WO2003062440A1 - Xanthone derivative - Google Patents

Abstract

A compound represented by the following formula: (1) wherein R3 represents hydrogen, carboxy, alkoxycarbonyl, etc.; R4 represents hydrogen, hydroxy, alkanoyloxy, cycloalkylcarbonyloxy, aroyloxy, etc.; R5 represents hydrogen, alkanoyl, cycloalkylcarbonyl, aroyl, etc.; and R1 and R2 are as follows: R1 represents methyl and R2 represents a group represented by the formula (3) etc., or R1 represents a group represented by the formula (8) etc., and R2 represents acetyl. The xanthone derivative is useful as a preventive or therapeutic agent for various neuropathic diseases/neurodegenerative diseases.

Description

 Xanthone derivative

Technical field

 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. Background art

Nerve cells are special tissues that have no division ability in adults. Therefore, once a failure is sustained, it continues for a long time. In particular, 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. Furthermore, since regeneration requires a long period of time, nerve cells are often killed during this period, and the function cannot be restored in many cases. In the case of peripheral nerves having regenerative ability, they cannot be extended at all in the central nervous system environment such as the brain and spinal cord. For this reason, it is said that the central nervous system contains substances that inhibit nerve growth. When the nerve regeneration inhibitor present in the central nervous system is suppressed with an antibody or the like, the nerve regeneration occurs in a part of the central nervous system, and the function is restored. Recently, Nogo was discovered as a central nerve regeneration inhibitor (Nature 403, 434, 2000, Nature 403, 439, 2000). However, by inhibiting Nogo, some of the nerve fibers regenerate, and it is thought that other regeneration-inhibiting substances may be present. It has not been revealed so far. By the way, 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. As a study to analyze the function of semaphorin in vivo, studies have been conducted on knockout mice of neuropilin-11, a component of the Sema 3A receptor (Neuron 19, 995, 1997). Although the knockout mouse is embryonic lethal, it is known that some nervous systems, such as the trigeminal nerve, have abnormal running and abnormal blood vessel formation. On the other hand, similar nervous system running abnormalities are observed in Sema 3A knockout mice.

For other semaphorins, antagonistic antisense nucleotides such as antibodies to semaphorin W, semaphorin Y, and semaphorin Ζ should be used as central nervous system regeneration promoters (TO98 / 15628, W098 / 11216, W098 / 20928) Also, 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) is known. However, 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.

 That is, the present invention relates to the general formula (1)

[Wherein, 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⁾

(Wherein 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. Represents a group represented by), R ⁴ is a hydrogen atom, a hydroxyl group, C ₂ - 0 ₇ § Rukanoiruokishi group, a substituted C ₂ - C ₇ alkanoyloxy Noi Ruo alkoxy group, C ₄ -〇 ₈ cycloalkylcarbonyl O alkoxy group, Aroiruokishi group, a substituted Aroiruokishi group, CI- Ce an alkoxy group, monosubstituted C ₆ alkoxy group, 〇 ₃ _〇 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, substituted C ₂ - C ₇ aralkyl force Noiru groups, C ₄ i (3 ₈ cycloalkyl group, Aroiru group, a substituted Aroiru groups, C i-Ce alkyl group, monosubstituted C _e alkyl group, 〇 ₃ _〇 ₇ cycloalkyl groups, C ₂ -C ₆ Al Group, a substituted C ₂ - C ₆ alkenyl group, C ₂ -. C ₆ alkynyl group, an Ariru group, substitution Ariru group or tri (CI- Ce alkyl / phenyl) silyl groups R ¹ and R ^2, the following Is represented by either [I] or [Π].

[I] R ¹ represents a methyl group, and R ² represents a group represented by any of the general formulas (3), (4), (5) and (7).

(Wherein, 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 -〇 ₆ Arukiru 7 phenyl) Shiriruokishikaru Poniru group or the general formula (2)

(Wherein, R ⁶ and R ⁷ have the same meanings as described above.), Wherein R ⁹ is a hydrogen atom, a hydroxyl group, a C ₂ —C ₇ alkanoyloxy group, a substituted C ₂ —C ₇ Arca Noi 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 atom, C ₂ _C ₇ alkanoyl group, substitution ₂ — C ₇ alkanoyl group, (: ₄ _ ( ₈ cycloalkylcarbonyl group, aryloyl group, substituted aryloyl group, —C ₆ alkyl group, substitution — C ₆ alkyl groups, C ₃ — 〇 ₇ a cycloalkyl group, 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 tri (^ - C ₆ alkyl / phenyl) silyl group The table

(Wherein, 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. group, § b I group, a substituted Aroiru groups, C "C ₆ alkyl group, a substituted CfCe alkyl group, c ₃ -c ₇ cycloalkyl groups, C ₂ - C ₆ alkenyl group, a substituted C ₂ - C ₆ alkenyl group, C ₂ - C ₆ 7 Rukiniru group, a Ariru group, a substituted Ariru group or tri (Ci one C ₆ alkyl / phenyl) silyl group).

(Wherein, R ⁸ , R ⁹ and R ^1Q are as defined above. R ¹² is a hydrogen atom, a methoxymethyl group, or a compound represented by the general formula (6)

(Wherein, 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.)

(Is wherein, R ^8, R ⁹ and R ^1Q the same meanings as above 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).

[II] R ¹ represents a group represented by the general formula (8) or (9), and R ² represents an acetyl group. Represent.

(In the formula, R ⁸ , R ⁹ and R ^1Q are as defined above.)

(Wherein, 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.)

However, when both 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. ] It is related with the xanthone derivative represented by these. More specifically, general formula (10)

(Wherein, R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ and R ^{1 ()} are as defined above), and a compound represented by the general formula (11)

(Wherein, R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are as defined above), and a compound represented by the general formula (12)

(Wherein, R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ and R ¹⁰ are as defined above. R ¹² is a hydrogen atom, a methoxymethyl group, or a compound represented by the general formula (13)

(Wherein, R ¹³ has the same meaning as described above.) A compound represented by the general formula (14)

(Wherein, R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ^1Q and R ¹⁴ are as defined above), and a compound represented by the general formula (15)

(Wherein, 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.) And a compound represented by the general formula (16)

(Wherein R ³ , R ⁴ , R ⁵ and R ¹⁵ are as defined above). In any case, 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.

BEST MODE FOR CARRYING OUT THE INVENTION

 In the present invention, 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). More preferably, 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,

Mo 11. Ce 11. Neurosc i.13, 9-23 (1999)). Sequence information of these semaphorin-encoding genes is disclosed in the GenBank database (the above-mentioned literature). Further, 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.

For example, semaphorin 6 C (Sema 6C) 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.

 In the present invention, 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) The action of promoting nerve regeneration. Here, 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. In addition to the stimulatory effect, 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. This also includes the effect of promoting nerve regeneration when the tissue is In addition, 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. For the latter, specifically, 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. As the semaphorin inhibitor of the present invention, a compound having a central and peripheral nerve regeneration promoting action is particularly preferred. In addition, in the above, 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. After the state, 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) is added, and a predetermined time (for example, (1 hour, for example) This refers to the activity that disappears the growth cone observed after continued culture. In order to observe the elongated neurites and the growth cone at the tip of the neurites, cultivation of neurons in vitro is usually performed for 10 to 20 hours. Can be changed as appropriate. For example, in this experimental system, 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. Further, as 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. In addition, 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. Inhibition of semaphorin activity is achieved by inhibiting or blocking any part of these series of reactions. 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. That is, 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. As 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.For example, 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. Group, 3-methylpropyl group (isobutyl group), t-butyl group, pentyl group, neopentyl group, hexyl group and the like.

(: 丄 —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.

C in R ³ and R ⁸ ! An C ₆ alkoxycarbonyl group, specifically meth alkoxycarbonyl group, ethoxy Cal Poni group, propoxy Cal Poni group, Isopuropoki aryloxycarbonyl group, butoxide deer Lupo sulfonyl group, t one butoxycarbonyl group, pen Bok Kishika Ruponiru group, to Xyloxycarbonyl groups and the like can be mentioned.

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.

Specific examples of the 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. Group, pivaloyloxy group, pentanoyloxy group, hexanoyloxy group and the like. C ₃ —〇 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.

Specific examples of the 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.

^{R 5, R 1G, 11,} R 13, C in R ¹⁴ and R ¹⁵ ₄ -. _{What is an 8-} cycloalkyl group? ₃ — ( ₇ means a cyclopropyl-substituted radical; specifically, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl Can be mentioned.

The C ₄ ten ₈ cycloalkyl force Lupo two Ruokishi group for R ⁴ and R ^9, specifically cyclopropylcarbinyl Poni Ruo carboxymethyl group, a cycloalkyl Petit Luca Lupo sulfonyl O alkoxy group, consequent opening pliers Luca Lupo sulfonyl O alkoxy group, cyclohexyl Examples thereof include a carbonyloxy group and a cycloheptylcarboxy 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). Specific examples of the 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.

Specific examples of the aryloxy group in R ⁴ and R ⁹ include a phenoxy group, an 11-naphthyloxy group, and a 21-naphthyloxy group.

Specific examples of the 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.

Specific examples of the 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.

Specific examples of the 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 〇 "(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 i-C ₆ alkyl group, a methoxymethyl group, 2-methoxide Echiru group, ethoxy Kishimechiru group, 1 one Etokishechiru group, 2-Etokishechiru C i-C ₆ Arukoki sheet ₍₁ _〇 ₆ alkyl group such as a group, methylthiomethyl group, 2-Mechiruchioechiru group, 2-phenylene Such Ruchioechiru group (d-C e alkyl / phenyl) Chio C ^ - C ₆ alkyl group, a tri (C ^ one C ₆ alkyl / phenyl) silyl one C ₆ Al Kill group such as trimethyl silyl E butyl group, benzyl Groups, diphenylmethyl group, trityl group, 1-naphthylmethyl group, 2-naphthylmethyl group, phenyl (2-phenylethyl) group, 3-phenylpropyl group and other aryl C i-C ₆ alkyl groups, substituted aryls C—C e alkyl group (described later) and the like.

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. , cyclopentylmethoxy group, 2-cyclopentyl Rue butoxy group, hexyl methoxy cyclohexane, 2-cycloheteroalkyl alkoxy Ruetokishi group, C _3, such as Puchirume Bok alkoxy group to a consequent opening - C ₇ cycloalkyl C "C ₆ alkoxy group, C—Ce alkoxy Ci—Ce alkoxy group such as methoxymethoxy group, 2-methoxyethoxy group, ethoxymethoxy group, 1-ethoxyethoxy group, 2-ethoxyethoxy group, methylthiomethoxy group, 2-methylthio ethoxy, 2-Hue such as a two Lucio ethoxy (〇 ₁ over ₍₆ Arukiru phenyl) Chio C f C e alkoxy , Bokuri such trimethyl chill silyl E butoxy group (- C ₆ alkyl / phenyl) silyl one C ₆ alkoxy group, Benjiruokishi group, Jifue two Rumechiruokishi group, Torichiruokishi group, 1 one naphthylmethyl O alkoxy group, 2-naphthylmethyl be given like C ₆ alkoxy group (described below) - Okishi group, Fuenechiruokishi group (2 Fueniruechiru group), 3-phenylpropyl propoxy § Li Ichiru 0 ₁ -〇 ₆ alkoxy group such as a group, a substituted Ariru Ji丄it can.

Substitution at R ³ and R ⁸ — Specific examples of the alkoxycarbonyl group include halogenated C ₁ -C ₆ alkoxycarbonyl groups such as trifluoromethoxycarbonyl group, trichloroethoxycarbonyl group, and cyclopropylmethoxycarbonyl group. —Cyclopropylethoxycarbonyl, cyclobutylmethoxycarbonyl, cyclopentylmethoxycarbonyl, 2-cyclopentylethoxycarbonyl, cyclohexylmethoxycarbonyl, 2-cyclohexylethoxycarbonyl, cyclohexyl C _3, such as heptyl methoxycarbonyl group - C ₇ cycloalkyl C "C ₆ alkoxy force Lupo Group, 2-methoxy-E butoxy carboxymethyl group, 2-ethoxyethoxy carboxymethyl sulfonyl CI- C ₆ alkoxy one C ₆ alkoxycarbonyl alkylsulfonyl group such, 2methylthioethoxy E Toki deer Ruponiru group, 2-phenylene Lucio (Ci-Ce alkyl / phenyl) thio-C ₆ alkoxycarbonyl group such as ethoxycarponyl group, tri (C ^ -C ₆ alkyl / phenyl) silyl CC ₆ alkoxycarbonyl group such as trimethylsilylethoxycarbonyl group, benzyloxy Carbonyl group, diphenylmethyloxycarbonyl group, trityloxycarbonyl group, (1-naphthyl) methyloxycarbonyl group, (2-naphthyl) methyloxycarbonyl group, phenethyloxycarbonyl group (2-phenylene) Chirukaru Poniru group), Ariru one C ₆ alcohol such as 3 _ phenylalanine propoxycarbonyl group Shi carboxymethyl group, a substituted Ariru - alkoxy force Ruponiru group (described later), etc. can be mentioned.

