (compound 2—
[化 53]
Figure imgf000049_0001
[Chemical 53]
Figure imgf000049_0001
H— NMR(500MHz, DMSO— d )  H—NMR (500MHz, DMSO—d)
6  6
δ 4.40(d, J = 5.8 Hz, 2H) , 6.57 (d, J = 15.9 Hz, IH) , 7.00— 7 . 14 (m, 2H), 7.20— 7.38 (m, 6H) , 7.41 (d, J = 1.2 Hz, IH), 7.47( d, J = 15.9 Hz, IH), 7.78 (d, J = 1.5 Hz, IH), 8.01 (s, IH), 8.1 l(s, IH), 8.65(t, J = 5.8 Hz, IH), 11.06(s, IH) δ 4.40 (d, J = 5.8 Hz, 2H), 6.57 (d, J = 15.9 Hz, IH), 7.00—7.14 (m, 2H), 7.20— 7.38 (m, 6H), 7.41 (d, J = 1.2 Hz, IH), 7.47 (d, J = 15.9 Hz, IH), 7.78 (d, J = 1.5 Hz, IH), 8.01 (s, IH), 8.1 l (s, IH), 8.65 (t, J = 5.8 Hz, IH), 11.06 (s, IH)
(2E)— N ェチル N— (2 ヒドロキシェチル） 3— (5— ((3 ォキソ 3, 4— ジヒドロー 2H べンゾ [b][l, 4]チアジンー2 イリデン）メチル）チォフェンー3 ィ ノレ）アクリルアミド（化合物 2— 28) (2E) — N ethyl N— (2 hydroxyethyl) 3— (5— ((3 oxo 3, 4— dihydro-2H benzo [b] [l, 4] thiazine-2-ylidene) methyl) thiophene-3 ) Acrylamide (Compound 2-28)
[化 54] [Chemical 54]
Figure imgf000049_0002
Figure imgf000049_0002
H-NMR(500MHz, DMSO— d )  H-NMR (500MHz, DMSO—d)
6  6
δ 1.07(t, J = 7.0 Hz, 3Hxl/2), 1.16 (t, J = 7.0 Hz, 3Hxl/2) , 3.38-3.49 (m, 2H) , 3.50— 3.61 (m, 4H) , 4.71 (t, J = 5.2 Hz, 1 Hxl/2), 4.83 (t, J = 5.2 Hz, 1 Hxl/2), 7.00— 7. 10 (m, 3H) , 7.20 (m, IH), 7.35-7.55 (m, 2H) , 7.95— 8.05 (m, 2H) , 8.15(s, 1 Hxl/2 ), 8.20(s, lHxl/2), 11.02(s, IH) δ 1.07 (t, J = 7.0 Hz, 3Hxl / 2), 1.16 (t, J = 7.0 Hz, 3Hxl / 2), 3.38-3.49 (m, 2H), 3.50— 3.61 (m, 4H), 4.71 (t , J = 5.2 Hz, 1 Hxl / 2), 4.83 (t, J = 5.2 Hz, 1 Hxl / 2), 7.00— 7.10 (m, 3H), 7.20 (m, IH), 7.35-7.55 (m , 2H), 7.95— 8.05 (m, 2H), 8.15 (s, 1 Hxl / 2), 8.20 (s, lHxl / 2), 11.02 (s, IH)
(2E)— N— (4 メトキシベンジル） 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル）アクリルァ ミド (化合物 2— 29)  (2E) — N— (4 Methoxybenzyl) 3— (5— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) acrylamide (compound 2—29)
[化 55]
Figure imgf000050_0001
[Chemical 55]
Figure imgf000050_0001
H— NMR(500MHz, DMSO— d )  H—NMR (500MHz, DMSO—d)
6  6
δ 3.73(s, 3H), 4.32(d, J = 5.8 Hz, 2H) , 6.55 (d, J = 15.6 Hz, IH), 6.90 (d, J = 8.8 Hz, 2H) , 7.03— 7. ll(m, 2H) , 7.23 (m, IH), 7.22(d, J = 8.8 Hz, 2H) , 7.40 (d, J = 6.7 Hz, IH), 7.46 (d, J =δ 3.73 (s, 3H), 4.32 (d, J = 5.8 Hz, 2H), 6.55 (d, J = 15.6 Hz, IH), 6.90 (d, J = 8.8 Hz, 2H), 7.03— 7. ll ( m, 2H), 7.23 (m, IH), 7.22 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 6.7 Hz, IH), 7.46 (d, J =
15.9 Hz, IH), 7.77(s, IH), 8.00(s, IH), 8.10(s, IH), 8.57 (t, J = 5.8 Hz, IH), 11.06 (s, IH) 15.9 Hz, IH), 7.77 (s, IH), 8.00 (s, IH), 8.10 (s, IH), 8.57 (t, J = 5.8 Hz, IH), 11.06 (s, IH)
(2E)—N ェチノレ一 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1, 4]チァジン 2 イリデン）メチル）チォフェン 3 ィル） N (ピリジン一 3 ィル メチル）アクリルアミド（化合物 2— 30)  (2E) —N ethynole 3— (5— ((3 oxo 3, 4 dihydro 1 2H benzo [b] [1, 4] thiazine 2 ylidene) methyl) thiophen 3 yl) N (pyridine 1 yl methyl ) Acrylamide (compound 2-30)
[化 56] [Chemical 56]
Figure imgf000050_0002
Figure imgf000050_0002
HH—— NNMMRR((550000MMHHzz,, DDMMSSOO—— dd ))  HH—— NNMMRR ((550000MMHHzz ,, DDMMSSOO—— dd))
66  66
δδ 11..0077((tt,, JJ == 77..00 HHzz,, 33HHXX11//33)),, 11..1177((tt,, JJ == 77..00 HHzz,, 33HHXX22//33 )),, 33..1188--33..5500 ((mm,, 22HHXX22//33)) ,, 33..5577((qq,, JJ == 77..00 HHzz,, 33HHXX11//33)),, 44..6688 ((ss,, 22HHXX22//33)),, 44..8888((ss,, 22HHXX11//33)),, 77..0055—— 77..6600 ((mm,, 88HH)) ,, 77..8855—— 88..2266 (( mm,, 33HH)),, 88..5588 ((mm,, IIHH)),, 1111..0033((ss,, IIHH)) δδ 11..0077 ((tt ,, JJ == 77..00 HHzz ,, 33HHXX11 // 33)) ,, 11..1177 ((tt ,, JJ == 77..00 HHzz ,, 33HHXX22 // 33)) ,, 33..1188--33..5500 ((mm ,, 22HHXX22 // 33)) ,, 33..5577 ((qq ,, JJ == 77..00 HHzz ,, 33HHXX11 // 33)) ,, 44..6688 ((ss ,, 22HHXX22 // 33)) ,, 44..8888 ((ss ,, 22HHXX11 // 33)) ,, 77..0055—— 77..6600 ( (mm ,, 88HH)) ,, 77..8855—— 88..2266 ((mm ,, 33HH)) ,, 88..5588 ((mm ,, IIHH)) ,, 1111..0033 ((ss ,, IIHH))
((22EE))—— 33—— ((55—— ((((33 ォォキキソソ 33,, 44 ジジヒヒドドロロ一一 22HH ベベンンゾゾ [[bb]][[ll,, 44]]チチアアジジンン一一
Figure imgf000050_0003
((22EE)) —— 33—— ((55—— ((((33) 33 ,, 44 Dijihidodoro 22HH Bebenzozo [[bb]] [[ll ,, 44]] Tithiaazidin
Figure imgf000050_0003
[化 57] - 一べ ίί>^ -Ν- ( ί) ε—べエ^ ^ {Λ(^ (ベ ^i ^— z [Chemical 57] -One ίί> ^ -Ν- (ί) ε—Bee ^ ^ {Λ (^ (Be ^ i ^ — z
\ [q] ^>- -wz- ^→ 'ε— ^ 一 ε))— s)— ε— (ΉΖ)  \ [q] ^>--wz- ^ → 'ε— ^ one ε)) — s) — ε— (ΉΖ)
(HI 's)SO ·ΧΧ '(HI 's)6X ·8 '(HI 's)ZO ·8  (HI 's) SO · ΧΧ' (HI 's) 6X · 8' (HI 's) ZO · 8
'(HI 's)Z6 "Z '(HI <ZH 9 "SI = Γ 'Ρ)ΖΡ "Z '(HI <ZH 6 "Z = ί 'P) IP •Z '(HI <ZH 6 "Z = Γ ' )ZZ ·Ζ '(HI <ZH 9 "SI = Γ 'Ρ)ΖΧ ·Ζ '(HI <ZH '(HI' s) Z6 "Z '(HI <Z H 9" SI = Γ' Ρ) ΖΡ "Z '(HI <Z H 6" Z = ί' P) IP • Z '(HI <Z H 6 "Z = Γ ') ZZ · Ζ' (HI <Z H 9" SI = Γ 'Ρ) ΖΧ · Ζ' (HI <Z H
6 "Z = Γ 'Ρ)60 "Z '(HI <ZH 6 "Z = Γ '¾90 "Z '(HI <ZH 6 "Z = Γ 'P 6 "Z = Γ 'Ρ) 60"Z' (HI <Z H 6 "Z = Γ '¾90"Z' (HI <Z H 6 "Z = Γ 'P
)88 "9 '(HI 'ra)2S · '(HI '^)61 · '（HI .g '(HI ^)0Z Έ '(HI  ) 88 "9 '(HI' ra) 2S · '(HI' ^) 61 · '(HI .g' (HI ^) 0Z Έ '(HI
'ra)08 ·Ζ '(HZ -\-ZL "X '(Η6 'S)6S "X '(HZ '^)88 Ί-ΟΖ "X 9 'ra) 08 · Ζ' (HZ-\-ZL "X '(Η6' S ) 6S" X '(HZ' ^) 88 Ί-ΟΖ "X 9
(9p-os a <zHM00S)¾MN-HT [mo] ( 9 p-os a <z HM00S) ¾MN-H T [mo]
Figure imgf000051_0001
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000051_0002
