WO2012099129A1 - Composé ayant une activité anticancéreuse - Google Patents

Composé ayant une activité anticancéreuse Download PDF

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WO2012099129A1
WO2012099129A1 PCT/JP2012/050872 JP2012050872W WO2012099129A1 WO 2012099129 A1 WO2012099129 A1 WO 2012099129A1 JP 2012050872 W JP2012050872 W JP 2012050872W WO 2012099129 A1 WO2012099129 A1 WO 2012099129A1
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group
optionally substituted
compound
mmol
hydrogen atom
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PCT/JP2012/050872
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English (en)
Japanese (ja)
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正倫 岩尾
郁人 石橋
福田　勉
寛雄 長谷川
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国立大学法人 長崎大学
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Priority to JP2012553737A priority Critical patent/JP5888702B2/ja
Publication of WO2012099129A1 publication Critical patent/WO2012099129A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the present invention relates to a novel compound having excellent anticancer activity and useful as a preventive or therapeutic agent for various cancers.
  • Lamellarin is a marine natural product having 14-phenyl-6H- [1] benzopyrano [4 ′, 3 ′: 4,5] pyrrolo [2,1-a] isoquinolin-6-one as a common skeleton.
  • About 40 kinds of natural products having a plurality of hydroxyl groups and methoxy groups on the skeleton have been isolated from marine organisms such as sponge and sea squirt. Many of these natural products have useful physiological activities such as anticancer activity and anti-HIV activity, and are attracting attention as lead compounds for developing new drugs (Patent Documents 1 and 2).
  • Non-patent Document 1 lamellarin D triacetate, lamellarin N triacetate, and lamellarin K triacetate exhibit strong cell growth inhibitory activity against various cancer cells. These compounds have also been shown to be effective against multidrug resistant cancer cells for which normal anticancer drugs are ineffective. More interestingly, lamelaline I having a different substitution mode has a low cell growth inhibitory activity, but it has also been reported to have a multidrug resistance overcoming activity that restores the activity of the anticancer agent when used in combination with a normal anticancer agent. .
  • lamellarin D and H the first total synthesis of lamellar natural products
  • the present inventors synthesized 10 types of non-natural lamellarin D analogs using this technique, and conducted structure-activity relationship studies (Non-patent Document 3).
  • lamellarin D has a strong cell growth inhibitory activity over the uterine cancer cell HeLa over the control drug mitomycin C, and the hydroxyl groups at the 8th and 20th positions are essential for the expression of the activity. It was revealed.
  • Non-patent Document 4 A lamellarin D-DNA-topoisomerase I ternary complex model was also proposed by docking simulation. According to this, after intercalating between DNA base pairs, lamellarin D hydrogen bonds with Asn722, Glu356 and Arg364 of topoisomerase I at the hydroxyl group at position 8, the hydroxyl group at position 20, and the lactone ring carbonyl group, respectively. This stabilizes the ternary complex and indicates that the enzyme activity of topoisomerase I is inhibited.
  • Non-Patent Document 3 the present inventors have clarified that there is a good correlation between cell growth inhibitory activity and topoisomerase I inhibitory activity by lamellarin D analog by joint research with Baily et al. (Non-patent Document 5). .
  • Non-patent Document 6 the inventors reported the design and synthesis of various 1-dearyllamellarin D analogs in which the aromatic ring at position 1 of lamellarin D was removed or substituted (Non-patent Document 6).
  • R 1 represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, a substituted An optionally substituted carbamoyl group, an optionally substituted C 6-14 aryl group, or an optionally substituted aromatic heterocyclic group;
  • R 2 and R 3 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, an optionally substituted amino group, an optionally substituted C 1-6 alkyl group, or a substituted group.
  • R 4 and R 5 are the same or different and each represents (i) a hydrogen atom, (ii) an optionally substituted C 1-6 alkyl group, (iii) an optionally substituted C 1-6 alkyl group And a carbamoyl group which may be mono- or di-substituted with a substituent selected from an optionally substituted C 6-14 aryl group, (iv) an optionally substituted C 1-6 alkyl-carbonyl group, (v) an optionally substituted C 1-6 alkoxy-carbonyl group, (vi) an optionally substituted C 6-14 aryloxy-carbonyl group, (vii) an optionally substituted C 1-6 An alkylsulfonyl group, (viii) an optionally substituted C 6-14 arylsulfonyl group, (ix) —SO 3 X (wherein X is a hydrogen atom, an optionally substituted C 1-6 alkyl group)
  • X is a hydrogen atom, an optionally
  • R 1 ′ is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, a substituted An optionally substituted carbamoyl group, an optionally substituted C 6-14 aryl group, or an optionally substituted aromatic heterocyclic group;
  • R 2 ′ and R 3 ′ are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group;
  • R 4 ′ and R 5 ′ are the same or different and each is a substituent selected from a hydrogen atom, an optionally substituted C 1-6 alkyl group and an optionally substituted C 6-14 aryl group.
  • PO (OY) (OZ) (wherein, Y Oyo Z are the same or different, respectively hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 6-14 aryl group, or counterions.), Or -PO 3 Y '(Wherein Y represents a counter ion); R 6 ′ represents a hydrogen atom or a hydroxy group.
  • compound (I) Since the compound represented by the formula (I) (hereinafter sometimes referred to as compound (I)) or a salt thereof, or a prodrug thereof has excellent anticancer activity, it is a therapeutic or prophylactic agent for various cancers and the like. As useful.
  • Compound (I) in particular, a compound represented by the formula (I ′) (hereinafter sometimes referred to as compound (I ′)) has a molecular shape substantially equivalent to the pentacyclic skeleton of lamellarin, The position of the nitrogen atom on the 5-membered ring in the skeleton is different. Therefore, it is possible to produce analogs in which various substituents are introduced on the nitrogen atom, and physical properties and activities can be controlled by the effect of the substituents. Furthermore, since the electronic state is different between the compound (I) and the lamellarin skeleton, it is expected that specificity based on a new mechanism of action will be expressed.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • examples of the “C 1-6 alkyl group” include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.
  • Pentyl group isopentyl group, neopentyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, 2-methylbutyl group, hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group 3,3-dimethylbutyl group, 2-ethylbutyl group and the like.
  • examples of the “C 2-6 alkenyl group” include an ethenyl group, 1-propenyl group, 2-propenyl group, 2-methyl-1-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 3-methyl-2-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 4-methyl-3-pentenyl group, 1- Examples include a hexenyl group, a 3-hexenyl group, and a 5-hexenyl group.
  • examples of the “C 2-6 alkynyl group” include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, and a 3-butynyl group.
  • C 1-6 alkoxy group and “C 1-6 alkoxy” in a substituent include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group. Group, sec-butoxy group, tert-butoxy group, 2-methylbutyloxy group, pentyloxy group, hexyloxy group and the like.
  • examples of the “C 1-6 alkyl-carbonyl group” include an acetyl group, a propanoyl group, a butanoyl group, a 2-methylpropanoyl group, a pentanoyl group, and a 3-methylbutanoyl group. 2-methylbutanoyl group, 2,2-dimethylpropanoyl group, hexanoyl group, heptanoyl group and the like.
  • examples of the “C 1-6 alkoxy-carbonyl group” include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, and an isobutoxycarbonyl group. , Sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group and the like.
  • examples of the “C 1-6 alkylsulfonyl group” include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, sec- Butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, 1-ethylpropylsulfonyl group, 1,1-dimethylpropylsulfonyl group, 2-methylbutylsulfonyl group, hexylsulfonyl group And isohexylsulfonyl group, 1,1-di
  • examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] Decyl, adamantyl and the like.
  • examples of the “C 6-14 aryl group” and the “C 6-14 aryl” in the substituent include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. .
  • examples of the “C 6-14 aryloxy-carbonyl group” include phenyloxycarbonyl, naphthyloxycarbonyl, anthryloxycarbonyl, phenanthryloxycarbonyl, acenaphthylenyloxy, and the like. Examples include carbonyl and the like.