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. .

Specific examples of the substituted C ₂ -C ₇ alkanoyloxy group in R ⁴ and R ⁹ include a trichloroacetoxy group and a trifluoroacetoxy group.

Specific examples of the substituted C ₂ -C ₆ alkenyl group in R ⁵ R ¹⁰ R ¹¹ R ¹³ R ¹⁴ and R ¹⁵ include a styryl group and a cinnamyl group.

Specific examples of the substituted C ₂ -C ₆ alkenyloxy group in R ⁴ and R ⁹ include a styryloxy group and a cinnamyloxy group.

Specific examples of the 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. Rufueniru group (2, 3-xylyl 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-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group, 2, 4-dimethoxy-phenylene les group, 3, 4-dimethoxy Hue elm group, 4 one Etokishifue group, 4 one isopropoxide Schiff enyl, 4 one t- Butokishifueniru C i-C ₆ alkoxy substituent Ariru group such as, 4 (C—C ₆ alkyl / phenyl) thio-substituted aryl groups such as 4-methylthiophenyl group and 4-phenylthiophenyl group; and biaryl groups such as 4-piphenyl group.

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,

2-cyanophenoxy group, 3-cyanophenoxy group, 4-cyanophenoxy group, 2-methoxyphenoxy group, 3-methoxyphenoxy group, 4-methoxyphenoxy group, 2,

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) ! Okishikaruponiru group, 4 one triflumizole Ruo ii substituted C such as methyl full enoki deer Lupo alkylsulfonyl group - 0 ₆ alkyl substituted § Li one Ruo carboxymethyl local Poni group, 4-fluorophenyl enoki deer Lupo group, 3, 4 Jifuruoro phenoxy Halogen-substituted aryloxycarbonyl groups such as carbonyl groups, 2-nitrophenoxycarbonyl groups, 3-nitrophenoxycarbonyl groups, 4- Nitrophenoxycarbonyl, 2-cyanophenoxycarbonyl, 3-cyanophenoxycarbonyl, 4-cyanophenoxycarbonyl, 2-methoxyphenoxycarbonyl, 3-methoxyphenoxy Carbonyl group, 4-methoxyphenoxycarbonyl group, 2,3-dimethoxyphenoxycarbonyl group, 2,4-dimethoxyphenoxycarbonyl group, 3,4-dimethoxyphenoxycarbonyl group, 4-ethoxy Fuenokishikarubo two Le C i one C ₆ alkoxy substituted § Li one Ruo carboxymethyl local Poni Le group such as, 4-Mechiruchiofe Roh alkoxycarbonyl group, such as 4 one phenylene Ruchi off enoki aryloxycarbonyl group (C "C ₆ Alkyl Z phenyl) Biaryloxycarbonyl groups such as thio-substituted aryloxycarbonyl group and 4-biphenyloxycarbonyl group. Can.

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! One C ₆ alkyl substitution § Li one Rukaruponiru group, 4 one full O b benzo I group, 3, 4 halogen substituents Arirukarubo alkenyl group such Jifuruo port base Nzoi group, 2-two Torobenzoiru group, 3-nitro Benzoiru Group, 4-nitrobenzoyl group, 2-cyanobenzoyl group, 3-cyanoben Zyl group, 4-cyanobenzoyl group, 2-methoxybenzoyl group, 3-methoxybenzoyl group, 4-methoxybenzoyl group, 2,3-dimethoxybenzoyl group, 2,4-dimethyloxybenzoyl group, 3 (1 C ₆ alkyl / such as C i-C ₆ alkoxy-substituted arylcarbonyl, 4-methylthiobenzoyl, and 4-phenylthiobenzoyl, such as 4, 4-dimethylbenzoyl, and 4-ethoxybenzoyl) Phenyl) thio-substituted arylcarbonyl group, biarylcarbonyl group such as 4-phenylpentyl group and the like.

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_cyanobenzoyloxy, 2-methoxybenzoyloxy, 3-methoxybenzoyloxy, 4-methoxybenzoyloxy, 2,3-dimethoxybenzoyl A C ₆ alkoxy-substituted arylcarbonyloxy group such as an xy group, a 2,4-dimethoxybenzoyloxy group, a 3,4-dimethoxybenzoyloxy group, a 4-ethoxybenzoyloxy group, 4 _ methylthio base Nzoiruokishi group, 4 one-phenylene thioether benzo i Ruo alkoxy group such (C i one C _e alkyl phenyl) Chio substituted Ariru force Ruponiruokishi group, 4 - Biari one such phenylene point pen zone i Ruo alkoxy group Rukarupo Examples include a nitroxy group and the like.

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.

Substituted Ariru _{C i} - A c ₆ alkoxycarbonyl group, a Ariru C one C ₆ alkoxy force Ruponiru group having a substituent group as described above on the aromatic ring, specifically 2-methylbenzyl O propoxycarbonyl sulfonyl Group, 3-methylbenzyloxycarbonyl, 4-methylbenzyloxycarbonyl, 2-fluorobenzyloxycarbonyl, 3-fluorobenzyloxycarbonyl, 4-fluoro Benzyloxycarbonyl, 4-hydroxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2- (4-fluorophenyl) ethyloxycarbonyl, 3- (4-fluoro Phenyl) propyloxycarbonyl group and the like.

General formula for R ³ and R ⁸ (2) (2)

(Wherein, 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 cycloheptylaminocarbonyl, cyclohexylmethylaminopropyl, phenylaminopropyl, dimethylaminopropyl, dimethylaminocarbonyl, dipropylamino Carbonyl group, N-ethyl-N-methylaminocarbonyl group, N-methyl-N-propylaminocarbonyl group, N-benzyl-N-methylaminocarbonyl group, N- (4-fluorobenzyl) -1-N-methylaminocarbonyl group, N-benzyl _N-ethylaminoka Disubstituted aminocarbonyl groups, such as luponyl group, N-benzyl-1-N-propylpyruaminocarbonyl group, N-cyclohexyl N-methylaminocarbonyl group, pyrrolidinocarbonyl group, piperidinocarbonyl group, And cyclic aminocarbyl groups such as a ruphorinocarbyl group and a thiomorpholino-capillonyl group.

 The xanthone derivative of the present invention has the general formula (17) obtained from a culture of Penicillium sp. OPenicillium sp.

[Wherein, R ¹⁸ represents a hydrogen atom or a hydroxyl group, and 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].

[III] R ¹⁶ represents a methyl group, and R ¹⁷ represents a group represented by any of the general formulas (18), (19), (20) and (22).

(18)

(式中、 R²⁽⁾は水素原子又はカルボキシル基を表し、 R ²¹は水素原子又は水酸基を表 す。 )

(In the formula, R ^{2 ()} represents a hydrogen atom or a carboxyl group, and R ²¹ represents a hydrogen atom or a hydroxyl group.)

(Wherein, R ^2G and R ²¹ are as defined above.)

(Wherein, R ^2G and R ²¹ are as defined above. R ²² is a hydrogen atom, a methoxymethyl group, or a compound of the formula (21)

Represents )

(Wherein, R ^2G and R ²¹ are as defined above.)

[IV] R ¹⁶ represents a group represented by the general formula (23) or (24), and R ¹⁷ represents an acetyl group.

(In the formula, R ^2Q and R ²¹ are as defined above.)

 Can be synthesized by using a general organic synthetic chemistry method using the compound represented by

 As the compound obtained from the culture of the Penicillium sp, SPF-3059 strain,

General formula (25)

(Wherein, R ¹⁸ , R ¹⁹ , R ^2G and R ²¹ have the same meanings as described above.)-A general formula (26)

(Wherein, R ¹⁸ , R ¹⁹ , R ^2Q and R ²¹ have the same ^{meanings as} described above), and a compound represented by the general formula (27)

(Wherein, R ¹⁸ , R ¹⁹ , R ^{2 ()} , R ²¹ and R ⁸² have the same meanings as described above), and a compound represented by the general formula (28)

(Wherein R ¹⁸ , R ¹⁹ , R ^2Q and R ²¹ have the same ^{meanings as} described above), and a compound represented by the general formula (29)

(Wherein, R ¹⁸ , R ¹⁹ , R ^2Q and R ²¹ are as defined above), and a compound represented by the general formula (30)

(30)

(Wherein, R ¹⁸ and R ¹⁹ have the same meanings as described above.). Here, the compound represented by the general formula (25) and the compound represented by the general formula (26) Are in a tautomeric relationship, and generally both exist as a mixture.

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 Compounds (tautomers), compounds in which R ¹⁸ and R ^{2 Q} are carboxyl groups, R ¹⁹ is a hydrogen atom and R ²¹ is a hydroxyl group (tautomers), R ¹⁸ is a carboxyl group, and R ¹⁹ and Compounds in which R ²¹ is a hydroxyl group and R ^2D is a hydrogen atom (tautomers), compounds in which R ¹⁸ and R ² are a hydrogen atom and R ¹⁹ and R ²¹ are hydroxyl groups (tautomers), and the like. 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)

And a novel compound such as a compound which is a group represented by

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.

C EI. 1994, Vol. 66, pp. 2383-2386 and JP-A-6-506202), R ¹⁸ is a hydrogen atom, R ^{2 Q} is a lipoxyl group, and 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. Is a carboxyl group, 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, and R ²¹ is a hydroxyl group, New compounds such as compounds in which R ¹⁸ and R ^2G are hydrogen atoms and R ¹⁹ and R ²¹ are hydroxyl groups can be mentioned.

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.

Manufacturing method [A]

 General formula (17)

[Wherein, R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are as defined above. When the compound represented by the formula (1) has at least one propyloxyl group, the compound represented by the general formula (31) is obtained by esterifying the propyloxyl group.

[Wherein, 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.

[V] R ²³ represents a methyl group, and 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).

(Wherein, 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.)

(In the formula, R ²¹ and R ²⁶ are as defined above.)

(In the formula, R ²¹ , R ²² and R ²⁶ are as defined above.)

(Wherein, R ²¹ and R ²⁶ are as defined above.)

[VI] R ²³ represents a group represented by the general formula (36) or the formula (24), and R ²⁴ represents an acetyl group.

(Wherein, R ²¹ and R ²⁶ are as defined above.)

However, at least one of R ²⁵ and R ²⁶ is not a hydrogen atom. ] The xanthone derivative of the present invention represented by the formula:

As a specific method of 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. , For example 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 For example, in a polar aprotic solvent such as dimethylformamide (DMF) or N-methylpiberidinone (NMP), if necessary, for example, dimethylaminopyridine (DMAP) such as triethylamine and diisopropylethylamine. In the presence of a base, if necessary, an additive such as 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT), etc. Minopropyl) 1-Ethylcarbodiimide · hydrochloride (EDC, EDCI or WSC · HC 1) A method of condensing with various alcohols using a condensing agent such as 1,1,3-dicyclohexylcarposimide (DCC) can be exemplified.

Manufacturing method [B]

 When the compound represented by the general formula (17) has at least one propyloxyl group, the carboxyl group is amidated to form the compound represented by the general formula (37)

In the formula, R ²⁹ is a hydrogen atom or a general formula (2)

(Wherein, R ⁶ and R ⁷ have the same meaning as described above.), And R ¹⁹ has the same meaning as described above. R ²⁷ and R ²⁸ are represented by one of the following [VII] or [VIII].

[VII] R ²⁷ represents a methyl group, and 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).

(Wherein, R ²¹ is as defined above. R ^3G is a hydrogen atom or a general formula (2)

(Wherein, R ⁶ and R ⁷ have the same meanings as described above.). )

(In the formula, R ²¹ and R ^3Q are as defined above.)

(In the formula, R ²¹ , R ²² and R ³ ° are as defined above.)

(In the formula, R ²¹ and R ^3Q are as defined above.)

[VIII] R ²⁷ represents a group represented by the general formula (42) or (24), and R ²⁸ represents an acetyl group.

(In the formula, R ²¹ and R ^3Q are as defined above.)