]
Figure imgf000051_0003
'ε— ^ 一 ε))— s)— ε— /^ 一；ュ ]
Figure imgf000051_0003
'ε— ^ One ε)) — s) — ε— / ^ One;
(HI 's)90 "XX '(HI 'ΖΗ 8 "S = Γ '¾Ζ8 ·8 ' (HI 'ΖΗ S "X = Γ 'Ρ) (HI 's) 90 "XX' (HI ' Ζ Η 8" S = Γ' ¾Ζ8 8 '(HI' Ζ Η S "X = Γ 'Ρ)
ZL ·8 '(HI 's) l ·8 '(HI 's)XO ·8 ' (HI 'ΖΗ Q "X Ό ·8 = Γ 'ΡΡ)Ζ6 ·Ζ '( ΗΧ 'ΖΗ 0 ·8 = Γ 'Ρ)68 ·Ζ '(HI 's)X8 ·Ζ '(ΗΧ 'ΖΗ 6 "SX = Γ 'Ρ)6Ρ ·Ζ ZL 8 '(HI' s) l 8 '(HI' s) XO 8 '(HI' Ζ Η Q "X Ό 8 = Γ 'ΡΡ) Ζ 6 · Ζ' (ΗΧ ' Ζ Η 0 8 = Γ 'Ρ) 68 · Ζ' (HI 's) X8 · Ζ' (ΗΧ ' Ζ Η 6 "SX = Γ' Ρ) 6Ρ · Ρ
'(ΗΧ 'ΖΗ 0 ·8 = ΓΡ)0 ·Ζ '(ΗΧ 'ΖΗ 0 ·8 = Γ ^)ΖΖ ·Ζ ' (ΗΖ ¾)0Χ · Z-SO "Ζ '(ΗΧ <ΖΗ 6 "SX = Γ 'P)9S "9 ' (HZ <ΖΗ 8 "S = Γ 'P)SS 9 '(ΗΧ' Ζ Η 0 8 = ΓΡ) 0 · Ζ '(ΗΧ' Ζ Η 0 8 = Γ ^) ΖΖ · Ζ '(ΗΖ ¾) 0 Χ Z-SO "Ζ' (ΗΧ <Ζ Η 6 "SX = Γ 'P) 9S"9' (HZ <Ζ Η 8 "S = Γ 'P) SS 9
(9P-0SMQ <zHMOOS) MN-HT ( 9 P-0SMQ <z HMOOS) MN-H T
Figure imgf000051_0004
Figure imgf000051_0004
l.0l.0/.00Zdf/X3d 617 C98CS0/800Z OAV ド 塩酸塩 (化合物 2— 33) l.0l.0 / .00Zdf / X3d 617 C98CS0 / 800Z OAV Dehydrochloride (Compound 2-33)
[化 59]  [Chemical 59]
Figure imgf000052_0001
Figure imgf000052_0001
H— NMR(500MHz, DMSO— d )  H—NMR (500MHz, DMSO—d)
6  6
δ 1.30-1.52 (m, 2Η) , 1.90— 2.10 (m, 2Η) , 2.75 (m, IH), 3.18 (m, IH) , 3.30 (m, IH) , 4.30 (m, IH) , 4.50 (m, IH) , 7.06 (t, J = 7.9 H z, IH), 7.10(d, J = 7.9 Hz, IH), 7. 19(d, J = 15.3 Hz, IH), 7.2 3(t,J = 7.9 Hz, IH), 7.41 (d, J = 7.9 Hz, IH) , 7.49 (d, J = 15 .3 Hz, IH), 7.98(s, IH), 8.02(s, IH), 8.09 (br s, 2H) , 8.10 (br d, IH), 8.21 (s, IH), 11.04(s, IH) δ 1.30-1.52 (m, 2Η), 1.90— 2.10 (m, 2Η), 2.75 (m, IH), 3.18 (m, IH), 3.30 (m, IH), 4.30 (m, IH), 4.50 (m , IH), 7.06 (t, J = 7.9 H z, IH), 7.10 (d, J = 7.9 Hz, IH), 7.19 (d, J = 15.3 Hz, IH), 7.2 3 (t, J = 7.9 Hz, IH), 7.41 (d, J = 7.9 Hz, IH), 7.49 (d, J = 15.3 Hz, IH), 7.98 (s, IH), 8.02 (s, IH), 8.09 (br s , 2H), 8.10 (br d, IH), 8.21 (s, IH), 11.04 (s, IH)
tert ブチノレ 4—((2E)—3—(5—((3 ォキソ 3, 4 ジヒドロー 2H—ベンゾ[ b][l, 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル）アタリロイル）ピペラ ジン 1 カルボキシレート（化合物 2— 34) tert Butinole 4 — ((2E) —3— (5 — ((3 oxo 3, 4 dihydro-2H—benzo [b] [l, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) taliloyl) piperazine 1 carboxy Rate (compound 2-34)
[化 60] [Chemical 60]
Figure imgf000052_0002
Figure imgf000052_0002
H— NMR(500MHz, DMSO— d )  H—NMR (500MHz, DMSO—d)
6  6
δ 1.42(s, 9H), 3.30— 3.41 (m, 4H) , 3.50— 3.60 (m, 2H) , 3.65— 3. 72 (m, 2H), 7.06 (t, J = 7.9 Hz, IH), 7.09 (d, J = 7.9 Hz, IH), 7 . 16(d, J = 15.3 Hz, IH), 7.22 (t, J = 7.9 Hz, IH), 7.41 (d, J = 7.9 Hz, IH), 7.51 (d, J = 15.3 Hz, IH), 7.97(s, IH), 8.01 (s, 1 H), 8.20(s, IH), 11.03(s, IH) δ 1.42 (s, 9H), 3.30—3.41 (m, 4H), 3.50—3.60 (m, 2H), 3.65—3.72 (m, 2H), 7.06 (t, J = 7.9 Hz, IH), 7.09 (d, J = 7.9 Hz, IH), 7.16 (d, J = 15.3 Hz, IH), 7.22 (t, J = 7.9 Hz, IH), 7.41 (d, J = 7.9 Hz, IH), 7.51 (d, J = 15.3 Hz, IH), 7.97 (s, IH), 8.01 (s, 1 H), 8.20 (s, IH), 11.03 (s, IH)
2— ((4— ((E)— 3 ォキソ 3— (4— (ピリミジン一 2 ィル）ピぺラジン 1—ィル) プロペン 1ーィノレ）チォフェン 2—ィノレ）メチレン） 2H—べンゾ [b] [1 , 4]チア ジン 3 (4H) オン（化合物 2— 35) 2— ((4— ((E) — 3 oxo 3— (4— (pyrimidine 1 2 yl) piperazine 1 — yl) Propene 1-inore) thiophene 2-inole) methylene) 2H-benzo [b] [1, 4] thiazin 3 (4H) on (compound 2-35)
[化 61] [Chemical 61]
Figure imgf000053_0001
Figure imgf000053_0001
H-NMR(500MHz, DMSO— d ) H-NMR (500MHz, DMSO—d)
6  6
δ 3.60-3.90(m, 8Η) , 6.68(t, J = 4.9 Hz, IH), 7.06 (t, J = 7. 9 Hz, IH), 7.10(d, J = 7.9 Hz, IH), 7.22 (d, J = 15.3 Hz, IH), 7.22 (t, J = 7.9 Hz, IH), 7.41 (d, J = 7.9 Hz, IH), 7.54 (d, J =δ 3.60-3.90 (m, 8Η), 6.68 (t, J = 4.9 Hz, IH), 7.06 (t, J = 7.9 Hz, IH), 7.10 (d, J = 7.9 Hz, IH), 7.22 ( d, J = 15.3 Hz, IH), 7.22 (t, J = 7.9 Hz, IH), 7.41 (d, J = 7.9 Hz, IH), 7.54 (d, J =
15.3 Hz, IH), 7.99(s, IH), 8.04 (s, IH), 8.22(s, IH), 8.40 (d, J = 4.9 Hz, 2H), 11.03(s, IH) 15.3 Hz, IH), 7.99 (s, IH), 8.04 (s, IH), 8.22 (s, IH), 8.40 (d, J = 4.9 Hz, 2H), 11.03 (s, IH)
(2E)-N-(3, 5 ジメトキシフエ二ル）一 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H べンゾ [b][l, 4]チアジンー2 イリデン）メチル）チォフェンー3 ィル）アタリ ルアミド（化合物 2— 36)  (2E) -N- (3,5 dimethoxyphenyl) 1 3— (5— ((3 oxo 3, 4 dihydro 1 2H benzo [b] [l, 4] thiazine-2 ylidene) methyl) thiophene-3 ) Atarylamide (Compound 2-36)
[化 62]  [Chemical 62]
Figure imgf000053_0002
Figure imgf000053_0002
H— NMR(500MHz, DMSO— d )  H—NMR (500MHz, DMSO—d)
6  6
δ 3.73(s, 6H), 6.24(d, J = 2. 1 Hz, IH), 6.66 (d, J = 15.6 Hz, IH), 6.96 (d, J = 2.1 Hz, 2H) , 7.05— 7. 15(m, 2H) , 7.23 (m, IH), 7.41 (d, J = 7.9 Hz, IH), 7.58 (d, J = 15.6 Hz, IH), 7.81 (s, IH ), 8.03(s, IH), 8.18(s, IH) , 10.20(s, IH) , 11.09(s, IH) δ 3.73 (s, 6H), 6.24 (d, J = 2.1 Hz, IH), 6.66 (d, J = 15.6 Hz, IH), 6.96 (d, J = 2.1 Hz, 2H), 7.05— 7. 15 (m, 2H), 7.23 (m, IH), 7.41 (d, J = 7.9 Hz, IH), 7.58 (d, J = 15.6 Hz, IH), 7.81 (s, IH), 8.03 (s, IH ), 8.18 (s, IH), 10.20 (s, IH), 11.09 (s, IH)
(2E)— N— ((S)— 1—ヒドロキシ一 3— (IH インドール一 3—ィル）プロパン一 2— 4ージヒドロー 2H べンゾ [b][l, 4]チアジン ；—ィル）アクリルアミド（化合物 2— 37) (2E) — N— ((S) — 1-hydroxy 1 3— (IH indole 1 3-yl) propane 2— 4-dihydro-2H benzo [b] [l, 4] thiazine; -yl) acrylamide (compound 2-37)
Figure imgf000054_0001
Figure imgf000054_0001
H— NMR(500MHz, DMSO— d ) H—NMR (500MHz, DMSO—d)