  • examples of the “C 6-14 arylsulfonyl group” include phenylsulfonyl, naphthylsulfonyl, anthrylsulfonyl, phenanthrylsulfonyl, acenaphthylenylsulfonyl and the like.
  • examples of the “aromatic heterocyclic group” include an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and nitrogen other than a carbon atom as a ring-constituting atom.
  • examples thereof include 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group and condensed aromatic heterocyclic group containing 1 to 4 heteroatoms selected from atoms.
  • examples of the condensed aromatic heterocyclic group include these 4 to 7-membered monocyclic aromatic heterocyclic groups and 5- or 6-membered aromatic heterocyclic rings containing 1 or 2 nitrogen atoms (eg, pyrrole).
  • Imidazole pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocyclic ring containing one sulfur atom (eg, thiophene), or a group in which one or two benzene rings are condensed.
  • Furyl eg, 2-furyl, 3-furyl
  • thienyl eg, 2-thienyl, 3-thienyl
  • pyridyl eg, 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrimidinyl eg, 2-pyrimidinyl
  • 5-pyrimidinyl pyridazinyl
  • pyridazinyl eg, 3-pyridazinyl, 4-pyridazinyl
  • pyrazinyl eg, 2-pyrazinyl
  • pyrrolyl eg, 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl eg, 1 -Imidazolyl, 2-imidazolyl, 4-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • thiazolyl eg, 2-thiazolyl, 4-thi
  • non-aromatic heterocyclic group for example, as a ring-constituting atom, in addition to a carbon atom, an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and Examples thereof include 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group and condensed non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atoms.
  • condensed non-aromatic heterocyclic group examples include, for example, these 4- to 7-membered monocyclic non-aromatic heterocyclic groups and 5- or 6-membered aromatic or non-aromatic groups containing 1 or 2 nitrogen atoms.
  • Heterocycle eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a 5-membered aromatic or non-aromatic heterocycle containing one sulfur atom eg, thiophene
  • a benzene ring examples include a group having two condensed groups.
  • Pyrrolidinyl eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl
  • piperidinyl eg, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl
  • homopiperidinyl eg, homopiperidino, 2-homopiperidinyl, 3-homopiperidinyl, 4-homopiperidinyl
  • tetrahydropyridyl eg, 1,2,3,6-tetrahydropyridin-1-yl
  • dihydropyridyl eg, 2,3-dihydropyridin-4-yl
  • morpholinyl eg, morpholino, 2- Morpholinyl
  • thiomorpholinyl eg, thiomorpholino
  • 1,1-dioxidethiomorpholinyl eg, 1,1-dioxidethiomorpholinyl
  • W represents O or NH.
  • W is preferably O.
  • W is preferably NH.
  • R 1 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, a substituted And an optionally substituted carbamoyl group, an optionally substituted C 6-14 aryl group, or an optionally substituted aromatic heterocyclic group.
  • the “optionally substituted C 1-6 alkyl group”, “optionally substituted C 2-6 alkenyl group” and “optionally substituted C 2-6 alkynyl group” represented by R 1 may have 1 to 3 substituents at any substitutable position.
  • Such substituents include: (1) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a C 1-6 alkyl-carbonyl group, and (e) an amino group optionally mono- or di-substituted with a substituent selected from a C 1-6 alkoxy-carbonyl group; (2) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a C 3-10 cycloalkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, and (e) an oxo group; (3) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a
  • C 2-6 alkenyloxy group for example, ethenyloxy, 1-propenyloxy, 2-propenyloxy, 2-methyl-1-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy, 1-pentenyloxy, 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 4-methyl-3-pentenyloxy, 1-hexenyloxy, 3-hexenyloxy, 5-hexenyl Examples include oxy.
  • C 7-13 aralkyloxy group examples include benzyloxy, phenethyloxy, naphthylmethyloxy (1-naphthylmethyloxy, 2-naphthylmethyloxy), biphenylylmethyloxy and the like.
  • C 6-10 aryloxy group examples include phenyloxy, naphthyloxy (1-naphthyloxy, 2-naphthyloxy) and the like.
  • C 1-6 alkyl-carbonyloxy group examples include acetyloxy, propanoyloxy, butanoyloxy, 2-methylpropanoyloxy, pentanoyloxy, 3-methylbutanoyloxy, 2-methylbutanoyl Examples include oxy, 2,2-dimethylpropanoyloxy, hexanoyloxy, heptanoyloxy and the like.
  • C 1-6 alkylthio group examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.
  • C 7-13 Ararukichio group benzylthio, phenethylthio, naphthyl methylthio (1-naphthyl-methylthiophenyl, 2-naphthylmethyl thio) include biphenylylmethyl thio like.
  • C 6-14 arylthio group examples include phenylthio, naphthylthio, anthrylthio, phenanthrylthio, acenaphthylenylthio, biphenylylthio and the like.
  • nitrogen-containing heterocycle of such “optionally substituted nitrogen-containing heterocycle” includes, for example, at least one nitrogen atom in addition to carbon atoms as a ring-constituting atom, and further oxygen atom, sulfur atom (The sulfur atom may be oxidized) and a 5- to 7-membered nitrogen-containing heterocycle which may contain 1 or 2 heteroatoms selected from nitrogen atoms.
  • nitrogen-containing heterocycle examples include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, oxopiperazine and the like.
  • the “nitrogen-containing heterocycle” may have 1 to 3 substituents at substitutable positions. Such substituents include: (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a halogen atom, (e) An oxo group and the like can be mentioned. When there are two or more substituents, each substituent may be the same or different.
  • the “carbamoyl group” of the “optionally substituted carbamoyl group” represented by R 1 may be substituted with 1 or 2 substituents.
  • substituents include: (1) Substituent groups exemplified as the substituents that the “C 1-6 alkyl group” of the “ optionally substituted C 1-6 alkyl group” may have, (2) (a) a halogen atom, (b) a carboxyl group, (c) a hydroxy group, (d) a C 1-6 alkoxy group, (e) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group, (f) a C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms, (g) a C 3-10 cycloalkyl group, (h) a C 1-6 alkyl-carbonyl group, (i) a C 1-6 alkoxy-carbonyl group, (j) an aromatic heterocyclic group, (k
  • the two substituents may be the same or different, and together with the nitrogen atom to which they are bonded may be substituted.
  • Nitrogen heterocycles may be formed.
  • Such "nitrogen-containing heterocyclic ring which may be substituted” the may be "C 1-6 alkyl group” such as the "optionally substituted C 1-6 alkyl group” has As an “optionally substituted nitrogen-containing heterocycle” that two substituents of “amino group” and “carbamoyl group” as substituents may be formed together with the nitrogen atom to which they are bonded. Those mentioned above can be mentioned.
  • C 6-14 aryl group” and “aromatic heterocyclic group” of “ optionally substituted C 6-14 aryl group” and “ optionally substituted aromatic heterocyclic group” represented by R 1 May have 1 to 3 substituents at any substitutable position.
  • substituents include the substituents exemplified as the substituent that the “carbamoyl group” of the “optionally substituted carbamoyl group” may have. When there are two or more substituents, each substituent may be the same or different.
  • R 1 is preferably a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2-6 alkynyl group. More preferably a hydrogen atom, an optionally substituted C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, and still more preferably (i) a hydrogen atom, (ii) An amino group (preferably a dimethylamino group) optionally mono- or di-substituted with a C 1-6 alkyl group (preferably a methyl group), a hydroxy group and a C 1-6 alkoxy-carbonyloxy group (preferably methoxycarbonyl 1-3 is also C 1-6 alkyl group (preferably optionally substituted with a substituent selected from the group), a methyl group, an ethyl group), (iii) C 2-6 alkenyl group Preferably, 2-propenyl group),
  • R 1 is preferably an amino group (preferably, mono- or di-substituted by (i) a hydrogen atom, (ii) a C 1-6 alkyl group (preferably a methyl group). A C 1-6 alkyl group (preferably a methyl group, an ethyl group) optionally substituted with a dimethylamino group), (iii) a C 2-6 alkenyl group (preferably a 2-propenyl group), (iv) A C 2-6 alkynyl group (preferably a 2-propynyl group);
  • R 2 and R 3 are the same or different and are each a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, an optionally substituted amino group, an optionally substituted C 1-6 alkyl group, or a substituted group.
