Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/18—One oxygen or sulfur atom
  • C07D231/20—One oxygen atom attached in position 3 or 5
  • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/18—One oxygen or sulfur atom
  • C07D231/20—One oxygen atom attached in position 3 or 5
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/18—One oxygen or sulfur atom
  • C07D231/20—One oxygen atom attached in position 3 or 5
  • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
  • C07D231/24—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms having sulfone or sulfonic acid radicals in the molecule
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/20—Carbocyclic rings
  • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
  • C07H7/06—Heterocyclic radicals

Definitions

• the present invention relates to pyrazolone compounds and pyrazolonating agents.
• Patent Document 1 A method is known in which the formyl group of a protein such as an antibody is modified with a pyrazolone compound and a fluorescent molecule or the like is introduced (Patent Document 1 and Non-Patent Documents 1 to 3).
• the present inventors used 3-methyl-1-phenyl-5-pyrazolone as a pyrazolone compound to modify the formyl group of sugar to produce a pyrazolonated compound.
• 3-methyl-1-phenyl-5-pyrazolone as a pyrazolone compound to modify the formyl group of sugar to produce a pyrazolonated compound.
• the obtained pyrazolonated compound was easily decomposed and had low stability. Therefore, it is an object of the present invention to provide pyrazolonated compounds with high stability.
• R 1 is a halogen atom, a nitro group, a cyano group, a haloalkyl group having 1 to 10 carbon atoms (one or more halogen atoms are bonded to the carbon atom at the 1st position), or a halogen atom having 2 to 10 carbon atoms.
• Alkyl group having 1 to 60 carbon atoms optionally substituted alkenyl group having 1 to 60 carbon atoms, optionally substituted alkynyl group having 1 to 60 carbon atoms, optionally substituted carbon Aralkyl group with 1 to 60 carbon atoms, optionally substituted aryl group with 6 to 60 carbon atoms, optionally substituted alkoxy group with 1 to 60 carbon atoms, optionally substituted Alkenyloxy group having 1 to 60 carbon atoms, optionally substituted alkynyloxy group having 1 to 60 carbon atoms, optionally substituted aralkyloxy group having 1 to 60 carbon atoms, and/or case is an aryloxy group having 6 to 60 carbon atoms , which may be substituted by group, carboxy group, optionally substituted alkyl group having 1 to 60 carbon atoms, optionally substituted alkenyl group having 1 to 60 carbon atoms, optionally substituted carbon number 1 ⁇ 60 alkynyl group, an optionally substituted aral
• a pyrazolonated compound exhibiting high stability can be obtained.
• 1 is a graph examining the stability of pyrazolonated compounds (compounds 5 to 10) produced using the pyrazolone compound of the present invention.
• 1 is a graph examining the stability of pyrazolonated compounds (compounds 5 and 28 to 31) produced using the pyrazolone compound of the present invention.
• 1 is a graph examining the stability of pyrazolonated compounds (compounds 5 and 32 to 36) produced using the pyrazolone compound of the present invention.
• 1 is a graph examining the stability of pyrazolonated compounds (compounds 5 and 37 to 41) produced using the pyrazolone compound of the present invention.
• 1 is a graph examining the stability of pyrazolonated compounds (compounds 5 and 42 to 45) produced using the pyrazolone compound of the present invention.
• the pyrazolone compound of the present invention has the following formula (1): This is a compound represented by R 1 is a halogen atom, a nitro group, a cyano group, a haloalkyl group having 1 to 10 carbon atoms (one or more halogen atoms are bonded to the carbon atom at the 1st position), or a perfluoropolyether group having 2 to 10 carbon atoms.
• R 3 is a halogen atom, a nitro group, a cyano group, a haloalkyl group having 1 to 10 carbon atoms, a perfluoropolyether group having 2 to 10 carbon atoms, a carboxy group, or a carbon number that may be optionally substituted.
