WO2003062440A1 - Derive de xanthone - Google Patents

Derive de xanthone Download PDF

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WO2003062440A1
WO2003062440A1 PCT/JP2003/000438 JP0300438W WO03062440A1 WO 2003062440 A1 WO2003062440 A1 WO 2003062440A1 JP 0300438 W JP0300438 W JP 0300438W WO 03062440 A1 WO03062440 A1 WO 03062440A1
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group
substituted
hydrogen atom
alkyl
general formula
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PCT/JP2003/000438
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Japanese (ja)
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Hiroshi Miyauchi
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Sumitomo Pharmaceuticals Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes 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 in position 9
    • C07D311/86—Oxygen atoms, e.g. xanthones

Definitions

  • the present invention relates to novel xanthone derivatives, semaphorin inhibitors containing them as active ingredients, agents for promoting central or peripheral nerve regeneration, and agents for preventing and treating neuropathic diseases and neurodegenerative diseases.
  • Nerve cells are special tissues that have no division ability in adults. Therefore, once a failure is sustained, it continues for a long time.
  • the central nervous system such as the brain and spinal cord has no regenerative ability.
  • the lack of treatment for neurodegenerative diseases such as extrinsic injury represented by spinal cord injury, Alzheimer's disease, Parkinson's disease, and other factors is partly due to the inability to regenerate the central nervous system. it can.
  • Peripheral nerves on the other hand, have the ability to regenerate, and axons regenerate and recover their function after being cut. However, even in this case, the period required for regeneration is extremely long, from several months to more than one year, and the pain for the patient is great.
  • Semaphorin was originally isolated as a factor involved in the development of the nervous system in the bat during development, but it was later used in nematodes, fish, mammals, and certain viruses. Semaphorin genes are now classified into eight gene subfamilies, a class, in terms of structure (Cell 97, 551, 1999). . Semaphorin is an endogenous protein identified as a factor that represses nerve growth cones and suppresses axonal outgrowth, and approximately 20 molecular species have been known so far (Cell 97 , 551, 1999) are not known to be familiar with most functions of many semaphorin families.
  • the best studied is the subfamily of genes called class 3 and all of these translation products are secreted proteins. It is known that the proteins encoded by these genes have strong neurite outgrowth inhibitory activity and growth cone retraction activity in the mouth, but under certain conditions it is reported that they act stimulatively on neurite outgrowth. There is also. Among them, semaphorin 3 A (Sema 3A) (Cel 75, 217, 1993, Cel 75, 1389, 1993) is the best studied, and this protein has a low concentration of 10 pM. Induces the growth cone retraction of the cultured neurons in a short time.
  • Semaphorin 3 A Semaphorin 3 A
  • antagonistic antisense nucleotides such as antibodies to semaphorin W, semaphorin Y, and semaphorin ⁇ should be used as central nervous system regeneration promoters (TO98 / 15628, W098 / 11216, W098 / 20928)
  • central nervous system regeneration promoters TO98 / 15628, W098 / 11216, W098 / 20928
  • a method of inducing neurite outgrowth by contacting a nerve cell with an antibody that specifically binds to human collabsin US Pat. No. 5,416,197
  • low-molecular-weight conjugates that specifically inhibit semaphorin have not been known at all. Disclosure of the invention
  • An object of the present invention is to provide a semaphorin inhibitor, a peripheral or central nerve regeneration promoter containing such a semaphorin inhibitor as an active ingredient, or a neuropathic disease or nerve containing such a nerve regeneration promoter.
  • An object of the present invention is to provide a prophylactic or therapeutic agent for a degenerative disease.
  • the present inventors have developed a compound group found in the culture of Penicillium sp. Strain SPF-3059 (Accession No. FERM BP-7663, Patent Organism Depositary, National Institute of Advanced Industrial Science and Technology). They have found that chemically modified derivatives thereof have semaphorin inhibitory activity, and have completed the present invention.
  • the present invention relates to the general formula (1)
  • R 3 is a hydrogen atom, a propyloxyl group, a ⁇ —C 6 alkoxycarbonyl group, a substituted C x -C 6 alkoxycarbonyl group, a C 3 _C 7 cycloalkyloxycarbonyl group, a C 2 — C 6 alkenyloxycarbonyl, substituted C 2 -C 6 alkenyloxycarbonyl, C 2 _C 6 alkynyloxycarbonyl, 7 aryloxycarbonyl, substituted aryloxycarbonyl, tri (Ci one c 6 alkyl / phenyl) silyl O carboxymethyl carbonylation group or the general formula (2) (2)
  • R 6 and R 7 each represent a hydrogen atom, a C—C 6 alkyl group, a substituted —C 6 alkyl group, a C.—C 7 cycloalkyl group, an aryl group or a substituted aryl group, Alternatively, R 6 and R 7 together represent a C 3 -C 7 alkylene group or an alkylene group containing a heteroatom.
  • R 4 is a hydrogen atom, a hydroxyl group, C 2 - 0 7 ⁇ Rukanoiruokishi group, a substituted C 2 - C 7 alkanoyloxy noisy Ruo alkoxy group, C 4 - ⁇ 8 cycloalkylcarbonyl O alkoxy group, Aroiruokishi group, a substituted Aroiruokishi group, CI- Ce an alkoxy group, monosubstituted C 6 alkoxy group, ⁇ 3 _ ⁇ 7 cycloalkoxy groups, C 2 _C 6 alkenyl Ruokishi group, a substituted C 2 - C 6 Arukeniruokishi groups, C 2 — represents a C 6 alkynyloxy group, aryloxy group, substituted aryloxy group or tri (1-C 6 alkyl Z phenyl) silyloxy group, R 5 is a hydrogen atom, C 2 —C 7 alkanol group,
  • R 1 represents a methyl group
  • R 2 represents a group represented by any of the general formulas (3), (4), (5) and (7).
  • R 8 is a hydrogen atom, a carboxyl group, a —C 6 alkoxycarbonyl group, a substituted C x -C 6 alkoxycarbonyl group, a C 3 —C 7 cycloalkyloxycarbonyl group, a C 2 —C 6 alkenyl O carboxymethyl Cal Poni group, a substituted C 2 - C 6 alkenyl O alkoxycarbonyl group, C 2 - C 6 alkynyl O carboxy Cal Poni group, ⁇ reel O carboxymethyl Cal Poni group, a substituted ⁇ reel O carboxymethyl Cal Poni group, tri ( ⁇ 3 1 - ⁇ 6 Arukiru 7 phenyl) Shiriruokishikaru Poniru group or the general formula (2)
  • R 9 is a hydrogen atom, a hydroxyl group, a C 2 —C 7 alkanoyloxy group, a substituted C 2 —C 7 Arca noisy Ruo alkoxy group, C 4 one Ji 8 cycloalkyl Cal Poni Ruo alkoxy group, Aroiruokishi group, a substituted Aroiruokishi group, CI- Ce alkoxy group, monosubstituted C 6 alkoxy group, C 3 - (7 cycloalkoxy, C 2 - C 6 Arukeniruokishi group, a substituted C 2 _C 6 Arukeniruokishi group, Ji 2 - (6 Arukini Ruokishi group, Ariruokishi group, a substituted Ariruokishi group or tri ( ⁇ - represents the Ce alkyl / phenyl) Shiriruokishi group, R 1G is Hydrogen
  • R 8 , R 9 and R 1G have the same meanings as described above, and R 11 is a hydrogen atom, a C 2 _C 7 alkanol group, a substituted C 2 _C 7 alkanoyl group, a C 4 -C 3 cycloalkyl carbonyl group.
  • R 12 is a hydrogen atom, a methoxymethyl group, or a compound represented by the general formula (6)
  • R 13 is a hydrogen atom, C 2 - C 7 Arukanoiru group, a substituted C 2 - C 7 Arukanoiru group, ⁇ 3 4-0 8 cycloalkyl ⁇ Le kills carbonyl group, Aroiru group, a substituted Aroiru group, CI- Ce Al kill group, monosubstituted C 6 alkyl group, C 3 - Ji 7 cycloalkyl, C 2 _C 6 alkenyl group, a substituted C 2 - C 6 alkenyl group, C 2 - C 6 alkynyl group, Ariru group, a substituted Ariru group or Represents a tri (C “C 6 alkylphenyl) silyl group.) Represents.)
