WO2020090700A1 - Nouveau composé ynone et son utilisation - Google Patents

Nouveau composé ynone et son utilisation Download PDF

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WO2020090700A1
WO2020090700A1 PCT/JP2019/042086 JP2019042086W WO2020090700A1 WO 2020090700 A1 WO2020090700 A1 WO 2020090700A1 JP 2019042086 W JP2019042086 W JP 2019042086W WO 2020090700 A1 WO2020090700 A1 WO 2020090700A1
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group
formula
alkyl group
hydrogen atom
compound
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PCT/JP2019/042086
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中山　淳
順平 寺町
正博 安倍
康祐 難波
伊藤　孝司
大輔 辻
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国立大学法人徳島大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel inone compound and its use.
  • Non-Patent Document 1 The following formula, obtained from the fermentation broth of the fungus Curvularia verruculosa: The enone compound represented by is known to have a strong anti-inflammatory action (Non-Patent Document 1).
  • An object of the present invention is to provide a novel inone compound useful for inducing endoplasmic reticulum stress response and the like.
  • the inventors of the present invention have conducted extensive studies to achieve the above-mentioned object, and as a result, found that a compound having an inone skeleton induces an endoplasmic reticulum stress response.
  • the present inventors have completed the present invention through further studies based on such findings.
  • the present invention includes the following aspects. Item 1.
  • a 1 is an aromatic ring which may have a substituent
  • X 1 is an oxygen atom, a sulfur atom, or a group represented by the formula: —N (R X1 ) —
  • R X1 is a hydrogen atom or an alkyl group
  • X 2 is a single bond or a double bond
  • R 1 and R 2 are the same or different and each is a hydrogen atom or an alkyl group
  • R 3 and R 4 are the same or different and are a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, or R 3 O and R 4 O are together with two adjacent carbon atoms.
  • Item 2 The compound according to Item 1, wherein A 1 is a C 6-10 aromatic hydrocarbon ring which may have a substituent, or a 5- to 10-membered aromatic heterocycle which may have a substituent. Or its salt.
  • R 5 is —OR 5a or —NR 5b R 5c
  • R 5a is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group
  • R 5b and R 5c are each independently a hydrogen atom, an alkyl group, or an aryl group
  • n is an integer of 0 to 4, If n is an integer of 2 or more, the plurality of R 5, may be the same or different from each other.
  • X 3 is a single bond, a double bond, or a triple bond
  • R 6 is a hydrogen atom, an alkyl group which may have a substituent, or an aromatic ring group which may have a substituent
  • R 7 and R 8 are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group, or R 7 O and R 8 O may form a ring with two adjacent carbon atoms
  • R 9 is a hydrogen atom, an alkyl group, or an aryl group.
  • the compounds represented by are excluded.
  • Item 11. Item 11.
  • a 1 is an aromatic ring which may have a substituent
  • X 1 is an oxygen atom, a sulfur atom, or a group represented by the formula: —N (R X1 ) —
  • R X1 is a hydrogen atom or an alkyl group
  • X 2 is a single bond or a double bond
  • R 1 and R 2 are the same or different and each is a hydrogen atom or an alkyl group
  • R 3 and R 4 are the same or different and are a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, or R 3 O and R 4 O are together with two adjacent carbon atoms.
  • X 3 is a single bond, a double bond, or a triple bond
  • R 6 is a hydrogen atom, an alkyl group which may have a substituent, or an aromatic ring group which may have a substituent
  • R 7 and R 8 are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group, or R 7 O and R 8 O may form a ring with two adjacent carbon atoms
  • R 9 is a hydrogen atom, an alkyl group, or an aryl group.
  • a pharmaceutical composition comprising at least one selected from: Item 16.
  • Item 16. The pharmaceutical composition according to Item 15, which is an endoplasmic reticulum stress response inducer.
  • Item 18. The pharmaceutical composition according to any one of Items 15 to 17, which is at least one prophylactic or therapeutic agent selected from cancer, bone disease, and rheumatism.
  • the compound of the present invention is capable of inducing an endoplasmic reticulum stress response, and is useful for the prevention or treatment of diseases associated with endoplasmic reticulum stress. Moreover, the compound of the present invention can inhibit the activity of protein disulfide isomerase (PDI), and is useful for the prevention or treatment of diseases associated with PDI. Furthermore, the compound of the present invention is useful for the prevention or treatment of at least one disease selected from cancer, bone disease, and rheumatism. Moreover, since the compound of the present invention does not inhibit normal hematopoiesis, it has few side effects.
  • PDI protein disulfide isomerase
  • FIG. 1 is a diagram showing expression levels of CHOP relating to endoplasmic reticulum stress response in Examples 2, 8 and 9.
  • FIG. 2 is a diagram showing the inhibition of tumor progression of the compound of Example 2 in myeloma model mice.
  • FIG. 3 is a diagram showing the inhibition of tumor progression by the compound of Example 8 in myeloma model mice.
  • FIG. 4 is a graph showing the effect of the compound of Example 2 on cytotoxic activity on hematopoietic stem cells.
  • FIG. 5 is a graph showing the effect of the compound of Example 8 on the cytotoxic activity on hematopoietic stem cells.
  • FIG. 6 shows the inhibition of osteoclast formation by the compound of Example 8.
  • 7 is a figure which shows the osteoclast formation suppression of the compound of Example 2.
  • FIG. 8 is a figure which shows the cancer bone lesion formation suppression of the compound of Example 8.
  • FIG. 9 is a graph showing the antirheumatic effect of the compound of Example 2.
  • C ab means that the target carbon number is an integer of a or more and b or less.
  • aromatic ring is a concept including an aromatic hydrocarbon ring and an aromatic heterocycle.
  • the aromatic hydrocarbon ring means an aromatic ring in which the ring-constituting atoms consist of carbon atoms only.
  • the number of constituent atoms of the aromatic hydrocarbon ring is not particularly limited, but can be, for example, 6 to 20.
  • the aromatic hydrocarbon ring can be monocyclic or fused polycyclic. Examples of the monocyclic aromatic hydrocarbon ring include benzene.
  • the condensed polycyclic aromatic hydrocarbon ring examples include two rings (eg, indene, naphthalene), three rings (eg, fluorene, anthracene, phenanthrene), and four rings (eg, pyrene).
  • the aromatic heterocycle means an aromatic ring containing carbon atoms and heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like as the constituent atoms of the ring.
  • the number of constituent atoms of the aromatic heterocycle is not particularly limited, but can be, for example, 5 to 20.
  • the number of heteroatoms among the constituent atoms of the aromatic heterocycle is not particularly limited, but can be, for example, 1 to 4.
  • the aromatic heterocycle can be monocyclic or fused polycyclic.
  • monocyclic aromatic heterocycles examples include 5-membered rings (eg, furan, isoxazole, oxazole, thiophene, isothiazole, thiazole, pyrrole, pyrazole, imidazole, triazole), 6-membered rings (eg, pyridine, pyridazine). , Pyrimidine, pyrazine, triazine).
  • the condensed ring aromatic heterocycle examples include two rings (eg, benzofuran, benzothiophene, indole, indazole, benzimidazole, purine, quinoline, isoquinoline, cinoline, quinoxaline, phthalazine, 1,8-naphthyridine, putediline), There are three rings (eg, carbazole, acridine, phenazine, phenanthridine, phenanthroline, phenoxazine, phenothiazine).
  • the “aromatic ring group” refers to a group obtained by removing one hydrogen atom from the aromatic ring.
  • the aromatic ring group examples include aryl groups such as phenyl group and naphthyl group; and heteroaryl groups such as furanyl group, thienyl group and pyridyl group.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • alkyl group is a concept including a linear alkyl group and a branched alkyl group.
  • linear alkyl group examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • the straight-chain C 1-10 alkyl group of Examples of the branched chain alkyl group include a branched chain C 3-10 alkyl group such as isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl, 2-ethylhexyl and the like.
  • examples of the “cycloalkyl group” include C 3-10 cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl and the like.