6  6
δ 2.82(dd, J = 14.4, 7.0 Hz, IH), 2.98 (dd, J = 14.4, 6.4 Hz, IH), 3.40-3.50 (m, 2H) , 4.12 (m、 IH), 4.80 (m, IH), 6.56 (d, J = 15.6 Hz, IH), 6.98 (m, IH), 7.03— 7.13(m, 4H) , 7.23 (m, IH), 7.3 2(d, J = 7.9 Hz, IH), 7.39(d, J = 15.6 Hz, IH), 7.40 (d, J = 8 .2 Hz, IH), 7.64 (d, J = 7.9 Hz, IH), 7.74 (s, IH), 8.00(s, IH), 8.00(s, IH), 8.07(s, IH), 10.77(s, IH), 11.07(s, IH) δ 2.82 (dd, J = 14.4, 7.0 Hz, IH), 2.98 (dd, J = 14.4, 6.4 Hz, IH), 3.40-3.50 (m, 2H), 4.12 (m, IH), 4.80 (m, IH ), 6.56 (d, J = 15.6 Hz, IH), 6.98 (m, IH), 7.03— 7.13 (m, 4H), 7.23 (m, IH), 7.3 2 (d, J = 7.9 Hz, IH), 7.39 (d, J = 15.6 Hz, IH), 7.40 (d, J = 8.2 Hz, IH), 7.64 (d, J = 7.9 Hz, IH), 7.74 (s, IH), 8.00 (s, IH ), 8.00 (s, IH), 8.07 (s, IH), 10.77 (s, IH), 11.07 (s, IH)
(2E) -3- (5— ((3 ォキソ 6— (トリフルォロメチル） 3, 4 ジヒドロ一 2H ベ ンゾ [b][l, 4]チアジン— 2 イリデン)メチル）チォフェン— 3 ィル）—N— (ピリジ ン— 3 ィルメチル）アクリルアミド（化合物 2— 38) (2E) -3- (5— ((3 oxo 6— (trifluoromethyl) 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine-2 ylidene) methyl) thiophene-3 yl ) —N— (Pyridin—3-methyl) acrylamide (Compound 2-38)
[化 64] [Chemical 64]
Figure imgf000054_0002
Figure imgf000054_0002
H— NMR(400MHz, DMSO— d )  H—NMR (400MHz, DMSO—d)
6  6
δ 4.42(d, J = 5.8 Hz, 2H) , 6.55 (d, J = 15.9 Hz, IH) , 7.35— 7 .39 (m, 3H), 7.48 (d, J = 15.9 Hz, IH), 7.66 (d, J = 8.6 Hz, IH) , 7.70 (d, J = 7.9 Hz, IH), 7.83(s, IH), 8.05(s, IH), 8. 16(s, IH) , 8.47(d, J = 4.9 Hz, IH), 8.53(s, IH), 8.72 (t, J = 5.8 Hz, IH ), 11.27(s, IH) δ 4.42 (d, J = 5.8 Hz, 2H), 6.55 (d, J = 15.9 Hz, IH), 7.35— 7.39 (m, 3H), 7.48 (d, J = 15.9 Hz, IH), 7.66 ( d, J = 8.6 Hz, IH), 7.70 (d, J = 7.9 Hz, IH), 7.83 (s, IH), 8.05 (s, IH), 8. 16 (s, IH) , 8.47 (d, J = 4.9 Hz, IH), 8.53 (s, IH), 8.72 (t, J = 5.8 Hz, IH), 11.27 (s, IH)
(2E) -3- (5— ((3 ォキソ 6— (トリフルォロメチル） 3, 4 ジヒドロ一 2H ベ ンゾ [b][l, 4]チアジン— 2 イリデン)メチル）チォフェン— 3 ィル）—N— (ピリジ ン— 4 ィルメチル）アクリルアミド（化合物 2— 39)  (2E) -3- (5— ((3 oxo 6— (trifluoromethyl) 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine-2 ylidene) methyl) thiophene-3 yl ) —N— (Pyridin-4-ylmethyl) acrylamide (Compound 2-39)
[化 65]  [Chemical 65]
Figure imgf000055_0001
Figure imgf000055_0001
[0141] H— NMR(500MHz, DMSO— d ) [0141] H—NMR (500MHz, DMSO—d)
6  6
δ 4.43(d, J = 5.8 Hz, 2H) , 6.59 (d, J = 15.9 Hz, IH), 7.28 (d, J = 6.1 Hz, 2H), 7.35-7.39 (m, 2H) , 7.50 (d, J = 15.9 Hz, IH) , 7.66 (d, J = 8.6 Hz, IH), 7.85(s, IH), 8.06 (s, IH), 8. 18(s, IH) , 8.51 (d, J = 6.1 Hz, 2H), 8.72 (t, J = 5.8 Hz, IH), 11.27(s, 1 H)  δ 4.43 (d, J = 5.8 Hz, 2H), 6.59 (d, J = 15.9 Hz, IH), 7.28 (d, J = 6.1 Hz, 2H), 7.35-7.39 (m, 2H), 7.50 (d, J = 15.9 Hz, IH), 7.66 (d, J = 8.6 Hz, IH), 7.85 (s, IH), 8.06 (s, IH), 8. 18 (s, IH), 8.51 (d, J = 6.1 Hz, 2H), 8.72 (t, J = 5.8 Hz, IH), 11.27 (s, 1 H)
2— ((4— ((E)— 3— (4 メチルビペラジン 1—ィル） 3 ォキソプロペン 1— ィノレ）チォフェンー2 ィノレ）メチレン）ー6 （トリフルォロメチル） 2H べンゾ [b] [ 1, 4]チアジン 3(4H)—オン（化合物 2— 40)  2— ((4— ((E) — 3— (4 Methylbiperazine 1-yl) 3 -xopropene 1-inole) Thiophene-2 Inole) Methylene) -6 (Trifluoromethyl) 2H Benzo [b] [1 , 4] thiazine 3 (4H) -one (compound 2-40)
[化 66]  [Chemical 66]
Figure imgf000055_0002
Figure imgf000055_0002
[0142] ifi— NMR(500MHz, DMSO— d ) [0142] ifi— NMR (500 MHz, DMSO— d)
6  6
δ 2.22(s, 3Η), 2.25— 2.40 (m, 4H) , 3.50— 3.80 (m, 4H) , 7. 18(d, J = 15.3 Hz, IH), 7.35-7.40 (m, 2H) , 7.49(d, J = 15.3 Hz, IH ), 7.67(d, J = 8.6 Hz, IH), 8.00(s, IH), 8.06 (s, IH), 8.23(s, IH ), 11.24 (s, IH) δ 2.22 (s, 3Η), 2.25— 2.40 (m, 4H), 3.50— 3.80 (m, 4H), 7. 18 (d, J = 15.3 Hz, IH), 7.35-7.40 (m, 2H), 7.49 (d, J = 15.3 Hz, IH ), 7.67 (d, J = 8.6 Hz, IH), 8.00 (s, IH), 8.06 (s, IH), 8.23 (s, IH), 11.24 (s, IH)
2— ( (4— ( (E)— 3 モルホリノ一 3 ォキソプロペン一 1—ィル）チォフェン一 2 ィ ル）メチレン）ー6—（トリフルォロメチル） 2H—べンゾ [b] [1, 4]チアジン 3 (4H) —オン (化合物 2— 41)  2— ((4— ((E) — 3 Morpholino 1-oxopropene 1-yl) thiophene 2-yl) methylene) -6- (trifluoromethyl) 2H-Benzo [b] [1, 4] Thiazine 3 (4H) —one (compound 2—41)
[化 67]  [Chemical 67]
Figure imgf000056_0001
Figure imgf000056_0001
[0143] H— NMR(500MHz, DMSO— d ) [0143] H— NMR (500 MHz, DMSO— d)
6  6
δ 3.50-3.80 (m, 8Η) , 7.16(d, J = 15.3 Hz, IH), 7.35— 7.40 (m , 2H), 7.52(d, J = 15.3 Hz, IH), 7.66 (d, J = 8.6 Hz, IH), 8.00 (s, IH), 8.05(s, IH), 8.24 (s, 1H)11.24 (s, IH)  δ 3.50-3.80 (m, 8Η), 7.16 (d, J = 15.3 Hz, IH), 7.35— 7.40 (m, 2H), 7.52 (d, J = 15.3 Hz, IH), 7.66 (d, J = 8.6 Hz, IH), 8.00 (s, IH), 8.05 (s, IH), 8.24 (s, 1H) 11.24 (s, IH)
2— ( (4— ( (E)— 3— (3 (ジメチノレアミノ）ピロリジン一 1—ィル） - 3 ォキソプロぺ ン 1 ィル）チォフェンー2 ィノレ）メチレン）ー6 （トリフルォロメチル） 2H べ ンゾ [b][l, 4]チアジン 3(4H) オン（化合物 2— 42)  2— ((4— ((E) — 3— (3 (Dimethylolamino) pyrrolidine 1-yl) -3 oxopropene 1-yl) thiophene-2-inole) methylene) -6 (Trifluoromethyl) 2H Nzo [b] [l, 4] thiazine 3 (4H) ON (compound 2-42)
[化 68]  [Chemical 68]
Figure imgf000056_0002
Figure imgf000056_0002
[0144] H— NMR(500MHz, DMSO— d ) [0144] H—NMR (500MHz, DMSO—d)
6  6