  • R 14 is a hydrogen atom, C 2 - C 7 alkanol I group, a substituted C 2 - C 7 Arukanoiru group, C 4 i (:. 8 Cycloalkyl carbonyl, aryl, substituted aryl, —C 6 alkyl, substituted C 6 alkyl, c 3 -c 7 cycloalkyl, C 2 —C 6 alkenyl, substituted C 2 —C 6 alkenyl, C 2 - C 6 7 Rukiniru group, a Ariru group, a substituted Ariru group or tri (over alkyl Z phenyl) silyl group).
  • R 1 represents a group represented by the general formula (8) or (9), and R 2 represents an acetyl group. Represent.
  • R 15 is a hydrogen atom, C 2 -. C 7 Arukanoiru group, a substituted C 2 - C 7 Arukanoiru group, C 4 ten 8 cycloalkyl Cal Poni group, Aroiru group, a substituted Aroiru group, C ⁇ - C 6 Alkyl group, substituted C 6 alkyl group, C 3 — ( 7 cycloalkyl group, C 2 —C 6 alkenyl group, substituted C 2 —C 6 alkenyl group, C 2 -C 6 alkynyl group, aryl group, substituted aryl group or Bokuri represents (an C 6 alkyl / phenyl) silyl group.)
  • R 3 and R 8 are a hydrogen atom or a hydroxyl group
  • at least one of R 4 and R 9 is neither a hydrogen atom nor a hydroxyl group, or R 5 , R 10 -R 11, at least one of R 13, R 14 or R 15 is not a hydrogen atom.
  • R 1 is a group represented by the general formula (8)
  • R 2 is an acetyl group
  • R 3 and R 8 are methoxycarbonyl groups
  • R 4 and R 9 are methoxy groups.
  • R 5 and R 10 exclude the compounds in which they are methyl groups.
  • R 12 is a hydrogen atom, a methoxymethyl group, or a compound represented by the general formula (13)
  • R 3 , R 4 , R 5 , R 8 , R 9 and R 1Q are as defined above, provided that R 3 and R 8 are methoxycarbonyl groups, and R 4 and R 9 are methoxy groups And R 5 and R 1G are methyl groups, R 3 and R 8 are methoxycarbonyl groups, R 4 and R 9 are methoxy groups, and R Except for compounds in which 5 and R 10 are methyl groups.
  • R 3 , R 4 , R 5 , R 8 , R 9 and R 1Q are as defined above, provided that R 3 and R 8 are methoxycarbonyl groups, and R 4 and R 9 are methoxy groups And R 5 and R 1G are methyl groups, R 3 and R 8 are methoxycarbonyl groups, R 4 and R 9 are methoxy groups, and R Except for compounds in which 5 and R 10 are methyl groups.
  • both R 3 and R 8 are hydrogen atoms or When it is a ropoxyl group, at least one of R 4 and R 9 is neither a hydrogen atom nor a hydroxyl group, or at least one of R 5 , R 10 , R 11 R 13 , R 14 or R 15 Is not a hydrogen atom.
  • the present invention also provides a semaphorin inhibitor comprising these xanthone derivatives as an active ingredient, a nerve regeneration promoter comprising the semaphorin inhibitor as an active ingredient, and a nerve regeneration
  • the present invention relates to a preventive or therapeutic agent for a neurological disorder and a neurodegenerative disease, which comprises an accelerator.
  • semaphorin is a generic name for proteins having a semaphorin domain having a similar structure consisting of about 500 amino acid residues (Neuron 14, 941-948, 1995). However, the present invention is not limited to these known semaphorins. Such semaphorins include human semaphorins of mammals, preferably semaphorins of class 3, 4, 5, or 6 defined in the literature (Cell 97, 551, 1999).
  • class 3 or class 6 semaphorins can be exemplified, and most preferably, class 3 semaphorins include semaphorin 3A (Cell 75, 217, 1993, Cell 75, 1389, 1993), and For class 6 semaphorins, semaphorin 6C (WO 988181216 pamphlet,
  • the semaphorin in the present invention is not limited to a natural type 'recombinant' protein, but may be one in which only the extracellular domain of a membrane-bound semaphorin is expressed and soluble, such as an antibody or alkaline phosphatase. It also includes fusion proteins with other proteins, or those tagged with a his tag or flag, as well as mutants in which some amino acids have been deleted, replaced, or added.
  • Semaphorin 6 C is a membrane-bound protein, and when measuring the activity of a test substance using the activity promoting / suppressing activity of Sema 6C, for example, Usually the extracellular domain of Sema 6C is used. Two isoforms are known in the extracellular domain of Sema6C (WO 98/11216 pamphlet and ioll. Cell. Neurosci. 13, 9-23 (1999)). It has regression activity. Such an extracellular domain of Sema 6C, a marker protein and / or A fusion protein linked to a peptide tag can also be used to advantage in measuring the activity of a test substance, as long as it does not impair Sema 6C activity.
  • Marker proteins such as alkaline phosphatase (Cell 63, 185-194 (1990)), the Fc region of the antibody (Genbank accession number M87789), conventionally well-known marker proteins such as HRP, and peptide tags such as Mick tag, His tag, A well-known peptide evening such as a flag tag can be mentioned.
  • the semaphorin inhibitor refers to an activity possessed by any of the above semaphorins, for example, cell migration activity, cell death inducing activity, cell morphological changes such as cell spheroidization and growth cone retraction, It refers to a substance that inhibits neurite outgrowth inhibitory or promoting activity, nerve cell dendritic outgrowth promoting or inhibitory activity, nerve axon guidance activity, and the like.
  • Such semaphorin inhibitors include substances that inhibit the semaphorin activity If so, it is not particularly limited, but is preferably a compound having a central and / or peripheral nerve regeneration promoting action, more preferably a growth cone regression activity of semaphorin and / or nerve elongation in collagen gel.
  • a compound having an inhibitory activity on the inhibitory activity, more preferably a growth cone retraction activity of semaphorin and collagen Compounds having an inhibitory effect on both the nerve elongation inhibitory activity in gengel can be mentioned.
  • the central and Z or peripheral nerve regeneration-promoting effects include the central (tissue) consisting of the brain and spinal cord, and / or peripheral / non-central (tissue) peripheral / peripheral parts of the body surface and peripheral organs (Tissue)
  • tissue The action of promoting nerve regeneration.
  • the nerve regeneration promoting action at the center includes the regeneration of nerves such as retinal nerves and cerebral cortical nerves, which are nerve cells in the central area, and nerves that emit thorax and project to other nerve cells also located in the center.
  • the environment in which nerve axons are regenerated is also central to nerves originating from peripheral nerve cell bodies such as the central fibers of the olfactory nerve and dorsal root ganglion sensory nerve.
  • the peripheral nerve regeneration promoting action is not only the nerve regeneration promoting action from the nerve cell body in the periphery and extending in the peripheral tissue, but also the nerve cell body located in the center (brain and spinal cord, etc.). Even for nerves, the effect of promoting nerve regeneration when the environment to be regenerated is peripheral (tissue) is included.
  • An example is an action of promoting regeneration of nerves such as preganglionic nerves of the autonomic nervous system, such as the motor nerve, sympathetic nerve, and parasympathetic nerve. It also includes the action of promoting regeneration of nerves such as the sciatic nerve, including both nerves.
  • the center (tissue) is a tissue composed of the brain, medulla oblongata, spinal cord, eyes, and the like, and specifically, an area in which transport of high molecular weight substances is restricted by a structure such as the blood-brain barrier and the blood-retinal barrier.
  • Peripheral tissue refers to the rest of the body. In general, nerve fibers can regenerate in peripheral tissues but not in central tissues.
  • the growth cone retraction (collabs) activity possessed by the semaphorin refers to the fact that a nerve cell (usually a ganglion tissue fragment) is cultured in vitro for a predetermined time, and the elongated neurite and the growth cone at the tip of the neurite can be observed.
  • the semaphorin having a predetermined concentration for example, about 3 units Zm 1; 1 unit Zml has a concentration of semaphorin that causes 50% growth cone regression
  • a predetermined time for example, (1 hour, for example
  • cultivation of neurons in vitro is usually performed for 10 to 20 hours. Can be changed as appropriate.
  • the compound when a compound of an appropriate concentration was added in advance about 1 hour before adding semaphorin, and when the retraction of the growth cone by semaphorin was suppressed, the compound was added to the semaphorin. It can be said that the compound has a phosphorus inhibitor, in particular, a compound having an inhibitory action on the growth cone retraction activity of semaphorin.