• Alkyl group having 1 to 60 carbon atoms optionally substituted alkenyl group having 1 to 60 carbon atoms, optionally substituted alkynyl group having 1 to 60 carbon atoms, optionally substituted carbon Aralkyl group with 1 to 60 carbon atoms, optionally substituted aryl group with 6 to 60 carbon atoms, optionally substituted alkoxy group with 1 to 60 carbon atoms, optionally substituted Alkenyloxy group having 1 to 60 carbon atoms, optionally substituted alkynyloxy group having 1 to 60 carbon atoms, optionally substituted aralkyloxy group having 1 to 60 carbon atoms, optionally substituted R 4 is an aryloxy group having 6 to 60 carbon atoms, and R 4 is a halogen atom, a nitro group, a cyano group, a haloalkyl group having 1 to 10 carbon atoms, a perfluoropolyether group having 2 to 10 carbon atoms, or a carboxy group.
• an optionally substituted alkyl group having 1 to 60 carbon atoms an optionally substituted alkenyl group having 1 to 60 carbon atoms, an optionally substituted alkenyl group having 1 to 60 carbon atoms Alkynyl group, optionally substituted aralkyl group with 1 to 60 carbon atoms, optionally substituted aryl group with 6 to 60 carbon atoms, optionally substituted with 1 to 60 carbon atoms an alkoxy group, an optionally substituted alkenyloxy group having 1 to 60 carbon atoms, an optionally substituted alkynyloxy group having 1 to 60 carbon atoms, an optionally substituted carbon number Aralkyloxy group having 1 to 60 carbon atoms, optionally substituted aryloxy group having 6 to 60 carbon atoms, optionally substituted alkylcarbonyl group having 1 to 60 carbon atoms, optionally substituted an alkenylcarbonyl group having 1 to 60 carbon atoms, an optionally substituted alkynylcarbonyl group
• Oxycarbonyl group optionally substituted alkynyloxycarbonyl group having 1 to 60 carbon atoms, optionally substituted aralkyloxycarbonyl group having 1 to 60 carbon atoms, optionally substituted It is an aryloxycarbonyl group having 6 to 60 carbon atoms, and in the case of formula (4), R 4 is 0 to 4, and in the case of formulas (5) to (7), R 4 is 0 to 3. ) is an electron-withdrawing group selected from the group consisting of.
• R 2 is a hydrocarbon group having 1 to 1000 carbon atoms that may contain a heteroatom.
• n is an integer from 0 to 2.
• the pyrazolone compound of the present invention can be used to convert a formyl group-containing compound into a pyrazolone.
• the pyrazolone compound of the present invention may be the CH form of formula (1), but may be of the following formula (8): A structural isomer (OH form) represented by or the following formula (9): It may be a structural isomer (NH form) represented by Since R 1 of the present invention is an electron-withdrawing group, the pyrazolonated compound produced using the pyrazolone compound of the present invention is resistant to decomposition and can be a stable pyrazolonated compound.
• halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
• pyrazolone compounds in which R 1 is a halogen atom include, but are not limited to, can be mentioned.
• a nitro group is a group represented by -NO 2 .
• Examples of pyrazolone compounds in which R 1 is a nitro group include, but are not limited to, can be mentioned.
• a cyano group is a group represented by -CN.
• Examples of pyrazolone compounds in which R 1 is a cyano group include, but are not limited to, can be mentioned.
• a haloalkyl group having 1 to 10 carbon atoms is one in which one or more hydrogen atoms of the alkyl group is a fluorine atom, chlorine atom, bromine atom, iodine atom, etc. means an alkyl group having 1 to 10 carbon atoms substituted with one or more halogen atoms, preferably a haloalkyl group having 1 to 8 carbon atoms, more preferably a haloalkyl group having 1 to 6 carbon atoms, More preferred is a haloalkyl group having 1 to 4 carbon atoms.
• the alkyl group may be a linear alkyl group, a branched alkyl group, or a cyclic alkyl group.
• the haloalkyl group can function as an electron-withdrawing group.
• the "1-position carbon atom" of a haloalkyl group means the carbon atom bonded to -(CH 2 )n- of R1.
• the haloalkyl group having 2 to 10 carbon atoms preferably, one or more (preferably two or more) halogen atoms are bonded to the carbon atom at the 2-position, although this is not limited.
• the haloalkyl group includes a chloromethyl group, a 2,2,2-trichloroethyl group, or a 2,2,2-trifluoroethyl group.
• a group in which all hydrogen atoms of an alkyl group are substituted with halogen atoms is referred to as a perhalogenoalkyl group.