δ 2.65(bs, 8H), 3.50— 3.70 (m, 4H) , 3.80— 4.00 (m, IH), 7.16(d, J = 15.3 Hz, IH), 7.35-7.40 (m, 2H) , 7.52(d, J = 15.3 Hz, IH ), 7.66 (d, J = 8.6 Hz, IH), 8.00(s, IH), 8.05(s, IH), 8.24 (s, IH )11.24 (s, IH) Z "X '6 ' = f'PP)S ·8 '(HI 's) 8 ·Ζ '(HI <ZH 9 "Z = Γ 'Ρ)Ζ9 ·Ζ '( HI <ZH 6 "Z = Γ 'P)S9 ' L '(HI 's)X9 ' L '(HI <ZH 9 "Z = f'P)9 ' L ' (HI <ZH 6 "SI = Γ 'P)ZS ·Ζ '(HI <ZH 6 · '6 ' L = Γ 'PP)SS ' L '(HI ' ZH Z ·8 = Γ 'P)OS ·Ζ '(HI 'ΖΗ 6 ·Ζ = Γ 'Ρ)9Χ ·Ζ '(ΗΧ ^)ΖΙ ·Ζ '(ΗΧ 'ΖΗ 6 "SX = Γ 'Ρ)68 "9 '(ΗΖ <ΖΗ 8 "S = f'P) 6S · '（HZ 's) SO · 9 δ 2.65 (bs, 8H), 3.50— 3.70 (m, 4H), 3.80— 4.00 (m, IH), 7.16 (d, J = 15.3 Hz, IH), 7.35-7.40 (m, 2H), 7.52 (d , J = 15.3 Hz, IH), 7.66 (d, J = 8.6 Hz, IH), 8.00 (s, IH), 8.05 (s, IH), 8.24 (s, IH) 11.24 (s, IH) Z "X '6' = f'PP) S · 8 '(HI' s) 8 · Ζ '(HI <Z H 9" Z = Γ' Ρ) Ζ9 · Ζ '(HI <Z H 6 "Z = Γ 'P) S9' L '(HI' s) X9 'L' (HI <Z H 9 "Z = f'P) 9 'L' (HI <Z H 6" SI = Γ 'P) ZS '(HI <Z H 6 ·' 6 'L = Γ' PP) SS 'L' (HI 'ZH Z · 8 = Γ' P) OS · Ζ '(HI' Ζ Η 6 · Ζ = Γ 'Ρ) 9Χ · Ζ '(ΗΧ ^) ΖΙ · Ζ' (ΗΧ ' Ζ Η 6 "SX = Γ' Ρ) 68" 9 '(ΗΖ <Ζ Η 8 "S = f'P) 6S ·' (HZ 's) SO9
( v-oswa <ζΗΜΟΟ^)ΉΜΝ-Ητ (v-oswa <ζ ΗΜΟΟ ^) ΉΜΝ-Η τ
Figure imgf000057_0001
Figure imgf000057_0001
( (
(HI 's)9Z ·χχ '((HI 's) 9Z
HZ 'sjq)S6 ·8 ' (HI 's)9Z ·8 ' (HI 's)PO ·8 ' (HI 's)00 ·8 ' (HI 'ΖΗ 6 ·Ζ = Γ 'Ρ)99 ·Ζ '(ΗΧ 'ΖΗ 8 "SX = Γ 'P)SS ·Ζ ' (HI 's)0 ·Ζ '(HI 'ΖΗ 6 · Ζ = Γ 'Ρ)88 "Ζ '(ΗΧ <ΖΗ ε "SI = Γ'Ρ)8Χ "Ζ '(Η8 '^)00 - -OZ Έ 9 HZ 'sjq) S6 8' (HI 's) 9Z 8' (HI 's) PO 8' (HI 's) 00 8' (HI ' Ζ Η 6 · Ζ = Γ' Ρ) 99 Ζ '(ΗΧ' Ζ Η 8 "SX = Γ 'P) SS · Ζ' (HI 's) 0 · Ζ' (HI 'Ζ Η 6 · Ζ = Γ' Ρ) 88" Ζ '(ΗΧ <Ζ Η ε "SI = Γ'Ρ) 8Χ" Ζ '(Η8' ^) 00--OZ Έ 9
( P-OSMQ <zHMOOS) MN-HT (P-OSMQ <z HMOOS) MN-H T
Figure imgf000057_0002
Figure imgf000057_0002
[69 ]
Figure imgf000057_0003
ベ —（HWS ベ[69]
Figure imgf000057_0003
Be — (HWS Be
-^[Ρ Ί] [q] ^>^-HZ- ( /^ α //: fH) -9- { Λ^ W " -^ [Ρ Ί] [q] ^> ^-HZ- (/ ^ α //: fH) -9- {Λ ^ W "
^
Figure imgf000057_0004
— ε ^ ε ））一 ））一 ^
Figure imgf000057_0004
— Ε ^ ε)) One) One)
ILOlLO/LOOZdT/lDd 99 C98CS0/800Z OAV Hz, 1H) , 8. 50 (d, J = 2. 2 Hz, 1H) , 8. 57 (t, J = 5. 8 Hz, 1H) , 11. 86 (s, 1H) ILOlLO / LOOZdT / lDd 99 C98CS0 / 800Z OAV Hz, 1H), 8. 50 (d, J = 2.2 Hz, 1H), 8.57 (t, J = 5.8 Hz, 1H), 11. 86 (s, 1H)
[製造例]  [Production example]
本発明化合物の代表的な製造例を以下に示す。  Representative production examples of the compound of the present invention are shown below.
[0147] 1)錠剤 [0147] 1) Tablet
処方 1 lOOmg中  Formula 1 in lOOmg
本発明化合物 lmg  Compound of the present invention lmg
乳糖 66. 4mg  Lactose 66. 4mg
トウモロコシデンプン 20mg  Corn starch 20mg
カルボキシメチルセルロースカルシウム 6mg ステアリン酸マグネシウム 0· 6mg  Carboxymethylcellulose calcium 6mg Magnesium stearate 0 · 6mg
上記処方の錠剤に、コーティング剤（例えば、ヒドロキシプロピルメチルセルロース、 マクロゴール、シリコーン樹脂等の通常のコーティング剤） 2mgを用いてコーティング を施し、 目的とするコーティング錠を得る。また、本発明化合物並びに添加物の種類 及び量を適宜変更することにより、所望の錠剤を得ることができる。  The tablet with the above formulation is coated with 2 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the desired coated tablet. Desired tablets can be obtained by appropriately changing the type and amount of the compound of the present invention and additives.
[0148] 2)カプセル剤 [0148] 2) Capsule
処方 2 150mg中  Formula 2 150 mg
本発明化合物 5mg  Compound of the present invention 5mg
乳糖 145mg  Lactose 145mg
本発明化合物と乳糖の混合比を適宜変更することにより、所望のカプセル剤を得るこ と力 Sできる。  A desired capsule can be obtained by appropriately changing the mixing ratio of the compound of the present invention and lactose.
[0149] 3)点眼剤 [0149] 3) Eye drops
処方 3 lOOmL中  Formula 3 in lOOmL
本発明化合物 lOOmg  Compound of the present invention lOOmg
塩化ナトリウム 900mg  Sodium chloride 900mg
ポリソルベー卜 80 200mg  Polysorbate 80 200mg
水酸化ナトリウム 適量 塩酸 適量 Sodium hydroxide Hydrochloric acid
滅菌精製水 適量  Sterilized purified water
本発明化合物並びに添加物の種類及び量を適宜変更することにより、所望の点眼 斉 IJを得ること力 sでさる。  By changing the kind and amount of the compound of the present invention and additives as appropriate, the desired eye drop IJ can be obtained with the power s.
[0150] [薬理試験]  [0150] [Pharmacological study]
1.血管新生阻害効果の評価試験  1. Evaluation test of angiogenesis inhibitory effect
薬物の血管新生阻害効果を評価する汎用される方法の一つとして、 VEGF誘発 H As one of the widely used methods for evaluating the anti-angiogenic effect of drugs, VEGF-induced H
UVEC増殖反応評価系を用いた細胞増殖阻害作用試験が Cancer Res. , 59, 9Cell growth inhibition test using UVEC proliferation response evaluation system is Cancer Res., 59, 9
9— 106 (1999)に報告されている。そこで、前記文献記載の方法に準じて、本発明 化合物の細胞増殖阻害作用試験を行い、その細胞増殖阻害率を算出して、それを 指標に本発明化合物の血管新生阻害効果を評価した。 9—106 (1999). Therefore, according to the method described in the above literature, the cell growth inhibitory action test of the compound of the present invention was conducted, the cell growth inhibition rate was calculated, and the angiogenesis inhibitory effect of the compound of the present invention was evaluated using this as an index.
[0151] (被験化合物溶液の調製） [0151] (Preparation of test compound solution)
被験化合物をジメチルスルホキシド（以下、 DMSO)に溶解し、得られた溶液を巿 販のリン酸緩衝溶液（以下、 PBS)で希釈し、 SO ^ g/mLの被験化合物溶液を調製 した。  The test compound was dissolved in dimethyl sulfoxide (hereinafter DMSO), and the resulting solution was diluted with a commercially available phosphate buffer solution (hereinafter PBS) to prepare a test compound solution of SO ^ g / mL.
[0152] (HUVEC懸濁液の調製）  [0152] (Preparation of HUVEC suspension)
HUVECを 0. 5%ゥシ胎児血清（以下、 FBS)含有 F12K培地に懸濁し、 2 X 104c ells/mLの HUVEC懸濁液を調製した。  HUVEC was suspended in F12K medium containing 0.5% urine fetal serum (hereinafter FBS) to prepare a HUVEC suspension of 2 × 104 cells / mL.
