[go: up one dir, main page]

WO2014109256A1 - Analogue de dinucléotide cyclique lié à un triazol - Google Patents

Analogue de dinucléotide cyclique lié à un triazol Download PDF

Info

Publication number
WO2014109256A1
WO2014109256A1 PCT/JP2013/085042 JP2013085042W WO2014109256A1 WO 2014109256 A1 WO2014109256 A1 WO 2014109256A1 JP 2013085042 W JP2013085042 W JP 2013085042W WO 2014109256 A1 WO2014109256 A1 WO 2014109256A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
cyclic
cyclic dinucleotide
group
independently
Prior art date
Application number
PCT/JP2013/085042
Other languages
English (en)
Japanese (ja)
Inventor
寛之 磯部
智子 藤野
滉大 岡田
Original Assignee
国立大学法人東北大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立大学法人東北大学 filed Critical 国立大学法人東北大学
Priority to JP2014513396A priority Critical patent/JP6153116B2/ja
Publication of WO2014109256A1 publication Critical patent/WO2014109256A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring 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
    • C07D491/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a triazole-linked cyclic dinucleotide analog.
  • Cyclic dinucleotide is a natural physiologically active substance that functions as a second messenger for bacteria.
  • cyclic bis (3'-5 ') diguanylic acid (c-di-GMP) a cyclic dinucleotide derived from bacteria, is a physiological film that controls biofilm biosynthesis and motility of pestis, cholera and salmonella. Has activity.
  • c-di-GMP diguanylic acid
  • c-di-GMP a cyclic dinucleotide derived from bacteria
  • Patent Document 1 describes a method for efficiently synthesizing cyclic bis (3'-5 ') dinucleotide by an intramolecular cyclization reaction of dinucleotide.
  • a natural nucleotide such as a cyclic dinucleotide has a structure in which a plurality of nucleosides composed of a base and an aldpentose type sugar are linked to each other via a phosphodiester bond formed at the hydroxyl group of the sugar. Due to the structural features described above, natural nucleotides have low stability of the phosphodiester binding moiety against hydrolases present in vivo. Moreover, since all of a base part, a sugar part, and a phosphodiester bond part are polar groups with low liposolubility, natural type nucleotides have low cell membrane permeability for migration into target cells. These properties are a major problem when natural nucleotides are applied to pharmaceutical uses.
  • Patent Document 2 is a compound including a polyamide skeleton having a plurality of ligands, wherein the plurality of ligands individually bind to nitrogen atoms located in the skeleton, and at least one of the ligands is a natural nucleic acid.
  • the compounds are described as being bases, unnatural nucleobases, DNA intercalators or nucleobase binding groups.
  • the compound described in the document includes a peptide nucleic acid (PNA) in which a phosphodiester bond portion of a nucleotide is substituted with a peptide chain.
  • PNA peptide nucleic acid
  • Patent Document 3 is a nucleoside derivative in which a sugar and a base moiety are formed by linking a sugar and a pyrimidine base or a purine base, and the sugar-base moiety contains a 1,2,3-triazole ring. Said nucleoside derivative comprising a structure linked via a group is described.
  • Non-Patent Document 3 discloses that c-di-GMP has a monophosphorothioic acid diester group in which one of the phosphodiester binding moieties is substituted. GMP analogs are described.
  • the present invention provides a means for improving chemical stability and fat solubility in an artificial cyclic nucleoside conjugate, which is an analog of a natural cyclic dinucleotide, while maintaining structural similarity to the natural form. For the purpose.
  • the present inventor has formed two phosphodiester bond portions of a natural cyclic dinucleotide by a cycloaddition reaction between azide and ethynyl 1,2
  • the present inventors have found that chemical stability and lipophilicity can be improved by substituting a linking group containing a 1,3-triazole ring.
  • the gist of the present invention is as follows.
  • Y 1 and Y 2 are each independently represented by the following formulas (YI) to (Y-IV): [Where: * a indicates the position of attachment to the nucleoside moiety containing X a * b represents the position of binding to the nucleoside moiety containing X b , Z a and Z b are each independently a divalent hydrocarbon group which may have a direct bond or a hetero atom]
  • the cyclic dinucleotide analogue according to (2) selected from the group consisting of
  • X a and X b are the same base, and Y 1 is formula (YI) or formula (Y-III) and Y 2 is formula (Y-II) or formula (Y-IV) Or Y 1 is the formula (Y-II) or the formula (Y-IV) and Y 2 is the formula (YI) or the formula (Y-III), described in the above (2) or (3) A cyclic dinucleotide analog of
  • FIG. 1 is a diagram showing an analytical HPLC chromatogram of compound (5) using HPLC connected with a triazole-modified-hydrophilic interaction chromatography (HILIC) column.
  • FIG. 2 is a diagram showing an analytical HPLC chromatogram of compound (8) using HPLC connected with a triazole-modified-hydrophilic interaction chromatography (HILIC) column.
  • Cyclic dinucleotide analogs > The present invention relates to cyclic dinucleotide analogs.
  • the cyclic dinucleotide analog of the present invention may have two nucleoside moieties containing a purine base or a pyrimidine base, and two linking groups that link the two nucleoside moieties to each other to form a cyclic structure. is necessary.
  • the cyclic dinucleotide analog of the present invention is a cyclic nucleoside conjugate in which two nucleosides containing a purine base or a pyrimidine base are linked so that a cyclic structure is formed by two linking groups.