• a perfluoroalkyl group means an alkyl group in which all hydrogen atoms have been replaced with fluorine atoms.
• the perhalogenoalkyl group includes a trifluoromethyl group, 2,2,2-trifluoro-1,1-dichloroethyl group, perfluoroethyl group, perfluoropropyl group, perfluoroisopropyl group, perfluorobutyl group, Examples include perfluoro sec-butyl group, perfluoro tert-butyl group, perfluoropentyl group, perfluorohexyl group, trichloromethyl group, tribromomethyl group, and triiodomethyl group.
• Examples of pyrazolone compounds in which R 1 is a haloalkyl group having 1 to 10 carbon atoms (one or more halogen atoms are bonded to the carbon atom at the 1st position) include, but are not limited to, for example: can be mentioned.
• a haloalkyl group having 1 to 10 carbon atoms (one or more halogen atoms bonded to the carbon atom at position 1) has a strong electron-withdrawing effect if one or more halogen atoms are bonded to the carbon atom at position 1. , and the effects of the present invention can be obtained.
• a haloalkyl group in which a total of two or more halogen atoms are bonded to the carbon in the 1st position, or a haloalkyl group in which a total of two or more halogen atoms are bonded to the carbon in the 1st and 2nd positions is extremely strong. It has an electron-withdrawing effect and can obtain the effects of the present invention.
• a perfluoropolyether group having 2 to 10 carbon atoms is a perfluoroalkyl group containing an ether group (-O-). Specifically, but not limited to, can be mentioned.
• the carboxy group is a group represented by -COOH.
• Examples of pyrazolone compounds in which R 1 is a carboxy group include, but are not limited to, can be mentioned.
• Substituted aryl group having 6 to 60 carbon atoms (the benzene ring bonded to the pyrazolone skeleton side has at least one substituent, and the substituent is a halogen atom, a nitro group, a cyano group, a aryl group having 1 to 60 carbon atoms) 10 haloalkyl groups (one or more halogen atoms are bonded to the carbon atom at the 1st position), perfluoropolyether groups having 2 to 10 carbon atoms, carboxy groups, acyl groups having 2 to 61 carbon atoms, 1 to 1 carbon atoms 60 alkoxycarbonyl group, an alkoxy group having 1 to 60 carbon atoms, and an alkyl group having 1 to 60 carbon atoms, provided that the substituent is an alkoxy group having 1 to 60 carbon atoms, or in the case of an alkyl group having 1 to 60 carbon atoms, the substituent position is the meta-position of the benzene
• a group in which an atom is substituted with a substituent that is an electron-withdrawing group At least one hydrogen atom of the benzene ring bonded to the pyrazolone skeleton side is substituted, and has two substituents, three substituents, four substituents, or five substituents. Good too. In addition, when it has two or more substituents, the substituents may be the same or a combination of two or more of the above substituents. Moreover, the position of the substituent of the electron-withdrawing group is not limited, but is most preferably the para position. Examples of pyrazolone compounds in which R 1 is a substituted aryl group having 6 to 60 carbon atoms include, but are not limited to, for example: can be mentioned.
• the acyl group having 2 to 61 carbon atoms is a group represented by R 5 -OC-, where R 5 is a hydrocarbon group.
• R 5 include, but are not limited to, optionally substituted alkyl groups having 1 to 60 carbon atoms, optionally substituted alkenyl groups having 1 to 60 carbon atoms, and optionally substituted Examples include an alkynyl group having 1 to 60 carbon atoms which may be substituted, an aralkyl group having 1 to 60 carbon atoms which may be optionally substituted, or an aryl group having 6 to 60 carbon atoms which may optionally be substituted. It will be done.
• R 1 is the following formula (2): It may also be a group represented by R 3 is a halogen atom, a nitro group, a cyano group, a haloalkyl group having 1 to 10 carbon atoms, a perfluoropolyether group having 2 to 10 carbon atoms, a carboxy group, or a optionally substituted group having 1 to 60 carbon atoms.