[0153] (VEGF溶液の調製） [0153] (Preparation of VEGF solution)
VEGFを 0. 1 %ゥシ血清アルブミン含有 PBSに溶解し、得られた溶液を 0. 5%FB Dissolve VEGF in PBS containing 0.1% ushi serum albumin, and add the resulting solution to 0.5% FB.
S含有 F12K培地で希釈し、 400ng/mLの VEGF溶液を調製した。 A 400 ng / mL VEGF solution was prepared by diluting with S-containing F12K medium.
[0154] (試験方法及び測定方法） [0154] (Test method and measurement method)
1) 1型コラーゲンでコートした 96穴プレートの各穴に HUVEC懸濁液を 100 Lずつ 播種した（1穴あたり 2 X 103cells)。  1) 100 L of HUVEC suspension was seeded in each well of a 96-well plate coated with type 1 collagen (2 X 103 cells per well).
[0155] 2)播種 1日後、被験化合物溶液を 1穴あたり 5 Lずつ添加した。 [0155] 2) One day after sowing, 5 L of the test compound solution was added per well.
[0156] 3)被験化合物溶液の添加 1時間後、 VEGF溶液を 1穴あたり 5 Lずつ添加した。 [0156] 3) Addition of test compound solution One hour later, 5 L of VEGF solution was added per well.
[0157] 4)VEGF溶液の添加 3日後、 WST— 8アツセィ試薬（同仁化学）を 1穴あたり 10 し ずつ添加した。 [0158] 5) 3時間後、吸光光度計（マルチラベルカウンター ARVO)に前記プレートを装着し て、 450nmにおける各穴懸濁液（以下、被験化合物懸濁液）の吸光度を測定した。 [0157] 4) Addition of VEGF solution Three days later, WST-8 Atsey reagent (Dojin Chemical) was added in increments of 10 per well. 5) After 3 hours, the plate was attached to an absorptiometer (multi-label counter ARVO), and the absorbance of each well suspension (hereinafter referred to as test compound suspension) at 450 nm was measured.
[0159] 6)被験化合物溶液に代えて 1. 0%DMSOを使用し、他は前記 1〜5)と同じ方法で 試験を行い、その結果をコントロールとした。  [0159] 6) Instead of the test compound solution, 1.0% DMSO was used, and the other tests were performed in the same manner as in 1 to 5) above. The results were used as controls.
[0160] 尚、前記の各試験工程間は、全てインキュベータ内にて、 37°C、 5%二酸化炭素、 9 5%酸素の条件下で、インキュベーションを行った。  [0160] It should be noted that the incubation was performed in the incubator under the conditions of 37 ° C, 5% carbon dioxide, and 95% oxygen during each of the above test steps.
[0161] (細胞増殖阻害率の算出）  [0161] (Calculation of cell growth inhibition rate)
以下に示す計算式から、血管新生阻害効果の指標となる細胞増殖阻害率（％)を 算出した。  The cell growth inhibition rate (%), which is an index of the angiogenesis inhibitory effect, was calculated from the formula shown below.
[0162] (計算式） [0162] (Calculation formula)
細胞増殖阻害率（％)  Cell growth inhibition rate (%)
= 100— { (被験化合物懸濁液の吸光度—A) / (コントロールの吸光度—A) } X 10 0  = 100— {(absorbance of test compound suspension—A) / (absorbance of control—A)} X 10 0
A：細胞懸濁液（細胞 +培地）のみの吸光度  A: Absorbance of cell suspension (cell + medium) only
(試験結果及び考察）  (Test results and discussion)
試験結果の一例として、被験化合物（化合物 2— 10、化合物 2— 12及び化合物 2— 26の細胞増殖阻害率（％)を表 1に示す。  As an example of the test results, Table 1 shows the cell growth inhibition rates (%) of the test compounds (Compound 2-10, Compound 2-12, and Compound 2-26).
[表 1]  [table 1]
Figure imgf000060_0001
表 1に示されるとおり、本発明化合物は優れた細胞増殖阻害作用を示した。よって
Figure imgf000060_0001
As shown in Table 1, the compound of the present invention showed an excellent cell growth inhibitory action. Therefore
、本発明化合物は優れた血管新生阻害効果を有する。 The compound of the present invention has an excellent angiogenesis inhibitory effect.

Claims

請求の範 I 下記一般式 Claim category I
[化 1] [Chemical 1]
Figure imgf000062_0001
Figure imgf000062_0001
H  H
[式中、環 Aはァリール基又は芳香族複素環を示し； [Wherein ring A represents an aryl group or an aromatic heterocyclic ring;
Rは水素原子、ハロゲン原子、アルキル基又はハロゲノアルキル基を示し；  R represents a hydrogen atom, a halogen atom, an alkyl group or a halogenoalkyl group;
Xは S又は CHを示し；  X represents S or CH;
2  2
Yは水酸基、アルコキシ基又は NR Rを示し；  Y represents a hydroxyl group, an alkoxy group or NR R;
2 3  twenty three
Rと Rは同一又は異なって水素原子、水酸基、アルキル基、アルコキシ基、シクロア R and R are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group,
2 3 twenty three
ルキル基、ァリール基、芳香族複素環基又は非芳香族複素環基を示し； An alkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group;
Rと Rが一緒になつて非芳香族複素環を形成してもよく； R and R may join together to form a non-aromatic heterocycle;
2 3  twenty three
上記した各アルキル基は水酸基、アミノ基、カルボキシル基、アルキルカルボニル基 、アルキルォキシカルボニル基、アルキルアミノ基、ァリール基、芳香族複素環基及 び非芳香族複素環基から選択される 1又は複数の置換基を有してもよく； 上記した各ァリール基はハロゲン原子、アミノ基、ニトロ基、アルキル基、ハロゲノアル キノレ基、アルコキシ基、ヒドロキシアルキル基、アルキルカルボニル基、アルキルォキ シカルボニル基、アルキルアミノ基、アルキルカルボニルァミノ基、芳香族複素環基 及び非芳香族複素環基から選択される 1又は複数の置換基を有してもよく； 上記した各芳香族複素環基はハロゲン原子、アミノ基、アルキル基、ハロゲノアルキ ル基、ヒドロキシアルキル基、アルキルォキシカルボニル基、アルキルアミノ基及びァ ルキルカルボニルァミノ基から選択される 1又は複数の置換基を有してもよく； 上記した各非芳香族複素環基はハロゲン原子、アミノ基、アルキル基、ハロゲノアル キノレ基、ヒドロキシアルキル基、アルキルォキシカルボニル基、アルキルアミノ基、ァ ルキルカルボニルァミノ基及び芳香族複素環基から選択される 1又は複数の置換基 を有してもよい。 ] Each of the above alkyl groups is selected from a hydroxyl group, an amino group, a carboxyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylamino group, an aryl group, an aromatic heterocyclic group and a non-aromatic heterocyclic group 1 or Each aryl group described above may be a halogen atom, an amino group, a nitro group, an alkyl group, a halogenoalkynole group, an alkoxy group, a hydroxyalkyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkyl group. One or more substituents selected from an amino group, an alkylcarbonylamino group, an aromatic heterocyclic group and a non-aromatic heterocyclic group may be present; each aromatic heterocyclic group described above is a halogen atom, Amino group, alkyl group, halogenoalkyl group, hydroxyalkyl group, alkyloxycarbonyl group, alkyl One or a plurality of substituents selected from a mino group and an alkylcarbonylamino group; each non-aromatic heterocyclic group described above is a halogen atom, an amino group, an alkyl group, a halogenoalkynole group, a hydroxy group; An alkyl group, an alkyloxycarbonyl group, an alkylamino group, It may have one or more substituents selected from an alkylcarbonylamino group and an aromatic heterocyclic group. ]
[2] 一般式 [I]において、  [2] In general formula [I],
環 Aはベンゼン環又はチォフェン環を示し；  Ring A represents a benzene ring or a thiophene ring;
環 Aはハロゲン原子で置換されてもよく；  Ring A may be substituted with a halogen atom;
Rは水素原子又はハロゲノアルキル基を示し；  R represents a hydrogen atom or a halogenoalkyl group;
Xは S又は CHを示し；  X represents S or CH;
2  2
Yは水酸基、アルコキシ基又は NR Rを示し；  Y represents a hydroxyl group, an alkoxy group or NR R;
2 3  twenty three
Rと Rは同一又は異なって水素原子、水酸基、アルキル基、アルコキシ基、シクロア R and R are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group,
2 3 twenty three
ルキル基、ァリール基、芳香族複素環基又は非芳香族複素環基を示し；  An alkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group;
Rと Rが一緒になつて非芳香族複素環を形成してもよく；  R and R may join together to form a non-aromatic heterocycle;
2 3  twenty three
上記で規定したアルキル基は水酸基、アルキルォキシカルボニル基、ァリール基及 び芳香族複素環基から選択される 1又は複数の置換基を有してもよく；  The alkyl group defined above may have one or more substituents selected from a hydroxyl group, an alkyloxycarbonyl group, an aryl group, and an aromatic heterocyclic group;
上記で規定したァリール基はニトロ基、アルキル基、アルコキシ基、ヒドロキシアルキ ル基、アルキルカルボニル基及びアルキルォキシカルボニル基から選択される 1又 は複数の置換基を有してもよく；  The aryl group as defined above may have one or more substituents selected from a nitro group, an alkyl group, an alkoxy group, a hydroxyalkyl group, an alkylcarbonyl group and an alkyloxycarbonyl group;
上記で規定した芳香族複素環基はアルキル基及びハロゲノアルキル基から選択され る 1又は複数の置換基を有してもよく；  The aromatic heterocyclic group defined above may have one or more substituents selected from an alkyl group and a halogenoalkyl group;
上記で規定した非芳香族複素環基はアルキル基、アルキルアミノ基、アルキルォキ シカルボニル基及び芳香族複素環基から選択される 1又は複数の置換基を有しても ょレ、請求項 1記載の化合物又はその塩。  The non-aromatic heterocyclic group defined above may have one or more substituents selected from an alkyl group, an alkylamino group, an alkyloxycarbonyl group, and an aromatic heterocyclic group, 2. Or a salt thereof.