  • aryl group refers to a monovalent group derived from an aromatic hydrocarbon ring.
  • aryl group include C 6-10 aryl groups such as phenyl and naphthyl.
  • examples of the “aralkyl group” include a C 6-10 aryl C 1-4 alkyl group such as benzyl and phenethyl.
  • alkoxy group refers to a group represented by the formula: R A O— (in the formula, R A is an alkyl group).
  • R A is an alkyl group.
  • alkoxy group include C 1-4 alkoxy groups such as methoxy, ethoxy, propoxy (n-propoxy, isopropoxy), butoxy (n-butoxy, isobutoxy, s-butoxy, t-butoxy).
  • examples of the “alkoxyalkyl group” include groups represented by the formula: (C 1-4 alkyl) -O— (C 1-4 alkylene) -O—.
  • Examples of the group represented by the formula include C 1-3 alkoxy C 1-3 alkyl groups such as methoxymethyl, methoxyethyl, ethoxymethyl and ethoxyethyl.
  • examples of the “alkoxyalkoxy group” include groups represented by the formula: formula: (C 1-4 alkyl) -O— (C 1-4 alkylene)-.
  • Examples of the group represented by the formula include C 1-3 alkoxy C 1-3 alkyl groups such as methoxymethoxy, methoxyethoxy, ethoxymethoxy, and ethoxyethoxy.
  • alkoxyalkoxyalkyl group is represented by, for example, the formula: (C 1-6 alkyl) -O- (C 1-4 alkylene) -O- (C 1-4 alkylene)-.
  • Groups. Examples of the group represented by the formula include C 1-3 alkoxy C 1-3 alkoxy C 1 -such as methoxymethoxyethyl, methoxyethoxymethyl, ethoxymethoxymethyl, ethoxymethoxyethyl, ethoxyethoxymethyl, and ethoxyethoxyethyl. 3 alkyl groups are mentioned.
  • alkoxyalkoxyalkoxy group is represented by, for example, the formula: (C 1-6 alkyl) -O- (C 1-4 alkylene) -O- (C 1-4 alkylene) -O-. And the groups mentioned below.
  • Examples of the group represented by the formula include C 1-3 alkoxy C 1-3 alkoxy C 1- such as methoxymethoxyethoxy, methoxyethoxymethoxy, ethoxymethoxymethoxy, ethoxymethoxyethoxy, ethoxyethoxymethoxy, and ethoxyethoxyethoxy.
  • 3 alkoxy groups can be mentioned.
  • acyl group means a group represented by the formula: —C ( ⁇ O) —R B1 (in the formula, R B1 is a hydrocarbon group), and —C ( ⁇ O).
  • a group represented by —O—R B2 (in the formula, R B2 is a hydrocarbon group) is included.
  • the hydrocarbon group represented by R B1 and R B2 may be a chain hydrocarbon group (eg, alkyl), a saturated or unsaturated cyclic hydrocarbon group (eg, cycloalkyl, aryl), a combination thereof ( Example: aralkyl).
  • Acyl groups include alkylcarbonyl, arylcarbonyl, and aralkylcarbonyl groups.
  • alkylcarbonyl group examples include (C 1-10 alkyl) carbonyl groups such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl and decanoyl.
  • Arylcarbonyl groups include, for example, benzoyl or (C 6-14 aryl) carbonyl groups such as naphthoyl (ie, ⁇ -naphthoyl or ⁇ -naphthoyl).
  • aralkylcarbonyl group examples include (C 6-14 aryl C 1-4 alkyl) carbonyl groups such as benzylcarbonyl.
  • alkylthio group refers to a group represented by the formula: R C —S— (wherein R C is an alkyl group).
  • R C is an alkyl group.
  • alkylthio group include C 1-4 alkylthio groups such as methylthio, ethylthio, propylthio (n-propylthio, isopropylthio) and butylthio (n-butylthio, isobutylthio, s-butylthio, t-butylthio).
  • the “monoalkylamino group” refers to a group represented by the formula: R D1 —NH— (in the formula, R D1 is an alkyl group).
  • the monoalkylamino group for example, monomethyl amino, mono-ethylamino, monopropyl amino (mono n- propylamino, mono isopropylamino) include mono C 1-4 alkylamino group or the like.
  • dialkylamino group refers to a group represented by the formula: R D2 R D3 N— (in the formula, R D1 and R D3 are the same or different and each is an alkyl group).
  • examples of the dialkylamino group include diC 1-4 alkylamino groups such as dimethylamino, ethylmethylamino, diethylamino, propylmethylamino and the like.
  • the compound of the present invention or a salt thereof is a compound represented by formula (1) or a salt thereof (hereinafter, referred to as “compound (1)”): (In the formula, A 1 , X 1 , X 2 , R 1 , R 2 , R 3 , and R 4 are the same as above.)
  • a 1 is preferably a C 6-10 aromatic hydrocarbon ring which may have a substituent, or a 5- to 10-membered aromatic heterocycle which may have a substituent, and more preferably A C 6-10 aromatic hydrocarbon ring which may have a substituent, a 5- to 10-membered nitrogen-containing aromatic heterocycle which may have a substituent, and a substituent which may have 5 To 10-membered oxygen-containing aromatic heterocycle, or 5- to 10-membered sulfur-containing aromatic heterocycle which may have a substituent, more preferably C 6-10 aromatic hydrocarbon ring, particularly preferably Is a benzene ring which may have a substituent.
  • substituents examples include a halogen atom, a hydroxyl group, a mercapto group, an amino group, an alkyl group, an alkoxy group, an alkoxyalkoxy group, an alkoxyalkoxyalkoxy group, an acyl group, an alkylthio group, a monoalkylamino group and a dialkylamino group.
  • the number of substituents is not particularly limited, but is, for example, an integer of 0 to 4, preferably an integer of 1 to 4, and more preferably an integer of 1 to 3.
  • a 1 is the following formula: (In the formula, R 5 and n are the same as above.)
  • the ring represented by is preferable. -OR 5a or -NR 5b R 5c ,
  • R 5a is preferably a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, more preferably a hydrogen atom, a C 1-4 alkyl group, C 1-4 alkoxy C 1-4 alkyl group or C 1-4 alkoxy C 1-4 alkoxy C 1-4 alkyl group, particularly preferably hydrogen atom, C 1-2 alkyl group, C 1-2 alkoxy A C 1-2 alkyl group or a C 1-2 alkoxy C 1-2 alkoxy C 1-2 alkyl group.
  • R 5b and R 5c are preferably a hydrogen atom, a C 1-4 alkyl group, or a C 6-12 aryl group.
  • Examples of the combination of R 5b and R 5c include a combination in which R 5b and R 5c are hydrogen atoms, a combination in which one of R 5b and R 5c is a hydrogen atom and the other is an alkyl group, and a combination of R 5b and R 5c is an alkyl group.
  • a combination which is a group, a combination in which one of R 5b and R 5c is a hydrogen atom and the other is an aryl group, a combination in which R 5b and R 5c are an aryl group and the like are preferable.
  • n is preferably an integer of 1 to 4, more preferably an integer of 1 to 3.
  • a plurality of R 5 may be the same or different from each other, for example, a plurality of R 5 may be all —OR 5a , or —OR 5a and It may be a combination of —NR 5b R 5c .
  • a 1 is the following formula: (In the formula, R 51 , R 52 , R 53 , R 54 , and R 55 are the same as the above.)
  • the ring represented by is preferable.
  • a preferable combination of R 51 and R 52 is a combination in which R 51 is a hydrogen atom and R 52 is an alkyl group, R 51 is an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, and , R 52 is an alkyl group.
  • Suitable combinations of R 53 , R 54 , and R 55 include a combination in which R 51 is a hydrogen atom, R 54 is a hydrogen atom, and R 55 is an alkyl group.
  • X 1 is preferably an oxygen atom, a sulfur atom, or a formula: —N (R X11 ) — (wherein R X11 is a hydrogen atom or a C 1-4 alkyl group), and more preferably an oxygen atom or It is a sulfur atom, and particularly preferably an oxygen atom.
