WO2024043341A1 - シクロアルキン誘導体 - Google Patents

シクロアルキン誘導体 Download PDF

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WO2024043341A1
WO2024043341A1 PCT/JP2023/030810 JP2023030810W WO2024043341A1 WO 2024043341 A1 WO2024043341 A1 WO 2024043341A1 JP 2023030810 W JP2023030810 W JP 2023030810W WO 2024043341 A1 WO2024043341 A1 WO 2024043341A1
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compound
functional molecule
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French (fr)
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Inventor
修平 山腰
正俊 松本
政彦 杵渕
祥英 水越
喬介 上田
圭一 舛屋
孝憲 青木
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Peptidream Inc
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Peptidream Inc
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Priority to EP23857449.5A priority Critical patent/EP4578860A1/en
Priority to JP2024542894A priority patent/JPWO2024043341A1/ja
Priority to CN202380061686.2A priority patent/CN120092006A/zh
Priority to AU2023331268A priority patent/AU2023331268A1/en
Priority to IL319133A priority patent/IL319133A/en
Publication of WO2024043341A1 publication Critical patent/WO2024043341A1/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems

Definitions

  • the present disclosure relates to cycloalkyne derivatives and uses thereof.
  • Click chemistry is a method for synthesizing new molecules through carbon-heteroatom bonding reactions between compounds with relatively simple structures with high reactivity and selectivity (Non-Patent Document 1).
  • the 1,3-dipolar cycloaddition (AAC) of azide and alkyne is a representative reaction of click chemistry and can construct a stable 1,2,3-triazole ring. It is used in the synthesis of pharmaceuticals and functional materials as a method to firmly connect substrates.
  • SPAAC strain-promoted azide alkyne cycloaddition
  • the substrate of SPAAC is not only widely used as a substrate for click chemistry, but is also expected to be used for binding the carrier peptide and payload of a peptide-drug conjugate (PDC). Therefore, new substrates for SPAAC are needed.
  • Q 2 is selected from C 2-4 alkylene, or Q 1 is methylene and Q 2 is
  • Y 1 is selected from a hydrogen atom, C 1-6 alkanesulfonyl optionally substituted with one or more halogen atoms, and nitrobenzenesulfonyl
  • R 1 is a hydrogen atom, C 1-6 alkyl, (C 1-6 alkyl) carbonyl, (C 1-6 alkoxy) carbonyl, benzyloxycarbonyl, -CO-Q 3 -X 3 , -COO-Q 3 - selected from X 3 , -CONR 2 -Q 3 -X 3 , -SO 2 -Q 3 -X 3 and -SO 2 NR 2 -Q 3 -X 3
  • R 2 is a hydrogen atom or C 1-6 alkyl
  • X 3 is -COR 5 , -OL 1 or -NR 3 R 4
  • R 3 is a hydrogen atom or C 1-6 alkyl
  • R 4 is a hydrogen atom, (C 1-6 alkyl) carbonyl,
  • [1-2] The compound according to [1-1], or a salt thereof, wherein R 1 is selected from -CO-CH 2 -OH, benzyloxycarbonyl, and tert-butoxycarbonyl.
  • R 1 is selected from -CO-CH 2 -OH, benzyloxycarbonyl, and tert-butoxycarbonyl.
  • Y 1 is C 1-6 alkanesulfonyl, trifluoromethanesulfonyl, and 2-nitrobenzenesulfonyl.
  • [1-8] is an 8- to 9-membered heterocycle
  • Q1 is an 8- to 9-membered heterocycle
  • Q 2 is selected from C 2-4 alkylene, or Q 1 is methylene and Q 2 is
  • the method described above comprising obtaining a conjugate in which the first functional molecule and the second functional molecule are linked by a linker represented by.
  • the first functional molecule and the second functional molecule are each independently a pharmacologically active compound, a labeled compound, a peptide, a protein, a nucleic acid, or a molecule used for a drug delivery system [1-10 The method described in ].
  • Either the first functional molecule or the second functional molecule is a pharmacologically active compound, a labeled compound, a peptide, a protein, or a nucleic acid that has specific binding to a target, [1 -11].
  • the first functional molecule and the second functional molecule are A conjugate in which
  • the first functional molecule and the second functional molecule are each independently a molecule used for a pharmacologically active compound, a labeled compound, a peptide, a protein, a nucleic acid, or a drug delivery system, [1- 13].
  • Either the first functional molecule or the second functional molecule is a pharmacologically active compound, a labeled compound, a peptide, a protein, or a nucleic acid that has specific binding to a target, [1 -14].
  • X 1 , X 2 , Q 1 , and Q 2 are as defined in [1-1], provided that when a hydroxy group and an amino group are present, they are protected with a protecting group. , L is a leaving group] in the presence of a Lewis acid to obtain a corresponding closed ring product.