  • the compound having the activity of suppressing the growth cone retraction activity is not particularly limited, but is 100 g / ml or less, preferably 30 g / ml or less, and more preferably 10 zg Zml. Those exhibiting the above-mentioned inhibitory action at the following concentrations can be exemplified.
  • the semaphorin inhibitor a compound that does not substantially affect the proliferation of cells such as nerve cells and semaphorin-expressing cells may be used to confirm the effect of the semaphorin inhibitor of the present invention. It is also preferable in terms of safety when used as a pharmaceutical.
  • the semaphorin used in the above-mentioned semaphorin activity measurement is not limited to natural semaphorin, but may be one obtained by solubilizing only the extracellular domain of the above-mentioned membrane-bound semaphorin, an antibody, A fusion protein with another protein such as alkaline phosphatase, or a tag with a tag such as a his tag or a flag, or a fragment in which some amino acids are changed can also be used.
  • dorsal root ganglia extracted from 7-day-old and 8-day-old fetuses are convenient as neurons used for culture, but dorsal root ganglia of animals other than chickens.
  • any neurons that extend neurites in vitro such as sympathetic ganglia, retinal ganglia, and superior cervical ganglia, can be used. Culture conditions are not particularly limited as long as neurite outgrowth can be observed and semaphorin activity can be measured.
  • the mechanism of action of the semaphorin inhibitor in the present invention is considered as follows. That is, the expression of semaphorin's neurite outgrowth inhibitory activity or growth cone regression activity begins when semaphorin binds to a receptor on the nerve cell surface (growth cone) ⁇ Semaphorin-bound receptor Then, a signal is transmitted into the cell, which ultimately causes depolymerization of the actin fiber, resulting in suppression of neurite outgrowth and growth cone retraction.
  • the semaphorin receptor may be any one of the above-mentioned semaphorins, and if semaphorin can be bound, it may be a modified form thereof or a part thereof. . Specific examples include neuropilin-11, plexin and the like.
  • the semaphorin inhibitor in the present invention is not limited by the mechanism of action, and any of the above-mentioned mechanisms of action that inhibits any step is included in the scope of the present invention.
  • the compound that inhibits semaphorin activity by inhibiting a reaction related to intracellular signal transduction from receptor binding of semaphorin to actin fiber depolymerization is also included in the scope of the present invention.
  • a method for measuring the receptor-binding inhibition activity of semaphorin those skilled in the art Any method may be used as long as it is appropriately selected according to the method.
  • a tag such as a semaphorin fused with another protein such as the above-described antibody or alkaline phosphatase, or a tag such as a his-tag or a flag may be added.
  • a method for measuring the receptor binding inhibitory activity of semaphorin can be exemplified by binding the semaphorin to a cell expressing the semaphorin receptor or a receptor component in the presence of a test substance.
  • the substituents in the xanthone derivative of the present invention will be described below.
  • 1 C 6 alkyl group means an alkyl group having 1 to 6 carbon atoms, specifically, methyl, ethyl, propyl, 2-propyl (isopropyl), butyl, and 2-methylpropyl.
  • ⁇ —C 6 alkoxy group means an alkyloxy group having 1 to 6 carbon atoms, specifically, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, t-butoxy group, pentoxy group And hexyloxy groups.
  • the C 2 -C 7 alkanoyl group in R 5 , R 10 , R 11 , R 13 , R 14 and R 15 is a carbonyl group substituted by an alkyl group having 1 to 6 carbon atoms. It means acetyl group, propionyl group, butyryl group, isopyryl group, valeryl group, isovaleryl group, pivaloyl group, pentanoyl group, hexanoyl group and the like.
  • C 2 -C 7 alkanoyloxy group for R 4 and R 9 include an acetooxy group, a propionyloxy group, a petyryloxy group, an isoptyryloxy group, a pareryloxy group, and an isopareryloxy group.
  • C 3 — ⁇ 7 cycloalkyl group means a cyclic alkyl group having 3 to 7 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group. Can be mentioned.
  • C 3 — ( 7 cycloalkoxy group in R 4 and R 9 include a cyclopropyl pyroxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, and a cycloheptoxy group. be able to.
  • Examples of the C 3 -C 7 cycloalkyloxycarbonyl group for R 3 and R 8 include a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, a cyclopentyloxycarbonyl group, and a cyclohexyl group. Oxycarbonyl group and cycloheptoxycarbonyl group.
  • the C 2 -C 6 alkenyl group for R 5 , R 10 , 11 , R 13 , R 14 and R 15 means an alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group (ethenyl group), Examples thereof include a cis-l-propenyl group, a trans-l-l-propenyl group, an aryl group (2-propenyl group), and an isopropyl group (1-methylvinyl group).
  • the C 2 -C 6 alkynyl group in R 5 , R 10 , 11 , R 13 , R 14 and R 15 means an alkynyl group having 2 to 6 carbon atoms, specifically, an ethynyl group and a 1-propynyl group And 2-propynyl groups.
  • the C 2 -C 6 alkenyloxy group for R 4 and R 9 means an alkenyloxy group having 2 to 6 carbon atoms, specifically, a vinyloxy group (ethenyloxy group), a cis-
  • Examples thereof include a 1-propenyloxy group, a trans-1-propenyloxy group, an aryloxy group (a 2-propenyloxy group), an isopropyloxy group (a 1-methylvinyloxy group), and the like.
  • the C 2 -C 6 alkynyloxy group in R 4 and R 9 means an alkynyloxy group having 2 to 6 carbon atoms, specifically, an ethynyloxy group, an 11-propynyloxy group,
  • Examples thereof include a 2-propynyloxy group.
  • Examples of the C 2 -C 6 alkenyloxycarbonyl group for R 3 and R 8 include a vinyloxycarbonyl group (ethenyloxycarbonyl group), a cis-11-propyloxycarbonyl group, and a trans-1-oxycarbonyl group. Examples thereof include 1-propenyloxycarbonyl group, aryloxycarbonyl group (2-propenyloxycarbonyl group), and isopropenyloxycarbonyl group (1-methylvinyloxycarbonyl group).
  • C 2 -C 6 alkynyloxycarbonyl group for R 3 and R 8 include an ethynyloxycarbonyl group, a 1-propynyloxycarbonyl group, and a 2-propynyloxycarbonyl group. Can be mentioned.
  • the aryl group means a monocyclic or polycyclic aromatic hydrocarbon group, and specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
  • aryloxy group in R 4 and R 9 include a phenoxy group, an 11-naphthyloxy group, and a 21-naphthyloxy group.
  • aryloxycarbonyl group for R 3 and R 8 include a phenoxycarbonyl group, an 11-naphthyloxycarbonyl group, and a 2-naphthyloxycarbonyl group.
  • the aroyl group in R 5 , R 10 , shaku 11 , R 13 , R 14 and R 15 means a carbonyl group substituted with an aryl group, specifically, a benzoyl group, Examples thereof include a naphthoyl group and a 2-naphthoyl group.
  • Specific examples of the aroyloxy group in R 4 and R 9 include a benzoyloxy group, an 11-naphthoyloxy group, and a 2-naphthoyloxy group.
  • R 5 , R 10 , R 11 R 13 , R 14, and R 15 tri (Ci-Cealkyl / phenyl) silyl groups are the same or different alkyl groups having 1 to 6 carbon atoms or phenyl groups.
  • a 3-substituted silyl group specifically, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, triphenylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, etc. be able to.
  • tri (Ci-C 6 alkyl / phenyl) silyloxy group for R 4 and R 9 include a trimethylsilyloxy group, a triethylsilyloxy group, a triisopropyl pyrsilyloxy group, a triphenylsilyloxy group, and a t -Butyldimethylsilyloxy group, t-butyldiphenylsilyloxy group and the like.
  • tri (CC 6 alkylphenyl) silyloxycarbonyl group in R 3 and R 8 include a trimethylsilyloxycarbonyl group, a triethylsilyloxycarbonyl group, a triisopropylsilyloxycarbonyl group, and a triphenylphenyl group.
  • examples thereof include an riloxycarbonyl group, a t-butyldimethylsilyloxycarbonyl group, and a t-butyldiphenylsilyloxycarbonyl group.