  • X 2 is a single bond or a double bond as described above. Specifically, it is as follows. (In the formula, * indicates a bonding position with A 1. ) When X 2 is a double bond, compound (1) can be in cis form or trans form. X 2 is preferably a double bond.
  • R 1 is preferably an alkyl group, more preferably a C 1-4 alkyl group, and particularly preferably a C 1-2 alkyl group.
  • R 1 is an alkyl group
  • the carbon atom to which R 1 is attached is an asymmetric carbon atom.
  • the configuration of this asymmetric carbon atom may be either R configuration or S configuration, but it is preferably S configuration.
  • R 2 is preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group, and particularly preferably a hydrogen atom.
  • R 2 is an alkyl group
  • the carbon atom to which R 2 is attached is an asymmetric carbon atom.
  • the configuration of this asymmetric carbon atom may be either R configuration or S configuration, but it is preferably R configuration.
  • R 3 and R 4 are each preferably a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, and more preferably a hydrogen atom, a C 1-4 alkyl group, a C 1-4 alkoxyC. 1-4 alkyl group, or C 1-4 alkoxy C 1-4 alkoxy C 1-4 alkyl group, particularly preferably hydrogen atom, C 1-2 alkyl group, C 1-2 alkoxy C 1-2 alkyl. Or a C 1-2 alkoxy C 1-2 alkoxy C 1-2 alkyl group.
  • Suitable combinations of R 3 and R 4, combined combined R 3 and R 4 are both hydrogen atoms, R 3 and R 4 are both alkyl groups, R 3 and R 4 are both an alkoxyalkyl group Combinations can be mentioned.
  • R 3 O and R 4 O may form a ring with two adjacent carbon atoms, and the ring has the following formula: (In the formula, R 3a and R 4a are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group.) It may be a ring represented by. Each of R 3a and R 4a is preferably a hydrogen atom, a C 1-4 alkyl group, or a C 6-10 aryl group. Suitable combinations of R 3a and R 4a, the combination R 3a and R 4a are both alkyl groups, R 3a is a hydrogen atom, and, as combinations R 4a is an aryl group.
  • the carbon atom to which R 3 O and R 4 O are bonded is an asymmetric carbon atom.
  • the configuration of the asymmetric carbon atom to which R 3 O and R 4 O are bonded may be either the R configuration or the S configuration, but both are preferably the S configuration.
  • R 11 is an alkyl group, and R 31 and R 41 are the same or different and are a hydrogen atom, an alkyl group, or an alkoxyalkyl group.
  • R 11 is preferably a C 1-4 alkyl group, and more preferably a C 1-2 alkyl group.
  • R 31 and R 41 are each preferably a hydrogen atom, a C 1-4 alkyl group or a C 1-4 alkoxy C 1-4 alkyl group, more preferably a hydrogen atom, a C 1-2 alkyl group. Or a C 1-2 alkoxy C 1-2 alkyl group.
  • the compound (1) has at least two asymmetric carbon atoms (carbon atoms to which R 3 O and R 4 O are bonded), and includes both enantiomers and diastereomers.
  • the compound (1) may be a mixture containing two kinds of enantiomers.
  • the mixture may be a mixture in which one enantiomer is contained in an excessive amount, or may be an equivalent mixture (racemate) of two kinds of enantiomers.
  • the compound (1) is preferably a compound represented by the following formula (1A) or a salt thereof. (In the formula, A 1 , X 1 , X 2 , R 1 , R 2 , R 3 , and R 4 are the same as described above. However, the following formula: The compounds represented by are excluded. )
  • the compound (1) is preferably a compound selected from the following group or a salt thereof:
  • a compound in which the methoxy group bonded to the benzene ring is changed to a monoalkylamino group such as a monomethylamino group or a salt thereof is also preferable.
  • the salt is preferably a pharmaceutically acceptable salt.
  • the salt can be an inorganic salt or an organic salt.
  • examples of the salt include inorganic acid salts (eg, hydrofluoric acid salts, hydrochloric acid salts, hydrobromic acid salts, hydroiodic acid salts, nitrates, perchloric acid salts, sulfuric acid salts, phosphoric acid salts), organic acids.
  • Acid salts eg, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, malate, fumarate, succinate, citric acid
  • salts tartrates, oxalates, maleates
  • amino acid salts eg, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate.
  • the compound can be produced, for example, according to the following reaction scheme.
  • Z 1 is a leaving group
  • Z 2 is a hydrogen atom, an alkyl group, or an acyl group, or the group represented by the formula: Z 2 OC ( ⁇ O) — and the hydroxyl group which may be substituted at the ortho position are the same as those of the adjacent A 1 It may form a ring with the constituent atoms
  • Z 3 is a silyl group
  • M is an alkali metal
  • L is a leaving group
  • a 1 , X 1 , X 2 , and R 1 to R 4 are the same as above.
  • Step (A) is a step of reacting the compound represented by formula (1-1) with the compound represented by formula (3) to obtain the compound represented by formula (1-2).
  • the leaving group represented by Z 1 include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), alkylsulfonyloxy (eg, C 1-4 alkyl such as mesyloxy).
  • Z 2 is preferably a hydrogen atom, a C 1-4 alkyl group, or a C 1-4 alkylcarbonyl group.
  • the compound is preferably a compound represented by the following formula (1-1-1):
  • Z 21 and Z 22 are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group, and A 1 and Z 1 are the same as the above.
  • Z 21 and Z 22 are each preferably a hydrogen atom, a C 1-4 alkyl group, or a C 6-10 aryl group. Suitable combinations of Z 21 and Z 22, a combination combinations Z 21 and Z 22 are both hydrogen atoms, Z 21 and Z 22 are both alkyl groups, Z 21 is a hydrogen atom, and, Z 22 Is an aryl group.
  • examples of the alkali metal represented by M include lithium, sodium, and potassium.
  • the amount of the compound represented by the formula (3) used is usually 1 to 5 mol, preferably 1.5 to 3.0 mol, and further 1 mol with respect to 1 mol of the compound represented by the formula (1-1). It is preferably 1.5 to 2.0 mol.
  • the reaction of step (A) is preferably performed in the presence of a base.
  • the base include trialkylamine (eg, triC 1-4 alkylamine such as triethylamine) and carbonate (eg, alkali metal carbonate such as Na 2 CO 3 and K 2 CO 3 ). These bases can be used alone or in combination of two or more. Of these, trialkylamines are preferred.
  • the amount of the base used is usually 1 to 5 mol, preferably 1.5 to 3.0 mol, and more preferably 1.5 to 2 with respect to 1 mol of the compound represented by the formula (1-1). 0.0 mol.
  • the reaction of step (A) is preferably carried out in the presence of a catalyst.
  • the catalyst examples include a palladium catalyst [eg: tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), palladium carbon, dichloro [1,1′-bis (diphenylphosphino) ) Ferrocene] palladium (II), trans-dichlorobis (tricyclohexylphosphine) palladium (II), dichlorobis (tri-o-tolylphosphine) palladium (II), dichlorobis (triphenylphosphine) palladium (II), palladium acetate (II) )], A nickel catalyst [eg: dichloro [1,1′-bis (diphenylphosphino) ferrocene] nickel (II), dichlorobis (triphenylphosphine) nickel (II)], and a ruthenium catalyst.
  • a palladium catalyst
  • the catalysts can be used alone or in combination of two or more. Of these, palladium catalysts are preferred.
  • the amount of the catalyst used is usually 0.1 to 1.0 mol, preferably 0.1 to 0.5 mol, and more preferably 0.1 to 1.0 mol with respect to 1 mol of the compound represented by the formula (1-1). It is 1 to 0.2 mol.
  • the reaction of step (A) is preferably performed in the presence of a solvent.
  • the solvent include water, alcohol solvents (eg methanol, ethanol), ether solvents (eg chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, 20 to 200 ° C., preferably 30 to 150 ° C.