  • L is -OR 10 or a halogen atom
  • R 10 is a hydrogen atom, (C 1-6 alkyl) carbonyl, acetyl, tri(C 1-6 alkyl)silyl, C 1-6 alkyl, benzenesulfonyl, or C
  • Q 2 is selected from C 2-4 alkylene, or Q 1 is methylene and Q 2 is
  • Y 1 is selected from a hydrogen atom, C 1-6 alkanesulfonyl optionally substituted with one or more halogen atoms, and nitrobenzenesulfonyl
  • R 1 is a hydrogen atom, C 1-6 alkyl, (C 1-6 alkyl) carbonyl, (C 1-6 alkoxy) carbonyl, benzyloxycarbonyl, [(9H-fluoren-9-yl)methoxy] carbonyl, - From CO-Q 3 -X 3 , -COO-Q 3 -X 3 , -CONR 2 -Q 3 -X 3 , -SO 2 -Q 3 -X 3 , and -SO 2 NR 2 -Q 3 -X 3 selected
  • R 2 is a hydrogen atom or C 1-6 alkyl
  • X 3 is -COR 5 , -OL 1 , -NR 3 R 4 , or and R 3 is a hydrogen atom or C 1-6 al
  • [2-2] The compound according to [2-1], or a salt thereof, wherein Q 3 is ethylene or propylene.
  • R 1 is selected from -CO-CH 2 -OH, benzyloxycarbonyl, tert-butoxycarbonyl, [(9H-fluoren-9-yl)methoxy]carbonyl, [2-1] or [ 2-2] or a salt thereof.
  • Y 1 is C 1-6 alkanesulfonyl, trifluoromethanesulfonyl, and 2-nitrobenzenesulfonyl.
  • Q 2 is selected from C 2-3 alkylene, or Q 2 is
  • Q 2 is selected from C 2-4 alkylene, or Q 1 is methylene and Q 2 is
  • the method described above comprising obtaining a conjugate in which the first functional molecule and the second functional molecule are linked by a linker represented by.
  • the first functional molecule and the second functional molecule are each independently a pharmacologically active compound, a labeled compound, a peptide, a protein, a nucleic acid, or a molecule used for a drug delivery system [2-11 The method described in ].
  • Either the first functional molecule or the second functional molecule is a pharmacologically active compound, a labeled compound, a peptide, a protein, or a nucleic acid that has specific binding property to a target, [2 -12].
  • X 1 , X 2 , Q 1 , Q 2 and Q 6 are as defined in [2-11]]
  • the first functional molecule and the second functional molecule are each independently a pharmacologically active compound, a labeled compound, a peptide, a protein, a nucleic acid, or a molecule used for a drug delivery system, [2- 14].
  • first functional molecule or the second functional molecule is a pharmacologically active compound, a labeled compound, a peptide, a protein, or a nucleic acid that has specific binding property to a target, [2 -15].
  • X 1 , X 2 , Q 1 , and Q 2 are as defined in [2-1], provided that when a hydroxy group and an amino group are present, they are protected with a protecting group. , L is a leaving group] in the presence of an acid to obtain a corresponding closed ring product.
  • the acid is a Lewis acid or Br ⁇ nsted acid.
  • L is -OR 10 or a halogen atom
  • R 10 is a hydrogen atom, (C 1-6 alkyl) carbonyl, acetyl, tri(C 1-6 alkyl)silyl, C 1-6 alkyl
  • the production method according to [2-17] which is benzenesulfonyl or C 1-6 alkanesulfonyl.
  • novel cycloalkyne derivative having a spiro ring according to the present invention has high versatility as a cycloalkyne derivative that can be used in SPAAC, and is also useful for conjugation of PDC.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.
  • a halogen atom is used as a substituent for aryl, heteroaryl, etc.
  • examples thereof include fluorine atom, chlorine atom, and bromine atom.
  • a fluorine atom can be mentioned.
  • Specific examples of the group having a halogen atom as a substituent include trifluoromethyl, pentafluoroethyl, trifluoromethoxy, pentafluoroethoxy, trifluoromethylthio, and pentafluoroethylthio.
  • C 1-6 alkyl is a monovalent group derived by removing one arbitrary hydrogen atom from a linear or branched saturated aliphatic hydrocarbon having 1 to 6 carbon atoms. It means something. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, Examples include 1-ethylpropyl, hexyl, 4-methylpentyl and the like.
  • C 1-6 alkoxy means a C 1-6 alkyl-O- group, where C 1-6 alkyl is as defined above. Specific examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-pentyloxy, 1-hexyloxy, and the like.
  • (C 1-6 alkyl)carbonyl means a C 1-6 alkyl-C(O)- group, where C 1-6 alkyl is as defined above. Specific examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl, sec-butylcarbonyl, t-butylcarbonyl, 1-methylpropylcarbonyl, n-pentylcarbonyl.