  • Examples of the substituted d—C 6 alkyl group include a halogen atom, C 3 — ( 7 cycloalkyl group, C “C 6 alkoxy group, ( ⁇ —C 6 alkylthio group, tri (( ⁇ -alkyl phenyl) silyl group, Ariru group or later substituent Ariru group has been substituted ⁇ "(can be cited 6 ⁇ alkyl group include chloromethyl group, trichloromethyl group, di Furuoromechiru group, triflate Ruo Russia methyl, trichloro port Echiru Halogenated C 1 -C 6 alkyl, cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclo to Kishiruechiru, C 3, such as Puchirumechiru group to consequent opening - C 7 shea click port alkyl C
  • Examples of the substituted d-Ce alkoxy group include halogenated monofluoroalkyl groups such as trifluoromethoxy group, trifluoroethoxy group and the like, C 6 alkoxy group, cyclopropylmethoxy group, 2-cyclopropylethoxy group, cyclobutylmethoxy group.
  • alkoxycarbonyl group include halogenated C 1 -C 6 alkoxycarbonyl groups such as trifluoromethoxycarbonyl group, trichloroethoxycarbonyl group, and cyclopropylmethoxycarbonyl group.
  • the substituted C 2 -C 7 alkyl group means a carbonyl group substituted by a substituted C -C 6 alkyl group, and specific examples thereof include a trichloroacetyl group and a trifluoroacetyl group. .
  • substituted C 2 -C 7 alkanoyloxy group in R 4 and R 9 include a trichloroacetoxy group and a trifluoroacetoxy group.
  • R 5 R 10 R 11 R 13 R 14 and R 15 include a styryl group and a cinnamyl group.
  • substituted C 2 -C 6 alkenyloxy group in R 4 and R 9 include a styryloxy group and a cinnamyloxy group.
  • substituted C 2 -C 6 alkenyloxycarbonyl group in R 3 and R 8 include a styryloxycarbonyl group and a cinnamyloxycarbonyl group.
  • Examples of the substituted aryl group include a C—Ce alkyl group, a substituted C 6 alkyl group, a halogen atom, a nitro group, a tolyl group, a C ⁇ —C 6 alkoxy group, a ( ⁇ —Ce alkyl / phenyl) thio group or an aryl group.
  • Examples thereof include C 1 -C 6 aryl groups substituted by a mono group or the like, and specific examples thereof include an ortho tolyl group, a metatolyl group, a paratolyl group, and a 2,3-dimethyl group.
  • a mesityl group 4 one isopropyl phenylalanine group (4 Kumiru group) one C 6 alkyl substituted ⁇ Li Ichiru group such as, 4-triflate Ruo b substituent such as a methyl Hue sulfonyl group ( ⁇ — ( 6- alkyl substituted aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, .2,4-difluorophenyl, 3,4-difluoro Halogen-substituted aryl groups such as phenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 4-bromophenyl group, 2-nitrophenyl group, 3-nitrophenyl group, 4-nitrophenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2-me
  • the substituted aryloxy group in R 4 and R 9 is an aryloxy group having the above-mentioned substituent on the aromatic ring, specifically, an ortho-tolyloxy group, a meta-tolyloxy group, a para-tolyloxy group, and a mesityloxy group.
  • a C 6 alkyl-substituted aryloxy group such as a 4-isopropylphenoxy group (4-cumyloxy group); a C i-C 6 alkyl-substituted aryloxy group, such as a 4-trifluoromethylphenoxy group; Halogen-substituted aryloxy groups such as fluoroxy phenoxy group, 3,4-difluorophenoxy group, etc., 2-nitrophenoxy group, 3-nitrophenoxy group, 412-trophenoxy group,
  • Such as 3-dimethoxyphenoxy group, 2,4-dimethoxyphenoxy group, 3,4-dimethoxyphenoxy group, and 4-ethoxyphenoxy group (such as: 1 C 6 alkoxy-substituted aryloxy group, Vias such as (C i -C 6 alkyl / phenyl) thio-substituted aryloxy group, 4-biphenyloxy group such as 4-methylthiophenoxy group and 4-phenylthiophenoxy group And a phenyloxy group.
  • the substituted aryloxycarbonyl group represented by R 3 and R 8 is an aryloxycarbonyl group having the above-mentioned substituent on an aromatic ring, specifically, an ortho-tolyloxycarbonyl group and a metatolyloxy group.
  • Ci-Ce alkyl-substituted aryls such as carbonyl, paratriloxycarbonyl, mesityloxycarbonyl, 4-isopropylphenoxycarboxyl (4-cumyloxycarbonyl) !
  • the substituted aryloyl group represented by R 5 , R 10 , R 11 , R 13 , R 14 and R 15 is an arylcarbonyl group having the above-described substituent on an aromatic ring.
  • Orutotoru oil groups are, Metatoruoiru group, Paratoruoiru group, mesylate Chiruka Lupo group, 4 one isopropyl benzo I le radical (4- Kumirukaruponiru group) one C 6 alkyl substituted Ari Rukaruponiru group such as, 4 one triflumizole Ruo b methyl Substitution of benzoyl group etc. C!
  • the substituted aryloxy group in R 4 and R 9 is an aryloxy group having the above-described substituent on an aromatic ring, and specifically, an ortho-toluoyloxy group, a metatoluoyloxy group, and a paratoluoyloxy group
  • a C 6 alkyl-substituted arylcarbonyloxy group such as mesitylcarbonyloxy group, 4-isopropylpropylbenzoyloxy group (4-cumylcarponyloxy group), Halogen-substituted aryl groups such as C X -C 6 alkyl-substituted arylcarbonyl groups, 4-fluorobenzoyloxy groups and 3,4-difluorobenzoyloxy groups Ruponyloxy, 2-nitrobenzoyloxy, 3-nitrobenzoyloxy, 4-nitrobenzoyloxy, 2-cyanobenzoyloxy, 3-sia Benzoyloxy, 4_cyanobenzoyl
  • a substituted aryl-C 6 alkyl group is an aryl C i -C 6 alkyl group having the above-described substituent on an aromatic ring, specifically, 2-methylbenzyl group, 3-methylbenzyl group, 4-Methylbenzyl group, 2-fluorobenzyl, 3-fluorobenzyl Group, 4-fluorobenzyl group, 4-chlorobenzyl group, 4-methoxybenzyl group, 2- (4-fluorophenyl) ethyl group, 3- (4-fluorophenyl) propyl group, etc. Can be.
  • the substituted ⁇ Li Ichiru C i one C 6 alkoxy group, ⁇ Li Ichiru (3 1 having a substituent group as described above on the aromatic ring - a C 6 alkoxy group include 2-methylbenzyl Oxy group, 3-methylbenzyloxy group, 4-methylbenzyloxy group, 2-fluorobenzyloxy group, 3-fluorobenzoyloxy group, 4-fluorobenzoyloxy group, 4-fluorobenzoyloxy group, 4-chlorobenzoyl group And a 4- (4-fluorophenyl) ethyloxy group, a 3- (4-fluorophenyl) propyloxy group, and the like.
  • R 6 and R 7 have the same meanings as described above.
  • Specific examples of the group represented by are: rubamoyl group, methylaminocarbonyl group, ethylaminocarbonyl group, propylamino Carbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group, pentylaminocarbonyl group, hexylaminocarbonyl group, benzylaminocarbonyl group, (2-fluorobenzyl) aminocarbonyl group, (4- Fluorobenzyl) Aminocarbonyl group, (4-methoxybenzyl) aminocarbonyl group, phenethylaminocarbonyl group, cyclopropylaminocarbonyl group, cyclobutylaminocarbonyl group, cyclopentylaminocarbonyl group, cyclohexylaminocarbonyl group, Mono-substituted aminocarbonyl groups such as cyclohept
  • the xanthone derivative of the present invention has the general formula (17) obtained from a culture of Penicillium sp. OPenicillium sp.
  • R 18 represents a hydrogen atom or a hydroxyl group
  • R 19 represents a hydrogen atom or a hydroxyl group
  • R 16 and R 17 are represented by one of the following [III] or [IV].
  • R 16 represents a methyl group
  • R 17 represents a group represented by any of the general formulas (18), (19), (20) and (22).
  • R 2 () represents a hydrogen atom or a carboxyl group
  • R 21 represents a hydrogen atom or a hydroxyl group.
  • R 22 is a hydrogen atom, a methoxymethyl group, or a compound of the formula (21)
  • R 16 represents a group represented by the general formula (23) or (24), and R 17 represents an acetyl group.
  • More specific examples of the compound represented by the general formula (25) and the compound represented by the general formula (26) include, for example, R 18 and R 2 Q are carboxyl groups, and R 19 and R 21 are hydroxyl groups.