However, at least one of R ²⁹ and R ^3G is not a hydrogen atom. ] The xanthone derivative of the present invention represented by the formula:

 As a specific method of amidating a carboxyl group, for example, in a highly polar aprotic solvent such as dimethylformamide (DMF) or N-methylbiveridinone (NMP), if necessary, for example, dimethylaminopyridine (DMAP) ), In the presence of a base such as triethylamine, diisopropylethylamine or the like, if necessary, an additive such as 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT). In the presence of, for example, 11- (3-dimethylaminopropyl) -13-ethylcarbodiimide 'hydrochloride (EDC, EDC I or WSC · HC 1), 1,3-dicyclohexylcarbodiimide (DCC), etc. Examples of the method include condensing with various amines or salts thereof using a condensing agent.

Manufacturing method [C]

By reacting the compound represented by the general formula (17) with an alkylating agent or a silylating agent in the presence of a base, the compound represented by the general formula (43)

[Wherein 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 alkenyloxy group, a C ₂ —C ₆ alkynyloxy group, an aryloxy group, a substituted aryloxy group or a tri (1-C ₆ alkyl / phenyl) silyloxy group represents ³⁵ Haji ₁ _〇 ₆ Arukiru group, a substituted d-C ₆ alkyl group, 0 ₃ _ ₍₇ cycloalkyl, (:. ₂ -〇 ₆ Arukeniru group, a substituted 〇 ₂ -〇 ₆ Arukeniru group, ₂ -〇 ₆ Arukiniru group, Li Ichiru group, a substituted Ariru group or Application Benefits represents an (over-alkyl / phenyl) silyl group. R ³¹ and R ³² is represented by one of [IX] or [X] below.

[IX] R ³¹ represents a methyl group, and R ³² represents a group represented by any of the general formula (44), (45), (46) or (48).

(Wherein, 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 alkenyloxy groups, C ₂ —C ₆ alkynylo Represents a xy group, an aryloxy group, a substituted aryloxy group or a tri (Ci-Cealkyl / phenyl) silyloxy group. R ³⁵ is as defined above. )

(In the formula, R ³⁵ , R ³⁶ and R ³⁷ are as defined above.)

(Wherein, 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)

(Wherein, R ³⁵ has the same meaning as described above.) )

(In the formula, R ³⁵ , R ³⁶ and R ³⁷ are as defined above.) [X] R ³¹ represents a group represented by the general formula (49) or (50), and R ³² represents an acetyl group.

(In the formula, R ³⁵ , R ³⁶ and R ³⁷ are as defined above.)

(In the formula, R ³⁵ has the same meaning as described above.)] The xanthone derivative of the present invention represented by the formula:

 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.

Examples of the alkylating agent applicable to the present synthesis method include dimethyl sulfate, for example, alkyl halides such as methyl iodide, methyl bromide, butyl iodide, and tyl bromobromide, for example, benzyl bromide, 2-fluorobenzyl bromide. 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. Alkenyl, etc., silyl Examples of the drier include, but are not limited to, trimethyl silane chloride, triethyl silane chloride, t-butyl dimethyl dimethyl silane, and the like.

 When the halogen atom in the reagent such as an alkyl halide is a bromine atom or a chlorine atom, a phase transfer catalyst such as tetrabutylammonium iodide or benzyltributylammonium iodide may be used, if necessary. .

Manufacturing method [D]

 By modifying the hydroxyl group of the compound represented by the general formula (31) or (37), the compound represented by the general formula (51)

Wherein, R ⁴¹ is a hydrogen atom, (^ - Ce alkoxycarbonyl group, a substituted CfCe alkoxy Shikarubo group, C ₃ - ₍₇ cycloalkyl O alkoxycarbonyl group, 〇 ₂ -〇 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)

(Wherein, R ⁶ and R ⁷ have the same meanings as described above.), Wherein R ⁴² is a hydrogen atom, a C ₂ —C ₇ alkanoyloxy group, a substituted C ₂ —C ₇ alkanoy Ruokishi group, 〇 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. 1 C _fi alkynyloxy Shi group, Ariruokishi group, a substituted Ariruokishi group or tri - represents (C ^ Ce alkyl / Hue) yl Shiriruokishi group, 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丄_ｰ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 following [XI] or [XII].

[XI] R ³⁹ represents a methyl group, and R ⁴⁰ represents a group represented by any of the general formula (52), (53), (54) or (56).

(In the formula, 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

(2)

(2)

(Wherein, R ⁶ and R ⁷ have the same meanings as described above.), Wherein 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 (置換 —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. )

(In the formula, R ⁴³ , R ⁴⁴ and R ⁴⁵ are as defined above.)

(Wherein R ⁴³ , R ⁴⁴ and R ⁴⁵ have the same meanings as described above. R ⁴⁶ is a hydrogen atom, a methoxymethyl group, or a compound represented by the general formula (55)

( ⁵⁵ )

(In the formula, R ⁴³ has the same meaning as described above.) )

(In the formula, R ⁴³ , R ⁴⁴ and R ⁴⁵ are as defined above.)

[XII] R ³⁹ represents a group represented by the general formula (57) or (58), and R ⁴⁰ represents an acetyl group.

(Wherein, R ^{4 3,} R ⁴⁴ and R ^{4 5} is as defined above.)

(Wherein, R ^{4 3} is as defined above.) Can be obtained xanthone derivatives of the present invention represented by.

 Such alkylation and silylation of the hydroxyl group can be carried out by the above-mentioned production method [C]. At this time, as the reaction solvent, in addition to the above-mentioned highly polar aprotic solvent, an octogen solvent such as dichloromethane, 1,2-dichloroethane, cyclobenzene, dichlorobenzene, etc. can be used.

 In addition, 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 In the presence of an inorganic base such as lithium oxide, Agents can be synthesized by reacting the.

Examples of the acylating agent applicable to the present synthesis method 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.

 Alternatively, 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.

Manufacturing method [E]

When at least one of 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)

[Wherein, 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].

[XIII] R ⁴⁷ represents a methyl group, and R ⁴⁸ represents a group represented by any of the general formulas (60), (61), (62) and (63).

(式中、 R⁸、 R⁴³および R⁴⁵は前述と同義である。 ）

(In the formula, R ⁸ , R ⁴³ and R ⁴⁵ are as defined above.)

(In the formula, R ⁸ , R ⁴³ and R ⁴⁵ are as defined above.)

(Wherein, R ⁸ , R ⁴³ , R ⁴⁵ and R ⁴⁶ are as defined above.)

(In the formula, R ⁸ , R ⁴³ and R ⁴⁵ are as defined above.)

[XIV] R ⁴⁷ represents a group represented by the general formula (64) or (58), and R ⁴⁸ represents an acetyl group.

(In the formula, R ⁸ , R ⁴³ and R ⁴⁵ are as defined above.)

(Wherein, R ^{4 3} is as defined above.) Can be obtained xanthone derivatives of the present invention represented by.

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. However, this method cannot be applied when protecting groups on the hydroxyl group such as some acyl groups are simultaneously hydrolyzed by this method. Selective removal of tri (C _t one C ₆ alkyl Z phenyl) silyl O carboxymethyl Cal Poni Le group is, for example, methanol, ethanol, alcohol solvents such as isopropyl alcohol, tetrahydrofuran (TH F), ether solvents such Jiokisan or In these mixed solvents, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, paratoluenesulfonic acid, pyridinium paratoluenesulfonic acid in the presence of an equivalent or excess amount of water It can be synthesized by acting on a phosphate (PPTS), camphorsulfonic acid or the like, or by acting a base such as potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate or sodium carbonate. Alternatively, for example, in an alcoholic solvent such as methanol, ethanol, or isopropyl alcohol, 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. Is possible. Even when the protecting group of the hydroxyl group is (-alkyl Z-phenyl) silyl group, selective hydrolysis is possible by controlling the type of reagent, concentration, reaction temperature, etc. This method cannot be applied when the protecting group on the hydroxyl group in the (C i-c ₆ alkyl / phenyl) silyl group is simultaneously hydrolyzed by this method. One

 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.

 When performing alkylation, silylation or acylation by the method described in the above-mentioned production method [C] or [D], the type of reaction reagent to be used, the equivalent of the reaction reagent to be used, the reaction temperature, and the reaction temperature By appropriately controlling the time and the like, it is also possible to obtain a derivative in which some hydroxyl groups are not modified and remain as hydroxyl groups, and such derivatives are also included in the compounds of the present invention.

 Furthermore, 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.

 In order to isolate and purify the compound of the present invention synthesized by the above-mentioned method from the reaction solution, a means generally used for isolating and purifying the reaction product can be used. In other words, when isolating and purifying the target substance from the reaction mixture, 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.

In the compounds of the present invention, salts thereof, preferably pharmaceutically or veterinarily acceptable. Such salts are also included in the scope of the present invention. Here, examples of 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. Examples thereof include 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 according to the present invention is effective for nerve elongation repulsion factor inhibitors, and particularly for the above semaphorin inhibitors. There is no particular limitation as long as it contains the above-mentioned nerve regeneration promoter as a component, but ordinary pharmaceutically acceptable carriers, binders, stabilizers, excipients, and diluents 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. That is, it can be administered orally in a commonly used dosage form, for example, a powder, granule, capsule, syrup, suspension, etc., or, for example, a solution, emulsion, suspension, etc. In addition to the 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. Neurodegenerative disease, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis, Huntington's disease, cerebral infarction, traumatic neurodegenerative disease and the like. Furthermore, diseases associated with angiogenesis involving VEGF165 in which the receptor is neuropilin in common are also of interest.

 In addition, the use of the 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. Since 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. Example

 Hereinafter, the present invention will be described in more detail with reference to Production Examples and Examples, but the technical scope of the present invention is not limited to these Examples.

<Production of raw material compounds 【

 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.

 (a) Cultural and morphological properties

On malt extract agar, the growth of colonies is slow, with a diameter of 2 in 25 and 2 in 1 day. 8-2.9 cm, fluffy, white or yellow on the surface of the colony, dark yellow on the back of the colony, no production of soluble pigment and no sporulation. On potato-dalcose agar, the growth of colonies is slow, 3.2-3.3 cm in diameter and fluffy at 25 ° C, 21 days, the color of the colony surface is white or cream, and the back of the colony is Deep yellow or tan, no soluble pigment production and sporulation. 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. A rn in diameter, and usually have 10 vertical wrinkles on the surface. Teleomorphs are not allowed.

(b) Physiological properties

 ① Growth pH range

 In a submouth broth, 27, the growth in shaking culture for 3 days is as follows,

PH growth

3.1

 4.5 +

5.5 + + 7.1

 8.0 +++

 9.0

 10.0

② Growth temperature range

 Growth is observed on oatmeal agar medium at 38 for 5 days of culture.

 Based on the above bacteriological properties, 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. Examples of the carbon source include glucose, sucrose, glycerin, starch, dextrin, molasses, and the like. Examples of 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. In addition, 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. Further, various vitamins, nucleic acid-related compounds and the like may be added for the purpose of promoting the growth of bacteria. During the culture period, it is also possible to add 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.

 In order to isolate and purify the raw material compound represented by the above formula (17) from the culture solution, a commonly used isolation and purification means is used from a culture of the secondary metabolite produced by the microorganism. Can be. When isolating and purifying the target substance from the culture supernatant, 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. When isolating and purifying the target substance from cultured cells, 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. Production Example 1

 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.

After completion of the culture, 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. This was dissolved in 100 ml of methanol, subjected to column chromatography using Sephad ex ^™ LH-20 (Amersham Pharmacia Biotech), and eluted with methanol. The active fraction was collected, and the solvent was distilled off under reduced pressure to obtain 2.6 g of a crude product. This was dissolved in a 10 0 m 1 methanol, subjected to column chromatography using TSKg e 1 ^TM TO Y_〇 PE RL 'HW- 40 F (Higashisoichi) The active fractions eluted with methanol, the solvent Was distilled off under reduced pressure to obtain 1.6 g of a crude product. This was dissolved in lm 1 of dimethyl sulfoxide (DMSO) in 50 mg portions, and subjected to reverse phase HP LC. The conditions for reversed-phase HP LC are as follows: Column: Wa kopak ^TM — Wa kosi 1 ™ -II 5 C 18RS (connecting 20 X 50 mm and 20 X 250 mm, manufactured by Wako Pure Chemical Industries), Eluent A: 1% formic acid Aqueous solution, eluent B: methanol, gradient: B solution ratio: 35% to 65%, linear gradient for 90 minutes, flow rate: 5 ml / min, detection: absorbance at 260 nm. The eluted fractions with a retention time of 59 minutes, 74 minutes, and .81 minutes were collected, and the solvent was distilled off under reduced pressure to obtain compounds SPF-3059-5 (34.2 mg) and SPF-3059-1 (64. lmg) and SPF-305 9-2 (12. Omg). The physicochemical properties of the obtained compound are as follows. Compound SPF 3059-1

 · Properties: yellow powder

 • High-resolution high-speed electron impact mass spectrum (HRFAB-MS) m / z (M + H) + actual value: 577.0772

 Calculated value: 579. 0776

· Molecular formula: C ₂₈ H ₁₈ 〇 ₁₄

 • UV-visible absorption spectrum Am a X (in methanol) nm (ε):

241 (31, 600) 315 (23,400), 365 (16,500) 'Infrared absorption spectrum max (KB r) cm- ¹ :

 3400, 1701, 1615, 1570, 1457, 1273

^{- Χ Η- NMR (5 0 0MHz} , DMS O- d 6) δ p pm:

 2.28, 2.67, 2.69, 4.6 to 4.7, 5.02, 6.40, 6.91, 7.91, 8.52, 9.33, U.l to 11.6, 12.8

• ¹³ C—NMR (125 MHz, DMSO—d ₆ ) (5 ppm:

 16.5, 17.0, 32.4, 56.2, 65.7, 68.0, 102.3, 104.2, 108.8, 110.