  • (C 1-6 alkoxy)carbonyl means a C 1-6 alkoxy-C(O)- group, where C 1-6 alkoxy is as defined above. Specific examples include methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl, 2-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, 1-pentyloxycarbonyl, and 1- Includes hexyloxycarbonyl, etc.
  • tri(C 1-6 alkyl)silyl means a (C 1-6 alkyl) 3 Si- group, where C 1-6 alkyl is as defined above, and three alkyl The groups may be the same or different. Specific examples include trimethylsilyl, triethylsilyl, tripropylsilyl, tributylsilyl, tripentylsilyl, trihexylsilyl, and the like.
  • (C 1-6 alkyl)diphenylsilyl means a (C 1-6 alkyl)(C 6 H 5 ) 2 Si- group, where C 1-6 alkyl is as defined above. It is. A specific example is t-butyldiphenylsilyl.
  • C 1-6 alkanesulfonyl means a C 1-6 alkyl-SO 2 - group, where C 1-6 alkyl is as defined above. Specific examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, etc., such as methylsulfonyl.
  • C 1-10 alkylene is a group having a -(C n H 2n )- structure, where n is an integer of 1 to 10, and unless otherwise specified, unsubstituted Alternatively, it may be unsubstituted, and may be linear or branched.
  • C 1-10 alkylene includes C 1-6 alkylene. Specific examples include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, and decylene.
  • examples of C 2-10 alkylene with cyclo C 3-10 alkylene inserted include ethylene with cyclohexylene inserted, propylene with cyclohexylene inserted, butylene with cyclohexylene inserted, and cyclohexylene.
  • Examples include methylene (1,4-cyclohexylene)-, and -(cycloC 3-10 alkylene)-(C 1-10 alkylene)-, cyclopropylene methylene, cyclobutylene methylene, cyclopentylene methylene, cyclohexylene methylene, cycloheptylene methylene, cyclooctylene methylene, cyclononylene methylene, cyclodecylene Methylene, cyclopropylene ethylene, cyclobutylene ethylene, cyclopentylene ethylene, cyclohexylene ethylene, cycloheptylene ethylene, cyclooctylene ethylene, cyclononylene ethylene, cyclodecylene ethylene, cyclopropylene propylene, cyclobutylene propylene, cyclo Pentylene propylene, cyclohexylene propylene, cycloheptylene propy
  • C 2-4 alkylene is a group having a -(C m H 2m )- structure, and may be a straight chain or a branched chain, for example, a straight chain.
  • m is an integer of 2 to 4.
  • Specific examples include ethylene, propylene, and butylene.
  • the compound of formula (I) is an 8- to 9-membered heterocyclic compound.
  • the term “8- to 9-membered heterocycle” refers to a heterocyclic group containing N or O as a hetero atom and consisting of 8 to 9 ring atoms.
  • an “8- to 9-membered heterocycle” may have one triple bond.
  • the term "functional molecule” is not particularly limited, and is a molecule that imparts a desired function upon binding. Desired functions include, but are not limited to, pharmacologically active functions, labeling functions, purification functions, and delivery functions to target sites.
  • the term "functional molecule” as used herein includes pharmacologically active compounds, labeled compounds, peptides, proteins, nucleic acids, and molecules used in drug delivery systems. could be.
  • pharmacologically active compound refers to a compound that has pharmacological activity.
  • a pharmacologically active compound is, for example, a low molecular weight compound that has pharmacological activity.
  • labeled compound refers to a compound labeled with a dye, fluorescent substance, tag, or radioisotope.
  • the compound labeled with a radioactive isotope refers to a compound in which a low molecule, a middle molecule compound, an antibody, etc. is labeled with a radioactive isotope.
  • the label compound may be a dye, a fluorescent substance, a tag, or a radioactive isotope itself.
  • the radioactive isotope may be coordinately bonded to a chelating agent such as DOTA.
  • peptide may be any peptide that exhibits a useful function in the body.
  • protein may be any protein that exists in the body or that exhibits a useful function in the body, such as a protein that has pharmacological action, a protein that has molecular recognition action, etc. Can be mentioned. Specific examples include exportin/importin proteins, febronectin, avidin, antibodies, enzymes, and the like.
  • nucleic acid may be any polymer of nucleotides. Specific examples include DNA and RNA. As used herein, the nucleic acids may be modified, such as 2'-methoxyethyl (MOE) modification, the use of 2' deoxynucleosides in RNA, internucleoside linkages with phosphorothioates, internucleoside linkages with phosphodiesters, and cytosine Examples include modifications such as conversion to 5-methylcytosine.
  • MOE 2'-methoxyethyl
  • linker that binds to a functional molecule may be any known linker, such as an amino acid linker (peptide linker), a fatty acid linker, a nucleic acid linker, a sugar chain linker, and other chemical linkers (alkyl linker). , PEG linker, etc.), and may also be a complex of a chemical linker and a peptide linker.