  • a known compound such as a certain compound (tautomer, described in JP-A-5-239050); or, for example, R 18 is a hydrogen atom, R 19 and R 21 are hydroxyl groups, and R 2 Q is a lipoxyl group
  • New compounds can be mentioned.
  • More specific examples of the compound represented by the general formula (27) include, for example, a compound in which R 18 and R 20 are carboxyl groups, R 19 and R 21 are hydroxyl groups, and R 22 is a hydrogen atom, 18 and R 2 Q is R 19 is a hydroxyl group is the force Rupokishiru groups R 21 and R 22 is a water atom compounds, R 18 and R 2 Q is a carboxyl group R 19 and R 21 is a hydroxyl group A compound in which R 22 is a methoxymethyl group, a compound in which R 18 is a hydrogen atom, R 19 and R 21 are hydroxyl groups, R 2G is a carboxyl group, and R 22 is a methoxymethyl group, and R 18 and R 2 ° are R 19 and R 21 are hydroxyl groups and R 22 is a group represented by the formula (21)
  • More specific examples of the compound represented by the general formula (28) include, for example, novel compounds such as compounds in which R 18 and R 20 are hexoxy groups and R 19 and R 21 are hydroxyl groups. Can be.
  • More specific examples of the compound represented by the general formula (29) include, for example, R 18 and R Compound in which 20 is a carboxyl group and R 19 and R 21 are hydroxyl groups (Pure k Appl.
  • R 18 is a hydrogen atom
  • R 2 Q is a lipoxyl group
  • R 19 and R 21 are hydroxyl groups.
  • Known compounds such as certain compounds (described in Pure & Appl. Chem. 1994, Vol. 66, pp. 2383-2386), and R 18 and R 2 , for example.
  • R 19 is a hydrogen atom and R 21 is a hydroxyl group
  • R 18 and R 2 are carbonyl groups
  • R 19 is a hydroxyl group and R 21 is a hydrogen atom
  • R 18 is A compound in which R 19 and R 21 are hydroxyl groups and R 2 Q is a hydrogen atom
  • a compound in which R 18 is a carboxyl group, R 19 and R 2 Q are hydrogen atoms
  • R 21 is a hydroxyl group
  • More particular examples of the compound represented by the general formula (30), such as a compound R 18 are local Pokishiru group R 19 is a hydroxyl group, R 19 is R 18 is a hydrogen atom is a hydroxyl group compound And other novel compounds.
  • the xanthone derivative of the present invention can be synthesized from the above-mentioned compound obtained from a culture of Penicillium sp. SPF-3059 as a raw material, for example, by the following production methods [A] to [E]. Can be.
  • R 16 , R 17 , R 18 and R 19 are as defined above.
  • the compound represented by the general formula (31) is obtained by esterifying the propyloxyl group.
  • R 25 is a hydrogen atom, a C 6 alkoxycarbonyl group, a substituted C 6 alkoxycarbonyl group, a C 2 —C 6 alkenyloxycarbonyl group, a substituted C 2 —C 6 alkenyloxycarbonyl group, a C 2 —C 6 represents an alkynyloxycarbonyl group, an aryloxycarbonyl group or a substituted aryloxycarbonyl group, and R 19 has the same meaning as described above.
  • R 23 and R 24 is represented by one of [V] or [VI] below.
  • R 23 represents a methyl group
  • R 24 represents a group represented by any of the general formula (32), the general formula (33), the general formula (34) or the general formula (35).
  • R 21 is as defined above.
  • R 26 is a hydrogen atom, a C 6 alkoxycarbonyl group, a substituted C 6 alkoxycarbonyl group, a C 2 -C 6 alkenyloxycarbonyl group, a substituted C 2 —C 6 represents an alkenyloxycarbonyl group, a C 2 -C 6 alkynyloxycarbonyl group, an aryloxycarbonyl group or a substituted aryloxycarbonyl group.
  • R 23 represents a group represented by the general formula (36) or the formula (24), and R 24 represents an acetyl group.
  • esterification of a lipoxyl group for example, a method in which an excess amount of diazomethane or trimethylsilyldiazomethane is added dropwise to an alcoholic solvent such as methanol, ethanol, or isopropyl alcohol to act.
  • an alcoholic solvent such as methanol, ethanol, or isopropyl alcohol to act.
  • methanol Heating in an alcohol such as ethanol or isopropyl alcohol in the presence of an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as methanesulfonic acid, paratoluenesulfonic acid, trifluoromethanesulfonic acid or camphorsulfonic acid
  • an inorganic acid such as hydrochloric acid or sulfuric acid
  • an organic acid such as methanesulfonic acid, paratoluenesulfonic acid, trifluoromethanesulfonic acid or camphorsulfonic acid
  • a polar aprotic solvent such as dimethylformamide (DMF) or N-methylpiberidinone (NMP)
  • DMAP dimethylaminopyridine
  • R 29 is a hydrogen atom or a general formula (2)
  • R 27 and R 28 are represented by one of the following [VII] or [VIII].
  • R 27 represents a methyl group
  • R 28 represents the general formula (38), the general formula (39), the general formula (39) Represents a group represented by either 40) or the general formula (41).
  • R 21 is as defined above.
  • R 3G is a hydrogen atom or a general formula (2)
  • R 27 represents a group represented by the general formula (42) or (24), and R 28 represents an acetyl group.
  • a highly polar aprotic solvent such as dimethylformamide (DMF) or N-methylbiveridinone (NMP), if necessary, for example, dimethylaminopyridine (DMAP)
  • DMF dimethylformamide
  • NMP N-methylbiveridinone
  • DMAP dimethylaminopyridine
  • a base such as triethylamine, diisopropylethylamine or the like
  • an additive such as 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT).
  • EDC 11- (3-dimethylaminopropyl) -13-ethylcarbodiimide 'hydrochloride
  • DCC 1,3-dicyclohexylcarbodiimide
  • R 33 is a hydrogen atom, —C 6 alkoxycarbonyl group, substituted C 6 alkoxycarbonyl group, C 3 -C 7 cycloalkyloxycarbonyl group, 2 - 6 Arukeniru Okishikarubo group, a substituted c 2 -c 6 alkenyl O carboxymethyl Cal Poni group, c 2 _c 6 alkynyl O carboxy Cal Poni group, ⁇ reel O carboxymethyl Cal Poni group, a substituted ⁇ reel O propoxycarbonyl alkylsulfonyl group or tri ( C ⁇ - Ce alkyl / phenyl) represents a silyl O carboxymethyl Cal Po two Le group, R 34 is a hydrogen atom, CI- Ce alkoxy, substituted C ⁇ - Ce alkoxy groups, (: 3 - (- 7 consequent opening alkoxy group, A C 2 —C 6 alkenyloxy group, a substituted C 2 —C 6 alkeny
  • R 31 and R 32 is represented by one of [IX] or [X] below.
  • R 31 represents a methyl group
  • R 32 represents a group represented by any of the general formula (44), (45), (46) or (48).
  • R 36 is a hydrogen atom, a Ci—C 6 alkoxycarbonyl group, a substituted C—Ce alkoxycarbonyl group, C 3 — (: a 7 cycloalkyloxycarbonyl group, C 2 — C 6 Alkenyloxycarbonyl, substituted C 2 —C 6 alkenyloxycarbonyl, C 2 —C 6 alkyl Cycloalkenyl O carboxymethyl Cal Poni group, represent ⁇ reel O carboxymethyl Cal Poni group, a substituted ⁇ reel O propoxycarbonyl sulfonyl group, or a tri (one C 6 alkyl / phenyl) silyl O carboxymethyl Cal Po two group, R 37 is a hydrogen atom, ⁇ - C 6 alkoxy groups, substituted C ⁇ —Ce alkoxy groups, C 3 —C 7 cycloalkoxy groups, C 2 —C 6 alkenyloxy groups, substituted C 2 —C 6 alkenyl
  • R 35 , R 36 and R 37 are as defined above.
  • R 38 is a hydrogen atom, a methoxymethyl group, or a compound represented by the general formula (47)
  • R 35 , R 36 and R 37 are as defined above.
  • R 31 represents a group represented by the general formula (49) or (50), and R 32 represents an acetyl group.
  • the reaction solvent is preferably a highly polar aprotic solvent such as dimethylformamide (DMF) or N-methylbiveridinone (NMP).
  • the base used is cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, phosphoric acid.