• Alkyl group optionally substituted alkenyl group with 1 to 60 carbon atoms, optionally substituted alkynyl group with 1 to 60 carbon atoms, optionally substituted with 1 to 60 carbon atoms an optionally substituted aryl group having 6 to 60 carbon atoms, an optionally substituted alkoxy group having 1 to 60 carbon atoms, and an optionally substituted aryl group having 1 to 60 carbon atoms; 60 alkenyloxy group, optionally substituted alkynyloxy group having 1 to 60 carbon atoms, optionally substituted aralkyloxy group having 1 to 60 carbon atoms, and/or optionally substituted It is an aryloxy group sometimes having 6 to 60 carbon atoms.
• Examples of the haloalkyl group in which R 3 is a carbon number of 1 to 10 include a trifluoromethanesulfonyl group and a pentafluoroethanesulfonyl group.
• Examples of the alkyl group having 1 to 60 carbon atoms which may be optionally substituted for R 3 include methylsulfonyl group (mesyl group), ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-propylsulfonyl group, and n-propylsulfonyl group.
• aryl group having 6 to 60 carbon atoms which may be optionally substituted by R 3 include phenylsulfonyl group, methylphenylsulfonyl group, methylp-tolylsulfonyl group, methylmethatolylsulfonyl group, and methyl ortho-sulfonyl group.
• Examples include tolylsulfonyl group, 1-naphthylsulfonyl group, 2-naphthylsulfonyl group, 2-methylphenylsulfonyl group, and the like.
• the group represented by formula (2) functions as an electron-withdrawing group due to the sulfonyl group moiety close to the pyrazolone skeleton. Therefore, it is considered that R 3 bonded via a sulfonyl group close to the pyrazolone skeleton does not have a significant effect on the function as an electron-withdrawing group.
• R 3 may be an alkyl group or an aryl group that is not an electron-withdrawing group, or may be a halogen atom or a nitro group that is an electron-withdrawing group.
• Examples of pyrazolone compounds in which R 1 is a group represented by formula (2) include, but are not limited to, can be mentioned.
• R 1 is the following formula (3): It may also be a group represented by R 4 is a halogen atom, a nitro group, a cyano group, a haloalkyl group having 1 to 10 carbon atoms, a perfluoropolyether group having 2 to 10 carbon atoms, a carboxy group, or a optionally substituted group having 1 to 60 carbon atoms.
• Alkyl group optionally substituted alkenyl group with 1 to 60 carbon atoms, optionally substituted alkynyl group with 1 to 60 carbon atoms, optionally substituted with 1 to 60 carbon atoms an optionally substituted aryl group having 6 to 60 carbon atoms, an optionally substituted alkoxy group having 1 to 60 carbon atoms, and an optionally substituted aryl group having 1 to 60 carbon atoms; 60 alkenyloxy group, optionally substituted alkynyloxy group having 1 to 60 carbon atoms, optionally substituted aralkyloxy group having 1 to 60 carbon atoms, optionally substituted Aryloxy group having 6 to 60 carbon atoms, optionally substituted alkylcarbonyl group having 1 to 60 carbon atoms, optionally substituted alkenylcarbonyl group having 1 to 60 carbon atoms, optionally substituted an alkynylcarbonyl group having 1 to 60 carbon atoms which may be optionally substituted, an aralkylcarbonyl group
• R 4 is an optionally substituted alkoxy group having 1 to 60 carbon atoms, in one embodiment it is an alkoxy group having 1 to 30 carbon atoms, and in another embodiment it is an alkoxy group having 1 to 20 carbon atoms. , in one embodiment, is an alkoxy group having 1 to 10 carbon atoms.
• the group of formula (3) includes a methoxycarbonyl group, an ethoxycarbonyl group, a butoxycarbonyl group, and the like.
• the alkoxy group having 1 to 60 carbon atoms functions as an electron-withdrawing group due to the ester moiety (or carbonyl moiety) close to the pyrazolone skeleton.
• an alkoxy group having 60 carbon atoms can also function as an electron-withdrawing group.
• Examples of pyrazolone compounds in which R 1 is an optionally substituted alkoxy group having 1 to 60 carbon atoms include, but are not limited to, for example: can be mentioned.
• R 4 is an optionally substituted alkyl group having 1 to 60 carbon atoms, in one embodiment it is an alkyl group having 1 to 30 carbon atoms, and in another embodiment it is an alkyl group having 1 to 20 carbon atoms. , in one embodiment, is an alkyl group having 1 to 10 carbon atoms.