  • drug delivery system refers to a system that delivers active ingredients into target cells, and examples include carriers such as water-soluble polymers, nano-sized particles (nanospheres), liposomes, and micelles. can be mentioned.
  • the drug delivery system (DDS) molecule may further contain drugs such as low molecular weight compounds, proteins, peptides, nucleic acids, vaccines, etc.
  • conjugate refers to a complex of functional molecules containing two or more functional molecules.
  • the functional molecules contained in the “conjugate” may be the same functional molecule, or may be a combination of different types of functional molecules.
  • R 1 of the compound represented by formula (I) may be a general protecting group such as an Fmoc group or a Boc group.
  • X 4 of the compound represented by formula (I) may be, for example, a leaving group such as p-nitrophenoxy group.
  • examples of the salt of the compound represented by formula (I) include acid addition salts and base addition salts.
  • acid addition salts include hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate, sulfate, etc.; methanesulfonate, ethanesulfonate, benzenesulfonate, and sulfonates such as p-toluenesulfonate; acetate, citrate, malate, tartrate, succinate, salicylate, maleate, fumarate, benzoate, malonate, Examples include carboxylates such as glycolate, oxalate, glucuronate, adipate, glutarate, ketoglutarate, and hippurate.
  • base addition salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and ammonium salts such as tetraalkylammonium salts; amino acid salts such as lysine salts, arginine salts, glycine salts, valine salts, threonine salts, serine salts, proline salts and alanine salts. These salts are produced by contacting the compound with an acid or base that can be used in the production of pharmaceuticals.
  • the compound represented by formula (I) or a salt thereof may be an anhydrate or may form a solvate such as a hydrate.
  • solvate here refers to a solid in which a compound molecule and a solvent molecule form a complex; for example, if the solvent is water, it is called a hydrate.
  • Solvates other than hydrates include solids containing alcohols (eg, methanol, ethanol, n-propanol), N,N-dimethylformamide, and the like.
  • the compound represented by formula (I) and its salt can exist in several tautomers, such as keto form, enol form, imine form and enamine form, and mixtures thereof.
  • Tautomers exist in solution as mixtures of tautomers. In solid form, one tautomer usually predominates. Although one tautomer may be described, the invention includes all tautomers of the compounds of the invention.
  • the present invention includes all stereoisomers (e.g., enantiomers, diastereomers (including cis and trans geometric isomers)) of the compound represented by formula (I), racemates of said isomers, and other Contains mixtures.
  • the compounds of the present invention may have one or more asymmetric points and include racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds.
  • the compound represented by formula (I) When the compound represented by formula (I) is obtained as a free form, it can be converted into a salt that the compound may form, or a hydrate or solvate thereof according to a conventional method.
  • the compound represented by formula (I) when the compound represented by formula (I) is obtained as a salt, hydrate, or solvate of the compound, it can be converted into the free form of the compound according to a conventional method.
  • the element constituting the compound represented by formula (I) may be any isotope, and the present invention includes compounds of formula (I) containing the isotope.
  • An isotope of the compound is one in which at least one atom is replaced with an atom that has the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons).
  • isotopes contained in the compound of the present invention include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, sulfur atom, fluorine atom, chlorine atom, etc., respectively. 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S, 18 F, 36 Cl, etc. are included.
  • radioactive isotopes such as 3 H and 14 C, which emit radioactivity and decay, are useful for testing the distribution of pharmaceuticals or compounds in tissues in the body. Stable isotopes can be used safely because they do not decay, their abundance hardly changes, and they are not radioactive.
  • the isotope of the compound of the present invention can be converted according to a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope.
  • the halogen atom when L in formula (V) is a halogen atom, the halogen atom includes, for example, a chlorine atom.
  • R 10 in the compound represented by formula (V) include a hydrogen atom, methyl, acetyl, t-butyldimethylsilyl, trimethylsilyl, benzenesulfonyl, methanesulfonyl, and the like.
  • X 1 H of the compound represented by formula (V) when X 1 H of the compound represented by formula (V) is a hydroxyl group, the hydroxyl group may be protected with a silyl group such as TMS or TBS.
  • the compound of formula (I) can be used to form a 1,2,3-triazole ring by a 1,3-dipolar cycloaddition reaction with an azide compound (as practiced).
  • Example 6 That is, the present invention provides a method for producing a functional molecule conjugate by forming a 1,2,3-triazole ring using a compound represented by formula (I).
  • the reaction can be carried out in a solvent, and examples of solvents that can be used include dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, and the like.
  • the temperature at which the reaction is carried out is, for example, -78 to 50°C, specifically 0 to 25°C.