  • the C 1-6 alkoxy group which may be present is shown.
  • amino group” of the “optionally substituted amino group” represented by R 2 or R 3 may be substituted with 1 or 2 substituents.
  • substituents include the substituents exemplified as the substituent that the “carbamoyl group” of the “optionally substituted carbamoyl group” represented by R 1 may have. When there are two substituents, each substituent may be the same or different.
  • R optionally substituted C 1-6 alkoxy group represented by 2 or R 3, those similar to the "optionally substituted C 1-6 alkoxy group” represented by R 1 And a methoxy group is preferable.
  • R 2 and R 3 are preferably the same or different and are each (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxy group, (iv) a nitro group, or (v) an optionally substituted amino group.
  • a C 1-6 alkyl group (preferably a methyl group) (preferably a dimethylaminomethyl group) (preferably a dimethylaminomethyl group) which may be substituted with an optionally substituted amino group (preferably a dimethylamino group), (iv )
  • a C 1-6 alkoxy group (preferably a methoxy group), Still more preferably, they are the same or different and each is (i) a hydrogen atom, (ii) a C 1-6 alkoxy group (preferably a methoxy group), Particularly preferably, they are the same or different and each is a C 1-6 alkoxy group (preferably a methoxy group).
  • R 4 and R 5 are the same or different and each represents (i) a hydrogen atom, (ii) an optionally substituted C 1-6 alkyl group, (iii) an optionally substituted C 1-6 alkyl group And a carbamoyl group which may be mono- or di-substituted with a substituent selected from an optionally substituted C 6-14 aryl group, (iv) an optionally substituted C 1-6 alkyl-carbonyl group, (v) an optionally substituted C 1-6 alkoxy-carbonyl group, (vi) an optionally substituted C 6-14 aryloxy-carbonyl group, (vii) an optionally substituted C 1-6 An alkylsulfonyl group, (viii) an optionally substituted C 6-14 arylsulfonyl group, (ix) —SO 3 X (wherein X is a hydrogen atom, an optionally substituted C 1-6 alkyl group) Optionally substituted C 6-14 ants (X) -
  • R 4 or R 5 Represented by R 4 or R 5 as the "optionally substituted C 1-6 alkyl group", those similar to the "optionally substituted C 1-6 alkyl group" represented by R 1 Can be mentioned.
  • R may be mono- or di-substituted with a substituent selected from an optionally substituted C 1-6 alkyl group and an optionally substituted C 6-14 aryl group represented by R 4 or R 5
  • the “optionally substituted C 1-6 alkyl group” and the “optionally substituted C 6-14 aryl group” in the “carbamoyl group” are each the “optionally substituted” represented by R 1 above. Examples thereof include the same as “C 1-6 alkyl group” and “optionally substituted C 6-14 aryl group”.
  • Optionally substituted C 1-6 alkyl-carbonyl group “optionally substituted C 1-6 alkoxy-carbonyl group” and “optionally substituted C” represented by R 4 or R 5 1-6 alkylsulfonyl group "of the" C 1-6 alkyl - carbonyl group "," C 1-6 alkoxy - carbonyl group “and” C 1-6 alkylsulfonyl group ", and 1 to any substitutable position
  • Optionally substituted C 6-14 aryloxy - carbonyl group represented by R 4 or R 5 and the "optionally substituted C 6-14 arylsulfonyl group", “C 6-14 aryloxy -
  • the “carbonyl group” and “C 6-14 arylsulfonyl group” may have 1 to 3 substituents at any substitutable position. Examples of such substituents include those that may be possessed by the “C 6-14 aryl group” of the “ optionally substituted C 6-14 aryl group” represented by R 1 above. A substituent etc. are mentioned. When there are two or more substituents, each substituent may be the same or different.
  • the “optionally substituted C 1-6 alkyl group” represented by X, Y or Z and the “optionally substituted C 6-14 aryl group” are each represented by the “substituted” represented by R 1 above. Examples thereof include the same as “ optionally substituted C 1-6 alkyl group” and “optionally substituted C 6-14 aryl group”.
  • the “counter ion” represented by X is not particularly limited as long as it is an ion paired with —SO 3 —, and examples thereof include alkali metal ions such as sodium ion, potassium ion and lithium ion, ammonium ion and the like. .
  • the "counterion” represented by Y or Z, respectively -PO (OZ) O - or -PO (OY) O - is not particularly limited as long as the paired-ion, such as sodium ions, potassium ions, Examples include alkali metal ions such as lithium ions and ammonium ions.
  • the “counter ion” represented by Y ′ is not particularly limited as long as it is an ion that forms a pair with —PO 3 2 ⁇ , and examples thereof include alkaline earth metal ions such as magnesium ions.
  • R 4 and R 5 are preferably the same or different and are each (i) a hydrogen atom, (ii) an optionally substituted C 1-6 alkyl group, and (iii) an optionally substituted C 1- 6 alkyl-carbonyl group, (iv) —SO 3 X (wherein X represents a counter ion), (v) —PO (OY) (OZ) (wherein Y and Z are the same or different.
  • R 6 represents a hydrogen atom or a hydroxy group.
  • R 6 is preferably a hydrogen atom.
  • Compound (I) may have other substituents in addition to the substituents R 1 to R 3 , —OR 4 , —OR 5 , R 6 and the oxo group specified in formula (I). .
  • Such a substituent is not limited as long as it does not adversely affect the activity of the compound (I), and may be present in any number of substitutable positions.
  • Compound (I) is preferably W is O or NH;
  • R 1 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, a C 2-6 alkenyl group or a C 2-6 alkynyl group [preferably (i) a hydrogen atom, (ii) C 1-6 An amino group (preferably a dimethylamino group) optionally mono- or disubstituted with an alkyl group (preferably a methyl group), a hydroxy group and a C 1-6 alkoxy-carbonyloxy group (preferably a methoxycarbonyloxy group) C 1-6 alkyl group (preferably methyl group, ethyl group) optionally substituted by 1 to 3 substituents selected from (iii) C 2-6 alkenyl group (preferably 2 - propenyl), or (iv) C 2-6 alkynyl group (preferably, 2-propynyl group), more preferably a hydrogen atom, a methyl group, an ethyl group
  • compound (I) is preferably W is O or NH; R 1 is substituted with an amino group (preferably a dimethylamino group) which may be mono- or disubstituted with (i) a hydrogen atom, (ii) a C 1-6 alkyl group (preferably a methyl group).
  • An optionally substituted C 1-6 alkyl group (preferably a methyl group, an ethyl group), (iii) a C 2-6 alkenyl group (preferably a 2-propenyl group), or (iv) a C 2-6 alkynyl group ( Preferably 2-propynyl group);
  • R 2 and R 3 are the same or different and are each (i) a hydrogen atom or (ii) a C 1-6 alkoxy group (preferably a methoxy group);
  • R 4 and R 5 are the same or different and each represents (i) a hydrogen atom, (ii) an optionally substituted C 1-6 alkyl group, (iii) an optionally substituted C 1-6 alkyl- A carbonyl group, (iv) —SO 3 X (wherein X represents a counter ion), or (v) —PO (OY) (OZ) (wherein Y and Z are the same or different, Represents an optionally substituted C 1-6
  • compound (I) is preferably compound (I ′).
  • compound (I ′) is demonstrated in detail.
  • R 1 ′ is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, a substituted An optionally substituted carbamoyl group, an optionally substituted C 6-14 aryl group, or an optionally substituted aromatic heterocyclic group;
  • Optionally substituted C 1-6 alkyl group represented by R 1 ′, “optionally substituted C 2-6 alkenyl group”, “optionally substituted C 2-6 alkynyl group” , “optionally substituted carbamoyl group”, “optionally substituted C 6-14 aryl group” and “optionally substituted aromatic heterocyclic group”, “substituted represented by R 1 Optionally substituted C 1-6 alkyl group ”,“ optionally substituted C 2-6 alkenyl group ”,“ optionally substituted C 2-6 alkynyl group ”,“ optionally substituted ” This is the same as “carbamoyl group”, “optionally substituted C 6-14 aryl group” and “ optionally substituted aromatic heterocyclic group”.