118.2, 118.5, 120.6, 122.2, 125.8, 127.7, 132.4, 134.9, 137.6, 139.1, 140.7, 140.8, 150.1, 150.2, 152.2, 153.8, 154.5, 156.3, 167.5, 167,6, 172.7, 172.8, 186.3, 199.1, 202.7, 202.9

 From these, the structural formula of compound SPF—3059—1 is represented by the following formula:

 (Tautomer).

Compound S PF-30 30-2

 • Properties: Cream powder

 'High-resolution high-speed electron impact mass spectrum (HRFAB-MS) m / z (M + H) + actual value: 53.3.0710

 Calculated value: 5 3 3. 0 7 2 1

Molecular formula: C ₂₇ H ₁₆ 〇 ₁₂

UV-visible absorption spectrum Am a X (in methanol) nm (ε) 209 (40,600), 236 (42,600), 283 (28,500), 323 (25,400)

Infrared absorption spectrum max (KB r) cm- ¹ :

 3266, 1678, 1654, 1623, 1562, 1471, 1296

• One NMR (DMS〇_ d ₆ ) δ p pm:

 2.53 (6H, s), 6.93 (lH, s), 6.95 (lH, s), 7.47 (lH, s), 8.15 (lH, s),

8.54 (lH, s), 9.38 (lH, brs), 9.89 (1H, brs), 10.78 (1H, brs), 11.37 (1H, brs), 12.68 (lH, brs)

• ¹³ C—NMR (DMSO-d ₆ ) ά p pm:

 29.1, 32.1, 102.3, 103. 108.7, 112.5, 113.5, 119.6, 119.8, 120.9, 126.2, 132.4, 133.6, 136.1, 141.7, 144.5, 150.71, 150.74, 152.49, 152.54, 152.7, 154.4, 167.4, 172.9, 173.4, 199 丄 201.2

 From these, the structural formula of the compound SPF—3059—2 is represented by the following formula:

It was decided. Compound SPF-30 30-5

 'Properties: cream powder

 'High-resolution high-speed electron impact mass spectrum (HRFAB-MS) m / z (M + H) Found: 577.0615

 Calculated value: 577.0619

'Molecular formula: C ₂₈ H ₁₆ 〇 ₁₄

■ UV-visible absorption spectrum Ama X (in methanol) nm (ε): 229 (35,800), 284 (22,600), 322 (21,000)

• Infrared absorption spectrum vmax (KB r) cm— ¹ :

 3260, 1684, 1626, 1567, 1467, 1288

• One NMR (DMSO-d ₆ ) δ p pm:

 2.53 (3H, s), 2.55 (3H, s), 6.93 (lH, s), 6.96 (lH, s), 8.17 (lH, s), 8.53 (lH, s), 9.5 ~ 13.0 (6H)

• ¹³ C—band R (DMSO-d ₆ ) δ p pm:

 29.1, 32. 102.26, 102.32, 109.9, 112.4, 119.6, 119.8, 120.3, 120.9, 126.3, 132.5, 133.4, 136.2, 141.2, 141.7, 150.4, 150.8, 152.1, 152.68, 152.73, 154.5, 167.4, 167.5, 172.5, 172.9, 199.1, 201.1 From these, the structural formula of compound SPF-3059-5 is

製造例 2

Production Example 2

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. 125 medium with the same composition as above in 5 500 ml Erlenmeyer flasks After dispensing m 1 each, the solution was sterilized by autoclaving, and the above pre-pre-culture solution was added thereto in an amount of 4 ml each, followed by rotary shaking culture at 27 t :, 180 rpm for 4 days to obtain pre-culture. In a 50-liter jar arm mentor, 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.

After completion of the culture, 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 ^™ 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 ^™ 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. This was dissolved in 20 ml of 2 ml of dimethyl sulfoxide (DMSO) and subjected to preparative reversed-phase HP LC. The conditions for preparative reversed-phase HP LC are as follows: Column: Wako pak ™ Wakosi 1 ™ -II 5 C 18HGp rep (connecting φ 5 X 10 cm and φ 5 X 25 cm, manufactured by Wako Pure Chemical Industries), eluent A: 1% aqueous solution of formic acid, eluent B: methanol, gradient: linear gradient of solution B from 45% to 75% for 2 hours, flow rate: 25 ml / min, detection: absorbance at 260 nm, and elution The solution was separated for 1 minute. The fractions collected above were analyzed using an analytical HP LC. Conditions analytical HP LC, the force ^{ram: Wako p ak TM Wa kosi 1} ™ -II 5 C 18 RS (4. 6 X 15 0mm, manufactured by Wako Pure Chemical Industries), eluent A: 1% aqueous formic acid, elution Liquid B: methanol, gradient: liquid B ratio from 20% to 67% 7 1. 1 minute linear gradient, flow rate: 1.3 ml / min, detection: absorbance at 260 nm. 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 ™ 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.

Table 2 Amount of compound obtained (mg) Retention time in analytical HPLC (min)

SPF-3059- 12 6.2 34.4

 SPF-3059- 24 28.0 34.5

 S PF-3059- 4 10.2 36.0

 SPF-3059- 25 4.0 39.3

 SPF-3059- 34 2.9 40.8

 SPF-3059- 6 34. 9 45. 6

 S PF— 3059— 27 17. 4 46. 1

 S PF-3059- 26 6.2 46.5

 SPF-3059- 28 1 1.8 46.6

 SPF— 3059— 7 13. 0 47. 0

 SPF-3059- 39 2.8 49. 95

 SPF— 3059— 37 4. 0 50. 0

SPF-3059- 3 1 18.2 50.1 S PF-3059- 35 1 1 0 5 1 5 S PF-3059- 9 1 00 9 52 7

S PF-3059- 29 45 6 54 0

S PF— 3059— 36 3 7 57 8

SPF—3059—30 23 5 63 0 The physicochemical properties of the compound obtained are as follows.

S PF-30 59-3

 • Appearance: yellow powder

 • Molecular weight: 534

• Molecular formula: C ₂₇ H _ls O ₁₂

 'Fast electron impact mass spectrum (FAB-MS) mZz (ositiv): 535 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) mZz (negative): 533 (M-H)-

'High-resolution high-speed electron impact mass spectrum (HRFAB-MS) m / z (M + H) Observed value: 535.090 5

Calculated value: 535. 0877 (C ₂₇ H ₁₉ 0 ₁₂ )

 • UV-visible absorption spectrum Am a X (in methanol) nm (ε): '

 242 (30,800), 317 (22,700), 367 (14,000)

'Infrared absorption spectrum ma X (KB r) cm- ¹ :

 3356, 1700, 1652, 1610, 1515, 1475, 1283

• One NMR (DMS〇— d ₆ ) δ p pm:

2.28, 2.29, 2.68, 2.69, 4.62, 4.62, 4.64, 4.72, 5.03, 6.38, 6.40, 6.90, 6.91, 7.44, .7.98, 8.54, 8.90-11.10, 12.70 • ¹³ C—NMR (DMSO-d ₆ ) <5 p pm:

 16.5, 17.0, 32.3, 32.4, 56.2, 65.8, 68.0, 103.0, 104.2, 108.7, 108.8,

109.4, 113.5, 118.2, 118.6, 122.2, 125.7, 127.5, 129.8, 132.0, 132.6, 134.8,

137.6, 137.9, 138.8, 144.3, 150.5, 150.6, 152.0, 152.6, 154.2, 154.5, 155.5, 156.3, 167.6, 167.7, 173.4, 183.5, 186.2, 199,2, 202.8, 203.0

 • Solubility: insoluble in water and hexane, soluble in methanol and DMSO

From these, the structural formula of SPF-3059-3 was determined as the following formula (tautomer)

S PF— 3059— 4

 • Appearance: cream color powder

 • Molecular weight: 560

'Molecular formula: C ₂₈ H ₁₆ 0 ₁₃

 • Fast electron impact mass spectrum (FAB-MS) m / z (p os i t i v e): 56 1 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) m / z (negativi): 559 (M-H)-

'High-resolution high-speed electron impact mass spectrum (HRFAB-MS) m / z (M + H) + actual value: 56 1.0667

Calculated value: 561. 0670 (C ₂₈ H ₁₇ 0 ₁₃ )

 • UV-visible absorption spectrum Am a X (in methanol) nm (ε):

221 (35, 600), 250 (38,100), 276sh (25, 800), 323 (24, 30.0) 'Infrared absorption spectrum vmax (KB r) cm- ¹ :

 3412, 1665, 1619, 1563, 1465, 1427, 1263

^-X H— NMR (DMSO-d ₆ ) 5 p pm:

2.53 (3H, s), 2.56 (3H, s), 6.84 (1H, d, 2.1), 6.95 (lH, s), 6.96 (1H, d, 2.1), 8.17 (1H, s), 8.52 (1H, s), 10.10~11.40 (3H, brs ), 12.71 (1H, brs), 13.26 (lH, brs) • 13 C- NMR (DMSO-d 6) δ p pm:

 29.2, 32.1, 102.3, 103.2, 110.1, 112.4, 112.8, 119.6, 120.3, 120.8, 126.3, 133.1, 133.4, 136.7, 137.5, 141.7, 150.8, 152.3, 152.7, 152.8, 157.2, 163.9, 167.4, 169.3, 172.2, 172.9, 199.3, 201.0

 'Solubility: insoluble in water, hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF-3059-14 was determined as follows.

S P F— 30 59— 6

 • Appearance: cream color powder

 • Molecular weight: 592

'Molecular formula: C ₂₉ H _2Q 0 ₁₄

 • High-speed electron impact mass spectrum (FAB-MS) m / z (positive): 593 (M + H) +

 • High-speed electron impact mass spectrum (F AB-MS) m / z (neg a t i V e): 59 1 (M-H)-

'High-resolution fast electron impact mass spectrum (HRFAB—MS) m / z (M + H) + found: 593.0949 Calculated value: 5 9 3. 0 9 3 2 (C ₂₉ H ₂₁ 0 ₁₄ )

• UV-visible absorption spectrum Am ax (in methanol) nm (ε):

 210sh (45,900), 223 (47,700), 317 (25,800), 358sh (14, 700)

• Infrared absorption spectrum max (KB r) cm- ¹ :

 3418 1701 1617 1565 1465 1301

^-X H— NMR (DMS O-d ₆ ) p pm:

 2.22 (3H, s), 2.72 (3H, s), 3.11 (3H, s), 3.98 (2H, brs), 6.78 (1H, s), 6.88 (m, s), 8.2K1H, s), 9.00 13.00 (6H brs)

• ¹³ C—NMR (DMSO—d ₆ ) δ p pm:

 16.8, 32.4 57.8 64.4 102.1 102.3 109.3 111.9 118.4 118.6 119.1. 119.6 127.6 128.2 131.6 139.0 141.6 142.150.7 (2C), 151.9 152.9 155.5 162.0 167.8 167.9 172.4 174.6 202.6

 'Solubility: insoluble in water and hexane, soluble in methanol and DMSO

From these, the structural formula of SPF-3059-16-1 was determined as follows ₍

S P F— 3 0 5 9— 7

 • Appearance: yellow powder

 • Molecular weight: 5 6 2

'Molecular formula: C ₂₈ Hi ₈ 0 丄₃

Fast electron impact mass spectrum (FAB-MS) m / z (positive): 5 6 3 (M + H) +

 • High-speed electron impact mass spectrum (FAB-MS) m / z (negatieve): 561 (M-H)-

'High-resolution high-speed electron impact mass spectrum (HRFAB-MS) m / z (M + H) + actual value: 5 6 3.084 3

Calculated value: 5 6 3. 0 8 2 6 (C ₂₈ H ₁₉ 0 ₁₃ )

• UV-visible absorption spectrum Ama X (in methanol) nm (ε):

 242 (31,600), 312 (24,500), 385 (10,200)

'Infrared absorption spectrum ma X (KB r) cm— ¹ :

 3424, 1701, 1603, thigh, 1448, 1420, 1270

^- Χ Η- NMR (DMS_〇 one d ₆₎ <5 p pm:

 2.28, 2.29, 2.68, 2.69, 4.62, 4.67, 4.71, 5.04, 6.38, 6.41, 6.81, 6.92, 6.93, 7.95, 8.52, 9.33, 11.22, 11.35, 12.93

• ¹³ C—NMR (DMSO—d ₆ ) δ p pm:

 16.6, 17.0, 32.3, 32.4, 56.2, 65.7, 67.9, 102.3, 102.8, 103.1, 104.3, 108.7, 109.3, 110.1, 112.5, 112.6, 118.5, 118.7, 121.6, 122.125.9, 127.6, 130.131.9, 132.4, 135.3, 137.4, 137.6, 138.9, 139.7, 151.9, 152.3, 154.5, 155.5, 156.2, 157.1, 163.6, 167.6, 169.3, 172.7, 172.8, 183.7, 186.2, 199.1, 202.5, 202.7

 'Solubility: insoluble in water and hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF-359- 7 was determined as the following formula (tautomer).