[3] 一般式 [I]において、 [3] In general formula [I],
環 Aはベンゼン環又はチォフェン環を示し；  Ring A represents a benzene ring or a thiophene ring;
環 Aがベンゼン環の場合、該ベンゼン環はハロゲン原子で置換されてもよく；  When ring A is a benzene ring, the benzene ring may be substituted with a halogen atom;
Rは水素原子又はハロゲノアルキル基を示し；  R represents a hydrogen atom or a halogenoalkyl group;
Xは S又は CHを示し；  X represents S or CH;
2  2
Yは水酸基、アルコキシ基又は NR Rを示し；  Y represents a hydroxyl group, an alkoxy group or NR R;
2 3  twenty three
Rと Rは同一又は異なって水素原子、水酸基、アルキル基、アルコキシ基、シクロア ルキル基、ァリール基、芳香族複素環基又は非芳香族複素環基を示し； R and R are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloa An alkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group;
R又は Rがアルキル基の場合、該アルキル基は水酸基、アルキルォキシカルボニル When R or R is an alkyl group, the alkyl group is a hydroxyl group, an alkyloxycarbonyl
2 3 twenty three
基、ァリール基、アルコキシァリール基、芳香族複素環基及びハロゲノアルキル芳香 族複素環基から選択される 1又は複数の置換基を有してもよく； May have one or more substituents selected from a group, an aryl group, an alkoxyaryl group, an aromatic heterocyclic group and a halogenoalkyl aromatic heterocyclic group;
R又は Rがァリール基の場合、該ァリール基はニトロ基、アルキル基、アルコキシ基 When R or R is an aryl group, the aryl group is a nitro group, an alkyl group, or an alkoxy group.
2 3 twenty three
、ヒドロキシアルキル基、アルキルカルボニル基及びアルキルォキシカルボ二ル基か ら選択される 1又は複数の置換基を有してもよく；  , May have one or more substituents selected from a hydroxyalkyl group, an alkylcarbonyl group and an alkyloxycarbonyl group;
R又は Rが芳香族複素環基の場合、該芳香族複素環基はアルキル基で置換され When R or R is an aromatic heterocyclic group, the aromatic heterocyclic group is substituted with an alkyl group.
2 3 twenty three
てあよく； Well;
R又は Rが非芳香族複素環基の場合、該非芳香族複素環基はアルキルォキシ力 When R or R is a non-aromatic heterocyclic group, the non-aromatic heterocyclic group is an alkyloxy group.
2 3 twenty three
ルポニル基で置換されてもよく； Optionally substituted with a sulfonyl group;
Rと Rが一緒になつて非芳香族複素環を形成してもよく；  R and R may join together to form a non-aromatic heterocycle;
2 3  twenty three
Rと Rが一緒になつて非芳香族複素環を形成する場合、該非芳香族複素環はアル When R and R together form a non-aromatic heterocycle, the non-aromatic heterocycle is
2 3 twenty three
キル基、アルキルアミノ基、アルキルォキシカルボニル基及び芳香族複素環基から 選択される 1又は複数の置換基を有してもよい請求項 1記載の化合物又はその塩。 一般式 [I]において、 2. The compound or a salt thereof according to claim 1, which may have one or more substituents selected from a kill group, an alkylamino group, an alkyloxycarbonyl group, and an aromatic heterocyclic group. In general formula [I]:
環 Aはベンゼン環、フルォロベンゼン環又はチォフェン環を示し； Ring A represents a benzene ring, a fluorobenzene ring or a thiophene ring;
Rは水素原子又はトリフルォロメチル基を示し； R represents a hydrogen atom or a trifluoromethyl group;
Xは S又は CHを示し； X represents S or CH;
2  2
Yは水酸基、 tert ブトキシ基、ヒドロキシァミノ基、 tert ブトキシァミノ基、ピリジン 2 ィルメチルァミノ基、ピリジン一 3 ィルメチルァミノ基、ピリジン一 4 ィルメチ ルァミノ基、 2 トリフルォロメチルピリジン 5 ィルメチルァミノ基、ベンジルァミノ基 、 4ーメトキシベンジルァミノ基、 n ペンチルァミノ基、 3—メトキシカルボニルプロピ ノレアミノ基、 N ェチルー N—ピリジンー3 ィルメチルァミノ基、 N ェチルー N— 2 ーヒドロキシェチルァミノ基、シクロプロピルアミノ基、シクロペンタンアミノ基、フエニル アミノ基、 3—ヒドロキシメチルフエニルァミノ基、 4 プロピルフエニルァミノ基、 4ーメト キシフエニルァミノ基、 4 メチルカルボユルフェニルァミノ基、 4ーメトキシカルボニル フエニルァミノ基、 4一二トロフエニルァミノ基、 3, 5—ジメトキシフエニルァミノ基、ピリ ジンー2 ィルァミノ基、ピリジンー4 ィルァミノ基、 5 メチルピリジンー2 ィルアミ ノ基、ピぺリジンー4 ィルァミノ基、 1—tert ブトキシカルボ二ルビペリジンー4ーィ ルァミノ基、 3—ジメチルァミノピロリジン 1ーィル基、ピぺリジン 1ーィル基、ピぺ ラジン 1ーィル基、 4ーメチルビペラジン 1ーィル基、 4 ピリミジン 2 ィルピぺ ラジン 1ーィル基、 Y is a hydroxyl group, a tert butoxy group, a hydroxyamino group, a tert butoxyamino group, a pyridine-2-methylmethylamino group, a pyridine-1-methylmethylamino group, a pyridine-4-methylmethylamino group, a 2-trifluoromethylpyridine-5-methylmethylamino group, a benzylamino group, 4- Methoxybenzylamino group, n-pentylamino group, 3-methoxycarbonylpropinoreamino group, N-ethyl-N-pyridine-3-methylmethylamino group, N-ethyl-N-2-hydroxyethylamino group, cyclopropylamino group, cyclopentaneamino group, Phenylamino group, 3-hydroxymethylphenylamino group, 4 propylphenylamino group, 4-methoxyphenylamino group, 4 methylcarbophenylphenylamino group, 4-methoxycarbonyl phenylamino group, 4-12 Trophenyl Amino group, 3,5-dimethoxyphenylamino group, pyri Gin-2-ylamino group, pyridine-4-ylamino group, 5-methylpyridine-2-ylamino group, piperidine-4-ylamino group, 1-tert butoxycarbonylbiperidine-4-ylamino group, 3-dimethylaminopyrrolidine-1-ylamino group, piperidine 1-yl group, piperazine 1-yl group, 4-methylbiperazine 1-yl group, 4-pyrimidine 2-pilpazine 1-yl group,
4 tert ブトキシカルボニルピペラジン 1ーィル基、モルフ ォリン一 4—ィル基、ァゼパン一 1—ィル基又は 1—ヒドロキシ一 3— (1H—インドール 3 ィル)プロパン 2 ィルァミノ基を示す請求項 1記載の化合物又はその塩。 4. A tert-butoxycarbonylpiperazine 1-yl group, a morpholine 4-yl group, an azepane 1-yl group or a 1-hydroxy-1- (1H-indole 3yl) propane 2-ylamino group. Or a salt thereof.