  • R 1 ′ is preferably a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2-6 alkynyl group.
  • an amino group preferably a dimethylamino group
  • a C 1-6 alkyl group preferably a methyl group
  • a hydroxy group preferably a hydroxy group
  • a C 1-6 alkyl group preferably a methyl group, an ethyl group
  • a carbonyloxy group preferably a methoxycarbonyloxy group
  • a C 2-6 alkenyl group preferably a 2-propenyl group
  • the C 2-6 alkynyl group preferably a 2-propynyl group
  • R 2 ′ and R 3 ′ are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group.
  • R 2 'or R 3' are shown in the "optionally substituted C 1-6 alkyl group” and "optionally substituted C 1-6 alkoxy group” represented by R 2 or R 3 This is the same as the “optionally substituted C 1-6 alkyl group” and the “optionally substituted C 1-6 alkoxy group”.
  • R 2 ′ and R 3 ′ are preferably the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, or a C 1-6 alkoxy group, more preferably ,
  • a hydrogen atom, a halogen atom preferably a chlorine atom, a bromine atom
  • an amino group preferably a dimethylamino group
  • a C 1-6 alkyl group preferably a methyl group
  • a C 1-6 alkyl group preferably a methyl group
  • optionally substituted with a C 1-6 alkoxy group preferably a methoxy group
  • R 4 ′ and R 5 ′ are the same or different and each is a substituent selected from a hydrogen atom, an optionally substituted C 1-6 alkyl group and an optionally substituted C 6-14 aryl group.
  • a carbamoyl group which may be mono- or di-substituted with a substituent selected from an aryl group ”,“ an optionally substituted C 1-6 alkyl-carbonyl group ”,“ an optionally substituted C 1-6 “Alkoxy-carbonyl group”, “optionally substituted C 6-14 aryloxy-carbonyl group”, “optionally substituted C 1-6 alkylsulfonyl group”, “optionally substituted C 6-” 14 ants Sulfonyl group "," -SO 3 X (wherein X represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 6-14 aryl group or a counter ion.
  • Y and Z are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C). 6-14 aryl group or counter ion) ”and“ —PO 3 Y ′ (wherein Y ′ represents a counter ion) ”.
  • R 4 ′ and R 5 ′ are preferably a hydrogen atom, a C 1-6 alkoxy-carbonyl group (preferably a tert-butoxycarbonyl group) which may be substituted with an amino group which may be substituted with an amino group.
  • a 1-6 alkyl-carbonyl group preferably an isobutylcarbonyl group).
  • R 6 ′ represents a hydrogen atom or a hydroxy group.
  • R 6 ′ is preferably a hydrogen atom.
  • Compound (I ′) is preferably R 1 ′ is a hydrogen atom, an optionally substituted C 1-6 alkyl group [preferably a C 1-6 alkyl group (preferably a methyl group), an amino group optionally mono- or di-substituted ( Preferably, a dimethylamino group) or a C 1-6 alkyl group (preferably a methyl group, ethyl group) optionally substituted with a C 1-6 alkoxy-carbonyloxy group (preferably a methoxycarbonyloxy group)]
  • An optionally substituted C 2-6 alkenyl group preferably a 2-propenyl group
  • a C 2-6 alkynyl group preferably a 2-propynyl group
  • R 2 ′ and R 3 ′ are the same or different and each represents a hydrogen atom, a halogen atom (preferably a chlorine atom or a bromine atom), an optionally substituted C 1-6 alkyl group [preferably C 1- A C
  • Examples of the salt of compound (I) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • pharmaceutically acceptable salts are preferred.
  • the compound (I) and salts thereof are collectively referred to as the compound of the present invention.
  • any one of the isomers and a mixture are also included in the compound of the present invention.
  • an optical isomer exists in the compound of the present invention
  • an optical isomer separated from a racemate is also encompassed in the compound of the present invention.
  • These isomers are known per se synthesis methods, separation methods (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.), optical resolution methods (eg, fractional recrystallization method, chiral column method, diastereomer method, etc.) ) Etc., each can be obtained as a single item.
  • the compound of the present invention may be a crystal, and the compound of the present invention includes a single crystal form or a mixture of crystal forms.
  • the crystal can be produced by crystallization by applying a crystallization method known per se.
  • the compound of the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • the compound of the present invention may be a solvate (eg, hydrate etc.) or a non-solvate (eg, non-hydrate etc.), and both are included in the compound of the present invention.
  • Compounds labeled with isotopes eg, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.
  • deuterium converters are also encompassed in the compounds of the present invention.
  • a prodrug of the compound of the present invention is a compound that is converted into the compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidizes, reduces, hydrolyzes, etc.
  • a compound in which the amino group of the compound of the present invention is acylated, alkylated or phosphorylated eg, the amino group of the compound of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated, (5 -Methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, t-butylated compounds, etc.); compounds of the present invention Compounds in which the hydroxy group is acylated, alkylated, phosphorylated, borated (eg, the hydroxy group of the compound of the present invention is acety
  • the prodrug of the compound of the present invention changes to the compound of the present invention under physiological conditions as described in Drug Development, Volume 7 (Molecular Design), pp. 163-198 (Hirokawa Shoten). May be.
  • the compound of the present invention or a prodrug thereof has excellent anticancer activity against mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). It can be used as a preventive or therapeutic agent for diseases such as cancer in animals.
  • diseases such as cancer '', for example, retinoblastoma, childhood cancer, brain tumor, glioma, oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, breast cancer, lung cancer, esophageal cancer, Gastric cancer, kidney cancer, uterine cancer, skin cancer, melanoma, prostate cancer and the like can be mentioned.
  • the compound of the present invention or a prodrug thereof has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.), and stability and pharmacokinetics ( Since it is excellent in absorption, distribution, metabolism, excretion, etc., it is useful as a pharmaceutical product.
  • low toxicity eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.
  • stability and pharmacokinetics Since it is excellent in absorption, distribution, metabolism, excretion, etc., it is useful as a pharmaceutical product.
  • the medicament containing the compound of the present invention or a prodrug thereof is prepared by the compound of the present invention or the method according to a method known per se (eg, the method described in the Japanese Pharmacopoeia)
  • the prodrug alone or mixed with a pharmacologically acceptable carrier, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders , Granules, capsules (including soft capsules and microcapsules), lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release preparations) Microcapsule), aerosol, film (eg, orally disintegrating film, oral mucosal film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), point Preparations, transdermal preparations, o
  • Oral or parenteral eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, intratumoral, proximal to tumor, lesion, etc.
  • the content of the compound of the present invention or a prodrug thereof in the medicament of the present invention is about 0.01 to 100% by weight of the whole medicament.
  • the dosage of the pharmaceutical agent of the present invention varies depending on the administration subject, administration route, disease, symptoms, etc., but for example, when orally administered to an adult patient for the purpose of cancer treatment, the pharmaceutical compound of the present invention or a prodrug thereof is about 0.001 to about 100 mg / kg body weight, preferably about 0.005 to about 50 mg / kg body weight, more preferably about 0.01 to about 2 mg / kg body weight. It is desirable to administer about 1 to 3 times.
  • the pharmacologically acceptable carrier examples include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, lubricants, binders and disintegrants in solid preparations, or solvents in liquid preparations. , Solubilizers, suspending agents, tonicity agents, buffers, soothing agents, and the like. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy
  • hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the compound of the present invention or a prodrug thereof When the compound of the present invention or a prodrug thereof is applied to each of the above-mentioned diseases, it can be appropriately used in combination with a drug or a therapeutic method usually used for those diseases.