HOOC 0 OH Me 0 HOOC 0 0 Me 0 S PF-30 59-9

 • Appearance: yellow powder

• Molecular weight: 534

• Molecular formula: C ₂₇ H ₁₈ 〇 ₁₂

 • High-speed electron impact mass spectrum (FAB-MS) m / z (osit i ve): 535 (M + H) +

 • Fast electron impact mass spectrum (FAB—MS) m / z (negat ive): 533 (M—H)-

'High-resolution high-speed electron impact mass spectrum (HRFAB—MS) m / z (M + H) + actual value: 535.0876

Calculated value: 535. 0877 (C ₂₇ H ₁₉ 〇 ₁₂ )

 'UV-visible absorption spectrum Ama X (in methanol) nm (ε):

 207 (47,600), 243 (41,800), 314 (34,000), 369 (23,000)

'Infrared absorption spectrum ma X (KB r) cm— ¹ :

 3444, 1702, 1614, 1474, 1289

^{- Χ Η- NMR (DMSO - d} 6) <5 p pm:

 2.29, 2.31, 2.67, 2.70, 4.60, 4.65, 4.69, 5.97, 6.32, 6.35, 6.89, 6.90, 7.03, 7.17, 7.94, 8.50, 12.50, 9.10 to 10.80

• ¹³ C—NMR (DMSO-d ₆ ) δ p pm:

 16.6, 17.1, 32.3, 32.4, 56.2, 65.9, 68.2, 102.3, 103.0, 103 103.9, 109.9, 110.0, 110.4, 110.5, 111.9, 112.2, 118.2, 118.6, 120.5, 125.7, 127.7, 130.0, 131.9, 132.4, 134.8 , 138 丄 139,1, 140.9, 141.1, 141.5, 150.2, 150.3, 151.7, 152.2, 154.1, 154.6, 154.9, 155.8, 156.6, 167.5, 172.6, 172.7, 183.5, 187.2, 199.3, 202.7, 202.9

 • Solubility: insoluble in water and hexane, soluble in methanol and DMSO

From these, the structural formula of SPF-3059-9 was determined as the following formula (tautomer).

SPF— 3059— 12

 • Appearance: cream powder

 • Molecular weight: 560

'Molecular formula: C ₂₈ H ₁₆ 〇 ₁₃

 ■ High-speed electron impact mass spectrum (FAB—MS) m / z (positiv): 56 1 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) mZz (negatiev): 559 (M-H)-

'High-resolution high-speed electron impact mass spectrum (HRFAB-MS) m / z (M + H) + actual value: 56 1.0680

Calculated value: 561. 0670 (C ₂₈ H ₁₇ 0 ₁₃ )

 'UV-visible absorption spectrum Am a X (in methanol) nm (ε):

232 (37,400), 250sh (34, 800), 285 (28,000), 308sh (23, 200), 360sh (9,000) 'Infrared absorption spectrum vmax x (KBr) cm " ¹ :

 3080, 1698, 1608, 1468, 1291

^-X H— NMR (DMSO-d ₆ ) δ p pm:

 2.54C3H, s), 2.55 (3H, s), 6.82 (1H, d, 2.1), 6.87 (lH, s), 6.95 (1H, d, 2.1), 8.22 (lH, s), 8.55 (1H, s) ) 9.50 to 13.50 (5H, brs)

• ¹³ C—NMR (DMS〇_d ₆ ) δ p pm:

29.32.2, 102.1, 103.0, 109.4, 112.1, 113.5, 119.8, 120.0, 121.7, 126.6, 132.0, 133.3, 135.9, 136.7, 141.7, 150.6, 152.1, 153.0, 155.4, 157.6, 162.4 167.4 167.6 172.2 172.9 199.1 201.1

 'Solubility: insoluble in water and hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF—3059-12 was determined as

S PF-30 59-24

 'Appearance: cream powder

 • Molecular weight: 532

• molecular formula: C 2 ₇ H! ₆ O! Two

 'Fast electron impact mass spectrum (FAB-MS) m / z (ositive): 533 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) mZz (negativi): 53 1 (M-H)-

'High-resolution high-speed electron impact mass spectrum (HRFAB-MS) m / z (M + H) + actual value: 53 1.0621

Calculated value: 53 1. 0 564 (C ₂₇ H ₁₇ 0 ₁₂ )

 • UV-visible absorption spectrum Ama X (in methanol) nm (ε):

 212 (36, 900), 229sM34 500), 283 (26,300), 323 (21,700)

'Infrared absorption spectrum max (KB r) cm- ¹ :

 3447 1697 1629 1578 1470 1290

-NMR (DMSO— d ₆ ) δ p pm:

2.52 (3H, s), 2.54 (3H s), 6.92 (lH, s), 6.93 (1H, s), 7.28 (lH, s), 8.13 (1H, s), 8.54 (lH s), 9.50 13.00 ( 5H, brs) • ¹³ C—NMR (DMSO—d ₆ ) <5 ppm:

 29.L 32.3, 102.3, 102.9, 107.9, 110.0, 115.8, 119.8, 120.4, 120.7, 126.5, 133.0, 133.3, 136.0, 141.2, 145.0, 150.4, 151.1, 152.2, 152.9, 153.0, 154.3, 167.5, 172.6, 173.6 , 199.1, 201.1

 • Solubility: insoluble in water and hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF-3059-24 was determined as follows.

S PF-3059-25

 • Appearance: cream color powder

 • Molecular formula: C H ^ Ou

 'Fast electron impact mass spectrum (FAB-MS) m / z (positive): 517 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) mZz (negative): 51 5 (M-H)-

'High-resolution high-speed electron impact mass spectrum (HRFAB-MS) m / z (M + H) + found: 517.0778

 Calculated value: 517. 0771 (C ^ H ^ O ^)

 UV-visible absorption spectrum Ama X (in methanol) nm (ε)

 215 (35,000), 253 (35,100), 276sh (25, 200), 323 (23,400)

Infrared absorption spectrum max (KB r) cm— ¹ :

3417, 1691, 1625, 1471, 1293 _{^{- Χ Η- NMR (DMSO- d 6}} ) δ p pm:

 2.54 (6H, s), 6.82 (lH, brs), 6.92 (2H, brs), 7.27 (lH, s), 8.14 (m, s),

8.53 (lH, s), 9.5 ~ U.0 (4H, brs)

^{- 13 C- NMR (DMSO-d} 6) δ p pm:

 29.2, 32.3, 102.9, 103.0, 107.8, 109.9, 113.0, 115.7, 120.4, 120.6,

126.4, 133.3, 133.4, 136.4 (20, 145.0, 151.2, 152.3, 152.98, 153.01, 157.3,

164.2, 169.4, 172.6, 173.6, 199.2, 201.0

 • Solubility: insoluble in water and hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF-30 59-25 was determined as follows.

S PF— 3059— 26

 -Appearance: cream powder

 • Molecular weight: 488

• Molecular formula: C ₂₆ H ₁₆ 〇 _{1 ()}

 'Fast electron impact mass spectrum (FAB—MS) mZz (positive): 489 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) m / z (negativi): 487 (M-H)-

'High-resolution high-speed electron impact mass spectrum (HRFAB-MS) m / z (M + H) + actual value: 489.0823

_{Calculated: 489. 0822 (C 26 H 17} O 10)

UV-visible absorption spectrum Ama X (in methanol) nm (ε) 212 (31,500), 235 (30,900), 284 (23,900), 324 (19,500)

'Infrared absorption spectrum max (KB r) cm— ¹ :

 3454, thigh, 1625, 1517, 1471, 1293

• — NMR (DMSO-d ₆ ) <5 p pm:

 2.53 (3H, s), 2.54 (3H, s), 6.91 (1H, s), 6.92 (1H, s), 7.27 (lH, s), 7.47 (1H, s). 8.11 (lH, s), 8.57 (lH, s)

^{- 13 C- NMR (DMSO-d} 6) (5 p pm:

 29.32.2, 102.9, 103.0, 107.9, 108.5, 113.3, 115.7, 119.8, 120.7, 126.3, 132.7, 133.5, 135.8, 144.6, 145.0, 150.8, 151.1, 152.5, 152.9 (20, 154.7, 173.3, 173.6, 199.1, 201.2

 ■ Solubility: Insoluble in water and hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF-3059-26 was determined as follows.

S PF— 3059— 27

S PF— 3059— 27

 • Appearance: yellow powder

 • Molecular weight: 642

• Molecular formula: C ₃₃ H ₂₂ 〇 ₁₄

 • High-speed electron impact mass spectrum (FAB-MS) m / z (ositive): 643 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) m / z (negativi): 641 (M-H)-

'High-resolution fast electron impact mass spectrum (HRFAB—MS) m / z (M + H) ⁺ Found: 643.1 088

Calculated: 643. 1089 (C ₃₃ H ₂₃ 〇 ₁₄₎

'UV-visible absorption spectrum λπι ax (in methanol) nm (ε):

 213 (46,100), 246 (46,600), 287 (31,700), 354 (19,900)

'Infrared absorption spectrum ma X (KB r) cm— ¹ :

 3400, 1694, Hoshi, 1604, 1468, 1290

^{- Χ Η- NMR (DMSO - d} 6) <3 p pm:

2.4K3H, s), 2.45 (3H, s), 2.67 (3H, s), 6.34 (lH, s), 6.63 (lH, s), 6.90 (lH, s), .48 (lH, d, 2.1) , 7.97 (m, d, 2.1), 8.49 (1H, s), 11.9 (1H, brs), 12.5 (lH, brs) • ¹³ C—NMR (DMSO—d ₆ ) δ p pm:

 27.4, 30.2, 32.7, 102.3, 102.8, 109.8, 111.8, 117.4, 119.6, 119.7, 120.3, 26.7, 127.5, 128.4, 133.0, 133.4, 135.1, 135.8, 138.6, 139.9, 141.3, 150.5, 51.7, 154.6, 155.8, 157.5, 158.3, 167.5, 172.5, 196.3, 200.0, 201.6, 205.3 'Solubility: insoluble in water, hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF-3059-27 was determined as follows.

S PF-30 59-28

 'Appearance: cream powder

 • Molecular weight: 532

'Molecular formula: C ₂₇ H ₁₆ 0 ₁₂

'Fast electron impact mass spectrum (FAB-MS) mZz (postive) 533 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) m / z (negativi): 531 (M-H)-

'High-resolution high-speed electron impact mass spectrum (HRFAB-MS) m / z (M + H) + actual value: 533. 0735

Calculated value: 533. 0721 (C ₂₇ H ₁₇ 0 ₁₂ )

• UV-visible absorption spectrum Ama X (in methanol) nm (ε):

 217 (35,300), 236 (34,100), 309 (26,100)

'Infrared absorption spectrum ma X (KB r) cm- ¹ :

 3502, 3096, 1690, 1598, 1503, 1434, 1303

-NMR (DMS〇— d ₆ ) δ p pm:

 2.39 (3H, s), 2.7K3H, s), 6.52 (lH, s), 6.85 (1H, d, 2.1), 6.92 (1H, d, 2.1),

 .98 (m, d, 2.1), 8.25C1H, s), 9.5 to 13.5 (5H, brs)

_{^{- 13 C- NMR (DMSO- d 6}} ) δ p pm:

 17.3, 32.4, 102.3, 103.3, 110.0, 112.1, 112.3, 113.4, 118.8, 120.6,

127.6, 128.9, 132.1, 136.1, 138.8, 140.9, 150.2, 152.0, 154.1, 157.8, 162.2, 162.6, 167.5, 169.2, 172.6, 175.3, 202.7

 • Solubility: insoluble in water and hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF-3059-28 was determined as follows.