• the group of formula (3) includes an acetyl group, a propionyl group, a butanoyl group, a 2-methylpropionyl group, a heptanoyl group, a 2-methylbutanoyl group, a 3-methylbutanoyl group, an octanoyl group, and a decanoyl group.
• R 4 is an optionally substituted aryl group having 6 to 60 carbon atoms, in one embodiment it is an aryl group having 6 to 30 carbon atoms, and in another embodiment it is an aryl group having 6 to 22 carbon atoms. , in one embodiment is an aryl group having 6 to 10 carbon atoms.
• examples of the group of formula (3) include benzoyl group, methylbenzoyl group, ethylbenzoyl group, propylbenzoyl group, butylbenzoyl group, dimethylbenzoyl group, 1-phthylcarbonyl group, naphthylcarbonyl group, etc. .
• the carbonyl group portion close to the pyrazolone skeleton functions as an electron-withdrawing group. Therefore, it is considered that the aryl group bonded to the pyrazolone skeleton via the carbonyl group does not have a large effect on the function as an electron-withdrawing group. Therefore, for example, an aryl group having 60 carbon atoms can also function as an electron-withdrawing group.
• Examples of pyrazolone compounds in which R 1 is an optionally substituted aryl group having 6 to 60 carbon atoms include, but are not limited to, for example: can be mentioned.
• R 1 is represented by the following formulas (4) to (7): It may also be a group represented by R 4 is a halogen atom, a nitro group, a cyano group, a haloalkyl group having 1 to 10 carbon atoms, a perfluoropolyether group having 2 to 10 carbon atoms, a carboxy group, or a optionally substituted group having 1 to 60 carbon atoms.
• Alkyl group optionally substituted alkenyl group with 1 to 60 carbon atoms, optionally substituted alkynyl group with 1 to 60 carbon atoms, optionally substituted with 1 to 60 carbon atoms an optionally substituted aryl group having 6 to 60 carbon atoms, an optionally substituted alkoxy group having 1 to 60 carbon atoms, and an optionally substituted aryl group having 1 to 60 carbon atoms; 60 alkenyloxy group, optionally substituted alkynyloxy group having 1 to 60 carbon atoms, optionally substituted aralkyloxy group having 1 to 60 carbon atoms, optionally substituted Aryloxy group having 6 to 60 carbon atoms, optionally substituted alkylcarbonyl group having 1 to 60 carbon atoms, optionally substituted alkenylcarbonyl group having 1 to 60 carbon atoms, optionally substituted an alkynylcarbonyl group having 1 to 60 carbon atoms which may be optionally substituted, an aralkylcarbonyl group
• the group represented by formula (4) is a pyridyl group that may be optionally substituted, and is a residue obtained by removing one hydrogen atom from pyridine (C 5 H 5 N).
• the position on the pyridine ring excluding one hydrogen atom may be any carbon atom at the ortho, meta or para position relative to the nitrogen atom. That is, the pyridyl group includes a 2-pyridyl group, a 3-pyridyl group, or a 4-pyridyl group.
• R 4 is a pyridyl group in which one or more hydrogen atoms are substituted, and may have one substituent, two substituents, three substituents, or four substituents.
• R 4 When R 4 is 0, it means a pyridyl group having no substituent. In addition, when it has two or more substituents, the substituents may be the same or a combination of two or more of the above substituents. Examples of pyrazolone compounds in which R 1 is a group represented by formula (4) include, but are not limited to, can be mentioned.
• the groups represented by formulas (5) to (7) are optionally substituted diazine groups, and are residues obtained by removing one hydrogen atom from diazine (C 4 H 4 N 2 ).
• Diazine includes three types of isomers depending on the position of the nitrogen, ie, pyrazine, pyrimidine, or pyridazine, but the position excluding one hydrogen atom may be any carbon atom position.
• R 4 is a diazine group in which one or more hydrogen atoms are substituted, and may have one substituent, two substituents, or three substituents. When R 4 is 0, it means a pyrazine group, a pyrimidine group, or a pyridazine group having no substituent.
• substituents when it has two or more substituents, the substituents may be the same or a combination of two or more of the above substituents.
