WO2008053863A1 - Nouveau composé ayant un squelette de 1,4-benzothiazin-3-one ou un squelette de 3,4-dihydroquinolin-2-one - Google Patents

Nouveau composé ayant un squelette de 1,4-benzothiazin-3-one ou un squelette de 3,4-dihydroquinolin-2-one 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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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

L'objectif est de synthétiser un nouveau composé ayant un squelette de 1,4-benzothiazin-3-one ou un squelette de 3,4-dihydroquinolin-2-one et de trouver l'activité pharmacologique du composé. Un composé représenté par la formule [I] est particulièrement proposé. Le composé peut être aussi représenté par un sel de celui-ci [dans laquelle l; l'anneau A représente un groupe aryle, un groupe hétérocyclique aromatique ou d'autres groupes similaires; R1 représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle, un groupe halogénoalkyle ou d'autres groupes similaires; X représente S, CH2 ou d'autres atomes similaires; Y représente un groupe hydroxy, un groupe alcoxy, NR2R3 ou d'autres groupes similaires; et R2 et R3 représentent indépendamment un atome d'hydrogène, un groupe hydroxy, un groupe alkyle, un groupe alcoxy, un groupe cycloalkyle, un groupe aryle, un groupe hétérocyclique aromatique, un groupe hétérocyclique non aromatique ou d'autres groupes similaires.
PCT/JP2007/071071 2006-10-30 2007-10-30 Nouveau composé ayant un squelette de 1,4-benzothiazin-3-one ou un squelette de 3,4-dihydroquinolin-2-one WO2008053863A1 (fr)

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WO2010077680A3 (fr) * 2008-12-08 2010-10-14 Vm Discovery Inc. Compositions d'inhibiteurs de tyrosine kinase de récepteur protéique
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EP2714048A1 (fr) * 2011-05-27 2014-04-09 Temple University - Of The Commonwealth System of Higher Education 2-benzylidène-2h-benzo[b][1,4]thiazin-3(4h)-ones substituées, dérivés de celles-ci, et leurs utilisations thérapeutiques
KR101475590B1 (ko) * 2013-02-06 2014-12-23 부산대학교 산학협력단 피부미백 활성을 갖는 신규 화합물 및 이의 의학적 용도
US8999992B2 (en) 2013-03-15 2015-04-07 Vm Pharma Llc Crystalline forms of tryosine kinase inhibitors and their salts
US10301271B2 (en) 2014-09-17 2019-05-28 Purdue Pharma L.P. Crystalline forms of tyrosine kinase inhibitors and their salts

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WO2010042925A3 (fr) * 2008-10-10 2010-07-29 Vm Discovery Inc. Compositions et méthodes pour traiter les troubles liés à la consommation d'alcool, la douleur et d'autres maladies
WO2010042925A2 (fr) 2008-10-10 2010-04-15 Vm Discovery Inc. Compositions et méthodes pour traiter les troubles liés à la consommation d'alcool, la douleur et d'autres maladies
CN102177153A (zh) * 2008-10-10 2011-09-07 Vm生物医药公司 治疗酒精使用障碍，疼痛和其他疾病的药物组合与方法
CN102177153B (zh) * 2008-10-10 2016-09-21 Vm生物医药公司 治疗酒精使用障碍，疼痛和其他疾病的药物组合与方法
JP2012511054A (ja) * 2008-12-08 2012-05-17 ブイエム ファーマ エルエルシー タンパク質受容体チロシンキナーゼ阻害薬の組成物
WO2010077680A3 (fr) * 2008-12-08 2010-10-14 Vm Discovery Inc. Compositions d'inhibiteurs de tyrosine kinase de récepteur protéique
US9738659B2 (en) 2008-12-08 2017-08-22 Purdue Pharma L.P. Compositions of protein receptor tyrosine kinase inhibitors
US8809530B1 (en) 2008-12-08 2014-08-19 Vm Pharma Llc Compositions of protein receptor tyrosine kinase inhibitors
AU2009333537A8 (en) * 2008-12-08 2016-07-07 Mundipharma International Corporation Limited Compositions of protein receptor tyrosine kinase inhibitors
AU2009333537B2 (en) * 2008-12-08 2016-01-28 Mundipharma International Corporation Limited Compositions of protein receptor tyrosine kinase inhibitors
US9040508B2 (en) 2008-12-08 2015-05-26 Vm Pharma Llc Compositions of protein receptor tyrosine kinase inhibitors
JP2014522396A (ja) * 2011-05-27 2014-09-04 テンプル・ユニバーシティ−オブ・ザ・コモンウェルス・システム・オブ・ハイアー・エデュケイション 置換２−ベンジリデン−２Ｈ−ベンゾ［ｂ］［１，４］チアジン−３（４Ｈ）−オン、その誘導体及びその治療上の使用
US9242945B2 (en) 2011-05-27 2016-01-26 Temple University—Of the Commonwealth System of Higher Education Substituted 2-benzylidene-2H-benzo[b][1,4]thiazin-3(4H)-ones, derivatives thereof, and therapeutic uses thereof
EP2714048A4 (fr) * 2011-05-27 2014-11-05 Univ Temple 2-benzylidène-2h-benzo[b][1,4]thiazin-3(4h)-ones substituées, dérivés de celles-ci, et leurs utilisations thérapeutiques
EP2714048A1 (fr) * 2011-05-27 2014-04-09 Temple University - Of The Commonwealth System of Higher Education 2-benzylidène-2h-benzo[b][1,4]thiazin-3(4h)-ones substituées, dérivés de celles-ci, et leurs utilisations thérapeutiques
CN102875479B (zh) * 2012-10-24 2015-06-10 南京化工职业技术学院 喹唑啉二酮衍生物及其制备方法、其药物组合物及用途
CN102875479A (zh) * 2012-10-24 2013-01-16 南京化工职业技术学院 喹唑啉二酮衍生物及其制备方法、其药物组合物及用途
KR101475590B1 (ko) * 2013-02-06 2014-12-23 부산대학교 산학협력단 피부미백 활성을 갖는 신규 화합물 및 이의 의학적 용도
US8999992B2 (en) 2013-03-15 2015-04-07 Vm Pharma Llc Crystalline forms of tryosine kinase inhibitors and their salts
US9718794B2 (en) 2013-03-15 2017-08-01 Purdue Pharma L.P. Crystalline forms of tyrosine kinase inhibitors and their salts
US9388146B2 (en) 2013-03-15 2016-07-12 Purdue Pharma L.P. Crystalline forms of tyrosine kinase inhibitors and their salts
US9993473B2 (en) 2013-03-15 2018-06-12 Purdue Pharma L.P. Crystalline forms of tyrosine kinase inhibitors and their salts
US10124002B2 (en) 2013-03-15 2018-11-13 Purdue Pharma, L.P. Crystalline forms of tyrosine kinase inhibitors and their salts
US10301271B2 (en) 2014-09-17 2019-05-28 Purdue Pharma L.P. Crystalline forms of tyrosine kinase inhibitors and their salts

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