  • the reaction time is, for example, 12 to 24 hours, preferably 12 to 14 hours.
  • Step (B) is a step of reacting the compound represented by formula (1-2) with the compound represented by formula (4) to obtain the compound represented by formula (1-3).
  • the silyl group represented by Z 3 is not particularly limited, and examples thereof include trialkylsilyl (eg, triC 1-4 such as trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl and the like).
  • Alkylsilyl) and alkyldiarylsilyl eg, C 1-4 alkyldiC 6-10 arylsilyl such as t-butyldiphenylsilyl.
  • the amount of the compound represented by the formula (4) to be used is usually 1.0 to 1.5 mol, preferably 1.0 to 1. mol, relative to 1 mol of the compound represented by the formula (1-2). It is 2 mol, and more preferably 1.0 to 1.1 mol.
  • the reaction of step (B) is preferably performed in the presence of a base.
  • the base include alkali metal amides such as lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), sodium hexamethyldisilazide (NaHMDS) and potassium hexamethyldisilazide (KHMDS). .. These bases can be used alone or in combination of two or more.
  • the amount of the base used is usually 1 to 3 mol, preferably 1.5 to 2.5 mol, and more preferably 2.0 to 2. 1 mol based on 1 mol of the compound represented by the formula (1-2). It is 5 mol.
  • the reaction of step (B) is preferably performed in the presence of a solvent.
  • the solvent include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C.
  • the reaction time is, for example, 0.2 to 2.0 hours, preferably 0.5 to 1.0 hours.
  • Step (C) is a step of removing the silyl group Z 3 from the compound represented by formula (1-3) to obtain the compound represented by formula (1-4).
  • the silyl group Z 3 can be removed by a conventional method.
  • a method of reacting the compound represented by the formula (1-3) with a fluorine compound include amine complexes of hydrogen fluoride, metal fluorides (eg, potassium fluoride), ammonium fluoride, and tetrabutylammonium fluoride (TBAF). These fluorine compounds may be used alone or in combination of two or more. Of these, TBAF is preferred.
  • the reaction of step (C) is preferably carried out in the presence of a solvent.
  • the solvent include carboxylic acid solvents (eg acetic acid), ether solvents (eg chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more. Of these, carboxylic acid solvents are preferred.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, ⁇ 5 ° C. to 40 ° C., preferably 0 to 30 ° C.
  • the reaction time is, for example, 6 to 24 hours, preferably 12 to 15 hours.
  • Step (D) is a step of reacting the compound represented by formula (1-4) with the compound represented by formula (5) to obtain the compound represented by formula (1-5).
  • the leaving group represented by L in the formula (5) include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), alkylsulfonyloxy (eg, C 1-4 alkylsulfonyloxy such as mesyloxy).
  • Haloalkylsulfonyloxy eg, perfluoroC 1-4 alkylsulfonyloxy such as trifluoromethylsulfonyloxy
  • arylsulfonyloxy eg, C 6-10 arylsulfonyloxy such as tosyloxy
  • N (R L1 ) examples thereof include a group represented by (R L2 )-(wherein R L1 and R L2 are the same or different and each is an alkyl group or an alkoxy group).
  • the group represented by the formula: N (R L1 ) (R L2 ) — is preferable.
  • R L1 and R L2 are preferably a C 1-4 alkyl group or a C 1-4 alkoxy group. Suitable combinations of R L1 and R L2 include combinations in which R L1 is an alkyl group and R L2 is an alkoxy group.
  • the amount of the compound represented by the formula (5) used is usually 1.0 to 1.5 mol, preferably 1.0 to 1. mol, relative to 1 mol of the compound represented by the formula (1-4). It is 2 mol, and more preferably 1.0 to 1.1 mol.
  • the reaction of step (D) is preferably performed in the presence of a base.
  • the base examples include alkyl alkali metal salts (eg: butyl lithium) and alkali metal amides (eg: LDA, LHMDS, NaHMDS, KHMDS). These bases can be used alone or in combination of two or more. Of these bases, alkyl alkali metal salts are preferred.
  • the amount of the base used is usually 1.0 to 1.5 mol, preferably 1.0 to 1.2 mol, and more preferably 1. mol to 1 mol of the compound represented by the formula (1-3). It is 0 to 1.1 mol.
  • the reaction of step (D) is preferably performed in the presence of a solvent.
  • the solvent examples include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • ether solvents eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane. These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C.
  • the reaction time is, for example, 0.2 to 1.0 hour, preferably 0.3 to 0.5 hour.
  • Step (E) is a step of reacting the compound represented by formula (1-5) with a triple bond protecting agent to obtain the compound represented by formula (1-6).
  • the triple bond protecting agent include Co 2 CO 8 .
  • the amount of the triple bond protecting agent used is usually 2 to 10 mol, preferably 3 to 6 mol, and more preferably 4 to 5 mol, relative to 1 mol of the compound represented by the formula (1-5). is there.
  • the reaction of step (E) is preferably performed in the presence of a solvent.
  • the solvent include halogen-based solvents (eg, dichloromethane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C.
  • the reaction time is, for example, 6 to 24 hours, preferably 12 to 15 hours.
  • Step (F) is a step of obtaining a compound represented by formula (1-7) by cyclizing the compound represented by formula (1-6) and optionally hydrogenating.
  • the cyclization can be performed by a conventional method.
  • the compound represented by formula (1-6) can be cyclized by a metathesis reaction in the presence of a catalyst.
  • the catalyst include a catalyst represented by the following formula (second-generation Pierce-Grubbs catalyst).
  • the amount of the catalyst used is usually 0.1 to 1.0 mol, preferably 0.2 to 1.0 mol, and more preferably 0.1 to 1.0 mol with respect to 1 mol of the compound represented by the formula (1-6). It is 4 to 1.0 mol.
  • the reaction of step (F) is preferably performed in the presence of a solvent.
  • the solvent include halogen-based solvents (eg, dichloromethane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C.
  • the reaction time is, for example, 96 to 144 hours, preferably 96 to 120 hours.
  • Step (G) is a step of obtaining a compound represented by formula (1) by removing a protective group for triple bond from the compound represented by formula (1-7).
  • Deprotection can be performed by a conventional method.
  • a compound represented by the formula (1-7) is treated with a deprotecting agent [eg, ammonium hexanitratocerium (IV) (CAN), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ ), N-methylmorpholine N-oxide, a combination thereof] to remove the triple bond protecting group.
  • a deprotecting agent eg, ammonium hexanitratocerium (IV) (CAN), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ ), N-methylmorpholine N-oxide, a combination thereof
  • the amount of deprotecting agent used is usually 4 to 10 mol, preferably 4 to 8 mol, and more preferably 4 to 6 mol, relative to 1 mol of the compound represented by the formula (1-7).
  • the reaction of step (G) is preferably performed in the presence of a solvent.
  • the solvent include halogen solvents (eg dichloromethane), ether solvents (eg chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane), ketone solvents (eg acetone, methyl ethyl ketone). Be done. These solvents may be used alone or in combination of two or more. Of these, ketone solvents are preferred.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C.
  • the reaction time is, for example, 1 to 8 hours, preferably 1 to 2 hours.
  • the method for producing the compound (1) may include a step of purifying the intermediate product and / or the final product, if necessary. Purification can be carried out by a conventional method such as filtration or chromatography. In addition, a suitable protecting group may be introduced before the reaction and the protecting group may be removed after the reaction. Protection and deprotection can be performed by a conventional method.
  • the method for producing the compound (1) may include a step of separating isomers if necessary. Separation of isomers can be performed by a conventional method.
  • the compound of the present invention or a salt thereof is a compound represented by formula (2) or a salt thereof (hereinafter, referred to as “compound (2)”): (In the formula, X 3 and R 6 to R 9 are the same as above.)