S PF— 3059— 29 • Appearance: cream color powder

 • Molecular weight: 548

• Molecular formula: C ₂₈ H _2Q 0 ₁₂

 • High-speed electron impact mass spectrum (FAB-MS) m / z (positive): 549 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) m / z (negativi): 547 (M-H)-

'High-resolution fast electron impact mass spectrum (HRFAB-MS) m / z (M + H) ⁺ actual value: 549.1027

_{Calculated: 549. 1 034 (C 28 H} 21 〇 ₁₂₎

'UV-visible absorption spectrum Ama X (in methanol) nm (ε):

 226 (48,900) .316 (26,200), 352s (17,400)

'Infrared absorption spectrum max (KB r) cm— ¹ :

 3388, 1687, 1662, 1626 ', 1469, 1296

• One NMR (DMS〇_d ₆ ) δ p pm:

 2.23 (3H, s), 2.72 (3H, s), 3.11 (3H, s), 3.98 (2H, brs), 6.89 (lH, s), 6.93 (lH, s), 7.40H, s), 8.27 ( lHs), 9.00-13.00 (5H, brs)

• ¹³ C—band R (DMSO-d ₆ ) δ p pm:

 16.8, 32.4, 57.8, 64.4, 102.3, 103.1, 108.6, 112.0, 113.5, 118.46,

118.48, 119.1, 127.7, 128.1, 131.8, 138.9, 141.8, 144.3, 150.6, 150.7, 151.9, 152.6, 154.2, 162.1, 167.8, 173.5, 174.6, 202.7

 'Solubility: insoluble in water and hexane, soluble in methanol and DMSO

From these, the structural formula of SPF-3059-29 was determined as follows. 0, No Me

HOOC 0 O

 "Me

S PF— 30 59— 30

• Appearance: cream color powder

• Molecular weight: 490

'Molecular formula: C ₂₆ H _1S 0 _{1 C)}

 'Fast electron impact mass spectrum (FAB-MS) m / z (ositive): 491 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) m / z (negativi): 489 (M-H)-

'High-resolution high-speed electron impact mass spectrum (HRFAB—MS) m / z (M + H) ⁺ actual value: 491.0966

Calculated value: 49 1. 0979 (C ₂₆ H ₁₉ 〇 ₁₀ )

 'UV-visible absorption spectrum Ama X (in methanol) nm (ε):

 206 (36,000) 240 (32,700), 315 (26, 500), 372 (17, 900)

'Infrared absorption spectrum ma X (KB r) cm- ¹ :

 3396, 1704, 1618, 1518, 1479, 1294

• — NMR (DMSO-d ₆ ) δ p pm:

 2.28, 2.30, 2,67, 2.69, 4.62, 4.66, 4.70, 4.96, 6.32, 6.36, 6.90, 6.91, 7.03, 7.17, 7.43, 7.98, 8.54, 9.10 to 10.80

• ¹³ C—NMR (DMSO-d ₆ ) (5 p pm:

16.5, 17.0, 32.3, 32.4, 56.2, 65.9, 68.3, 103.0, 103.2, 103.8, 108.6, 110.4, 111.8, 113.4, 118.6, 125.6, 127.5, 129.5, 132.1, 132.6, 134.4, 137.9, 138,8, 141.2, 141.5, 144.3, 150.6, 152.0, 152.5, 154.3, 154.6, 154.9, 155.8, 156.6, 172.6, 173.4, 183.5, 187.2, 199.3, 202.7, 202.9

 • Solubility: insoluble in water and hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF—3059-30 was determined as the following formula (tautomer)

SPF-3059-34

 • Appearance: yellow powder

 • Molecular weight: 550

• molecular formula: C ₂₇ H i ₈ 0丄₃

 'Fast electron impact mass spectrum (FAB-MS) m / z (ositive): 551 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) mZz (negatiev): 549 (M-H)-

• High-resolution high-speed electron impact mass spectrum (HRFAB—MS) m / z (M + H) + actual value: 55 1.0846

Calculated value: 55 1. 0826 (C ₂₇ H ₁₉ 〇 ₁₃ )

 UV-visible absorption spectrum Ama X (in methanol) nm (ε):

 211 (35,600), 240 (31, 100), 283 (24,100), 349 (14,500)

ΧΗ— NMR (DMSO-d ₆ ) (5 p pm:

2.18 (3H, s), 2.66 (3H, s), 4.39 (1H, d, 11.9), 4.64 (1H, d, 11.9), 6.37 (lH, s) 6.84 (lH, s), 7.09 (lH, s), 8.47 (lH, brs)

• ¹³ C—NMR (DMSO-d ₆ ) (5 p pm:

 16.8, 32.4, 72.5, 80.0, 102.1, 103.0, 109.5, 110.6, 111.1, 117.7, 120.0, 126.5, 131.8, 133.6, 138.6, 141.4, 141.5, 150.5, 151.7, 154.9, 155.0, 156.2, 167.7, 172.6, 188.5, 202.8, 204.0

 • Solubility: insoluble in water and hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF-3059-34 was determined as follows.

S PF-3059- 35

S PF-3059- 35

 • Appearance: cream powder

 • Molecular weight: 546

'Molecular formula: C ₂₈ H ₁₈ 0 ₁₂

 • High-speed electron impact mass spectrum (FAB-MS) m / z (positive): 547 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) mZz (negatiev): 545 (M-H)-

'High-resolution high-speed electron impact mass spectrum (HRFAB-MS) m / z (M + H) + actual value: 547.09 1 1

Calculated: 547. 0877 (C ₂₈ H ₁₉ 〇 ₁₂₎

 UV-visible absorption spectrum Am a X (in methanol) nm (ε)

216 (38, 600) 237 (37, 300), 307 (30,100), 356sh (8, 800) • Infrared absorption spectrum max (KB r) cm— ¹ :

 3460, 3076, 1734, 1699, 1629, 1466, 1302

• One NMR (DMSO— d ₆ ) <5 p pm:

 2.39 (3H, s), 2.71 (3H, s). 3.82 (3H, s), 6.49 (lH, s), 6.86 (1H, d, 2.1),

6.92 (1H, s), 7.01 (lH, d, 2.1), 8.25 (lH, s), 9.5 to 13.5 (4H, brs)

• ¹³ C—NMR (DMSO-d ₆ ) δ p pm:

 17.3, 32.4, 52.5, 102.3, 103.8, 110.0, 112.1, 112.8, 113.5, 118.8, 120.6,

127.7, 129.0, 132.U 134.3, 138.8, 140.9, 150.3, 152.154.1, 157.7, 162.2,

162.8, 167.5, 168.6, 172.6, 175.1, 202.7

 • Solubility: insoluble in water and hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF—359-35 was determined as follows.

S PF— 3059— 36

S PF— 3059— 36

 -Appearance: cream powder

 • Molecular weight: 598

'Molecular formula: C ₃₂ H ₂₂ 0 ₁₂

 • High-speed electron impact mass spectrum (FAB-MS) mZz (positiv): 599 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) mZz (negatieve): 597 (M-H)-

'High-resolution fast electron impact mass spectrum (HRFAB-MS) mZz (M + H) + Found: 599. 1198

Calculated value: 599. 1190 (C ₃₂ H ₂₃ 0 ₁₂ )

• UV-visible absorption spectrum Ama X (in methanol) nm (ε):

 213 (46,300), 246 (48,700)> 287 (33,200), 360 (20,000)

■ One NMR (DMSO—d ₆ ) δ p pm:

 2.4K3H, s), 2.45 (3H, s) 2.66 (3H, s), 6.34 (lH, s), 6.63 (lH, s), 6.90 (1H, s), .46 (lH, d, 2.0), 7.46 (1H, s), 7.95 (1H, d, 2.0), 8.52 (1H, s)

• ¹³ C—NMR (DMSO—d ₆ ) δ p pm:

 27.3, 30.2, 32.7, 102.8, 103.1, 108.6, 111.7, 113.4, 117.3, 119.6 (20, 26.7, 127.5, 128.5, 133 133.4, 135.1, 135.6, 138.6, 139.7, 144.6, 150.8, 52.1, 154.6, 155.9, 157.5 , 158.4, 173.3, 196.3, 200.0, 201.6, 205.2

 'Solubility: insoluble in water and hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF-30 59-36 was determined as follows.

S PF-3059 -37

 • Appearance: yellow powder

 • Molecular weight: 806

• Molecular formula: C ₄₁ H ₂₆ 〇 ₁₈

• Fast electron impact mass spectrum (FAB-MS) m / z (ositve) 807 (M + H) + 'Fast electron impact mass spectrum (FAB-MS) mZz (negati ve): 805 (M-H)-

• High-resolution high-speed electron impact mass spectrum (HRFAB—MS) m / z (M—H) Observed: 807.1197

Calculated value: 807.1 198 (C ₄₁ H ₂₇ 〇 ₁₈ )

 • UV-visible absorption spectrum Ama X (in methanol) nm (ε):

 219 (68,900), 323 (30,700), 349 (30, 600)

• One NMR (DMSO-d ₆ ) ά p pm:

 2.08 (3H, s), 2.20 (3H, s), 2.53 (3H, s), 3.42 (1H, d 15.6), 3.56 (1H, d 15.6), .64 (lH d 13.4), 4.7K1H, d, 13.4), 6.27 (lH, s), 6.83 (1H, s), 6.84 (lH s),

6.88 (lH, s), 8.15 (ms), 9.0 13.0 (8H brs)

• ¹³ C—NMR (DMSO—d ₆ ) δ p pm:

 16.6 17.7, 20.0 32.0 62.3 102.1 102.25 103.8 106.0 108.4 108.7 109.9 111.55 118.56 119.2 119.6 120.4 121.7 127.9 129.13 131.1 139.5 140.6 141.00, 141.7 150.150.23 150.46 150.51 151.6 152.3 154.09 154.17 158.7 161.1 167.7 168.0 172.5 173.2 175.1 202.2 ' Insoluble in hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF-3059-37 was determined as follows.

S P F— 3059— 39

SPF— 3059— 39

 Appearance: yellow powder

 Molecular weight: 548

Molecular formula _{: 27} H _: 〇ι

 • Fast electron impact mass spectrum (FAB-MS) mZz (ositive): 549 (M + H) +

 'Fast electron impact mass spectrum (FAB-MS) mZz (negatiev): 547 (M-H)-

'UV-visible absorption spectrum Amax (in methanol) nm (ε):

 223 (40,000), 319 (23,900), 349 (20, 100)

^{- Χ Η- NMR (DMS 0- d} 6) <5 p pm:

 2.37 (3H, s), 2.71 (3H, s), 6.47 (3H, s), 6.91 (lH, s), 6.98 (lH, s), 8.22 (1H, s) 9.0-13.0 (6H, brs)

• ¹³ C—NMR (DMSO—d ₆ ) (5 ppm:

 17.3, 32.4, 102.3, 102.7, 109.9, 111.49, 112.4, 118.64, 118.8, 120.5, 127.5, 129.12, 132.1, 138.8, 140.96, 142.5, 150.29, 151.1, 152.0, 152.6, 154.24, 162.1, 167.5, 167.9, 172.6, 175.5, 202.7

 'Solubility: insoluble in water and hexane, soluble in methanol and DMSO

 From these, the structural formula of SPF-3059-39 was determined as follows.

Example 1 5-Acetyl-7 _ [(6,7-Dihydroxy-5-methoxycarboxy-4_oxo-1H-1-Benzopyran-1 3 (4H) -ylidene) hydroxymethyl] — 2,3-Dihydroxy-6— Methyl-9-oxo-9H-xanthene-1-force rubonic acid methyl ester (65)

 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. Under ice-cooling, a hexane solution of trimethylsilyldiazomethane (2.0 M) was added dropwise while monitoring the reaction by high performance liquid chromatography (HPLC). After confirming the burning of the raw material by HP LC, the mixture was further stirred for 1 hour under ice cooling. The solvent was distilled off under reduced pressure to obtain 58. Omg of a yellow powder mainly containing the target product (65).