[5] . (2E)— tert ブチル 3—（4— ( (3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b] [ 1， 4]チアジン 2 イリデン）メチル）フエニル）アタリレート、 [5]. (2E) — tert butyl 3— (4— ((3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylate
•(2E)— tert ブチル 3— (3 フルオロー 4— ( (3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）フエニル）アタリレート、 •(2E)— tert ブチル 3—（4— ( (2 ォキソ 1 , 2 ジヒドロキノリンー3 (4H)— イリデン)メチル）フエニル）アタリレート、  • (2E) — tert butyl 3— (3 fluoro-4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylate, • (2E) — tert Butyl 3— (4— ((2 oxo 1,2 dihydroquinoline-3 (4H) —ylidene) methyl) phenyl) atarylate,
•(2E)— tert ブチル 3—（2— ( (2 ォキソ 1 , 2 ジヒドロキノリンー3 (4H)— イリデン)メチル）フエニル）アタリレート、  • (2E) — tert butyl 3— (2— ((2 oxo 1,2 dihydroquinoline-3 (4H) —ylidene) methyl) phenyl) atarylate,
•(2E)— tert ブチル 3—（5— ( (3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b] [ 1 , 4]チアジン— 2 イリデン）メチル）チォフェン— 3 ィル）アタリレート、  • (2E) — tert butyl 3— (5— ((3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] thiazine-2 ylidene) methyl) thiophene-3 yl) talate,
• (2E)—tert ブチル 3—（5— ( (3 ォキソー6 （トリフルォロメチル） 3, 4 ジ ヒドロー 2H べンゾ [b] [l , 4]チアジンー2 イリデン）メチル）チォフェンー3 ィル )アタリレート、  • (2E) —tert butyl 3— (5— ((3 oxo 6 (trifluoromethyl) 3, 4 dihydro-2H benzo [b] [l, 4] thiazine-2-ylidene) methyl) thiophene-3 yl ) Atarirate,
•(2E)— tert ブチル 3—（5— ( (2 ォキソ 1 , 2 ジヒドロキノリンー3 (4H)— イリデン）メチル）チォフェンー3—ィル）アタリレート、  • (2E) — tert butyl 3— (5— ((2 oxo 1,2 dihydroquinoline-3 (4H) —ylidene) methyl) thiophene-3-yl) talate,
•(2E)—3—(4—( (3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b] [l , 4]チアジン 2—イリデン)メチル)フエニル）アクリル酸、  • (2E) —3— (4— ((3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] thiazine 2-ylidene) methyl) phenyl) acrylic acid,
• (2E) - 3- (3 フルォロ一 4— ( (3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1 , 4]チアジン 2 イリデン)メチル）フエニル）アクリル酸、  • (2E)-3- (3 Fluoro 4-— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylic acid,
. (2E) - 3- (4— ( (2 ォキソ 1 , 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル）アクリル酸、 (2E)-3- (4— ((2 oxo 1,2 dihydroquinoline 1 3 (4H) —ylidene) methyl) phenyl) acrylic acid,
. (2E) -3- (2— ((2 ォキソ 1, 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル）アクリル酸、 (2E) -3- (2 — ((2 oxo 1,2 dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) acrylic acid,
•(2E)— 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル）アクリル酸、  • (2E) — 3— (5— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) acrylic acid,
• (2E) -3- (5— ((3 ォキソ 6— (トリフルォロメチノレ) 3, 4 ジヒドロ一 2H— ベンゾ [b] [1, 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル）アクリル酸、 • (2E) -3- (5— ((3 oxo 6— (trifluoromethinole) 3, 4 dihydro- 1H— benzo [b] [1, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) Acrylic acid,
. (2E) -3- (5— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル） チォフェン 3—ィル）アクリル酸、 (2E) -3- (5— ((2—oxo 1,2-dihydroquinoline 1 3 (4H) -ylidene) methyl) thiophene 3-yl) acrylic acid,
•(2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン —2 イリデン)メチル）フエニル） N— (ピリジン— 3 ィルメチル）アクリルアミド、 • (2E) — 3— (4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine-2 ylidene) methyl) phenyl) N— (pyridine-3-ylmethyl) acrylamide,
• 2— 4 E)— 3 ォキソー 3 （ピペリジン 1 ィル）プロペン 1 ィル）ベン ジリデン） 2H べンゾ [b] [1, 4]チアジン 3 (4H) オン、 • 2— 4 E) — 3 oxo 3 (piperidine 1 yl) propene 1 yl) benzylidene) 2H benzo [b] [1, 4] thiazine 3 (4H) ON,
•(2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン —2—イリデン）メチル）フエ二ル）一 N— (ピリジン一 2—ィル）アクリルアミド、  • (2E) — 3— (4— ((3 oxo 3, 4 dihydro-1 2H benzo [b] [l, 4] thiazine —2-ylidene) methyl) phenyl) 1 N— (pyridine 1 2— Le) acrylamide,
-メチル 4—((2E)—3—(4—((3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b] [1, 4 ]チァジン 2—イリデン)メチル）フエニル）アクリルアミド）ベンゾ ト、 -Methyl 4 — ((2E) —3— (4 — ((3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] thiazine 2-ylidene) methyl) phenyl) acrylamide) benzoto,
• (2E)—N シクロペンチ 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベン ゾ [b][l, 4]チアジンー2 イリデン）メチル）フエニル）アクリルアミド、  • (2E) —N cyclopentyl 3— (4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine-2-ylidene) methyl) phenyl) acrylamide,
•(2E)— 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン 2—イリデン）メチル）フエニル） N ペンチルアクリルアミド、  • (2E) — 3— (4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine 2-ylidene) methyl) phenyl) N pentylacrylamide,
• (2E) -N- (4 メトキシフエニル） 3— (4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [ 1 , 4]チアジン 2 イリデン)メチル）フエニル）アクリルアミド、  • (2E) -N- (4 methoxyphenyl) 3— (4— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylamide,
. (2E) -N- (3 （ヒドロキシメチル）フエニル）ー3—（4— ((3 ォキソ 3, 4 ジヒ ドロー 2H ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）フエニル）アクリルアミド  (2E) -N- (3 (Hydroxymethyl) phenyl) -3- (4— ((3 oxo 3, 4 dihydro 2H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylamide
-メチル 4—((2E)—3—(4—((3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b] [1, 4]チアジン 2 イリデン)メチル)フエニル）アクリルアミド）酪酸、 -Methyl 4 — ((2E) —3— (4 — ((3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) acrylamide) butyric acid,
• (2E) -3- (3 フルォロ一 4— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1 , 4]チアジン 2 イリデン）メチル）フエニル） Ν—(ピリジン 3 ィルメチル）ァク リルアミド、 • (2E) -3- (3 Fluoro 4— ((3 oxo 3, 4 dihydro 1H benzo [b] [1 , 4] thiazine 2 ylidene) methyl) phenyl) Ν- (pyridine 3-ylmethyl) acrylamide,
• (2Ε)—Ν シクロプロピノレー 3— (3 フノレオ口一 4— ((3 ォキソ 3, 4 ジヒドロ -2Η-ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）フエニル）アタリノレアミド、 • (2Ε) —Ν Cyclopropinole 3— (3 Funoleo mouth 1—— ((3 oxo 3, 4 dihydro-2Η-benzo [b] [1, 4] thiazine 2 ylidene) methyl) phenyl) attalinoleamide ,
. (2E) -3- (4— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N— (ピリジンー3—ィルメチル）アクリルアミド、 (2E) -3- (4— ((2—Oxo 1,2-dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) N— (pyridine-3-ylmethyl) acrylamide,
• (2E)一 N シクロプロピノレー 3—（4一（（2 ォキソ一 1, 2 ジヒドロキノリン一 3 (4 H) イリデン)メチル）フエニル）アクリルアミド、  • (2E) -N-cyclopropynole 3- (4-(((2 oxo 1,2 dihydroquinoline 1 3 (4 H) ylidene) methyl) phenyl) acrylamide),
• 3—（4一（（E)— 3—（ァゼパン一 1一ィル）一 3—ォキソプロペン一 1一ィル）ベンジ リデン） 3, 4 ジヒドロキノリン 2(1H)—オン、  • 3— (4 ((E) —3— (Azepan 1 1 1) 1 3-oxopropene 1 1 1) Benzylidene) 3, 4 Dihydroquinoline 2 (1H) —On,
•(2E)— N— (3, 5 ジメトキシフエ二ル）一 3— (4— ((2 ォキソ 1, 2 ジヒドロキ ノリンー 3 (4H)—イリデン)メチル）フエニル）アクリルアミド、  • (2E) —N— (3,5 dimethoxyphenyl) 1 3— (4 — ((2oxo1,2 dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
. (2E) -3- (4— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N— (ピリジン一 4—ィル）アクリルアミド、  (2E) -3- (4— ((2—oxo 1,2-dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) N— (pyridine 1-yl) acrylamide,
• (2E) -N- (4 ァセチルフエニル） 3— (4— ((2 ォキソ 1, 2 ジヒドロキノリ ン— 3 (4H)—イリデン)メチル）フエニル）アクリルアミド、  • (2E) -N- (4 acetylphenyl) 3— (4— ((2 oxo 1,2 dihydroquinolin— 3 (4H) —ylidene) methyl) phenyl) acrylamide,
. (2E) -3- (4— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N— (4—プロピルフエ二ノレ）アクリルアミド、  (2E) -3- (4— ((2—oxo 1,2-dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) N— (4-propylphenolinole) acrylamide,
• (2E)—N tert ブトキシー3—（4ー（（2 ォキソーl, 2 ジヒドロキノリンー3 (4 H) イリデン)メチル）フエニル）アクリルアミド、  • (2E) —N tertbutoxy 3— (4-((2 oxol, 2 dihydroquinoline-3 (4 H) ylidene) methyl) phenyl) acrylamide,
• (2E)—N ヒドロキシー3—（4— ((2 ォキソ 1, 2 ジヒドロキノリン 3(4H)— イリデン)メチル）フエニル）アクリルアミド、  • (2E) —N Hydroxy-3— (4 — ((2 oxo 1,2 dihydroquinoline 3 (4H) —ylidene) methyl) phenyl) acrylamide,