  • X 3 is a single bond, a double bond, or a triple bond as described above. Specifically, it is as follows. (In the formula, * indicates a bonding position with R 9. ) When X 3 is a double bond and R 9 is an alkyl group or an aryl group, the compound (2) can be in the cis form or the trans form.
  • R 6 is preferably a hydrogen atom, an alkyl group which may have a substituent, or a heteroaryl group which may have a substituent (eg, a furanyl group, a thienyl group, a pyridyl group), and It is preferably an alkyl group which may have a substituent, more preferably a C 1-6 alkyl group which may have a substituent, and particularly preferably a C 1-6 which may have a substituent. It is a 1-4 alkyl group. Examples of the substituent include a hydroxyl group, a mercapto group, an amino group, an alkoxy group, an alkoxyalkoxy group, and an alkoxyalkoxyalkoxy group.
  • R 6 is preferably of the formula: (In the formula, X 4 is a hydroxyl group, a mercapto group, or an amino group, and R 61 and R 62 are the same or different and are a hydrogen atom or an alkyl group.) Is a group represented by.
  • X 4 is preferably a hydroxyl group.
  • R 61 is preferably an alkyl group, more preferably a C 1-4 alkyl group, and particularly preferably a C 1-2 alkyl group.
  • R 61 is an alkyl group
  • the carbon atom to which R 61 is bonded is an asymmetric carbon atom.
  • the configuration of this asymmetric carbon atom may be either R configuration or S configuration, but it is preferably S configuration.
  • R 62 is preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group, and particularly preferably a hydrogen atom.
  • R 62 is an alkyl group
  • the carbon atom to which R 62 is attached is an asymmetric carbon atom.
  • the configuration of this asymmetric carbon atom may be either R configuration or S configuration, but it is preferably R configuration.
  • R 7 and R 8 are each preferably a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an aryl group, more preferably a hydrogen atom, an alkyl group, or an alkoxyalkyl group, and further preferably hydrogen.
  • R 7 O and R 8 O preferably form a ring with two adjacent carbon atoms, and the ring has the following formula: (In the formula, R 7a and R 8a are the same as the above, and * represents the bonding position to the carbonyl carbon).
  • the ring represented by is preferable.
  • Each of R 7a and R 8a is preferably a hydrogen atom, a C 1-4 alkyl group, or a C 6-10 aryl group. Suitable combinations of R 7a and R 8a, a combination combinations R 7a and R 8a are hydrogen atoms, R 7a and R 8a are both alkyl groups, R 7a is a hydrogen atom, and, R 8a And the combination is an aryl group.
  • the carbon atom to which R 7 O and R 8 O are bonded is an asymmetric carbon atom.
  • the configuration of the asymmetric carbon atom to which R 7 O and R 8 O are bonded may be either the R configuration or the S configuration, but both are preferably the S configuration.
  • R 9 is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom or a C 1-4 alkyl group, particularly preferably a hydrogen atom or a C 1-2 alkyl group, and most preferably a hydrogen atom. is there.
  • the compound (2) has at least two asymmetric carbon atoms (carbon atoms to which R 7 O and R 8 O are bonded) and includes both enantiomers and diastereomers.
  • the compound (2) may be a mixture containing two kinds of enantiomers.
  • the mixture may be a mixture in which one enantiomer is contained in an excessive amount, or may be an equivalent mixture (racemate) of two kinds of enantiomers.
  • Compound (2) is, in a preferred embodiment, a compound represented by the following formula (2A) or a salt thereof: . (Wherein, X 3, R 6, R 7, R 8, and R 9 are the same as above except the following formula: The compounds represented by are excluded. )
  • Compound (2) is, in another preferred embodiment, a compound selected from the following group or a salt thereof:
  • the salt is preferably a pharmaceutically acceptable salt.
  • the salt can be an inorganic salt or an organic salt.
  • examples of the salt include inorganic acid salts (eg, hydrofluoric acid salts, hydrochloric acid salts, hydrobromic acid salts, hydroiodic acid salts, nitrates, perchloric acid salts, sulfuric acid salts, phosphoric acid salts), organic acids.
  • Acid salts eg, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, malate, fumarate, succinate, citric acid
  • salts tartrates, oxalates, maleates
  • amino acid salts eg, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate.
  • R 7 and R 8 are the same or different and each is an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group (corresponding to a protective group for a hydroxyl group), or a salt thereof,
  • a compound or a salt thereof in which R 7 O and R 8 O form a ring (corresponding to a protecting group for a hydroxyl group) with two adjacent carbon atoms can be produced, for example, according to the following reaction scheme.
  • Q 1 to Q 3 are the same or different and each is an alkyl group or an aryl group
  • Q 4 is a halide ion
  • Q 5 is a trialkylsilyl group or an alkyldiarylsilyl group
  • R 10 and R 11 are the same or different and each is an alkyl group, an alkoxy group, or an aryl group
  • R 6 to R 9 are the same as above.
  • Step (a) is a step of reacting the compound represented by formula (2-1) with the compound represented by formula (6) to obtain the compound represented by formula (2-2).
  • Q 1 to Q 3 are each preferably an aryl group, and more preferably a C 6-10 aryl group.
  • Q 4 is preferably a bromide ion or a chloride ion.
  • Examples of the compound represented by the formula (6) include methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide, propyltriphenylphosphonium bromide, butyltriphenylphosphonium bromide, pentyltriphenylphosphonium bromide, hexyltriphenylphosphonium bromide, Examples include heptyltriphenylphosphonium bromide, benzyltriphenylphosphonium bromide, (1-naphthylmethyl) triphenylphosphonium bromide, and their corresponding chlorides. These compounds can be used alone or in combination of two or more.
  • the amount of the compound represented by the formula (6) used is usually 1 to 5 mol, preferably 2 to 4 mol, and further preferably 3 to 1 mol of the compound represented by the formula (2-1). 4 mol.
  • the reaction of step (a) is preferably performed in the presence of a base.
  • the base include alkyl alkali metal (eg, n-butyl lithium) and alkali metal amide (eg, LDA, LHMDS, NaHMDS, KHMDS).
  • the amount of base used will usually be 1-5 mol, preferably 2-4 mol, and more preferably 3-4 mol, per 1 mol of the compound represented by formula (2-1).
  • the reaction of step (a) is preferably performed in the presence of a solvent.
  • the solvent examples include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • ether solvents eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane. These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, ⁇ 100 to 10 ° C., preferably ⁇ 80 ° C. to 0 ° C.
  • the reaction time is, for example, 1 to 24 hours, preferably 4 to 12 hours.
  • Step (b) is a step of hydrogenating the compound represented by formula (2-2) to obtain the compound represented by formula (2-3).
  • the amount of hydrogen used will usually be 1-50 mol, preferably 2-40 mol, and more preferably 10-20 mol, relative to 1 mol of the compound represented by formula (2-2).
  • the reaction of step (b) is preferably carried out in the presence of a catalyst.
  • the catalyst include catalysts conventionally used in hydrogenation, and examples thereof include palladium carbon and platinum carbon.
  • the amount of the catalyst used is usually 0.01 to 1 mol, preferably 0.1 to 0.5 mol, and more preferably 0.2 to 1 mol with respect to 1 mol of the compound represented by the formula (2-2). It is 0.3 mol.
  • the reaction of step (b) is preferably performed in the presence of a solvent.
  • the solvent include alcohol solvents (eg: methanol, ethanol), ether solvents (eg: chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran, dioxane). These solvents may be used alone or in combination of two or more. Of these, alcohol solvents are preferred.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, 0 to 50 ° C, preferably 5 ° C to 35 ° C.
  • the reaction time is, for example, 1 to 24 hours, preferably 10 to 12 hours.
  • step (b) is omitted, and before step (e), the compound of formula (2-5) in which X 3 is a double bond is hydrogenated in the same manner as in step (b), Among (2-5), a compound in which X 3 is a single bond may be obtained.
  • Step (c) is a step of reacting the compound represented by formula (2-1) with the compound represented by formula (7) to obtain the compound represented by formula (2-4).