(65)

 Lc-MS m / z 607 (M + H) +

_{^ -NMR (CD 3 D, 3} 0 0MHz) δ 7.93 (s, 1H 6.82 (s, 1H 6.30 (s, 1H), 4.57 (br. S, 2H), 3.82 (s, 3H), 2.61 (s, 3H), and 2.30 (s, 3H).

Example 2

5-Acetyl—7 — [(6,7—Diacetoxy 5—Methoxycarbonyl—4oxo-1 2H_1—Benzopyran-1 3 (4H) —Iridene) Acetoxymethyl] -2,3-Diacexy 6—Methyl-1 9-oxo 9H-xanthene-1-cal Bonic acid methyl ester (66)

 5-Acetyl-7-[(6,7-dihydroxy-5-methoxy-l-ponyl- 14-oxo- 1H- 1-benzo-pyran-1 3 (4H) -ylidene) hydroxymethyl] obtained in Example 1 3-Dihydroxy-6-methyl-9-oxo-9-H-xanthen-11-force rubonic acid methyl ester (65) (7.3 mg, 12. O ^ mo 1) was degassed under reduced pressure in advance and then argon The suspension was suspended in 4.0 ml of dichloromethane, which had been replaced, degassed under reduced pressure, and replaced with argon. Under ice cooling, pyridine (0.1 ml) was added dropwise, followed by acetic anhydride (501). After stirring for 1 hour under ice cooling, the mixture was further stirred at room temperature for 20 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (20 ml) and extracted with chloroform (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to silica gel column chromatography (1.8 cm φ X 10 cm), and purified by elution with a chloroform-containing form containing 1% of methanol to give 6.1 mg of the desired product (66 mg). ) Was obtained as a pale yellow powder.

( ⁶⁶ )

 LC-MS m / z 8 17 (M + H) +, 839 (M + Na) +

_{XH-NMR (CDC 1 3,} 300MHz) δ 8.15 (s, 1H), 7.56 (s, 1H) 7.05 (s, 1H), 5.18 (m, 2H), 4.02 (s, 3H), 3.97 (s, 3H ), 2.70-2.20 (m, 21H).

5-Acetyl-Ί-[(6,7-Dimethoxy-5-methoxycarbonyl-4-oxo- 2Η- 1-benzopyran-1 3 (4Η) -ylidene) methoxymethyl] 1 2 3-Dimethoxy-6-methyl-9-oxo-1 9Η —Xanthene methyl ester of rubonic acid (67) ■ Penicillium sp. SPF—Isolated from a culture of 3059 strain ■ Purified 5-acetyl-7 _ [(5-carboxy-1,6,7-dihydroxy-4-oxo1-2H—1 _ Benzopyran-1- (4H) -ylidene) hydroxymethyl] -2,3-dihydroxy-16-methyl-9-oxo-9H-xanthene-11-one mixture with rubonic acid and its tautomer (SPF-3059 — 1) (30.0 mg, 51.9 / mol) was dissolved in 5.Oml of dimethylformamide (DMF), which had been degassed under reduced pressure and then replaced with nitrogen, and degassed under reduced pressure. It was replaced with nitrogen. Under ice cooling, anhydrous potassium carbonate (288 mg, granular) was added, and dimethyl sulfate (1001) was added dropwise with stirring over about 5 minutes. After stirring for 1 hour under ice cooling, the mixture was further stirred at room temperature for 17 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (30 ml) and extracted with ethyl acetate (50 ml). The organic layer was separated, washed with saturated saline (20 ml), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (1.8 cm <i) x 15 cm), and purified by elution with a filter-form to afford 23.3 mg of the desired product (67) as a pale yellow powder. As obtained.

(67)

 L C-MS m / z 677 (M + H) +

_{^ -NMR (CDC 1 3, 300MHz} ) <5 7.94 (s, 1H), 6.86 (s, 1H),

6.41 (s, 1H), 5.25 (d, 1H, J = 13 Hz), 5.05 (d, 1H, J = 13 Hz), 3.96 (s, 6H) _:

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).

5 _acetyl- 7- [(5-aryloxycarbonyl 6, 7-diaryloxy —4oxo- 1 2 H— 1-benzopyran-1 3 (4H) —ylidene) aryloxymethyl] 1,2,3-diallyloxy-16-methyl _9-oxo-9 H-xanthenene-1-arylpyruonic acid allylic ester (68)

 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. Under ice-cooling, potassium carbonate (72 mg, granular) was added, and while stirring, aryl iodide (20 ^ 1) was added dropwise. After stirring for 1 hour under ice cooling, the mixture was further stirred at room temperature for 21 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (20 ml) and extracted with ethyl acetate (50 ml). The organic layer was separated, washed with saturated saline (20 ml), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (1.8 cm (|) x 10 cm), and purified by elution with a black hole form to give 5.8 mg of the desired product (68) in pale yellow. Obtained as a powder. .

 L C-MS m / z 859 (M + H) +, 88 1 (M + Na) +

_{iH- NMR (CDC 1 3, 3} 0 0MHz) δ 8.08 (s, 1H), 6.86 (s, 1H),

6.43 (s, 1H), 6.15-5.60 (m, 7H), 5.50-4.30 (m, 30H), 2.59 (s, 3H) and 2.02 (s,

3H). Example 5

 5-Acetyl-7-[(5-benzyloxycarbonyl 2,7-dibenzyloxy-4-oxo-2H-1-benzopyran-13 (4H) -ylidene) benzyloxymethyl] -2,3-dibenzyloxy 1-6-Methyl-9-oxo-9H-Xanthen-11-Benzyl rubonic acid ester (69)

 Penicillium sp. SPF—Isolated from a culture of 3059 strain —Purified 5-Acetyl-7 — [(5-Capuloxy-6,7—dihydroxy—

4-oxo-2H-1-benzopyran-1 (4H) -1-ylidene) hydroxymethyl] -1,2,3-dihydroxy-1-6-methyl-9-oxo-1H-xanthene-1 1-yl rubonic acid and its tautomerism Mixture with body (SPF-3059-1) (5.

0 mg, 8.6 umo 1) was dissolved in 1.5 ml of dimethylformamide (DMF), which had been degassed under reduced pressure in advance and then replaced with nitrogen, degassed under reduced pressure and replaced with nitrogen. Potassium carbonate (72 mg, granular) and tetrabutylammonium iodide (32 mg) were added, and benzyl bromobenzene1) was added dropwise with stirring. After stirring for 1 hour under ice cooling, the mixture was further stirred at room temperature for 20 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (30 ml) and extracted with ethyl acetate (50 ml). The organic layer was separated, washed successively with saturated aqueous ammonium chloride (20 ml) and then with saturated saline (20 ml), dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (1.8 cm (i) x 10 cm), and purified by elution with a column form to give 6.6 mg of the desired product (69) as a pale yellow powder. As obtained.

FD-MS m/z 1208 (M⁺) (69)

FD-MS m / z 1208 (M ⁺ )

_{iH- NMR (CDC 1 3, 300MHz} ) (38.08 (s, 1H), 7.45-6.95 (m, 36H), 6.44 (s, 1H), 5.20-4.60 (m, 14H), 4.07 (1H, d, / = 12 Hz), 3.74 (1H, d, / = 12 Hz), 2.43 (s, 3H) and 1.87 (s, 3H).

 5-Acetyl-7-[(6,7-Dibenzoyloxy-5-methoxycarbonyl-4-oxo-1H-2 Benzopyran-1 3 (4H) -Ilidene) benzoyloxymethyl] _2,3-dibenzoyl Xyl-6-methyl-19-oxo-9H-Xanthene-1-carboxylic acid methyl ester (70)

 5-Acetyl-7-[(6,7-dihydroxy-5-methoxypropanol-1 4-oxo-2H-1-benzopyran-1 3 (4H) -ylidene) hydroxymethyl] obtained in Example 1 —Dihydroxy-1-6-methyl-9-oxo-9H—kisanthen-11-Rubonic acid methyl ester (65) (6.Omg, 9.9 ^ mo1) was previously degassed under reduced pressure, and then replaced with argon. The residue was suspended in 4.0 ml of dichloromethane, degassed under reduced pressure, and replaced with argon. Under ice cooling, pyridine (801) was added dropwise, and then benzoyl chloride (291) was added dropwise. After stirring for 1 hour under ice cooling, the mixture was further stirred at room temperature for 20 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (20 ml) and extracted with chloroform (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (1.8 cmci × 10 cm), and purified by elution with a filter form to obtain 8.7 mg of the desired product (70) as a pale yellow powder.

tH— NMR (CDC 1 ₃、 3 0 0MH z) δ 8.25-7.95 (m, 11H), 7.70- 7.29 (m, 17H), 5.35 (brs, 2H), 3.99 (s， 3H)， 3.93 (s, 3H), 2.71 (s, 3H) and 2.38 (s, 3H). 実施例 7 (70)

_{tH- NMR (CDC 1 3, 3} 0 0MH z) δ 8.25-7.95 (m, 11H), 7.70- 7.29 (m, 17H), 5.35 (brs, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 2.71 (s, 3H) and 2.38 (s, 3H).

 The following compounds (71), (72), (73) and (74) were synthesized in the same manner as in Example 6.

 5-Acetyl-7-[(6,7-Divaleryloxy-5-methoxyethoxycarbonyl 4-oxo-2H-1-Benzopyran-1 3 (4H) -Ilidene) valeryloxymethyl] -2,3-Divaleryloxy-6_ Methyl _ 9 _ oxo _ 9H-Xanthene-1-carboxylic acid methyl ester (71)

 Pale yellow oil. 4.3 mg.

_{^ -NMR (CDC 1 3, 3} 0 0MHz) δ 8.22 (s, 1H), 7.58 (s, 1H), 6.97 (s, 1H), 5.22 (br. S, 2H), 4.02 (s, 3H), 3.93 (s, 3H), 2.70-2.40 (m, 16H) _; 1.75-1.35 (m, 20H) and 0.97 (t, 15H, / = 7.4 Hz).

5-Acetyl-7-[(6,7-Dipivaloyloxy-5-Methoxycarbonyl-14-oxo-2H_1Henzopyran-1 3 (4H) —Ilidene) Bivaloyloxymethyl] —2,3-Dipipa Yloxy 6-methyl-9-oxo-9H-xanthen-1-yl rubonic acid methyl ester (72)

Light yellow powder. 6.8 mg.

_{^{Σ H- NMR (CDC 1 3,}} 300MHz) δ 8.13 (s, 1H), 7.52 (s, 1H), 7.01 (s, 1H), 5.19 (d, 1H, J = 13.9 Hz), 5.07 (d, 1H , / = 13.9 Hz), 3.99 (s, 3H), 3.75 (s, 3H), 2.67 (s, 3H), 2.31 (s, 3H) and 1.24 (br.s, 45H).

5-Acetyl-7-[(6,7-Dicyclohexylcarbonyloxy _5-Methoxycarboxy-4 _oxo-1H-1-Benzopyran-1 3 (4H) -Ilidene) Hexylcarbonyloxy Methyl] -2,3_dicyclohexylcaronyloxy 6-methyl-9-oxo-9H-xanthene-1-methyl rubonic acid ester (73)

 Pale yellow oil. Yield 6. Omg.

'H-NMR (CDC 13 ^ 300MHz) δ 8.12 (s, 1H), 7.55 (s, 1H), 7.02 (s, 1H), 5.15 (d, 1H, /-14 Hz), 5.05 (d, 1H, J = 14 Hz), 3.99 (s, 3H) _; 3.74 (s, 3H), 2.66 (s, 3H), 2.45-2.25 (m, 8H) and 2.00-1.15 (m, 50H). 5-Acetyl-7-[(6,7-Dipropionyloxy-5-methoxycarbonyl-1-4-oxo-2H-1-benzopyran-13 (4H) -ylidene) propionyloxymethyl] 1,2,3-di Propionyloxy-6-methyl-9 9-year-old oxo-9H-xanthene-11-yl rubonic acid methyl ester (74)

 Light yellow powder. 4.lmg

_{- NMR (CDC 1 3, 300} MH z) d 8.14 (s, 1H), 7.58 (s, 1H), 6.99 (s, 1H), 5.20 (d, 1H, J = 14 Hz), 5.10 (d, 1H , Not 14 Hz), 4.01 (s, 3H), 3.75 (s, 3H), 2.70-2.45 (m, 13H), 2.31 (s, 3H), and 1.35-1.15 (m, 15H). possibility

 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.