  • the combination agent of the present invention the combined use of the compound of the present invention or a prodrug thereof and a concomitant drug is referred to as “the combination agent of the present invention”.
  • the concomitant drug include an antimetabolite, an alkylating agent, a topoisomerase inhibitor, a microtubule polymerization inhibitor, a microtubule depolymerization inhibitor, a molecular target drug, and the like.
  • the compound of the present invention or a prodrug thereof By combining the compound of the present invention or a prodrug thereof and a concomitant drug, (1) The dose can be reduced compared to the case where the compound of the present invention or a prodrug thereof, or a concomitant drug is administered alone. (2) The combination drug can be selected according to the patient's symptoms (mild, severe, etc.) (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention or a prodrug thereof, the treatment period can be set longer. (4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention or a prodrug thereof, the therapeutic effect can be sustained. (5) By using the compound of the present invention or a prodrug thereof together with a concomitant drug, excellent effects such as a synergistic effect can be obtained.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention or a prodrug thereof, or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier in accordance with a method known per se.
  • a pharmacologically acceptable carrier for example, tablets (including sugar-coated tablets, film-coated tablets, etc.), powders, granules, capsules, solutions, emulsions, suspensions, injections, suppositories, sustained-release agents (eg, sublingual tablets, microcapsules, etc.) It can be safely administered orally or parenterally (eg, subcutaneous, topical, rectal, intravenous administration, etc.) as a patch, orally disintegrating tablet, orally disintegrating film and the like.
  • Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients and lubricants in solid preparations. , Binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • the timing of administration of the compound of the present invention or its prodrug and the concomitant drug is not limited, and the compound of the present invention or its prodrug or its pharmaceutical composition, the concomitant drug or its pharmaceutical composition, May be administered to the administration subject at the same time or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration mode of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention or a prodrug thereof and a concomitant drug, and (2) use in combination with the compound of the present invention or a prodrug thereof.
  • the compounding ratio of the compound of the present invention or its prodrug and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention or a prodrug thereof in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation. About 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation.
  • the same content may also be used when the compound of the present invention or a prodrug thereof and a concomitant drug are formulated separately.
  • a compound in which W is O in compound (I) (hereinafter referred to as compound (I) -1) can be synthesized, for example, using compound 14 produced by the method described in the following scheme as an intermediate. Note that any of the compounds described in the following schemes is an important intermediate in the production of compound (I) -1.
  • isovanillin (1) (25.0 g, 164 mmol), potassium carbonate (45.4 g, 329 mmol), isopropyl bromide (23.1 mL, 247 mmol) and dimethyl sulfoxide (300 mL) was stirred at 55 ° C. for 2 hours. After allowing to cool, water was added and extracted with ether. The extract was washed successively with water, 10% aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and then ether was distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain Compound 2 as a colorless and transparent oil (29.0 g). Yield 91%.
  • a solution of Compound 2 (195 mg, 1.00 mmol) in dry dimethylformamide (4.0 mL) was added N-bromosuccinimide (356 mg, 2.00 mmol) in dry dimethylformamide ( 2.0 mL) solution was added dropwise. Thereafter, the temperature was raised to room temperature and stirred at the same temperature for 30 hours. Water was added, and the mixture was extracted with dichloromethane. The extract was washed successively with aqueous sodium sulfite solution, water and saturated brine, and dried over anhydrous sodium sulfate.
  • reaction solution was again cooled to ⁇ 78 ° C., and a tetrahydrofuran solution (30 mL) of compound 5 (16.7 g, 100 mmol) was added dropwise to the solution, followed by stirring at the same temperature for 1 hour.
  • Trimethyl borate (16.7 mL, 150 mmol) was added at ⁇ 78 ° C., and the mixture was stirred at the same temperature for 1 hour, then warmed to room temperature, and further stirred at the same temperature for 15 hours.
  • a saturated aqueous ammonium chloride solution was added to the reaction solution, and the solvent was distilled off under reduced pressure.
  • Acetic acid was added to the residue to adjust the pH to 3, followed by extraction with ether.
  • a mixture of Compound 3 (82.2 mg, 0.301 mmol), Compound 6 (75.9 mg, 0.360 mmol) and Pd (PPh 3 ) 4 (35.1 mg, 30.3 ⁇ mol) was degassed with argon.
  • Tetrahydrofuran (7 mL) was added to this solid mixture and dissolved by stirring.
  • an aqueous sodium carbonate solution [Na 2 CO 3 (0.210 g, 1.98 mmol) + water (0.60 mL)] degassed with argon was added.
  • the mixture was stirred and refluxed for 19 hours.
  • the solvent was depressurizingly distilled after standing_to_cool. Water was added to the residue and extracted with dichloromethane.
  • a mixture of (methoxymethyl) triphenylphosphonium chloride (2.68 g, 7.82 mmol) and dry tetrahydrofuran (39 mL) at 0 ° C. under an argon atmosphere potassium tert-butoxide (1.05 g) was added.
  • 9.36 mmol) in dry tetrahydrofuran (9.4 mL) was added dropwise.
  • a solution of compound 7 (2.31 g, 6.26 mmol) in dry tetrahydrofuran (27 mL) was added dropwise.
  • water was added and it heated up to room temperature.
  • Step (g): Synthesis of Compound 9 Methanesulfonic acid (25.0 ⁇ L, 0.385 mmol) was added dropwise at 0 ° C. to a solution of Compound 8 (1.49 g, 3.85 mmol) in dry dichloromethane (25 mL) at the same temperature. Stir for 23 hours. Sodium carbonate (103.7 mg, 0.978 mmol) and magnesium sulfate (101.8 mg, 0.846 mmol) were added and the suspension was filtered. The solvent of the filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 10: 1) to obtain Compound 9 as a white powder (1.26 g).
  • Compound 10 (394 mg, 0.907 mmol), arylboronic acid (11) (369 mg, 1.37 mmol), Na 2 CO 3 (624 mg, 5.89 mmol) and Pd (PPh 3 ) 4 (105 mg, 0.0909 mmol) was replaced with argon by vacuum degassing.
  • 1,2-dimethoxyethane (13.4 mL) was added and stirred. Further argon degassed water (2.6 mL) was added and the mixture was refluxed for 19 hours.
  • the solvent was depressurizingly distilled after standing_to_cool. Water was added to the residue and extracted with dichloromethane.
  • a solution of Compound 13 (481 mg, 0.731 mmol) in tetrahydrofuran (20 mL) at ⁇ 78 ° C. in an argon atmosphere was added to a tert-butyllithium pentane solution (1.59 M, 1.01 mL, 1.60). mmol) was added dropwise. After stirring at the same temperature for 1 hour, a solution of methyl chloroformate (169 ⁇ L, 2.19 mmol) in tetrahydrofuran (8.0 mL) was added dropwise and stirred at the same temperature for 1 hour.
  • Compound (I) -1 can be synthesized by introducing or converting each substituent by a method known per se using a compound obtained from compound 14 by the same method as in Example 1 below.
  • compound (I) -1 can also be synthesized by using a raw material having a substituent corresponding to desired substituents R 1 to R 6 in the synthesis step of compound 14.
  • A represents a leaving group; other symbols are as defined above.
  • Examples of the “leaving group” represented by A include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), and preferably a bromine atom.
  • Step (a) Compound B-5 can be synthesized by reacting compound B-1 and compound B-2 in the presence of a palladium catalyst and a base in a solvent that does not adversely influence the reaction.
  • a palladium catalyst and a base in a solvent that does not adversely influence the reaction.
  • the base include sodium carbonate, potassium carbonate, cesium carbonate, thallium carbonate, cesium fluoride, potassium fluoride, potassium phosphate, and the like, preferably potassium phosphate and potassium carbonate.
  • the palladium catalyst examples include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, and the like. Preferred is tetrakis (triphenylphosphine) palladium.
  • Examples of the solvent that does not adversely influence the reaction include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, benzene, toluene and the like, preferably 1,2-dimethoxyethane, 1,4-dioxane. is there.