  • Inorganic bases such as potassium, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, and pyridine, lutidine, coridine, dimethylaminopyridine (DMAP ), Triethylamine, diisopropylethylamine, imidazole, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like.
  • DMF dimethylformamide
  • NMP N-methylbiveridinone
  • Halogenated alkyls having a substituent such as 3-fluorobenzyl bromide, 4-fluorobenzyl, 4-fluorobenzyl, 3-methoxybenzyl, and halogenated alkyls such as allyl iodide and bromodiaryl.
  • the drier include, but are not limited to, trimethyl silane chloride, triethyl silane chloride, t-butyl dimethyl dimethyl silane, and the like.
  • a phase transfer catalyst such as tetrabutylammonium iodide or benzyltributylammonium iodide may be used, if necessary. .
  • R 41 is a hydrogen atom, ( ⁇ - Ce alkoxycarbonyl group, a substituted CfCe alkoxy Shikarubo group, C 3 - (7 cycloalkyl O alkoxycarbonyl group, ⁇ 2 - ⁇ 6 Arukeniru Okishikaruponiru group, a substituted C 2 —C 6 alkenyloxycarbonyl, c 2 -c 6 alkynyloxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, tri (C i _C 6 alkyl / phenyl) Silyloxycarbonyl group or general formula (2)
  • R 42 is a hydrogen atom, a C 2 —C 7 alkanoyloxy group, a substituted C 2 —C 7 alkanoy Ruokishi group, ⁇ 4 - ⁇ 8 consequent opening alkyl Cal Poni Ruo carboxymethyl group, Aroiruokishi group, a substituted Aroiruokishi group, CI- C 6 alkoxy group, a substituted C ⁇ - Ce alkoxy group, (3 - (7 Shikuroarukokishi group, C 2 - C fi alkenyloxy, substituted C 1 C fi alkenyloxy, C.
  • R 43 is C 2 - C 7 Arukanoiru group, a substituted C 2 - (3 7 Aruka Noiru group, (: 4-(8 cycloalkyl Cal Poni group, Aroiru group, a substituted Aroiru groups, C ⁇ _ ⁇ alkyl group, a substituted C ⁇ - Ce alkyl groups, C 3 - (7 cycloalkyl, C 2 -C 6 alkenyl group, a substituted C 2 — Represents a C 6 alkenyl group, a C 2 —C 6 alkynyl group, an aryl group, a substituted aryl group or a tri (Ci-Cealkyl / phenyl) silyl group, R 39 and R 4 are the
  • R 39 represents a methyl group
  • R 40 represents a group represented by any of the general formula (52), (53), (54) or (56).
  • R 44 is a hydrogen atom, a Ci—Ce alkoxycarbonyl group, a substituted ⁇ —Cealkoxycarbonyl group, a C 3 _C 7 cycloalkyloxycarbonyl group, a C 2 —C 6 alkenyloxycarbonyl group, a substituted C 2 — C 6 alkenyloxycarbonyl, C 2 _C 6 alkynyloxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, tri (— C 6 alkylphenyl) silyloxycarbonyl Group or general formula
  • R 45 is a hydrogen atom, a C 2 _C 7 alkanoyloxy group, a substituted C 2 —C 7 alkanoy Roxy group, C 4 —C 8 cycloalkylcarbonyloxy group, arylooxy group, substituted arylooxy group, C—C 6 alkoxy group, substituted ( ⁇ —C 6 alkoxy group, C 3 —C 7 cycloalkoxy group, C 2 — C 6 alkenyloxy, substituted C 2 — C 6 alkenyloxy, C 2 _C 6 alkynyloxy Shi group, a Ariruokishi group, a substituted Ariruokishi group or tri one c 6 alkyl z Hue) yl Shiriruokishi group.
  • R 43 has the same meaning as described above.
  • R 46 is a hydrogen atom, a methoxymethyl group, or a compound represented by the general formula (55)
  • R 39 represents a group represented by the general formula (57) or (58), and R 40 represents an acetyl group.
  • R 4 3, R 44 and R 4 5 is as defined above.
  • Such alkylation and silylation of the hydroxyl group can be carried out by the above-mentioned production method [C].
  • an octogen solvent such as dichloromethane, 1,2-dichloroethane, cyclobenzene, dichlorobenzene, etc. can be used.
  • such hydroxyl group is a highly polar aprotic solvent such as dimethylformamide (DMF) or N-methylbiberidinone (NMP), or dichloromethane, 1,2-dichloroethane, Pyridine, lutidine, collidine, dimethylaminopyridine (DMAP), triethylamine, diisopropylethylamine, imidazole, sodium methoxide, sodium ethoxide, potassium t-butoxide in halogen solvents such as benzene and dichlorobenzene
  • Organic bases such as cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium hydroxide, water
  • an inorganic base such as lithium oxide
  • Agents can be synthesized by reacting the.
  • acylating agent examples include acetic anhydride and trifluoroacetic anhydride.
  • Acid anhydrides such as acetic acid, for example, acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, 2-fluorobenzoyl chloride, 3-fluorobenzoyl chloride, 4-fluorobenzoyl chloride, salt Acid chlorides such as 4-methoxybenzoyl can be exemplified, but of course, this is not a limitation.
  • the hydroxyl group can be also carried out by the method described in the above-mentioned production method [B], that is, by a condensation reaction between the hydroxyl group and various carboxylic acids.
  • R 36 in R 33 of the compound represented by the above general formula (43) is an ester group or a tri (CA 6 alkyl / phenyl) silyloxycarbonyl group, or If one even without less of R 44 in R 41 of the compound represented by the formula (51) is an ester group, or (Ci one C 6 alkyl Z phenyl) Shiriruokishikaru Poniru group selectively hydrolyzing this other ester groups optionally amide or tri - by conversion to (C ⁇ C 6 alkyl / phenyl) silyl O alkoxycarbonyl group, the general formula (59)
  • R 3 , R 42 and R 43 have the same meaning as described above.
  • R 47 and R 48 are represented by one of the following [XIII] or [XIV].
  • R 47 represents a methyl group
  • R 48 represents a group represented by any of the general formulas (60), (61), (62) and (63).
  • R 8 , R 43 , R 45 and R 46 are as defined above.
  • R 47 represents a group represented by the general formula (64) or (58), and R 48 represents an acetyl group.
  • the method for hydrolyzing the ester group includes, for example, an alcoholic solvent such as methanol, ethanol and isopropyl alcohol; an ethereal solvent such as tetrahydrofuran (THF) and dioxane; It can be synthesized by reacting a base such as potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate and the like in the presence of an excess amount of water.
  • a base such as potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate and the like in the presence of an excess amount of water.
  • this method cannot be applied when protecting groups on the hydroxyl group such as some acyl groups are simultaneously hydrolyzed by this method.
  • an ethereal solvent such as tetrahydrofuran (THF) or dioxane, or a mixed solvent thereof in the presence of an equivalent or excess amount of water, Hydrofluoric acid, hydrogen fluoride-pyridine complex, tetrabutylammonium fluoride, etc.
  • THF tetrahydrofuran
  • hydrogen fluoride-pyridine complex tetrabutylammonium fluoride, etc.
  • Esterification, amidation or tri (C ⁇ -Ce alkyl / phenyl) silylation of the obtained carboxylic acid can be carried out, for example, by the method described in the above-mentioned production method [A], [B] or [C]. It can be carried out.
  • derivatives obtained by further alkylating, silylating or acylating such derivatives by the method described in the production method [C] or [D] are also included in the compound of the present invention.
  • the reaction temperature in each of the above-mentioned reactions can be appropriately selected within the range from ice-cooling to the boiling point of the solvent.
  • the reaction time for each reaction varies greatly depending on the reaction temperature and the type of reagent, but is generally between 30 minutes and 2-3 days.
  • a means generally used for isolating and purifying the reaction product can be used.
  • the usual isolation and purification methods from the reaction mixture such as solvent extraction, ion exchange resin, adsorption chromatography, partition chromatography, gel filtration chromatography, High performance liquid chromatography (HPLC), thin layer chromatography and the like can be used, and these isolation and purification methods can be performed alone or in combination.
  • salts thereof preferably pharmaceutically or veterinarily acceptable.
  • Such salts are also included in the scope of the present invention.
  • the salt include an inorganic base salt such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt, an aluminum salt, and an ammonium salt, a triethylammonium salt, a triethanolammonium salt, a pyridinium salt, and a diisonium salt.