• pyrazolone compounds in which R 1 is a group represented by formulas (5) to (7) include, but are not limited to, for example: can be mentioned.
• the halogen atom, nitro group, cyano group, haloalkyl group having 1 to 10 carbon atoms, or carboxy group of R 3 and R 4 are the same as those described in R 1 .
• an optionally substituted alkyl group having 1 to 60 carbon atoms, an optionally substituted alkenyl group having 1 to 60 carbon atoms, and an optionally substituted alkenyl group having 1 to 60 carbon atoms are optionally substituted alkyl group having 1 to 60 carbon atoms.
• an optionally substituted aryl group having 6 to 60 carbon atoms an optionally substituted aryloxy group having 6 to 60 carbon atoms, or an optionally substituted aryl group having 6 to 60 carbon atoms.
• the number of carbon atoms in the arylcarbonyl group of 60 is, in some embodiments, 6 to 30 carbon atoms, in some embodiments, 6 to 22 carbon atoms, and in some embodiments, 6 to 10 carbon atoms.
• the optionally substituted hydrogen atom substituents such as alkyl groups having 1 to 60 carbon atoms are not particularly limited as long as the effects of the present invention can be obtained, but include halogen atoms, nitro groups, cyano groups, Haloalkyl group having 1 to 10 carbon atoms, carboxy group, alkyl group having 1 to 10 carbon atoms, alkenyl group having 1 to 10 carbon atoms, alkynyl group having 1 to 10 carbon atoms, aralkyl group having 1 to 10 carbon atoms, 6 carbon atoms Aryl group with ⁇ 10 carbon atoms, alkoxy group with 1 ⁇ 10 carbon atoms, alkenyloxy group with 1 ⁇ 10 carbon atoms, alkynyloxy group with 1 ⁇ 10 carbon atoms, aralkyloxy group with 1 ⁇ 10 carbon atoms, carbon number 6 ⁇ 10 aryloxy group, alkylcarbonyl group having 1 to 10 carbon atoms, alkenylcarbonyl group having 1 to 10 carbon
• R 2 in the pyrazolone compound of the present invention is not particularly limited as long as the effects of the present invention can be obtained, but it is a hydrocarbon group having 1 to 1000 carbon atoms that may contain a hetero atom, and In one embodiment, it is a hydrocarbon group having 1 to 200 carbon atoms, and in another embodiment, it is a hydrocarbon group having 1 to 100 carbon atoms.
• heteroatoms include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), chlorine atom (Cl), iodine atom (I), A bromine atom (Br), a fluorine atom (F), or a silicon atom (Si) is included.
• the group R 2 may contain one or more of the above heteroatoms, or may contain two or more different types of heteroatoms.
• R 2 does not affect the stability of pyrazolonated compounds prepared using the pyrazolone compounds of the present invention, as described below. Therefore, R 2 is not fundamentally limited.
• the hydrocarbon group include saturated or unsaturated chain hydrocarbon groups, alicyclic hydrocarbon groups, aromatic groups, and polyethylene glycol groups. More specific hydrocarbon groups having 1 to 1000 carbon atoms that may contain heteroatoms include, for example, polymers containing polyethylene glycol, polyols, amino acids and derivatives thereof, peptides, proteins, nucleic acids, sugars and derivatives thereof, etc. can be mentioned.
• n is an integer from 0 to 2.
• the group -(CH 2 )n- is a group that connects the pyrazolone skeleton and R 1 . It is considered that the effects of the present invention can be exhibited as long as the distance between R 1 , which is an electron-withdrawing group, and the pyrazolone skeleton is below a certain level. That is, the group -(CH 2 ) n- is preferably shorter, and therefore n is preferably an integer of 0 or 1, more preferably 0.
• electron-withdrawing groups with a very strong electron-withdrawing effect for example, halogen atoms, nitro groups, cyano groups, haloalkyl groups having 1 to 10 carbon atoms (one or more halogen atoms bonded to the carbon atom at the 1st position) (2) and (perfluoropolyether group having 2 to 10 carbon atoms
• electron-withdrawing groups with a strong electron-withdrawing effect for example, carboxy groups and substituted aryl groups having 6 to 60 carbon atoms
• the pyrazolone compound of the present invention may be in the form of a salt acceptable as a pyrazolonating agent as described below. That is, it may form an acid addition salt or a salt with a base.