  • the amount of the base to be used is generally 3 molar equivalents to 10 molar equivalents, preferably 6 molar equivalents, relative to compound B-1.
  • the amount of the palladium catalyst to be used is generally 0.01 molar equivalent to 0.2 molar equivalent, preferably 0.1 molar equivalent, relative to compound B-1.
  • the reaction temperature is usually 20 ° C. to 200 ° C., preferably 60 ° C. to 120 ° C.
  • the reaction time is usually 1 hour to 72 hours, preferably 10 hours to 30 hours.
  • Compound B-5 can also be synthesized by the following step (b).
  • Step (b) Compound B-5 can be synthesized by reacting compound B-3 and compound B-4 in the presence of a palladium salt, a phosphine ligand and a base in a solvent that does not adversely influence the reaction.
  • a palladium salt include palladium acetate, palladium chloride, dichlorobis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, and the like. Is palladium acetate.
  • Examples of the phosphine ligand include 2- (di-tert-butylphosphino) biphenyl.
  • Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride and the like, preferably cesium carbonate.
  • Examples of the solvent that does not adversely influence the reaction include o-xylene, m-xylene, p-xylene, toluene, benzene and the like, and o-xylene is preferable.
  • the amount of the palladium salt to be used is generally 0.01 molar equivalent to 0.2 molar equivalent, preferably 0.1 molar equivalent, relative to compound B-3.
  • the amount of the phosphine ligand to be used is generally 0.01 molar equivalent to 0.4 molar equivalent, preferably 0.1 molar equivalent to 0.2 molar equivalent, relative to compound B-3.
  • the amount of the base to be used is generally 3 molar equivalents to 10 molar equivalents, preferably 6 molar equivalents, relative to compound B-3.
  • the reaction temperature is usually 20 ° C. to 200 ° C., preferably 80 ° C. to 170 ° C.
  • the reaction time is usually 1 hour to 72 hours, preferably 10 hours to 30 hours.
  • Step (c) Compound (I) -1 can be synthesized by reacting compound B-5 in the presence of a strong acid in a solvent that does not adversely influence the reaction.
  • strong acids include hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, aluminum chloride, and the like, with hydrochloric acid being preferred.
  • the solvent that does not adversely influence the reaction include methanol, ethanol, chloroform, dichloromethane, 1,2-dichloroethane, a mixed solvent thereof, and the like, and a methanol-chloroform mixed solvent is preferable.
  • the amount of the strong acid to be used is generally 1 mol equivalent to 100 mol equivalent, preferably 40 mol equivalent to 60 mol equivalent, relative to compound B-5.
  • the reaction temperature is usually 0 ° C. to 60 ° C., preferably 50 ° C.
  • the reaction time is usually 1 hour to 72 hours, preferably 10 hours to 24 hours.
  • a compound in which W is N in compound (I) (hereinafter referred to as compound (I) -2) can be produced, for example, by the method described in the following scheme.
  • Step (a) Compound C-2 can be synthesized by reacting compound B-1 and compound C-1 in the presence of a palladium catalyst and a base in a solvent that does not adversely influence the reaction.
  • a palladium catalyst and a base in a solvent that does not adversely influence the reaction.
  • the base include sodium carbonate, potassium carbonate, cesium carbonate, thallium carbonate, cesium fluoride, potassium fluoride, potassium phosphate and the like, preferably potassium phosphate.
  • the palladium catalyst examples include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, and the like. Preferred is tetrakis (triphenylphosphine) palladium.
  • Examples of the solvent that does not adversely influence the reaction include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, benzene, toluene, and the like, preferably 1,4-dioxane.
  • the amount of the base to be used is generally 3 molar equivalents to 10 molar equivalents, preferably 6 molar equivalents, relative to compound B-1.
  • the amount of the palladium catalyst to be used is generally 0.01 molar equivalent to 0.2 molar equivalent, preferably 0.1 molar equivalent, relative to compound B-1.
  • the reaction temperature is usually 20 ° C. to 200 ° C., preferably 80 ° C. to 120 ° C.
  • the reaction time is usually 1 hour to 72 hours, preferably 10 hours to 24 hours.
  • Step (b) Compound C-3 can be synthesized by removing compound tert-butoxycarbonyl by reacting compound C-2 in the presence of a strong acid in a solvent that does not adversely influence the reaction.
  • a strong acid include trifluoroacetic acid, hydrochloric acid, trifluoromethanesulfonic acid, aluminum chloride and the like, and trifluoroacetic acid is preferable.
  • the solvent that does not adversely influence the reaction include dichloromethane, 1,2-dichloroethane, benzene, toluene, nitromethane, and the like, preferably dichloromethane.
  • the amount of strong acid to be used is generally 1 molar equivalent or more, preferably 300 molar equivalents to 600 molar equivalents, relative to compound C-2.
  • the reaction temperature is usually 0 ° C. to 50 ° C., preferably 20 ° C. to 25 ° C.
  • the reaction time is usually 1 hour to 72 hours, preferably 10 hours to 24 hours.
  • Step (c) Compound (I) -2 can be synthesized by heating Compound C-3 under reduced pressure.
  • the heating temperature is usually 50 ° C. to 250 ° C., preferably 170 ° C. to 200 ° C.
  • the heating time is usually 1 hour to 72 hours, preferably 10 hours to 24 hours.
  • compound (I) -2 can also be synthesized from compound C-3 via compound C-4 as described in steps (d) and (e).
  • Step (d) Compound C-4 can be synthesized by subjecting compound C-3 to alkaline hydrolysis using a base in a solvent that does not adversely influence the reaction.
  • the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium cyanide, potassium cyanide and the like, preferably sodium hydroxide.
  • the solvent that does not adversely influence the reaction include water, ethanol, methanol, tetrahydrofuran, or a mixed solvent thereof, and a mixed solvent of water and ethanol is preferable.
  • the amount of the base to be used is generally 1 molar equivalent to 100 molar equivalents, preferably 10 molar equivalents, relative to compound C-3.
  • the reaction temperature is usually 20 ° C. to 200 ° C., preferably 70 ° C. to 100 ° C.
  • the reaction time is usually 1 hour to 72 hours, preferably 10 hours to 24 hours.
  • Step (e) Compound (I) -2 can be synthesized by treating compound C-4 with a dehydrating condensing agent in a solvent that does not adversely influence the reaction.
  • a dehydrating condensing agent examples include N, N′-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1,1′-carbonyldiimidazole, 2-chloro-1-methylpyridinium iodide.
  • 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is preferable.
  • Examples of the solvent that does not adversely influence the reaction include dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, benzene, toluene and the like, preferably tetrahydrofuran.
  • the amount of the dehydrating condensing agent to be used is generally 1 molar equivalent to 100 molar equivalents, preferably 80 molar equivalents, relative to compound C-4.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 20 ° C. to 30 ° C.
  • the reaction time is usually 1 hour to 72 hours, preferably 10 hours to 24 hours.
  • the compound in each of the above schemes includes a case where a salt is formed, and examples of such a salt include the same salts as the salt of compound (I).
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be easily purified.
  • a commercially available product can be used as it is.
  • the raw material compound or the production intermediate has a functional group such as an amino group, a carboxy group, or a hydroxyl group
  • these groups may be protected with a protecting group generally used in peptide chemistry or the like.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • Introduction or removal of these protecting groups a method known per se, for example, Wiley-Interscience, Inc. 1999 annual “Protective Groups in Organic Synthesis, 3 rd Ed. " (Theodora W. Greene, Peter GM Wuts Author) The method according to And so on.
  • a boron trichloride heptane solution (1.0 M, 2.58 mL, 2.58 mmol) was added to a solution of the compound obtained in Example 1 (99.1 mg, 0.215 mmol) in dry dichloromethane (37 mL) at ⁇ 78 ° C. under an argon atmosphere.
  • the solution was added dropwise and stirred at the same temperature for 30 minutes. Thereafter, the temperature was raised to 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Furthermore, after heating up to room temperature, it stirred for 22 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the solvent was distilled off under reduced pressure.