  • the compound represented by formula (I) can be used in an amount of, for example, 0.1 to 10 equivalents, specifically 0.5 to 1.5 equivalents, based on the reactable azide group.
  • the reaction time of the reaction can be appropriately determined by a person skilled in the art, and is, for example, 10 minutes to 96 hours, more specifically 30 minutes to 2 hours.
  • the first functional molecule having a group represented by formula (II) forms a 1,3-dipole with a second functional molecule comprising an azide group represented by formula (III). It can be used to form a conjugate in which functional molecules are linked by a linker represented by formula (IVa) or (IVb) containing a 1,2,3-triazole ring by a cycloaddition reaction.
  • the reaction can be carried out in a solvent, and solvents that can be used include dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, methanol, ethanol, tetrahydrofuran, dioxane, dichloromethane, Examples include a mixed solvent of the above-mentioned solvent and water, such as dimethyl sulfoxide or N,N-dimethylformamide.
  • the temperature at which the reaction is carried out is, for example, 0 to 100°C, specifically 0 to 25°C.
  • the first functional molecule is used in an amount of, for example, 0.5 to 1.5 equivalents, specifically 0.95 to 1.1 equivalents, relative to the reactable second functional molecule. I can do it.
  • the compound represented by formula (I) is prepared by ring-closing the compound represented by formula (V) by Nicholas reaction (Non-Patent Document 12), and then converting the compound into ammonium hexanitratocerate (IV) or tetra It can be obtained by treatment with butylammonium fluoride. That is, the present invention provides a method for producing a compound represented by formula (I), in which a compound represented by formula (V) is ring-closed by a Nicholas reaction, and then ammonium hexanitratocerate (IV) or tetra The above method is provided, comprising treating with butylammonium fluoride.
  • the Nicholas reaction can be carried out in a solvent, and solvents that can be used include dichloromethane, toluene, tetrahydrofuran, such as dichloromethane.
  • the Lewis acids that can be used in the Nicholas reaction include boron trifluoride diethyl ether complex, diethylaluminum chloride, ethylaluminum dichloride, trimethylsilyl triflate, zinc chloride, and silver triflate, and Bronsted acids that can be used include p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and methanesulfonic acid.
  • the temperature at which the Nicholas reaction is carried out is, for example, -78 to 50°C, specifically 0 to 25°C.
  • the reaction time of the Nicholas reaction can be appropriately set by a person skilled in the art, and is, for example, 10 minutes to 24 hours, more specifically 30 minutes to 2 hours.
  • the asymmetric compound has a 1,2,3-triazole ring formed by a 1,3-dipolar cycloaddition reaction with a sterically bulky azide compound. can be provided as a single positional isomer (Example 7).
  • the asymmetric compound is used for conjugation with a second functional molecule, such as a peptide or a nucleic acid, having a group represented by formula (III).
  • a 3-dipolar cycloaddition reaction can provide the 1,2,3-triazole ring as a single positional isomer. Therefore, the compound of the present invention is characterized in that it can be easily purified during production.
  • the symmetrical compound is capable of forming a 1,2-dipolar cycloaddition reaction between an azide and an alkyne without producing multiple positional isomers.
  • 3-triazole ring can be formed. Therefore, the compound of the present invention is characterized in that it can be easily purified during production.
  • the azide compound or the second functional molecule having a group represented by formula (III) is not particularly limited, and a synthesized one may be used, and a combination of an azide and an alkyne may be used. , 3-dipolar cycloaddition reaction, commercially available reagents may be used. Furthermore, the above-mentioned functional molecules having an azide group introduced therein may be used.
  • tert Tertiary; tBu: tert-butyl; Ac: acetyl; Boc: tert-butoxycarbonyl; Fmoc: 9-fluorenylmethyloxycarbonyl; Cbz: benzyloxycarbonyl; TMS: trimethylsilyl; TBS: tert-butyldimethylsilyl; TIPS: triisopropylsilyl; tBuSO 2 :tert-butylsulfonyl; nBuLi: normal butyl lithium; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; NMP: N-methylpyrrolidone; DIPEA: diisopropylethylamine; EtOAc or AcOEt: ethyl acetate; Na 2 SO 4 : sodium sulfate; DCM: dichloromethane; THF:
  • proton nuclear magnetic resonance ( 1 H-NMR) of the following synthesis examples was performed using JNM-ECP300 manufactured by JEOL, JNM-ECX300 manufactured by JEOL, or Bruker. It was measured in deuterated chloroform or deuterated dimethyl sulfoxide solvent using AscendTM500 (Bruker), and the chemical shift was expressed as a ⁇ value (ppm) when tetramethylsilane was used as an internal standard (0.0 ppm).
  • ACQUITY UPLC H-Class/QDa manufactured by Waters
  • ACQUITY UPLC H-Class/SQD2 manufactured by Waters
  • LC-20AD/Triple manufactured by Shimadzu Any of Tof5600 It was measured using
  • ESI+ is the positive mode of electrospray ionization and (M+H) + means protonated ion.