• Specific salts with bases include salts with inorganic bases, organic bases, and metal alkoxides. Salts can be formed by mixing the pyrazolone compounds of the invention with inorganic bases, organic bases, or metal alkoxides.
• Inorganic bases capable of forming salts include hydroxides, carbonates, bicarbonates, acetates, or hydrides of alkali metals (such as lithium, sodium, or potassium); alkaline earth metals (such as magnesium, etc.); , calcium, or barium) or hydrides.
• Organic bases that can form salts include dimethylamine, triethylamine, piperazine, pyrrolidine, piperidine, 2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, or collidine; metal alkoxides include sodium methoxide, potassium Examples include tert-butoxide, magnesium methoxide, and the like.
• Specific acid addition salts include salts with inorganic acids or organic acids. Acid addition salts can be produced by mixing the compound [1] of the present invention with an inorganic acid or an organic acid. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid.
• organic acids include formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, Ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, benzoic acid, camphorsulfonic acid, ethenesulfonic acid, gluconic acid, hydrobromic acid, isethionic acid, mucinic acid, pamonic acid, or pantothenic acid etc.
• the method for producing the pyrazolone compound of the present invention is not particularly limited, and methods known in the art can be used without restriction.
• the pyrazolonating agent of the present invention contains the pyrazolone compound of the present invention, and can convert the formyl group of a formyl group-containing compound into pyrazolonate. Specifically, as shown below, a pyrazolone compound of the present invention is reacted with a formyl group-containing compound such as a formyl group-containing protein, peptide, or sugar to form a pyrazolonated compound in which two molecules of the pyrazolone compound are bonded. can be obtained.
• a formyl group-containing compound such as a formyl group-containing protein, peptide, or sugar
• the pyrazolonating agent of the present invention does not contain a carrier (for example, water or a buffer), an excipient, a diluent, a preservative, a stabilizer, a preservative, an antioxidant, etc. as components other than the pyrazolone compound. But that's fine.
• the formyl group-containing compound is not particularly limited as long as it contains a formyl group, but includes, for example, antibodies, drugs, peptides, amino acids and derivatives thereof, peptides, proteins, nucleic acids, sugars, and Examples include derivatives thereof or sugars.
• the pyrazolone compound of the present invention and a formyl group-containing compound are brought into contact with each other.
• the reaction is usually carried out in a solvent, and the reaction temperature is usually 0°C to 100°C, preferably 10°C to 50°C from the viewpoint of reaction rate and reaction efficiency.
• the reaction time depends on the amount and type of substrate and solvent, the reaction temperature, etc., and is usually 5 minutes to 180 hours, and preferably 30 minutes to 48 hours from the viewpoint of reaction rate and reaction efficiency.
• the theoretical amount of the pyrazolone compound is 2 moles per 1 mole of the formyl group-containing compound, and the amount can be arbitrarily changed depending on the reaction situation.
• the amount of the pyrazolone compound is 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of the formyl group-containing compound.
• the reaction pressure is not particularly limited, and may be elevated pressure, normal pressure, or reduced pressure, and is usually 0.01 to 10 MPa (hereinafter, pressure is expressed as absolute pressure), preferably 0.1 to 1 MPa. It is.
• the pyrazolone compound and a formyl group-containing compound are brought into contact.
• the reaction conditions for the pyrazolone compound and the formyl group-containing compound may be the same as those for the pyrazolonization method of the formyl group-containing compound.
• the obtained pyrazolonated compound is difficult to decompose and is stable.
• a pyrazolone compound and a formyl group-containing compound are brought into contact with each other.
• the reaction conditions for the pyrazolone compound and the formyl group-containing compound may be the same as those for the pyrazolonization method of the formyl group-containing compound.
• the pyrazolonated compound of the present invention can be produced by the method for producing a pyrazolonated compound of the present invention.
• the mechanism by which the obtained pyrazolone compound is difficult to decompose and is stable has not been analyzed in detail, but it can be estimated as follows.
• the present invention is not limited by the following assumptions.