  • a boron trichloride heptane solution (1.0 M, 3.00 mL, 3.00 mmol) was added to a solution of the compound obtained in Example 3 (237 mg, 0.497 mmol) in dry dichloromethane (50 mL) at ⁇ 78 ° C. under an argon atmosphere. The solution was added dropwise and stirred at the same temperature for 30 minutes. Thereafter, the temperature was raised to 0 ° C., and the mixture was stirred at the same temperature for 7 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the solvent was distilled off under reduced pressure.
  • N- (tert-butoxycarbonyl) -L-valine 149.9 mg, 0.69 mmol
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 132.3 mg, 0.69 mmol
  • 4- A mixture of dimethylaminopyridine (6.2 mg, 0.0511 mmol) and dry dimethylformamide (7.0 mL) was stirred at room temperature for 10 minutes, and the compound obtained in Example 4 (50 mg, 0.128 mmol) was added. The mixture was stirred at the same temperature for 24 hours, and water was added. After diluting with dichloromethane, the organic layer and the aqueous layer were separated.
  • Example 9 A mixture of the compound obtained in Example 9 (20.5 mg, 0.0260 mmol) and trifluoroacetic acid (1.0 mL) was stirred at room temperature for 1 hour. Trifluoroacetic acid was distilled off under reduced pressure, followed by vacuum drying to obtain the target compound (25.4 mg). Yield 100%.
  • the precipitated solid was subjected to suction filtration, and the collected solid was washed successively with water, 2M hydrochloric acid and water, and vacuum-dried overnight to obtain the target compound as a pale yellow solid (12.9 mg). Yield 63%. Melting point (sealed tube) Changed from yellow to dark brown at 247-250 ° C.
  • Example 4 To a suspension of the compound obtained in Example 4 (24.7 mg, 0.0631 mmol) in dry acetonitrile (5.0 mL) at ⁇ 10 ° C. under an argon atmosphere, carbon tetrachloride (104 ⁇ L, 1.07 mmol), diisopropylethylamine (204 ⁇ L) were added. , 1.17 mmol), 4-dimethylaminopyridine (33.2 mg, 0.271 mmol) and dibenzyl phosphite (158 ⁇ L, 0.714 mmol) were sequentially added dropwise and stirred at the same temperature for 18 hours.
  • Bromotrimethylsilane (420 ⁇ L, 0.420 mmol) was added dropwise to a solution of the compound obtained in Example 16 (35.1 mg, 0.0700 mmol) in dry dichloromethane (6.0 mL) at room temperature under an argon atmosphere. Stir for hours. Thereafter, 1.0 M sodium methoxide-methanol solution (420 ⁇ L, 0.420 mmol) was added and stirred for 1 hour. Thereafter, the solvent was distilled off under reduced pressure. The residue was recrystallized from water-methanol, the precipitated solid was collected by suction filtration, and the collected solid was washed with methanol and dried in vacuo overnight.
  • Example 18 A mixture of the compound obtained in Example 18 (100 mg, 0.223 mmol), dichloromethane (2.0 mL) and trifluoroacetic acid (2.0 mL) was stirred at room temperature for 5 minutes. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (Sephadex LH-20, methanol) to obtain the target compound as a brown solid (115 mg). Yield 91%.
  • Compound 15 (3.51 g, 9.40 mmol) in dry dichloromethane (30 mL) was added to diisopropylethylamine (4.93 mL, 31.6 mmol) and chloromethyl methyl ether (2.52 mL, 31.64 mmol).
  • diisopropylethylamine (4.93 mL, 31.6 mmol)
  • chloromethyl methyl ether (2.52 mL, 31.64 mmol)
  • 10% aqueous ammonium chloride solution was added to stop the reaction, the organic layer was separated, and the aqueous layer was extracted twice with dichloromethane.
  • Compound 16 (5.06 g, 11.1 mmol) and tosyl were added to sodium hydride (1.46 g, 36.5 mmol) suspended in dry THF (10 mL) at ⁇ 30 ° C. under an argon atmosphere.
  • the reaction mixture was allowed to warm to room temperature and stirred for 30 minutes.
  • the reaction was quenched by slowly adding saturated aqueous ammonium chloride under ice cooling, and the mixture was extracted three times with ethyl acetate.
  • Compound 17 ′ was obtained as a yellow liquid from Compound 16 ′ by the same method as in Step (c). Yield 75%.
  • Compound 18 ′ was obtained as a yellow liquid from Compound 17 ′ by the same method as in Step (d). Yield 28%.
  • N-bromosuccinimide 955 mg, 5.37 mmol
  • water was added to stop the reaction.
  • the mixture was extracted three times with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated.
  • Compound 21 (12.72 g, 0.0825 mol) was dissolved in 48% hydrobromic acid (75 g) and methanol (150 mL) at 60 ° C. and cooled to 5 ° C. .
  • the reaction mixture was heated to 65 ° C. and stirred for 45 minutes, and methanol was distilled off at normal pressure. Furthermore, the bath temperature was raised to 110 ° C. and stirred for 20 minutes. After cooling to room temperature, it was diluted with water. The precipitated crystals were collected by filtration, and the filtrate was extracted three times with ethyl acetate and washed with 5% sodium bicarbonate solution. The crystalline product was dissolved in ethyl acetate and the insoluble material was filtered off. Both ethyl acetate extracts were combined, dried over anhydrous sodium sulfate and concentrated.
  • a mixture of Compound 22 (2.41 g, 11.0 mmol), anhydrous potassium carbonate (2.28 g, 16.5 mmol) and dry acetone (15 mL) was heated to reflux for 45 minutes.
  • Benzyl bromide (1.56 mL, 13.2 mmol) was added thereto, and the mixture was heated to reflux for 90 minutes. After returning to room temperature and filtering, the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water then brine, dried over anhydrous sodium sulfate and concentrated.
  • An appropriate amount of activated carbon powder was added to a methanol (36 mL) solution of Compound 23 (1.41 g, 4.57 mmol) and iron (III) chloride hexahydrate (343 mg, 1.27 mmol), Heated to reflux for 1 hour.
  • hydrazine monohydrate (0.888 mL, 18.2 mmol)
  • the filtrate was concentrated.
  • the residue was extracted with dichloromethane, washed 3 times with water and brine, dried over anhydrous sodium sulfate and concentrated.
  • a mixture of Compound 24 (502 mg, 1.79 mmol), di-tert-butyl dicarbonate (1.00 mL, 4.35 mmol) and 4- (dimethylamino) pyridine (catalytic amount) was added at 70 ° C. For 3 hours.
  • a 1.59 M tert-butyllithium-pentane solution (3.85 mL, 6.13 mmol) was added dropwise.
  • 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.714 mL, 3.50 mmol) was added and stirred for 100 minutes.
  • the reaction mixture was slowly warmed to room temperature and then poured into a 10% aqueous ammonium chloride solution to stop the reaction. Extracted three times with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated.
  • the obtained compound 26 (919.2 mg) was used in the next reaction without purification.
  • Step (a) Compound 19 (505 mg, 1.29 mmol) was dried in a suspension of sodium hydride (60% in oil, 234 mg, 5.85 mmol, washed with dry hexane) in dry DMF (2 mL) under ice-cooling and argon atmosphere. DMF (5 mL) solution was added dropwise over 10 minutes and stirred for 1 hour. Methyl iodide (0.32 mL, 5.19 mmol) was added dropwise to the reaction mixture, and the mixture was returned to room temperature and stirred for 3 hours. The reaction was quenched by adding ethanol followed by 10% aqueous ammonium chloride and extracted three times with ethyl acetate.
  • Step (b) A mixture of compound 20 (38.8 mg, 0.0955 mmol), compound 26 (121 mg, 0.286 mmol), 2M aqueous sodium carbonate (0.3 mL) and 1,4-dioxane (1 mL) was purged with argon gas for 3 minutes. To this mixture were added potassium chloride (21.3 mg, 0.286 mmol) and tetrakistriphenylphosphine palladium (11.0 mg, 0.00955 mmol), and the mixture was stirred at 100 ° C. for 8.5 hours under an argon atmosphere. The reaction mixture was poured into brine and extracted three times with ether. The ether layers were combined, dried over anhydrous sodium sulfate and concentrated.