. (2E) -3- (2— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N— (ピリジンー3—ィルメチル）アクリルアミド、  (2E) -3- (2— ((2—Oxo 1, 2-dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) N— (pyridine-3-ylmethyl) acrylamide,
• (2E) N シクロプロピノレー 3—（2—（（2 ォキソ 1, 2 ジヒドロキノリン 3 (4 H) イリデン)メチル）フエニル）アクリルアミド、  • (2E) N cyclopropynole 3— (2 — ((2 oxo 1,2 dihydroquinoline 3 (4 H) ylidene) methyl) phenyl) acrylamide,
• (2E) -N- (5 メチルピリジン一 2 ィル） 3— (2— ((2 ォキソ 1, 2 ジヒド 口キノリン一 3 (4H)—イリデン)メチル）フエニル）アクリルアミド、 • (2E) -N- (2 Methylpyridine 2-yl) 3— (2— ((2 oxo 1,2 Dihydrin quinoline 3 (4H) -Ilidene) methyl) phenyl) acrylamide,
. (2E) -3- (2— ((2—ォキソ 1, 2—ジヒドロキノリン一 3 (4H)—イリデン）メチル） フエニル） N フエニルアクリルアミド、 (2E) -3- (2— ((2—oxo 1,2-dihydroquinoline 1 3 (4H) -ylidene) methyl) phenyl) N phenylacrylamide,
• (2E) -N- (4 ニトロフエニル） 3— (2— ((2 ォキソ 1, 2 ジヒドロキノリン - 3 (4H)—イリデン)メチル）フエニル）アクリルアミド、  • (2E) -N- (4 Nitrophenyl) 3— (2— ((2 oxo 1,2 dihydroquinoline-3 (4H) —ylidene) methyl) phenyl) acrylamide,
•(2E)— 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン — 2 イリデン）メチル）チォフェン 3 ィル） N (ピリジン一 3 ィルメチル）ァク リルアミド、  • (2E) — 3— (5— ((3 oxo 3, 4 dihydro-1 2H benzo [b] [l, 4] thiazine — 2 ylidene) methyl) thiophene 3 yl) N (pyridine 1 -3-methyl) Rilamide,
• (2E)—N ベンジノレ一 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [ 1， 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル）アクリルアミド、  • (2E) —N Benzenore 3— (5— ((3 oxo 3, 4 dihydro 1H benzo [b] [1, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) acrylamide,
• (2E)— N ェチル N— (2 ヒドロキシェチル） 3— (5— ((3 ォキソ 3, 4— ジヒドロー 2H べンゾ [b][l, 4]チアジンー2 イリデン）メチル）チォフェンー3 ィ ル）アクリルアミド、  • (2E) — N ethyl N— (2 hydroxyethyl) 3— (5— ((3 oxo 3, 4— dihydro-2H benzo [b] [l, 4] thiazine-2-ylidene) methyl) thiophene-3 Le) acrylamide,
• (2E) -N- (4 メトキシベンジル） 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [ 1 , 4]チアジン 2—イリデン）メチル）チォフェン 3—ィル）アクリルァ ミド、  • (2E) -N- (4 methoxybenzyl) 3— (5— ((3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] thiazine 2-ylidene) methyl) thiophene 3-yl) acryla Mid,
• (2E)—N ェチノレ一 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b] [1 , 4]チアジン— 2 イリデン)メチル）チォフェン— 3 ィル）—N— (ピリジン— 3 ィ ルメチル）アクリルアミド、  • (2E) —N ethynole 1— (5 — ((3 oxo 3,4 dihydro-1H benzo [b] [1,4] thiazine-2 ylidene) methyl) thiophene-3yl) —N— (pyridine — 3-methyl) acrylamide,
•(2E)— 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン  • (2E) — 3— (5— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine
•tert ブチノレ 4—((2E)—3—(5—((3 ォキソ 3, 4 ジヒドロー 2H—ベンゾ[ b][l, 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル）アクリルアミド）ピペリ ジン 1一力ノレボキシレート、 • tert butynole 4 — ((2E) —3— (5 — ((3 oxo 3, 4 dihydro-2H—benzo [b] [l, 4] thiazine 2 ylidene) methyl) thiophene 3yl) acrylamide) piperidine 1 Noreboxylate,
•(2E)— 3— (5— ((3 ォキソ 3, 4 ジヒドロ一 2H ベンゾ [b][l, 4]チアジン — 2 イリデン）メチル）チォフェン 3 ィル） N (ピペリジン一 4 ィル）アクリル アミド 塩酸塩、  • (2E) — 3— (5— ((3 oxo 3, 4 dihydro- 1H benzo [b] [l, 4] thiazine — 2 ylidene) methyl) thiophene 3 yl) N (piperidine -4- yl) acrylic Amide hydrochloride,
•tert ブチノレ 4—((2E)—3—(5—((3 ォキソ 3, 4 ジヒドロー 2H—ベンゾ[ b][l, 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル）アタリロイル）ピペラ ジン 1一力ノレボキシレート、 • tert butynole 4 — ((2E) —3— (5 — ((3 oxo 3, 4 dihydro-2H—benzo [ b] [l, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) ataryloyl) piperazine 1
•2— ((4— ((E)— 3 ォキソ 3— (4— (ピリミジン一 2 ィル）ピぺラジン 1—ィル )プロペン 1ーィノレ）チォフェン 2—ィノレ）メチレン） 2H—べンゾ [b] [1 , 4]チア ジン 3 (4H)—オン、  • 2— ((4— ((E) — 3 oxo 3— (4— (pyrimidine 1 2 yl) piperazine 1 yl) propene 1 inore) thiophene 2 inore) methylene) 2H— benzo [b] [1, 4] thiazin 3 (4H) —one,
•(2E)— N— (3, 5 ジメトキシフエ二ル）一 3— (5— ((3 ォキソ 3, 4 ジヒドロ —2H べンゾ [b][l, 4]チアジンー2 イリデン）メチル）チォフェンー3 ィル）ァク リルアミド、  • (2E) — N— (3, 5 dimethoxyphenyl) 1 3— (5— ((3 oxo 3, 4 dihydro — 2H benzo [b] [l, 4] thiazine-2-ylidene) methyl) thiophene 3) acrylamide,
• (2E)— N— ((S)— 1—ヒドロキシ— 3— (1H—インドール— 3—ィル）プロパン— 2 ーィル）ー3—（5—（（3 ォキソ 3, 4 ジヒドロー 2H べンゾ [b][l, 4]チアジン - 2 イリデン)メチル）チォフェン— 3 ィル）アクリルアミド、  • (2E) — N— ((S) — 1—Hydroxy— 3— (1H—Indole— 3 —yl) propane— 2 —yl) −3— (5 — ((3 oxo 3, 4 dihydro-2H ben Zo [b] [l, 4] thiazine-2 ylidene) methyl) thiophene-3yl) acrylamide,
• (2E) -3- (5— ((3 ォキソ 6— (トリフルォロメチル） 3, 4 ジヒドロ一 2H— ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル） N—(ピリ  • (2E) -3- (5— ((3 oxo 6— (trifluoromethyl) 3, 4 dihydro- 1H— benzo [b] [1, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) N — (Piri
• (2E) -3- (5— ((3 ォキソ 6— (トリフルォロメチル） 3, 4 ジヒドロ一 2H— ベンゾ [b] [ 1 , 4]チアジン 2 イリデン）メチル）チォフェン 3 ィル） N—(ピリ • (2E) -3- (5— ((3 oxo 6— (trifluoromethyl) 3, 4 dihydro- 1H— benzo [b] [1, 4] thiazine 2 ylidene) methyl) thiophene 3 yl) N — (Piri
•2— ((4—（（E)— 3—（4 メチルビペラジン 1 ィル） 3 ォキソプロペン 1 ィル）チォフェンー2 ィノレ）メチレン）ー6 （トリフルォロメチル） 2H べンゾ [b ][1, 4]チアジン 3 (4H)—オン、 • 2 — ((4 — ((E) —3— (4 methylbiperazine 1 yl) 3 oxopropene 1 yl) thiophene-2 inole) methylene) -6 (trifluoromethyl) 2H benzo [b] [1 , 4] thiazine 3 (4H) —one,
•2- ((4- ((E)—3—モノレホリノ一 3—ォキソプロペン一 1—ィノレ）チォフェン一 2— ィル）メチレン）ー6 （トリフルォロメチル） 2H べンゾ [b] [1, 4]チアジン 3 (4 H) オン、  • 2- ((4- ((E) —3—Monolepholino 1-oxopropene 1-inole) thiophene 2-yl) methylene) -6 (Trifluoromethyl) 2H Benzo [b] [1 , 4] thiazine 3 (4 H) on,
• 2— ( (4— ( (E)— 3— (3 (ジメチノレアミノ）ピロリジン一 1—ィル） - 3 ォキソプロ ペン 1 ィル）チォフェンー2 ィノレ）メチレン）ー6 （トリフルォロメチル） 2H— ベンゾ [b][l, 4]チアジン 3 (4H)—オン、  • 2— ((4— ((E) — 3— (3 (Dimethinoreamino) pyrrolidine 1-yl)-3 -oxopropene 1 yl) thiophene-2 Inole) methylene) -6 (Trifluoromethyl) 2H— Benzo [b] [l, 4] thiazin 3 (4H) —one,
• 2—（（4一 （（E)— 3 ォキソ一 3 （ピペラジン一 1一ィル）プロペン一 1一ィル）チォ フェンー2—ィル）メチレン） -6- (トリフルォロメチル） 2H—べンゾ [b] [1, 4]チア ジン 3 (4H)—オン 塩酸塩、及び • 2 — ((4 ((E) —3 oxo 3 (piperazine 1 1 yl) propene 1 1 yl) thiophen 2 yl) methylene) -6- (trifluoromethyl) 2H —Benzo [b] [1, 4] Chia Gin 3 (4H) -one hydrochloride, and
. (2E) - 3- (5— ( (2 ォキソ 1 , 2 ジヒドロキノリン一 3 (4H)—イリデン）メチル) チォフェン一 3—ィル） -N- (ピリジン一 3—ィルメチル）アクリルアミド  (2E)-3- (5— ((2 oxo 1, 2 dihydroquinoline 1 3 (4H) -ylidene) methyl) thiophen 1 3-yl) -N- (pyridine 1-ylmethyl) acrylamide
から選択される化合物又はその塩。  Or a salt thereof selected from
[6] 請求項;!〜 5のいずれか記載の化合物又はその塩を含有する医薬組成物。 [6] A pharmaceutical composition comprising the compound according to any one of claims 5 to 5 or a salt thereof.
[7] 請求項 1〜5のいずれか記載の化合物又はその塩を含有する血管新生が関与する 疾患の治療剤。 [7] A therapeutic agent for a disease associated with angiogenesis, comprising the compound according to any one of claims 1 to 5 or a salt thereof.
[8] 血管新生が関与する疾患が癌、関節リウマチ、加齢黄斑変性、糖尿病網膜症、未熟 児網膜症、網膜静脈閉塞症、ポリープ状脈絡膜血管症、糖尿病黄斑浮腫、尋常性 乾癬又は粥状動脈硬化である請求項 7記載の治療剤。  [8] Diseases involving angiogenesis are cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris The therapeutic agent according to claim 7, which is arteriosclerosis.
[9] 患者に請求項 1〜5のいずれか記載の化合物又はその塩の治療上有効な量を投与 することからなる血管新生が関与する疾患の治療方法。 [9] A method for treating a disease associated with angiogenesis, comprising administering to a patient a therapeutically effective amount of the compound or salt thereof according to any one of claims 1 to 5.
[10] 血管新生が関与する疾患が癌、関節リウマチ、加齢黄斑変性、糖尿病網膜症、未熟 児網膜症、網膜静脈閉塞症、ポリープ状脈絡膜血管症、糖尿病黄斑浮腫、尋常性 乾癬又は粥状動脈硬化である請求項 9記載の治療方法。 [10] Diseases involving angiogenesis are cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris The treatment method according to claim 9, which is arteriosclerosis.
PCT/JP2007/071071 2006-10-30 2007-10-30 Novel compound having 1,4-benzothiazin-3-one skeleton or 3,4-dihydroquinolin-2-one skeleton WO2008053863A1 (en)

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