  • the trialkylsilyl group represented by Q 5 include triC 1-4 alkylsilyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl, and t-butyldimethylsilyl.
  • the alkyldiarylsilyl group represented by Q 5 include C 1-4 alkyldiC 6-10 arylsilyl such as t-butyldiphenylsilyl.
  • the amount of the compound represented by the formula (7) used is generally 1 to 5 mol, preferably 2 to 4 mol, and more preferably 3 to 1 mol of the compound represented by the formula (2-1). It is 4 mol.
  • the reaction of step (c) is preferably performed in the presence of a base.
  • the base include alkali metal amides (eg, LDA, lithium 2,2,6,6-tetramethylpiperazine, LHMDS, NaHMDS, KHMDS).
  • the amount of the base used is usually 0.8 to 1.2 mol, preferably 0.9 to 1.1 mol, and more preferably 1. mol to 1 mol of the compound represented by the formula (2-1). It is 0 to 1.1 mol.
  • the reaction of step (c) is preferably performed in the presence of a solvent.
  • the solvent include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, ⁇ 100 to 10 ° C., preferably ⁇ 80 ° C. to 0 ° C.
  • the reaction time is, for example, 1 to 24 hours, preferably 10 to 12 hours.
  • step (d) the compound represented by the formula (2-5) is reacted with the compound represented by the formula (2-2), (2-3) or (2-4) to give the compound represented by the formula (2-5). It is a process of obtaining.
  • the oxidizing agent include nitroxy radical type oxidizing agents such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and 2-azaadamantane-N-oxyl (AZADO).
  • TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl
  • AZADO 2-azaadamantane-N-oxyl
  • the amount of the oxidant used is usually 0.1 to 1.0 mol, preferably 1 to 1.0 mol of the compound represented by the formula (2-2), (2-3) or (2-4). The amount is 0.1 to 0.5 mol, more preferably 0.2 to 0.3 mol.
  • the oxidant can be used with the reoxidant.
  • the reoxidant include sodium hypochlorite and iodobenzene diacetate. These reoxidants can be used alone or in combination of two or more.
  • the amount of the reoxidant used is usually 1 to 3 mol, preferably 1.0, relative to 1 mol of the compound represented by the formula (2-2), (2-3) or (2-4). The amount is up to 2.5 mol, more preferably 2.0 to 2.5 mol.
  • the reaction of step (d) may be carried out in the presence of a base.
  • the reaction of step (d) is preferably carried out in the presence of a solvent.
  • the solvent examples include water, nitrile solvents (eg acetonitrile), and halogen solvents (eg dichloromethane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, ⁇ 20 to 15 ° C., preferably ⁇ 10 ° C. to 10 ° C.
  • the reaction time is, for example, 1 to 5 hours, preferably 3 to 4 hours.
  • Step (e) is a step of reacting the compound represented by formula (2-5) with the compound represented by formula (8) to obtain the compound represented by formula (2-6).
  • R 10 and R 11 are preferably C 1-4 alkyl group, C 1-4 alkoxy group, or C 6-12 aryl group, and preferably C 1-4 alkyl group or C 1 -4 alkoxy group, and more preferably C 1-2 alkyl group or C 1-2 alkoxy group.
  • Suitable combinations of R 10 and R 11 include combinations in which R 10 is an alkyl group and R 11 is an alkoxy group.
  • the amount of the compound represented by the formula (8) used is usually 1 to 2 mol, preferably 1.1 to 1.5 mol, and further 1 mol with respect to 1 mol of the compound represented by the formula (2-5). It is preferably 1.2 to 1.4 mol.
  • the reaction of step (e) is preferably carried out in the presence of a condensing agent.
  • the condensing agent include N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (dimethylaminopropyl) carbodiimide (EDC), 1- [bis (dimethylamino) methylene] -1H-1,2.
  • HATU 3-Triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate
  • HBTU 1- [bis (dimethylamino) methylene] -1H-benzotriazolium 3-oxide hexafluorophosphate
  • TATU 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide tetrafluoroborate
  • TBTU dipheni Luphosphoryl azide
  • the condensing agents can be used alone or in combination of two or more.
  • the amount of the condensing agent used is usually 1 to 3 mol, preferably 1.2 to 2.5 mol, more preferably 1.2 to 1 mol, relative to 1 mol of the compound represented by the formula (2-5). 0.5 mol.
  • the reaction of step (e) is preferably performed in the presence of a base.
  • the base include trialkylamine (eg, triC 1-4 alkylamine such as triethylamine), N-methylmorpholine, N, N-dimethylaminopyridine. These bases can be used alone or in combination of two or more kinds.
  • the amount of base used is usually 1 to 5 mol, preferably 1.1 to 2.0 mol, and more preferably 1.2 to 1.
  • the reaction of step (e) is preferably carried out in the presence of a solvent.
  • the solvent include halogen-based solvents (eg: dichloromethane) and ether-based solvents (eg: chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, ⁇ 20 to 15 ° C., preferably ⁇ 10 ° C. to 10 ° C.
  • the reaction time is, for example, 12 to 24 hours, preferably 12 to 20 hours.
  • Step (f) is a step of reacting the compound represented by formula (2-6) with the compound represented by formula (9) to obtain the compound represented by formula (2).
  • the amount of the compound represented by the formula (9) used is usually 1.0 to 1.5 mol, preferably 1.0 to 1. mol, relative to 1 mol of the compound represented by the formula (2-6). It is 3 mol, and more preferably 1.0 to 1.1 mol.
  • the reaction of step (f) is preferably carried out in the presence of a base.
  • the base include alkyl alkali metal salts (eg: butyl lithium) and alkali metal amides (eg: LDA, LHMDS, NaHMDS, KHMDS). These bases can be used alone or in combination of two or more.
  • alkyl alkali metal salts are preferred.
  • the amount of the base used is usually 1.0 to 1.5 mol, preferably 1.0 to 1.3 mol, and more preferably 1. to 1 mol of the compound represented by the formula (2-6). It is 0 to 1.1 mol.
  • the reaction of step (f) is preferably performed in the presence of a solvent.
  • the solvent include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C.
  • the reaction time is, for example, 1 to 5 hours, preferably 2 to 3 hours.
  • the compound in which R 7 and R 8 are hydrogen atoms is a compound obtained by following the above reaction scheme, in which R 7 and R 8 are hydroxyl-protecting groups, is deprotected by a conventional method. By doing so, it can be manufactured.
  • the method for producing the compound (2) may include a step of purifying the intermediate product and / or the final product, if necessary. Purification can be carried out by a conventional method such as filtration or chromatography. In addition, a suitable protecting group may be introduced before the reaction and the protecting group may be removed after the reaction. Protection and deprotection can be performed by a conventional method.
  • the method for producing the compound (2) may include a step of separating isomers if necessary. Separation of isomers can also be performed by a conventional method.
  • the pharmaceutical composition contains at least one selected from compounds (1) and (2) (hereinafter referred to as "active ingredient").
  • the lower limit of the content of the active ingredient is, for example, 0.001% by mass, preferably 0.01% by mass, more preferably 0.05% by mass, based on the total mass of the pharmaceutical composition. is there.
  • the upper limit of the content of the active ingredient is not particularly limited, but is, for example, 99% by mass, 95% by mass, or 90% by mass with respect to the total mass of the pharmaceutical composition.
  • the content of the active ingredient is within a range in which the lower limit value and the upper limit value are arbitrarily selected, for example, 0.001 to 99% by mass, preferably 0.01 to 95% by mass, more preferably 0.05 to 90% by mass. %.
  • the pharmaceutical composition may further contain additives, preferably pharmaceutically acceptable additives.
  • the pharmaceutical composition may be in the form of solid preparations (eg granules, powders, tablets, capsules, dry syrups), semisolid preparations (eg creams, ointments, gels), and liquid preparations (eg injections). Agent).
  • the solid preparation is prepared by, for example, mixing active ingredients and additives (eg, excipients, binders, disintegrating agents, lubricants, coloring agents), and if desired, granulating, sizing, compressing, and / or Alternatively, it can be produced by coating.