  • organic base salts such as propylammonium salt, and basic amino acid salts such as arginine and lysine.
  • These salts can be prepared by reacting a base with a suitable solvent such as water, methanol, ethanol, acetone, ethyl acetate, chloroform and ether.
  • the preventive or therapeutic agent for neuropathic disease and Z or neurodegenerative disease including the disease involving spinal nerve damage and Z or peripheral nerve damage is effective for nerve elongation repulsion factor inhibitors, and particularly for the above semaphorin inhibitors.
  • nerve regeneration promoter as a component
  • Ingredients for various preparations such as pH buffer, disintegrant, solubilizer, solubilizer, isotonic agent, etc. can be added.
  • These prophylactic or therapeutic agents can be administered orally or parenterally.
  • a powder, granule, capsule, syrup, suspension, etc. or, for example, a solution, emulsion, suspension, etc.
  • parenteral administration in the form of an injection it can also be administered intranasally in the form of a spray.
  • the dose and the number of times of administration vary depending on the administration method and the age, weight, and medical condition of the patient, but the method of local administration to the site of the bed is preferred. Nerve regeneration usually requires a period of several days to several months or more, and thus it is preferable to administer the nerve once or twice or more in order to suppress the activity of semaphorin. When administered twice or more, it is desirable to administer the drug daily or repeatedly at appropriate intervals.
  • the dose can be several hundred g to 2 g, preferably tens of mg or less as a semaphorin inhibitor per dose.Use a sustained-release formulation to reduce the number of doses, or use an osmotic pump. Can be administered in small doses over a long period of time. In any of these administration methods, the administration route and administration method must be such that the concentration at the site of action sufficiently inhibits the activity of semaphorin. It is preferable to employ it.
  • Neuropathic diseases and / or neurodegenerative diseases including the above-mentioned diseases involving spinal nerve damage and / or peripheral nerve damage include peripheral nerve and central nerve injuries, degenerative diseases, that is, olfactory disorders caused by aging, etc.
  • Nerve injury other than olfaction due to trauma such as spinal cord injury, neuropathy caused by cerebral infarction, facial nerve palsy, diabetic neurosis, glaucoma, retinitis pigmentosa, Alheimer's disease-Parkinson's disease, ALS, etc.
  • diseases associated with angiogenesis involving VEGF165 in which the receptor is neuropilin in common are also of interest.
  • nerve regeneration promoter of the present invention is not limited to pharmaceuticals such as preventive or therapeutic agents for neuropathic diseases and Z or neurodegenerative diseases, but may be used industrially as veterinary drugs and semaphorin signal inhibitors. It can also be used as an important experimental reagent.
  • the nerve regeneration-promoting agent of the present invention contains a semaphorin inhibitor as an active ingredient, regeneration of the olfactory nerve, which is a peripheral nerve, and the olfactory bulb in the brain and spinal cord, cerebral cortex, hippocampus, striatum, thalamus, It promotes the regeneration of nerves in the central nervous system, which is the area of the brain, midbrain, cerebellum, pons, medulla, medulla, medulla, retina, etc., which is separated by the cerebrospinal barrier.
  • a semaphorin inhibitor as an active ingredient
  • any of the raw material compounds represented by the above formula (17) can be effectively obtained by culturing mold SPF-359 strain belonging to the genus Penicillium isolated from soil in Osaka Prefecture.
  • the SPF-359 strain has the following mycological properties.
  • Colonies grow slowly on Wapec agar medium, 3.1-3.2 cm in diameter, fluffy on 25 and 21 days, white or gray on colony surface, creamy on colony back surface, soluble pigment Production and sporulation are not observed.
  • On an oatmeal agar medium (Nippon Pharmaceutical actinomycete medium No. 3 “Digo”), the colony grew slowly and exhibited a diameter of 2.0 to 2. lcm, fluffy at 25 ° C and 21 days. The colony surface is white, gray-green or yellow, and the colony back surface is cream or gray. No production of soluble pigment is observed, but conidia are formed.
  • the conidiophores are smooth, 5 to 20 / im in length, and 3 to 6 phialides are monotonous at the tip of the conidiophores.
  • the flies are 3-4 in length, with 2-10 conidia forming a chain from the tip.
  • Conidia are spherical, 2.2 to 2.
  • the strain was identified as a strain belonging to the genus Penicillium, and was named Penici Ilium sp. SPF-3059. Based on the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for Patent Procedures, the strain was deposited on July 13, 2001 with the Patent Organism Depositary of the National Institute of Advanced Industrial Science and Technology (AIST) under the accession number FERM. Deposited as BP-7663.
  • the medium used for culturing the above SPF-3059 strain may be liquid or solid, but usually shaking culture or aeration stirring culture using a liquid medium is advantageous.
  • the medium to be used is not particularly limited.
  • the carbon source include glucose, sucrose, glycerin, starch, dextrin, molasses, and the like.
  • the nitrogen source include peptone and casamino acid.
  • Organic nitrogen sources such as amino acids such as protein hydrolyzate, meat extract, yeast extract, soybean flour, cottonseed flour, corn steep liquor and histidine, and inorganic nitrogen sources such as ammonium salt and nitrate are used.
  • inorganic salts such as various phosphates, magnesium sulfate, sodium chloride, potassium chloride, and calcium carbonate can be added for osmotic pressure adjustment, pH adjustment, replenishment of trace components, and the like.
  • various vitamins, nucleic acid-related compounds and the like may be added for the purpose of promoting the growth of bacteria.
  • an antifoaming agent such as silicone oil, polypropylene dalicol derivative, and soybean oil.
  • the culture temperature is preferably in the range of 20 to 35 ° C, more preferably in the range of 25 to 30, and the pH of the culture medium is, for example, in the vicinity of neutrality.
  • the culture period may be, for example, in the range of 5 to 10 days. it can.
  • a commonly used isolation and purification means is used from a culture of the secondary metabolite produced by the microorganism.
  • the usual isolation and purification methods from the culture filtrate such as solvent extraction, ion exchange resin, adsorption chromatography, partition chromatography, gel filtration chromatography, and high-speed Liquid chromatography (HPLC), thin-layer chromatography and the like can be used, and these isolation and purification methods can be performed alone or in combination.
  • the cells collected by means such as filtration or centrifugation can be directly extracted using a water-soluble organic solvent such as acetone or methanol.
  • the target compound can be obtained from the extract in the same manner as in the isolation and purification from the culture supernatant.
  • Glucose 2%, sucrose 5%, cottonseed powder 2%, sodium nitrate 0.1%, L-histidine 0.1%, dipotassium phosphate 0.05%, potassium chloride 0.07%, magnesium sulfate 75 ml of a medium containing 0.0014% of heptahydrate and adjusted to pH 7.0 was dispensed into a 500 ml 1 Sakaguchi flask and sterilized by autoclaving.
  • a loopful of Penicillium sp. SPF-3059 (FERM BP-77663) which had been slope-cultured, was inoculated into the loop and precultured by shaking at 130 rpm at 27 ° C for 5 days.
  • Dispense 300 ml of medium of the same composition as above into 10 2-liter volume flasks and sterilize with autoclave.Add the above preculture solution at 6 ml each, and bring to 27 ° C and 110 rpm. For 7 days.
  • the culture was centrifuged at 4 ° (:, 10,000 rpm for 10 minutes to separate the supernatant and the cells, and the supernatant fraction was added to 3 liters of ethyl acetate-formic acid (99: The cell fraction was extracted with 3 liters of acetone, filtered, concentrated, and converted to an aqueous solution, then extracted with 1 liter of ethyl acetate-formic acid (99: 1). The eluates were mixed and concentrated under reduced pressure to obtain 10.4 g of a crude extract.
  • Glucose 2%, sucrose 5%, cottonseed powder 2%, sodium nitrate 0.1%, L-histidine 0.1%, dipotassium phosphate 0.055%, potassium chloride 0.07%, magnesium sulfate 10 ml of a medium conditioned by feeding 0.007% of heptahydrate to pH 7.0 was dispensed into a 5 Om1 Erlenmeyer flask and sterilized by autoclave.
  • a loopful of Penicillium sp. SPF-3059 strain (FERM BP-7663), which had been subjected to slope culture, was inoculated with one loopful, and cultured with rotary shaking at 27, 180 rpm for 4 days to obtain a pre-culture.