  • M-MeOH+H) + means an ion resulting from proton addition and methanol elimination.
  • (MC 4 H 8 SO 2 +H) + means an ion resulting from addition of a proton and elimination of a tert-butylsulfonyl group.
  • (MC 5 H 8 O 2 +H) + means an ion resulting from addition of a proton and elimination of a tert-butoxycarbonyl group.
  • MC 4 H 8 +H) + means an ion resulting from addition of a proton and elimination of a tert-butyl group.
  • (MH 2 O+H) + means an ion resulting from addition of protons and elimination of water.
  • ESI is the negative mode of electrospray ionization
  • MH means ions due to proton desorption
  • the obtained organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase DCM, 3% to 15% MeOH gradient), and the fraction containing the target product was concentrated under reduced pressure.
  • the title compound (3.71 g, 17.08 mmol) was obtained as a white powder.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-hexane, 0% to 100% ethyl acetate gradient, followed by mobile phase DCM, 20% MeOH gradient).
  • the fractions containing the target compound were concentrated under reduced pressure to obtain the title compound (346 mg, 0.700 mmol) as a colorless viscous substance.
  • Benzyl 3,3-bis(methanesulfonamidomethyl)azetidine-1-carboxylate obtained in Example 1-3 (190 mg, 0.469 mmol) was added to a mixed solvent of THF (1.9 mL) and DMF (0.47 mL). ) was dissolved, and sodium hydride (18.7 mg, 0.469 mmol, 60%, dispersed in liquid paraffin) was added under ice cooling, and the mixture was stirred for 10 minutes.
  • 1-Bromo-4-methoxy-2-butyne (76 mg, 0.469 mmol, CAS: 693-26-5, synthesized by the method described in the literature Journal of Organic Chemistry 2005, 70, 4059-4063) was added to the reaction solution.
  • Example 1-6 Benzyl 3',7'-dimethanesulfonyl-3',7'-diaza-10',11'-dicobaltaspiro[azetidine-3,5] obtained in Example 1-6 was added to diethyl ether (4.3 mL). '-tetracyclo[7.2.0.0 1,10 . 0 9,11 ]undecane]-1-carboxylate; Hexakis (methanidyridine oxidanium) (32 mg, 0.043 mmol) was suspended, and Wacosil (registered trademark) C-200 (1 g, CAS: 63231) was added under ice cooling.
  • Wacosil registered trademark
  • Methyl propargyl ether (2.05 g, 29.2 mmol, CAS: 627-41-8) was dissolved in THF (122 mL), and 2M nBuLi (13.4 mL, 26.8 mmol, cyclohexane solution) was added at -78 °C. The mixture was stirred for a minute. Thereafter, the temperature was raised to 0°C and stirred for 15 minutes. After cooling again to -78°C, a THF solution of benzyl 3-oxoazetidine-1-carboxylate (5.00 g, 24.36 mmol, CAS: 105258-93-3) was added and stirred at -78°C for 1 hour.
  • Benzyl 3-hydroxy-3-(3-methoxyprop-1-yn-1-yl)azetidine-1-carboxylate (3.00 g, 10.9 mmol) obtained in Example 2-1 was added to THF (18 mL). After dissolving, sodium hydride (0.654 g, 16.4 mmol, 60%, dispersed in liquid paraffin) was added at 0° C. and stirred for 20 minutes. Thereafter, a DMF solution (18 mL) of (3-bromopropoxy)(tert-butyl)dimethylsilane (4.14 g, 16.4 mmol, CAS: 89031-84-5) was added at 0°C, and the mixture was stirred at room temperature overnight. .
  • Methyl propargyl ether (0.59 g, 8.43 mmol, CAS: 627-41-8) was dissolved in THF (65 mL), and 2M nBuLi (3.9 mL, 7.78 mmol, cyclohexane solution) was added at -78 °C. The temperature was raised to 0°C and stirred for 10 minutes.
  • Benzyl 3-[(2-methylpropane-2-sulfinyl)imino]azetidine-1-carboxylate (2.00 g, 6.49 mmol, CAS: 1638764-74-5, the method described in US2020/0038378A1) was added to the reaction solution.
  • Example 3-1 After suspending sodium hydride (42.3 mg, 60%, dispersed in liquid paraffin) in THF (2.6 mL) at 0°C, benzyl 3-(3-methoxyprop-1) obtained in Example 3-1 was suspended. -yn-1-yl)-3-[(2-methylpropane-2-sulfinyl)amino]azetidine-1-carboxylate (0.200 g, 0.528 mmol) was added at 0°C and stirred for 10 minutes.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-hexane, 20% to 100% ethyl acetate gradient) to obtain the title compound as a colorless viscous substance (0.080 g, .145 mmol) was obtained.