  • the semi-solid preparation can be produced, for example, by mixing the active ingredient, the semi-solid carrier, and optionally other additives.
  • the liquid preparation includes, for example, an active ingredient, a liquid carrier [eg, an aqueous carrier (eg, purified water), an oil carrier], and optionally other additives (eg, an emulsifier, a dispersant, a suspending agent, a buffering agent, It can be produced by mixing an antioxidant, a surfactant, an osmotic pressure adjusting agent, a chelating agent, an antibacterial agent), and sterilizing if necessary.
  • a liquid carrier eg, an aqueous carrier (eg, purified water), an oil carrier
  • additives eg, an emulsifier, a dispersant, a suspending agent, a buffering agent, It can be produced by mixing an antioxidant, a surfactant, an osmotic pressure adjusting agent, a chelating agent, an antibacterial agent), and sterilizing if necessary.
  • the method for administering the pharmaceutical composition may be either oral administration or parenteral administration (eg, intravenous administration, intramuscular administration, subcutaneous administration).
  • the method of administration of the pharmaceutical composition may be local administration.
  • the subject of administration of the pharmaceutical composition may be any of humans, non-human mammals (eg, monkey, sheep, dog, mouse, rat) and non-mammals.
  • the endoplasmic reticulum stress response inducer contains at least one (active ingredient) selected from compounds (1) and (2).
  • the content of the active ingredient, the type of any additive, the dosage form, and the dosage form in the endoplasmic reticulum stress response-inducing agent can be the same as those described for the pharmaceutical composition.
  • the protein disulfide isomerase inhibitor contains at least one (active ingredient) selected from the compounds (1) and (2).
  • the content of the active ingredient the type of any additive, the dosage form, and the dosage form in the PDI inhibitor, the same as those described for the pharmaceutical composition can be adopted.
  • the preventive or therapeutic agent for diseases contains at least one (active ingredient) selected from compounds (1) and (2). Since the compound of the present invention can induce an endoplasmic reticulum stress response, the disease may be a disease involving endoplasmic reticulum stress. Moreover, since the compound of the present invention can inhibit the activity of PDI, the disease may be a disease associated with PDI.
  • the disease examples include cancer (eg, blood cancer such as multiple myeloma), diabetes (eg, type 1 diabetes, type 2 diabetes), inflammatory disease (eg, inflammatory bowel disease, rheumatism), neurodegeneration Diseases (eg, Parkinson's disease, Huntington's disease, Alzheimer's disease) and diseases associated with these diseases (eg, bone disease associated with multiple myeloma) are mentioned.
  • the disease is preferably at least one selected from cancer, bone disease, and rheumatism.
  • the content of the active ingredient, the type of any additive, the dosage form, and the dosage form in the preventive or therapeutic agent for diseases can be the same as those described for the pharmaceutical composition.
  • Example 1 11 E-inone macrolide A (1-1) (2S, 3S) -N-methoxy-2,3-bis (methoxymethoxy) -N-methylhex-5-enamide was synthesized as follows.
  • Known compound ((4R, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) After dissolving 4.07 g (23.6 mmo) of methanol in 80 mL of acetonitrile and 40 mL of purified water, , 17.0 g (52.0 mmol) of iodobenzene diacetate and 734 mg (4.70 mmol) of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical were added at room temperature.
  • the obtained crude product was dissolved in 192 mL of acetic acid and 48 mL of purified water, and then stirred at 60 ° C for 12 hours. After the solvent was distilled off under reduced pressure, acetic acid was removed by an azeotropic operation with the addition of toluene.
  • the composition organism thus obtained was dissolved in 118 mL of dichloromethane and then cooled to 0 ° C.
  • 611 mL (354 mmol) of N, N-diisopropylethylamine, 18.8 mL (236 mmol) of chloromethyl methyl ether, and 26.0 g (71.0 mmol) of tetrabutylammonium iodide were added at 0 degrees.
  • (1-2) (S) -Pent-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy) methoxy) -6-vinylbenzoate was synthesized as follows. After dissolving 1.26 g (8.08 mmol) of the known compound (S) -5- (trimethylsilyl) pent-4-yn-2-ol in 108 mL of tetrahydrofuran, 16.2 mL (16.2 mmol) of sodium bis (trimethylsilyl) amide solution was dissolved in 0 mL. Added in degrees.
  • the obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure.
  • 11E-Inone macrolide A was synthesized as follows. 86.0 mg (0.105 mmol) of the 11E-cyclized dicobalt hexacarbonyl produced in (1-5) was dissolved in 2.0 mL of acetone, and 57 mg (0.105 mmol) of cerium ammonium nitrate was added at 0 degrees. After stirring at 0 ° C for 15 minutes, the same amount of ceriam ammonium nitrate was added, and the mixture was stirred at 0 ° C for 15 minutes. The same work was repeated 3 times. After confirming the disappearance of the raw materials by thin layer chromatography, 1.0 mL of purified water was added, and the solution was separated with dichloromethane three times.
  • Example 2 11 E-inone macrolide A ' 11E-inone macrolide A' was synthesized as follows. 1.9 mL (4.14 mmol) of a mixed solution (1:10) of 47% hydrogen fluoride aqueous solution and acetonitrile was added to 11E-inone macrolide A 4.04 mg (0.00753 mmol) produced in (1-6). After stirring at room temperature for 5 hours, an aqueous solution of sodium hydrogen carbonate was added at 0 ° C, and the mixture was partitioned 3 times with ethyl acetate. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure.
  • Example 3 11Z-inone macrolide B 11Z-inone macrolide B was synthesized as follows. 87.0 mg (0.106 mmol) of the 11E-cyclized dicobalt hexacarbonyl produced in (1-6) was dissolved in 2.0 mL of acetone, and 57.7 mg (0.106 mmol) of cerium ammonium nitrate was added at 0 °. After stirring at 0 ° C for 15 minutes, the same amount of ceriam ammonium nitrate was added, and the mixture was stirred at 0 ° C for 15 minutes. The same work was repeated 3 times.
  • Example 4 11Z-Inone Macrolide C 11Z-inone macrolide C was synthesized as follows. 2.3 mL (4.92 mmol) of a mixed solution (1:10) of 47% hydrogen fluoride aqueous solution and acetonitrile was added to 4.8 mg (0.00975 mmol) of 11Z-inone macrolide B produced in Example 3. After stirring at room temperature for 1 hour, an aqueous solution of sodium hydrogen carbonate was added at 0 ° C, and the solution was separated with ethyl acetate three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure.
  • Example 5 11Z-Inone Macrolide D 11Z-inone macrolide D was synthesized as follows. 2.4 mL (5.0 mmol) of a mixed solution (1:10) of 47% hydrogen fluoride aqueous solution and acetonitrile was added to 4.9 mg (0.00975 mmol) of 11Z-inone macrolide B produced in Example 3. After stirring at room temperature for 8 hours, an aqueous solution of sodium hydrogen carbonate was added at 0 ° C, and the mixture was separated with ethyl acetate three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure.
  • Example 6 11 Saturated-Inone Macrolide A (6-1) 11-saturated-cyclized dicobalt hexacarbonyl was synthesized as follows. After dissolving 2.9 mg (0.00353 mmol) of the 11Z-cyclized dicobalt hexacarbonyl produced in (1-5) in 0.7 mL of methanol, 16 mg (0.00353 mmol) of rhodium carbon was added, and the mixture was cooled to -40 degrees. Then, the inside was replaced with hydrogen gas, and the mixture was stirred at -40 ° C for 3 days. After confirming the progress of the reaction by mass spectrometry, filter filtration was performed to remove rhodium carbon.