  • Step (c) Trifluoroacetic acid (0.4 mL) was added to a solution of compound 27 (8.6 mg, 0.0137 mmol) in dry dichloromethane (1 mL), and the mixture was allowed to stand at room temperature for 15 hours. The reaction was diluted with ethyl acetate and washed sequentially with 0.5M sodium hydroxide solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated, and then the residue was purified by HPLC (CAPCELL PAK C18 UG80, 10 x 250 mm, solvent, 80% CH 3 CN) to obtain compound 29 (6.0 mg, 0.0137 mmol, 100% ) Was obtained as white crystals.
  • HPLC CAPCELL PAK C18 UG80, 10 x 250 mm, solvent, 80% CH 3 CN
  • Step (d) Compound 29 (3.0 mg, 0.00572 mmol) was dissolved in ethanol (1 mL), 9M sodium hydroxide solution (0.5 mL) was added, and the mixture was heated to reflux for 3 hours. The mixture was diluted with water, ethanol was distilled off under reduced pressure, and the pH was adjusted to 6 using 1M hydrochloric acid. Extracted three times with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated.
  • the obtained crude amino acid was suspended in dry THF (2 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (9.0 mg, 0.469 mmol) was added, and the mixture was stirred at room temperature for 20 hours.
  • the reaction solution was poured into water and extracted three times with ethyl acetate.
  • the organic layers were combined, washed with 5% aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated.
  • the solid residue was washed with ether to obtain the target compound (0.7 mg, 0.0017 mmol, 30%) as white crystals. Mp 300 ° C or higher.
  • Step (a) Compound 19 (476 mg, 1.21 mmol) was dissolved in a mixed solvent of dry THF (5 mL) and dry N, N-dimethylformamide (DMF) (10 mL), and sodium hydride (60% in oil, 97) was added at 0 ° C. mg, 2.4 mmol) was added in 7 portions. After stirring for 15 minutes, (2-trimethylsilylethoxy) methyl chloride (0.390 mL, 2.20 mmol) was added dropwise. After stirring at room temperature for 15 minutes, the reaction mixture was poured into 10% aqueous ammonium chloride solution and extracted three times with ether. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated.
  • DMF dry N, N-dimethylformamide
  • Step (b) A mixture of compound 30 (133 mg, 0.255 mmol), compound 26 (216 mmol, 0.509 mmol), K 3 PO 4 (325 mg, 1.53 mmol) and dry dioxane (3.5 mL) was purged with argon gas for 5 minutes and degassed. did. Tetrakistriphenylphosphine palladium (30 mg, 0.0255 mmol) was added thereto, and the mixture was stirred at 100 ° C. for 16 hours in an argon atmosphere. After cooling to room temperature, the reaction was diluted with ethyl acetate and filtered through celite. The filtrate was washed with brine and the aqueous layer was extracted twice with ethyl acetate.
  • Step (c) A solution of compound 32 (18.3 mg, 0.0281 mmol) and tetrabutylammonium fluoride (1M THF solution, 0.200 mL, 0.200 mmol) in dry THF (2 mL) was heated to reflux for 3 hours. The reaction mixture was poured into 10% aqueous ammonium chloride and extracted twice with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by HPLC (CAPCELL PAK C18 UG80, 10 ⁇ 250 mm, solvent, 80% CH 3 CN) to obtain Compound 33 (13.0 mg, 0.0250 mmol, 89%).
  • HPLC CAPCELL PAK C18 UG80, 10 ⁇ 250 mm, solvent, 80% CH 3 CN
  • Step (d) Compound 33 (6.5 mg, 0.0125 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (0.5 mL) and anhydrous dichloromethane (1 mL) and allowed to stand at room temperature for 2 hours. The pH was adjusted to 6 using 1M aqueous sodium hydroxide solution, and the mixture was extracted twice with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was heated at 185 ° C.
  • Test Example 1 Evaluation of Growth Inhibitory Activity against HeLa Cells 200 cells / well of HeLa cells were seeded in a 48-well microplate, and MEM ⁇ medium containing 10% fetal bovine serum and penicillin (100 U%) was added to obtain various concentrations.
  • the DMSO-ethanol solution of the prepared sample was added and cultured at 37 ° C. for 72 hours in a 5% carbon dioxide / 95% air atmosphere.
  • a 1% methylene blue solution in 50% methanol (2 to 3 drops / well) was added and allowed to stand at room temperature for 30 minutes for staining, and the number of colonies formed was counted.
  • the inhibition rate was shown by the concentration (GI 50 ) that suppresses the number of colonies to 50% compared to the control group.
  • the results are shown in Table 1 below.
  • Test Example 2 Evaluation of Growth Inhibitory Activity against Hematopoietic Tumor Cells Healthy human peripheral blood separated from various hematopoietic tumor cell lines at 1 ⁇ 10 5 cells / mL and Ficoll using RPMI 1640 containing 10% fetal bovine serum as a culture solution DMSO solutions of samples prepared to various concentrations were added to mononuclear cells (PBMC). After seeding in a 96-well plate and culturing at 37 ° C. for 48 hours in a 5% carbon dioxide / 95% air atmosphere, an MTS assay was performed. The results were measured at a wavelength of 490 nm using a 96 well plate reader. Cells with no sample added were taken as controls, and the inhibition rate was shown as a 50% growth inhibitory concentration (GI 50 ) when the growth of control cells was taken as 100%. The results are shown in Table 2 below.
  • GI 50 50% growth inhibitory concentration
  • Test Example 3 Evaluation of Growth Inhibitory Activity against Various Cancer Cells Various cancer cells were seeded in a 96-well plate. On the next day, sample solutions prepared to various concentrations were added and cultured for 2 days, and then cell proliferation was measured by colorimetric determination with sulforhodamine B. The inhibition rate was shown by the concentration (GI 50 ) that suppresses the growth to 50% compared to the control. The results are shown in Tables 3 to 9 below.
  • the compound of the present invention has excellent anticancer activity equivalent to or better than that of lamellarin D, and has physical properties and the like due to the effects of various substituents on the 5-membered ring nitrogen atom in the pentacyclic skeleton. Since it may have excellent properties different from a compound having a lamellarin skeleton, it is very effective as a preventive or therapeutic agent for diseases such as cancer.

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Abstract

Cette invention concerne un nouveau composé ayant une excellente activité anticancéreuse. Composé représenté par la formule (I) (chaque symbole étant tel que défini dans la description), ou sel de celui-ci.
PCT/JP2012/050872 2011-01-17 2012-01-17 Composé ayant une activité anticancéreuse WO2012099129A1 (fr)

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CN105801577A (zh) * 2016-04-27 2016-07-27 复旦大学 一种多氟甲基取代的吡咯[3,2-c]并喹啉类化合物的制备方法
CN110396094A (zh) * 2018-04-24 2019-11-01 华东师范大学 一种喹啉酮并杂芳环类化合物及其衍生物和合成方法

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Publication number Priority date Publication date Assignee Title
JP2015172009A (ja) * 2014-03-11 2015-10-01 国立大学法人 岡山大学 多環芳香族化合物及びその製造方法
CN105801577A (zh) * 2016-04-27 2016-07-27 复旦大学 一种多氟甲基取代的吡咯[3,2-c]并喹啉类化合物的制备方法
CN105801577B (zh) * 2016-04-27 2018-02-27 复旦大学 一种多氟甲基取代的吡咯[3,2‑c]并喹啉类化合物的制备方法
CN110396094A (zh) * 2018-04-24 2019-11-01 华东师范大学 一种喹啉酮并杂芳环类化合物及其衍生物和合成方法
CN110396094B (zh) * 2018-04-24 2021-10-12 华东师范大学 一种喹啉酮并杂芳环类化合物及其衍生物和合成方法

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