• the pyrazolone compound is an isomer mixture of the CH form, the OH form, and the NH form. Therefore, the pyrazolonated compound obtained using a pyrazolone compound is also an isomer mixture of CH form, OH form, and NH form. According to the analysis by the present inventors, it was found that among the isomer mixture of the pyrazolonated compound, the CH form is easily decomposed.
• R 1 when R 1 is an electron-withdrawing group, it is considered that the pyrazolone ring becomes an OH form having a stable cyclic resonance structure. That is, when R 1 is an electron-withdrawing group, the resulting pyrazolonated compound has a stable OH structure, so it is presumed that the stability of the pyrazolonated compound is high and that it does not decompose.
• R 2 since R 2 does not participate in the conjugated system, it is considered that if R 1 is an electron-withdrawing group, it will not be affected by R 2 . Therefore, the structure of R 2 is presumed to have no effect on the stability of the pyrazolonated compound, and the structure of R 2 is not limited.
• Example 1 a pyrazolone derivative was produced.
• Example 1 Ethyl 4,4,5,5,5-pentafluoro-3-oxovalerate (0.38 mL, 2.2 mmol) was dissolved in acetic acid (5 mL), and phenylhydrazine (0.26 mL, 2.6 mmol) was added. Ta. After stirring at 90°C for 23 hours, the reaction solution was extracted with ethyl acetate. The organic phase was washed successively with water, saturated aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate.
• HPLC GL-7400 (GL Sciences Co., Ltd.)
• Mobile phase A H 2 O solution containing 0.1% TFA (v/v)
• Mobile phase B MeCN solution containing 0.1% TFA (v/v) Gradient (mobile phase B%): Compound 5, 30% (0 min), 60% (30 min), Compound 6, 45% (0 min), 80% (30 min), Compound 7, 60% (0 min) ), 90% (30 min), Compound 8, 50% (0 min), 80% (30 min), Compound 9, 50% (0 min), 80% (30 min), Compound 10, 30% (0 minutes), 80% (30 minutes).
• Detection wavelength Compound 5, 240 nm, Compound 6, 240 nm, Compound 7, 240 nm, Compound 8, 252 nm, Compound 9, 250 nm, Compound 10, 235 nm.
• Example 10 Ethyl (4-fluorobenzoyl)acetate (300 ⁇ L, 1.70 mmol) was dissolved in acetic acid (3.0 mL) under an argon atmosphere and phenylhydrazine (183 ⁇ L, 1.87 mmol) was added. After stirring at 85° C. for 17 hours, ethyl acetate was added to the reaction mixture, and the organic layer was washed successively with water, a saturated aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate.
• a pyrazolone compound was introduced into galactopyranoside to synthesize a pyrazolone-galactose complex.
• an aqueous solution of galactose oxidase (manufactured by Worthington Biochemical Corporation, 90 units/mL, 623 ⁇ L), an aqueous solution of wasabi-derived peroxidase (manufactured by Oriental Yeast Co., Ltd., 3 units/mL, 396 ⁇ L), a DMF solution of a pyrazolone compound (25 mM, 5.76 ⁇ L) Add L) , and shaken for 24 hours at 30°C in a constant temperature shaking bath at a shaking rate of 165 times/min.
• the reaction solution is transferred to a 1 L eggplant flask, methanol is added, and the solvent is concentrated under reduced pressure. After drying with a vacuum pump, the resulting residue is dissolved in methanol and insoluble matter is filtered off. The obtained filtrate is concentrated under reduced pressure and the obtained residue is purified to obtain a pyrazolone-galactose complex.
• Detection wavelength Compound 28, 262 nm, Compound 29, 277 nm, Compound 30, 270 nm, Compound 31, 226 nm.
• the pyrazolone compound of the present invention By using the pyrazolone compound of the present invention, it is possible to introduce a drug into the formyl group on an antibody under mild conditions, and it is also possible to produce a chemically and biochemically stable antibody-drug conjugate. Therefore, it is expected to contribute to drug development.
• the pyrazolone compound of the present invention can form a stable modified product with the formyl group at the reducing end of a sugar chain, making it possible to quantitatively and qualitatively analyze sugar chains, as well as to conduct detailed analyzes using enzymatic reactions. Since structural analysis is also possible, it is expected to contribute to biology and medicine, especially to diagnosis and pathological analysis.

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• 2023
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