  • glucose 1.43%, sucrose 3.57%, cottonseed powder 1.43%, sodium nitrate 0.07%, L-histidine 0.07%, phosphoric acid 2 Contains 0.036% of potassium, 0.055% of potassium chloride, 0.001% of magnesium sulfate 7 hydrate, 0.011% of Adekinol LG-295S (Asahi Denka defoamer), pH 7.0 After dispensing 30 liters of the prepared medium and sterilizing by high-pressure steam (121 ° C, 20 minutes), add 500 ml of the above pre-cultured solution, and at 27, 400 rpm, aeration rate of 15 liter / min. The cells were cultured with aeration and stirring for 9 days.
  • the culture was centrifuged at 10,000 rpm for 10 minutes to separate the supernatant and the cells, and the supernatant fraction was washed twice with 20 liters of ethyl acetate-formic acid (99: 1). Extracted.
  • the cell fraction was extracted with 30 liters of acetone, filtered, concentrated, and then converted to an aqueous solution, and then extracted with 10 liters of ethyl ethyl-formic acid (99: 1). Both extracts were mixed and concentrated under reduced pressure to obtain 224 g of a crude extract.
  • the crude extract (100 g) was dissolved in 50 Om 1 of methanol, subjected to column chromatography using Seadex TM LH-20 (Amersham Pharmacia Biotech), and eluted with methanol.
  • the active fractions were collected, and the solvent was distilled off under reduced pressure to obtain 48.8 g of an oil.
  • This was dissolved in 40 Om 1 of methanol and subjected to column chromatography using TSKgel TM TOYOPER L HW-40F (Tosoichi), and eluted with methanol.
  • the active fraction was collected, and the solvent was distilled off under reduced pressure to obtain 21.8 g of a crude product.
  • the eluted fractions of the preparative HP LC were collected using the retention time in this analytical HPLC as an index, the solvent was distilled off under reduced pressure, and the fraction was again subjected to the preparative HP LC and purified in the same manner as described above. Purify the product by column chromatography using TSK ge 1 TM TOYOP ERL HW-40F (Tosoichi) in the same manner as above, evaporate the solvent under reduced pressure, and dry to obtain the purified product shown below. Obtained.
  • Penicillium sp. SPF isolated from a culture of strain 3059—5-Acetyl-7-[(5-carboxy-1,6,7-dihydroxy-4-oxo-1H-2—1— Benzopyran-1 (4H) -ylidene) hydroxymethyl] 1-2,3-dihydroxy-6-methyl-9-oxo-9H-xanthene-11-Carboxylic acid and its tautomeric mixture (SPF-3059) — 1) (50.0 mg, 86 mo 1) was dissolved in 15 ml of methanol which had been degassed under reduced pressure and then purged with argon, degassed under reduced pressure and purged with argon.
  • Example 4 3.82 (s, 6H), 3.69 (s, 3H), 3.65 (s, 3H), 3.32 (s, 3H), 2.66 (s, 3H), and 2.18 (s, 3H).
  • Penicillium sp. SPF isolated from a culture of strain 3059—purified 5-acetyl _ 7— [(5-potassyloxy-1,6,7-dihydroxy-4-oxo-2H— 1-Benzopyran-1 3 (4H) -ylidene) hydroxymethyl] -2,3-dihydroxy-6_methyl_9-oxo-9H-xanthene-1-1
  • One-strength rubonic acid and mixtures with its tautomers (SPF-3059-1) (5.0 mg, 8.6 o 1) was dissolved in 1.5 ml of dimethylformamide (DMF), which had been degassed under reduced pressure and then replaced with nitrogen. The atmosphere was replaced with nitrogen.
  • DMF dimethylformamide
  • Penicillium sp. SPF isolated from a culture of 3059 strain —Purified 5-Acetyl-7 — [(5-Capuloxy-6,7—dihydroxy—
  • the xanthone derivative of the present invention has the growth cone regression activity of semaphorin, and therefore has a peripheral or central nerve regeneration-promoting action, and is used as a preventive agent for various neuropathic diseases and neurodegenerative diseases. It can be used advantageously as a therapeutic agent.

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Abstract

L'invention concerne un composé représenté par la formule suivante (1). R3 représente hydrogène, carboxy, alkoxycarbonyle, etc.; R4 représente hydrogène, hydroxy, alkanoyloxy, cycloalkylcarbonyloxy, aroyloxy, etc.; R5 représente hydrogène, alkanoyl, cycloalkylcarbonyl, aroyl, etc.; et R1 et R2 sont tels que définis ci-dessous: [I] R1 représente méthyle et R2 représente un groupe représenté par la formule (3), etc., ou [II] R1 représente un groupe représenté par la formule (8), etc., et R2 représente acétyle. Le dérivé de xanthone est utilisé en tant qu'agent prophylactique ou thérapeutique pour diverses maladies neurodégénératives/neuropathiques.
PCT/JP2003/000438 2002-01-21 2003-01-20 Derive de xanthone WO2003062440A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1693060A1 (fr) * 2003-12-05 2006-08-23 Dainippon Sumitomo Pharma Co., Ltd. Agents therapeutiques ou preventifs destines a la neuropathie ischemique
WO2012115182A1 (fr) 2011-02-25 2012-08-30 学校法人慶應義塾 Agent thérapeutique pour une lésion de nerf sensoriel cornéen contenant un inhibiteur de la sémaphorine en tant que principe actif
WO2017122722A1 (fr) 2016-01-15 2017-07-20 大日本住友製薬株式会社 Composé bihétérocyclique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992016517A1 (fr) * 1991-03-22 1992-10-01 Xenova Limited Derives de xanthone pour usage pharmaceutique
EP0896058A1 (fr) * 1995-12-06 1999-02-10 Sumitomo Pharmaceuticals Company, Limited Nouvelle semaphorine z et gene la codant
WO2002009756A1 (fr) * 2000-07-28 2002-02-07 Sumitomo Pharmaceuticals Company, Limited Promoteurs de la regeneration des nerfs contenant un inhibiteur de semaphorine en tant qu'ingredient actif

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992016517A1 (fr) * 1991-03-22 1992-10-01 Xenova Limited Derives de xanthone pour usage pharmaceutique
EP0896058A1 (fr) * 1995-12-06 1999-02-10 Sumitomo Pharmaceuticals Company, Limited Nouvelle semaphorine z et gene la codant
WO2002009756A1 (fr) * 2000-07-28 2002-02-07 Sumitomo Pharmaceuticals Company, Limited Promoteurs de la regeneration des nerfs contenant un inhibiteur de semaphorine en tant qu'ingredient actif

Non-Patent Citations (2)

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Title
"Unified nomenclature for the semaphorins/collapsins", CELL (SEMAPHORIN NOMENCLATURE COMMITTEE), vol. 97, 1999, pages 551 - 552, XP002940553 *
WRIGLEY S.K. ET AL.: "Structure elucidation of xanthone derivatives with CD4-binding activity from penicillium glabrum (Wehmer) Westling", PURE & APPL. CHEM., vol. 66, no. 10/11, 1994, pages 2383 - 2386, XP001052709 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1693060A1 (fr) * 2003-12-05 2006-08-23 Dainippon Sumitomo Pharma Co., Ltd. Agents therapeutiques ou preventifs destines a la neuropathie ischemique
EP1693060A4 (fr) * 2003-12-05 2008-09-17 Dainippon Sumitomo Pharma Co Agents therapeutiques ou preventifs destines a la neuropathie ischemique
JP4820170B2 (ja) * 2003-12-05 2011-11-24 大日本住友製薬株式会社 虚血性神経障害治療又は予防剤
WO2012115182A1 (fr) 2011-02-25 2012-08-30 学校法人慶應義塾 Agent thérapeutique pour une lésion de nerf sensoriel cornéen contenant un inhibiteur de la sémaphorine en tant que principe actif
WO2017122722A1 (fr) 2016-01-15 2017-07-20 大日本住友製薬株式会社 Composé bihétérocyclique
US10323024B2 (en) 2016-01-15 2019-06-18 Sumitomo Dainippon Pharma Co., Ltd. Biheterocyclic compound
US10870642B2 (en) 2016-01-15 2020-12-22 Sumitomo Dainippon Pharma Co., Ltd. Biheterocyclic compound
US11440905B2 (en) 2016-01-15 2022-09-13 Sumitomo Pharma Co., Ltd. Biheterocyclic compound
US11731960B2 (en) 2016-01-15 2023-08-22 Sumitomo Pharma Co., Ltd. Biheterocyclic compound

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