Claims

The scope of the claims  Equation (1)

[Wherein, R ³ is a hydrogen atom, a carboxyl group, a C ₆ alkoxycarbonyl group, a substituted C ^ —Ce alkoxycarbonyl group, a C ₃ —C ₇ cycloalkyloxycarbonyl group, a C ₂ -C ₆ alkenyloxycarbo Carbonyl group, substituted C ₂ -C ₆ alkenyloxycarbonyl group, C ₂ -C ₆ alkynyloxycarbonyl group, 7-aryloxycarbonyl group, substituted aryloxycarbonyl group, tri ((: _1- 〇 ₆ Arukiru phenyl) Shiriruokishi force Lupo two group or the general formula (2)  0 R ⁶ \ N '\ ( ² ) R ⁷ (In the formula, R ⁶ and R ⁷ represent a hydrogen atom, —C ₆ alkyl group, substituted — (: ₆ alkyl group, C ₃ — ( ₇ cycloalkyl group, aryl group or substituted aryl group, respectively) Or R ⁶ and R ⁷ together represent a C ₃ _C ₇ alkylene group or an alkylene group containing a hetero atom.), And R ⁴ represents a hydrogen atom, a hydroxyl group, a C ₂ — C ₇ 7 Rukanoiruokishi group, a substituted C ₂ - C ₇ alkanoyloxy Noi Ruo alkoxy group, C ₄ one C ₈ cycloalkyl Karuponiruokishi group, Aroiruokishi group, a substituted Aroiruokishi group, ^ chromatography ₍₆ Arukoki shea group, substituted - C ₆ alkoxy group, C ₃ —C ₇ cycloalkoxy group, C ₂ —C ₆ alkenyloxy group, substituted C ₂ —C ₆ alkenyloxy group, C ₂ —C ₆ alkynyloxy group, aryloxy group, substituted aryloxy group or tri ( Ci one C ₆ alkyl / It represents enyl) Siri Ruokishi group, R ⁵ is a hydrogen atom, C ₂ - C ₇ Arukanoiru group, a substituted C ₂ - C _{7 7} Luke Noiru group, -C _s cycloalkyl Cal Poni group, Aroiru group, a substituted Aroiru groups, C E - C ₆ alkyl group, a substituted CfCs alkyl group, C ₃ - (3 ₇ cycloalkyl, C ₂ -C ₆ alkenyl group, a substituted C ₂ - C ₆ alkenyl group, ₍₂ - ₆ Arukiniru group, Ariru group, It represents a substituted aryl group or a tri ((“C ₆ alkyl / phenyl) silyl group”. R ¹ and R ² are represented by one of the following [I] or [II]. [I] R ¹ represents a methyl group, and R ² represents a group represented by any of the general formulas (3), (4), (5) and (7).

(Wherein, R ⁸ is a hydrogen atom, a carbonyl group, a C ₆ alkoxycarbonyl group, a substituted C _x -C ₆ alkoxycarbonyl group, a C ₃ _C ₇ cycloalkyloxycarbonyl group, ₂ -C ₆ alkenyloxycarbonyl group, substituted C ₂ —C ₆ alkenyloxycarbonyl group, (C ₂ _C ₆ alkynyloxycarbonyl, 7-aryloxycarbonyl, substituted aryloxycarbonyl, trialkylphenyl) silyloxycarbonyl or general formula (2)  0 ^R , person (2) R ⁷ (Wherein, R ⁶ and R ⁷ have the same meanings as described above.), Wherein R ⁹ is a hydrogen atom, a hydroxyl group, a C ₂ —C ₇ alkanoyloxy group, a substituted C ₂ —C ₇ Alkanoyloxy group, C ₄ _C ₈ cycloalkylcarbonyloxy group, arylooxy group, substituted arylooxy group, di-C ₆ alkoxy group, substituted mono-C ₆ alkoxy group, C ₃ —C ₇ cycloalkoxy group, C ₂ _C ₆ Arukeniruokishi group, a substituted C ₂ _ C ₆ Arukeniruokishi groups, C ₂ - C ₆ Arukini Ruokishi group, an Ariruokishi group, a substituted Ariruokishi group or tri (CI- Ce alkyl / phenyl) Shiriruokishi radical, R ^1Q is a hydrogen atom, C ₂ - C ₇ Arukanoiru group, substitution <3 ₂ - C ₇ Arukanoiru group, C ₄ one C _s cycloalkyl Cal Poni group, Aroiru group, location Conversion Aroiru group, one c ₆ alkyl group, a substituted c "c ₆ alkyl group, c ₃ _c ₇ a cycloalkyl group, c ₂ - c ₆ alkenyl group, a substituted c ₂ - c ₆ alkenyl group, c ₂ - c ₆ alkynyl group Represents an aryl group, a substituted aryl group or a tri (Ci-Cealkyl / phenyl) silyl group.)

(Wherein, R ^8, R ⁹ and R ¹⁰ are as defined above, R ¹¹ is a hydrogen atom, C ₂ - C ₇ alkanol I group, a substituted C ₂ - C ₇ Arukanoiru group, C ₄ - C ₈ cycloalkyl Alkyl carbonyl group, aryl group, substituted aryl group, C `` C <sub>6</sub> alkyl group, substituted C `` C ₆ alkyl group, c ₃ -c ₇ cycloalkyl group, C ₂ _C ₆ alkenyl group, substituted C ₂ _C ₆ Represents an alkenyl group, a C ₂ -C ₆ T alkynyl group, an aryl group, a substituted aryl group or a tri (Ci-C ₆ alkyl / phenyl) silyl group.

(Wherein, R ⁸ , R ⁹ and R ^1Q are as defined above. R ¹² is a hydrogen atom, a methoxymethyl group, or a compound represented by the general formula (6)

(Wherein, R ¹³ is a hydrogen atom, C ₂ - C ₇ Arukanoiru group, a substituted C ₂ - C ₇ Arukanoiru group, C ₄ ten ₈ cycloalkyl carboxyalkyl group, Aroiru group, a substituted Aroiru group, one C ₆ Al Kill group, substituted C ^ —Ce alkyl group, C ₃ —C ₇ cycloalkyl group, 〇 ₂ —〇 ₆ alkenyl Group, a substituted C ₂ - C ₆ alkenyl group, C ₂ - C ₆ alkynyl group, Ariru group, a substituted Ariru group or tri ((: "represents a C ₆ alkyl / phenyl) silyl group.) Represents a).

(Wherein, R ^8, R ⁹ and R ¹⁰ are as defined above R ¹⁴ is a hydrogen atom, C ₂ -. C ₇ alkanol I group, a substituted C ₂ - C ₇ Arukanoiru group, C ₄ -C ₈ cycloalkyl Alkyl carbonyl group, aryl group, substituted aryl group, (C ₆ alkyl group, substituted C—C ₆ alkyl group, c ₃ -c ₇ cycloalkyl group, C ₂ —C ₆ alkenyl group, substituted C ₂ - C ₆ alkenyl group, C ₂ -〇 ₆ § Rukiniru group, an Ariru group, a substituted Ariru group or tri (over alkyl / phenyl) silyl group). [II] R ¹ represents a group represented by the general formula (8) or (9), and R ² represents an acetyl group.

(In the formula, R ⁸ , R ⁹ and R ^1Q are as defined above.)

(Wherein, R ¹⁵ is a hydrogen atom, a C ₂ -C ₇ alkanoyl group, a substituted C ₂ -C ₇ alkanoyl group, a C ₄ -C ₈ cycloalkylcarbonyl group, an aroyl group, a substituted aroyl group, a Ci—C ₆ alkyl Group, substituted C ^ —Ce alkyl group, C ₃ —C ₇ cycloalkyl group, 〇 ₂ —〇 ₆ alkenyl It represents the c ₆ alkenyl group, c ₂ -c ₆ alkynyl group, Ariru group, a substituted Ariru group or tri (Cf c ₆ alkyl / phenyl) silyl group - group, substituted c _2. ) Provided that when both R ³ and R ⁸ are a hydrogen atom or a hydroxyl group, at least one of R ⁹ is neither a hydrogen atom nor a hydroxyl group, or R ⁵ , R ¹⁰ , _Rll , R _At least one of ₁₃ , R14 or Ris is not a hydrogen atom. _Rl is a group represented by the general formula (8), wherein R ² is an acetyl group, R ³ and R ⁸ are methoxycarbonyl groups, R ⁴ and R ⁹ are methoxy groups, Excludes compounds where R ⁵ and R ¹⁰ are methyl groups. ] The compound represented by these.  2. General formula (10)

(Wherein, R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ and R ^1G have the same ^{meaning as} in claim 1. However, when both R ³ and R ⁸ are a hydrogen atom or a carboxyl group, Is a compound represented by the formula: at least one of R ⁴ or R ⁹ is not a hydrogen atom or a hydroxyl group, or at least one of R ⁵ or R ^1Q is not a hydrogen atom.  3. General formula (11)

(Wherein, R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ^1Q and R ¹¹ are as defined in claim 1. However, both R ³ and R ⁸ are a hydrogen atom or a carboxyl group. In this case, at least one of R ^{4 and} R ⁹ is not a hydrogen atom or a hydroxyl group, or at least one of R ⁵ , R ^1G or R ¹¹ is not a hydrogen atom. 4. General formula (12)

(Wherein, the ^{R 3, R 4, R 5} , R 8, R 9 and R ^1Q as defined in claim 1 ₍ R ¹² is a hydrogen atom, a methoxymethyl group, or a general formula (13)

(Wherein, R ¹³ has the same meaning as in claim 1). However, when both R ³ and R ⁸ are a hydrogen atom or a carboxyl group, at least one of R ⁴ or R ⁹ is neither a hydrogen atom nor a hydroxyl group, or one of R ⁵ , R ^1G or R ¹³ At least one is not a hydrogen atom. ) The compound represented by these.  5. General formula (14)

However, when both R ³ and R ⁸ are a hydrogen atom or a propyloxyl group, at least one of R ^{4 and} R ⁹ is neither a hydrogen atom nor a hydroxyl group, or R ⁵ , R ^1Q or R ¹⁴ At least one of them is not a hydrogen atom. ) The compound represented by these. 6. General formula (15)

(Wherein, R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ and R ^1Q have the same meaning as in claim 1. However, when both R ³ and R ⁸ are a hydrogen atom or a propyloxyl group) the, or not a hydroxyl group at one hydrogen atom even without least of R ⁴ or R ^9, or least one of R ⁵ or R ^1Q is not a hydrogen atom. in addition, R ³ and R ⁸ is A compound which is a methoxycarbonyl group, R ⁴ and R ⁹ are methoxy groups, and R ⁵ and R ¹⁰ are methyl groups.  7. General formula (16)

(In the formula, R ³ , R ⁴ , R ⁵ and R ¹⁵ have the same meaning as in claim 1. However, when R ³ is a hydrogen atom or a hydroxyl group, R ⁴ may be a hydrogen atom or a hydroxyl group. Or at least one of R ^{5 and} R ¹⁵ is not a hydrogen atom. 8. R ³ or at least one of either the serial mounting of the compounds of claims 1-7 is not a hydrogen atom in R ^8. 9. R ³ and A compound according to any one of claims 1 to 6 non-hydrogen atoms in both the R ^8. 10. R ⁴ or a compound according to any of claims 1 to 7 at least one is not hydrogen atom of R ^9. 11. R ³ and A compound according to any one of claims 1 to 6 non-hydrogen atoms in both the R ^9. 12. R ^3, R ^4, compounds according to any of claims 1 to 6 both are not hydrogen atom of R ⁸ and R ^9. 13. R ³ and R ⁸ is one C ₆ alkoxy compound of claims 1-7 noise Re wherein either a cull Poni Le group. 14. The method according to claim ^{1, wherein} R ¹ is a methyl group, and R ² is a group represented by any of the general formulas (3), (4), (5) and (7). A compound as described. 15. R ³ and R ⁸ are Ci— Ce alkoxycarbonyl groups, R ⁴ and R ⁹ are hydroxyl groups, C ₂ —C ₇ alkanoyloxy groups, substituted C ₂ _C ₇ alkanoyloxy groups, C ₄ -C ₈ cycloalkyl group, a propyloxy group, an aryloxy group or a substituted aryloxy group, wherein R ⁵ and R ¹⁰ are a hydrogen atom, a C ₂ -C ₇ alkanoyl group, a substituted C ₂ -C ₇ alkanoyl group, C ₄ one ₈ cycloalkyl Cal Poni group, compounds according to any of claims 1 to 6 is Aroiru group or a substituted Aroiru group.  16. A semaphorin inhibitor comprising the compound according to any one of claims 1 to 15 as an active ingredient.  17. The semaphorin inhibitor according to claim 16, which is a nerve regeneration promoter.  18. The agent for promoting nerve regeneration according to claim 17, which is an agent for preventing or treating a neuropathy disease and Z or a neurodegenerative disease.