  • the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-hexane, 30% to 100% ethyl acetate gradient).
  • Isolera Biotage; Sfaer HC Duo; mobile phase n-hexane, 30% to 100% ethyl acetate gradient.
  • the title compound (0.053 g, 0.117 mmol) was obtained.
  • the reaction was stopped by adding saturated aqueous sodium bicarbonate to the reaction solution, the aqueous layer was extracted with dichloromethane, and the organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-hexane, 20% to 50% ethyl acetate gradient) to obtain the title compound (0.013 g, .027 mmol) was obtained.
  • Example 2-2 Benzyl 3-(3-hydroxypropoxy)-3-(3-methoxyprop-1-yn-1-yl)azetidine-1-carboxylate (0.5 mL) obtained in Example 2-2 was added to toluene (1.5 mL). MsNH 2 (0.103 g, 1.08 mmol) and cyanomethylenebutylphosphorane (0.261 g, 1.08 mmol CAS: 157141-27-0) were added, and the mixture was stirred at room temperature overnight. .
  • the reaction was stopped by adding saturated aqueous sodium bicarbonate to the reaction solution, the aqueous layer was extracted with dichloromethane, and the organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-hexane, 20% to 60% ethyl acetate gradient) to give the title compound (0.093 g, .140 mmol) was obtained.
  • Benzyl 7'-methanesulfonyl-3'-oxa-7'-aza-10',11'-dicobaltaspiro[azetidine-3,2'-tetracyclo[7] obtained in Example 4-2 was added to diethyl ether (30 mL). .2.0.0 1,10 . 0 9,11 ]Undecane]-1-carboxylate; Dissolve hexakis (methanidyridine oxidanium) (0.200 g, 0.301 mmol), add Wakosil (registered trademark) C-200 (5 g), and then CAN (1.65g, 3.01mmol) was added at 0°C. After stirring at 0° C.
  • N-Boc-L-lysine (1.13 g, 4.57 mmol, CAS: 13734-28-6) was suspended in THF (11.6 mL), and N-methyl-N-trimethylsilylacetamide (1.53 mL, 9. 57 mmol) was added thereto, and the mixture was stirred at 50°C for 1 hour.
  • the reaction solution was ice-cooled to 0°C, DIPEA (0.89 mL, 5.22 mmol) and 2-bromoisobutyryl bromide (1.00 g, 4.35 mmol, CAS: 20769-85-1) were added, and the mixture was heated for 1 hour.
  • (2S)-6-(2-bromo-2-methylpropanamido)-2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ hexanoic acid (obtained in Example 5-1) was added to DMSO (1.7 mL). 200 mg, 0.506 mmol) was added thereto, and sodium azide (66 mg, 1.01 mmol) was added thereto, followed by stirring at 50°C for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase 100% ethyl acetate, followed by mobile phase DCM, 0% to 30% methanol gradient) to obtain the desired product.
  • the containing fractions were concentrated under reduced pressure to obtain the title compound (21 mg, 0.025 mmol) as a white powder.
  • the obtained organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase DCM, 0% to 30% methanol gradient), and the fraction containing the target product was concentrated under reduced pressure.
  • the title compound (23.2 mg, 0.030 mmol) was obtained as a white powder.
  • benzyl 5,9-dioxa-2-azaspiro[3.8]dodecy-11-yn-2-carboxylate which is a compound of the present invention, is similar to alkynes used in known click chemistry, It was shown that a click reaction can be performed with the compound.
  • Methyl propargyl ether (4.26 g, 60.7 mmol, CAS: 627-41-8) was dissolved in THF (156 mL), and 2M nBuLi (28.0 mL, 56.1 mmol, cyclohexane solution) was added at -78 °C. The mixture was stirred for a minute. Thereafter, the temperature was raised to 0°C and stirred for 10 minutes. After cooling to -78°C again, a THF solution of tert-butyl 3-oxoazetidine-1-carboxylate (8.00g, 46.7mmol, CAS: 398489-26-4) was added and stirred at -78°C for 20 minutes. did.
  • the intermediate obtained earlier was added to a THF (147 mL) solution, 1M TBAF (66.1 mL, 66.1 mmol) was added at 0°C, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction was stopped with a saturated aqueous ammonium chloride solution, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-heptane, 0% to 80% ethyl acetate gradient) to obtain the title compound (13.05 g, 43.6 mmol) was obtained.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-hexane, 20% to 50% ethyl acetate gradient) to obtain the title compound (5.20 g, 6 .06 mmol) was obtained.
  • the reaction was stopped by adding saturated aqueous sodium bicarbonate to the reaction solution, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-heptane, 20% to 50% ethyl acetate gradient) to give the title compound (2.88 g, 3 .48 mmol) was obtained.