  • Example 7 11 Saturated-Inone Macrolide B 11 Saturated-Inone macrolide B was synthesized as follows. 0.4 mL (0.8 mmol) of a mixed solution (1:10) of 47% hydrogen fluoride aqueous solution and acetonitrile was added to 0.8 mg (0.00146 mmol) of 11-saturated-inone macrolide A prepared in Example 6. After stirring at room temperature for 8 hours, an aqueous solution of sodium hydrogen carbonate was added at 0 ° C, and the mixture was separated with ethyl acetate three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure.
  • Example 8 (S) -1-((4S, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) -5-hydroxyhex-2-yn-1-one (8-1)
  • the known compound (3aR, 7aS) -2,2-dimethyltetrahydro-4H- [1,3] dioxolo [4,5-c] pyran-6-ol was synthesized as follows. After dissolving 6.0 g (44.7 mmol) of 2-deoxy-D-ribose in 90 mL of acetone, 18.8 mL of 2,2-dimethoxypropane was added, and the mixture was stirred at room temperature for 15 minutes.
  • Example 10 1-((4S, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) hex-2-yn- 1 -one
  • 1-((4S, 5R)- 5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) hex-2-yn-1-one was synthesized as follows. 4.3 ⁇ L (0.0436 mmol) of 1-pentyne was dissolved in 0.4 mL of tetrahydrofuran, cooled to ⁇ 78 ° C., and 16 ⁇ L (0.0436 mmol) of normal butyllithium was added.
  • Example 11 (S) -1-((4S, 5R) -2,2-Dimethyl-5-propyl-1,3-dioxolan-4-yl) -5-hydroxyhex-2-yn-1-one (11-1) (4S, 5R) -N-Methoxy-N, 2,2-trimethyl-5-propyl-1,3-dioxolane-4-carboxamide was synthesized as follows. 20 mg (0.0872 mmol) of (4S, 5R) -5-allyl-N-methoxy-N, 2,2-trimethyl-1,3-dioxolane-4-carboxamide prepared in (8-3) was added to 0.4 mL of methanol.
  • Test Example 2 Anti-cancer activity (1) Anti-cancer activity against human multiple myeloma cell line RPMI8226 Human multiple myeloma cell line RPMI8226 was seeded on a 96-well plate at a density of 1 ⁇ 10 4 cells / well, and 5 Incubated overnight at 37 ° C. in a% carbon dioxide atmosphere. Separately, the compound of Example was dissolved in dimethyl sulfoxide and added to each well so that the final concentration of the compound was 0.78125 ⁇ M, 1.5625 ⁇ M, 3.125 ⁇ M, 6.25 ⁇ M, 12.5 ⁇ M, 25 ⁇ M or 50 ⁇ M. . Then, after culturing at 37 ° C.
  • a cell culture / cytotoxicity measuring reagent (Cell Counting Kit-8, manufactured by Dojindo Co., Ltd.) was used to produce an orange dye (produced from living cells). The absorbance (420 nm) of formazan) was measured. The IC 50 value was determined from the relative absorbance when the absorbance without addition of the compound of the present invention or melphalan was 100.
  • Human cancer cell lines HCT116, A549, HeLa or human embryonic kidney-derived cells (HEK293) were seeded on a 96-well plate at a density of 1 ⁇ 10 4 cells / well.
  • Test Example 3 PDI activity measurement PDI activity measurement was carried out using Abcam's PDI Inhibitor Screening Assay Kit (detection sensitivity> 37 ⁇ M). First, was added Insulin solution diluted with Mill-Q H 2 O in 96well plates each Well (320 ⁇ M) or Mill-Q H 2 O (Blank ) so that 50 [mu] L / well. Next, PDI working solution or Mill-Q H 2 O (Negative control) was added to each well at 10 ⁇ L / well.
  • the diluted compound (a solution having a concentration of 8 times the final concentration) was added to each well so that the concentration was 10 ⁇ L / well (Mill-Q H 2 O was 10 ⁇ L / well for Untreated, Negative control, and Blank). Then, DTT was added to each well at 10 ⁇ L / well, and the plate was gently tapped to mix. Then, the mixture was incubated at room temperature for 30 minutes in the dark, and Stop Reagent working solution was added to each well at 10 ⁇ L / well. Furthermore, PDI Detection Reagent working solution was added to each well so that the concentration was 10 ⁇ L / well.
  • mice Mouse myeloma cell line 5TGM-1, which constantly expresses anti-cancer active luciferase in a mouse model , was transplanted into the right tibia bone marrow of a 6-week-old female ICR mouse by 10 6 cells, and 1 week later, engraftment was confirmed. After that, the mice were intraperitoneally administered every other day so that the final concentration of the compound of Example was 20 mg / kg. After administration for 2 weeks, in order to observe the proliferation of tumor cells in the body, luciferin was intraperitoneally administered and detected by the IVIS imaging system. The results are shown in FIGS. As shown in FIGS. 2-3, the compounds of Example 2 and Example 8 suppressed tumor progression in myeloma model mice.
  • Test Example 5 Effect on cytotoxic activity on hematopoietic stem cells
  • Human peripheral blood stem cells were seeded on a 12-well plate at a density of 2 ⁇ 10 6 cells / well, and the compound of the Example was separately dissolved in dimethyl sulfoxide to give a final concentration of 10 ⁇ M.
  • Each well was added as described above and cultured for 24 hours.
  • the cells were collected, and the collected cells were mixed in human hematopoietic stem cell colony measurement medium MethoCult at 2 ⁇ 10 5 cells / ml, seeded in 1 ml on a 35 mm dish, and cultured at 37 ° C. for 14 days in a 5% carbon dioxide atmosphere. .
  • CFU-GM leukocyte colonies
  • BFU-E erythroid colonies
  • Results are shown in FIG. As shown in FIG. 6, the compound of Example 8 suppressed osteoclast formation.
  • Test Example 7 Antirheumatic effect Bovine type II collagen was dissolved in 10 mM acetic acid to prepare a 2 mg / ml solution, which was then mixed with equal amounts of Complete Freund's adjuvant to prepare an emulsion. 100 ⁇ l of the prepared emulsion was intradermally injected into the base of the tail of 6-week-old male DBA / 1J mice. After 3 weeks, booster immunization was carried out in the same manner, and after 2 days, it was confirmed that arthritis was induced. After that, the mice were intraperitoneally administered every other day so that the final concentration of the compound was 20 mg / kg. To evaluate arthritis, clinical scores were measured every other day after the booster immunization.

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Abstract

Le problème à résoudre par la présente invention concerne la fourniture d'un composé ynone utile pour induire une réponse au stress du réticulum endoplasmique. La solution selon l'invention concerne un composé ynone représenté par la formule (1) [dans la formule, A1 est un cycle aromatique qui peut avoir un substituant, X1 représente un atome d'oxygène, un atome de soufre ou un groupe représenté par la formule : -N-(RX1)- (dans laquelle, RX 1 représente un atome d'hydrogène ou un groupe alkyle), X2 représente une liaison simple ou une double liaison, R1 et R2 sont identiques ou différents et représentent un atome d'hydrogène ou un groupe alkyle, R3 et R4 sont identiques ou différents et représentent un atome d'hydrogène, un groupe alkyle, un groupe acyle, un groupe alcoxy alkyle, ou un groupe alcoxy-alcoxy-alkyle, et R3O et R4O peut être lié à deux atomes de carbone adjacents pour former un cycle.].
PCT/JP2019/042086 2018-10-29 2019-10-28 Nouveau composé ynone et son utilisation WO2020090700A1 (fr)

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Citations (2)

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JPH01268684A (ja) * 1988-02-16 1989-10-26 Merck & Co Inc アセチレン性、トリイン環状カーボネート
WO2003076424A1 (fr) * 2002-03-08 2003-09-18 Eisai Co. Ltd. Composes macrocycliques utiles comme produits pharmaceutiques

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JPH01268684A (ja) * 1988-02-16 1989-10-26 Merck & Co Inc アセチレン性、トリイン環状カーボネート
WO2003076424A1 (fr) * 2002-03-08 2003-09-18 Eisai Co. Ltd. Composes macrocycliques utiles comme produits pharmaceutiques

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