  • reaction solution was added dropwise to a mixed solvent of ethyl acetate (50 mL)/saturated aqueous sodium bicarbonate solution (50 mL) cooled to 0°C to stop the reaction.
  • aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-hexane, 10% to 80% ethyl acetate gradient) to obtain a colorless solid compound.
  • reaction solution was concentrated under reduced pressure, diluted with ethyl acetate and water, and extracted with ethyl.
  • the organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-hexane, 20% to 100% ethyl acetate gradient) to obtain the title compound (130 mg, 0.29 mmol) as a white solid. ) was obtained.
  • reaction solution was added dropwise to a mixed solvent of ethyl acetate (200 mL)/saturated aqueous sodium hydrogen carbonate solution (100 mL) cooled to 0°C to stop the reaction.
  • aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-heptane, 10% to 50% ethyl acetate gradient) to obtain the title compound as a colorless viscous substance (0.041 g, .088 mmol) was obtained.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-heptane, 50% to 100% ethyl acetate gradient, followed by mobile phase ethyl acetate, 5% methanol gradient).
  • Isolera Biotage; Sfaer HC Duo; mobile phase n-heptane, 50% to 100% ethyl acetate gradient, followed by mobile phase ethyl acetate, 5% methanol gradient).
  • the title compound (0.018 g, 0.080 mmol) was obtained as a colorless powder.
  • the obtained organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase DCM, 3% to 15% MeOH gradient), and the fraction containing the target product was concentrated under reduced pressure.
  • the title compound (10.0 g, 40.8 mmol) was obtained as a colorless powder.
  • the aqueous layer was extracted with diethyl ether, and the organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-heptane, 10% to 40% ethyl acetate gradient) to obtain the title compound (0.025 g, .060 mmol) was obtained.
  • the obtained residue is purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-heptane, 10% to 40% ethyl acetate gradient), and the fraction containing the target product is concentrated under reduced pressure. This gave the title compound (0.192 g, 0.354 mmol) as a yellow oil.
  • Triethylamine (0.117 g, 1.15 mmol, CAS: 121-44-8) and ditertiary butyl dicarbonate (0.101 g, 0.461 mmol, CAS: 24424-99-5) were added to the reaction solution, and the mixture was heated at room temperature for 20 min. Stir for a minute.
  • the reaction solution was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-heptane, 5% to 80% ethyl acetate gradient) to give the title compound as a brown powder (0.055 g, 0.05%). 095 mmol) was obtained.
  • reaction solution was added dropwise to a mixed solvent of ethyl acetate/10% sodium bicarbonate aqueous solution cooled to 0°C to terminate the reaction.
  • the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting residue was purified by flash column chromatography using Isolera (Biotage; Sfaer HC Duo; mobile phase n-hexane, 10% to 40% ethyl acetate gradient) to give the title compound as a white powder (0.017 g, 0.057 mmol) was obtained.
  • NS-S01-20 The structural formula of the nucleic acid compound is shown in Figure 4.
  • click reagent X introducer A compound in which click reagent X is introduced into NS-S01-20 is shown below. (Hereinafter, it may be referred to as Click reagent X introducer).
  • a compound that is a conjugate of Click reagent X inductor and peptide F is shown below. (Hereinafter, it may be referred to as PN-S01-10).
  • Example 13-2 Purification of PN-S01-10
  • Mobile phase A (118 mL) of purification condition 1 was added to the PN-S01-10 crude solution to dilute it, and the solution was used as an injection solution, and purified under purification condition 1.
  • Preparative purification was performed. A fraction was collected from a retention time of 76 minutes to 85 minutes, and all fractionated solutions were combined. The fractionated solution was analyzed under analysis conditions 1 to obtain a purified solution of PN-S01-10 with a purity of 90.7% (recovery rate 100%).
  • Example 13-3 Desalting and elution of PN-S01-10 Add mobile phase A (100 mL) of desalting condition 1 to the purified solution of PN-S01-10, dilute the solution, use it as an injection solution, and desalt. Desalting was performed under Condition 1. After injecting into the column, two column volumes of water for injection were passed through the column, and it was confirmed that the conductivity was 50 ⁇ S/cm or less. Next, under elution conditions 1, PN-S01-10 retained in the column was eluted. Samples with a retention time of 10 minutes to 13 minutes were collected, and all sampled solutions were combined. The fractionated liquid was analyzed under analysis conditions 1 to obtain a desalted solution of PN-S01-10 with a purity of 92.2% (recovery rate 100%).
  • Example 13-4 Freeze-drying of PN-S01-10 Water for injection (42 mL) was added to the PN-S01-10 desalted solution (42 mL) to dilute it. After freezing the diluted solution, it was dried in a freeze dryer for 3 days. After drying, white solid PN-S01-10 (16.1 mg, purity 90.4%, yield 40.4%) was obtained.

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