  • purine base means a basic compound having a purine nucleus or a monovalent group obtained by removing a hydrogen atom on the 9-position nitrogen atom.
  • purine base include, but are not limited to, purine nucleobases such as adenine and guanine, and derivatives thereof.
  • the “pyrimidine base” means a basic compound having a pyrimidine nucleus or a monovalent group in which a hydrogen atom on the 1-position nitrogen atom is removed.
  • the pyrimidine base include, but are not limited to, pyrimidine nucleobases such as uracil, cytosine and thymine, and derivatives thereof.
  • the derivatives of pyrimidine nucleobase and purine nucleobase are not limited, for example, halogenated derivatives and deaminated derivatives of uracil, cytosine, thymine, adenine or guanine, wherein the oxygen atom of the compound is substituted with a sulfur atom Derivatives, C-5-modified bases of pyrimidines, C-7-modified bases of purines, and ring-expanded modified bases.
  • examples of purine nucleobases and derivatives thereof include compounds represented by the following formulae.
  • D 1 is an oxygen atom or a sulfur atom
  • D 2 is hydroxyl or amino
  • E 1 and E 2 are each independently a hydrogen atom, halogen, cyano, alkyl, alkenyl or alkynyl. is there.
  • the purine nucleobase and its derivative are linked to the 1-position carbon atom of the sugar of the nucleoside moiety via the 9-position nitrogen atom.
  • Examples of the purine nucleobase and derivatives thereof included in the compound include deaminoguanine derivatives such as hypoxanthine, halogenated guanine derivatives such as 8-fluoroguanine, 8-bromoguanine and 8-iodoguanine. And derivatives of guanine; halogenated adenine derivatives such as 8-fluoroadenine, 8-bromoadenine and 8-iodoadenine, and derivatives of adenine such as 1, N 6 -ethenoadenine.
  • deaminoguanine derivatives such as hypoxanthine
  • halogenated guanine derivatives such as 8-fluoroguanine, 8-bromoguanine and 8-iodoguanine.
  • derivatives of guanine halogenated adenine derivatives such as 8-fluoroadenine, 8-bromoadenine and 8-iodoadenine
  • examples of the pyrimidine nucleobase and derivatives thereof include compounds represented by the following formulae.
  • D 3 and D 4 are each independently an oxygen atom or a sulfur atom
  • D 5 is hydroxyl or amino
  • D 6 is a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy or an aminoalkoxy
  • E 3 is hydrogen atom, halogen, alkyl, alkenyl, alkynyl, or alkoxy.
  • the pyrimidine nucleobase and its derivative are linked to the 1-position carbon atom of the sugar of the nucleoside moiety via the 1-position nitrogen atom.
  • Examples of the pyrimidine nucleobase and derivatives thereof included in the compound include halogenated uracil derivatives such as 5-fluorouracil, 5-bromouracil and 5-iodouracil, 2-thiouracil, 4-thiouracil and 2,4- Derivatives of uracil, such as uracil derivatives having a sulfur atom in place of an oxygen atom such as dithiouracil, 5-methyluracil, 5-vinyluracil, and 5-ethynyluracil; 5-fluorocytosine, 5-bromocytosine and 5 -Derivatives of cytosine such as halogenated cytosine derivatives such as iodocytosine and cytosine derivatives having alkynyl such as 5-ethynylcytosine.
  • halogenated uracil derivatives such as 5-fluorouracil, 5-bromouracil and 5-iodouracil, 2-thiouracil, 4-thi
  • alkyl means a straight or branched chain aliphatic hydrocarbon group containing the specified number of carbon atoms.
  • C 1 ⁇ C 6 alkyl includes at least one and at most 6 carbon atoms means a hydrocarbon chain straight or branched chain.
  • Suitable alkyls include, for example, linear or branched C 1 -C 6 alkyls such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
  • alkylene means a divalent group in which one hydrogen atom of the alkyl is removed.
  • Suitable alkylenes include, for example, linear or branched C 1 -C 6 alkylenes such as methylene, ethylene, propylene, isopropylene, butylene, isobutylene, t-butylene, pentylene and hexylene.
  • alkenyl means a group in which one or more CC single bonds of the alkyl are substituted with double bonds.
  • Suitable alkenyl includes, for example, linear chains such as vinyl, allyl, propenyl, isopropenyl, 2-methyl-1-propenyl, 2-methylallyl, 3-butenyl, 4-pentenyl, 5-hexenyl and 1,3-butanedienyl. Mention may also be made of branched C 2 -C 6 alkenyl.
  • alkenylene means a divalent group in which one hydrogen atom of the alkenyl is removed.
  • Suitable alkenylenes include, for example, linear or branched chains such as vinylene, propenylene, isopropenylene, 2-methyl-1-propenylene, 3-butenylene, 4-pentenylene, 5-hexenylene and 1,3-butadienylene. Mention may be made of C 2 to C 6 alkenylene.
  • alkynyl means a group in which one or more CC single bonds of the alkyl are substituted with triple bonds. Suitable alkynyls include, for example, linear or branched C 2 -C 6 alkynyl such as ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-hexynyl and 2-penten-4-ynyl. be able to.
  • alkynylene means a divalent group in which one hydrogen atom of the alkynyl is removed.
  • cycloalkyl means an alicyclic alkyl containing the specified number of carbon atoms.
  • C 3 -C 6 cycloalkyl means a cyclic hydrocarbon group containing at least 3 and at most 6 carbon atoms.
  • Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • cycloalkylene means a divalent group in which one hydrogen atom of the cycloalkyl is removed.
  • cycloalkenyl means a group in which one or more C—C single bonds of the cycloalkyl are substituted with double bonds. Suitable cycloalkenyl includes, but is not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
  • cycloalkenylene means a divalent group in which one hydrogen atom of the cycloalkenyl is removed.
  • heterocyclyl means that one or more carbon atoms of the cycloalkyl or cycloalkenyl are each independently selected from a nitrogen atom (N), a sulfur atom (S), and an oxygen atom (O). This means a group substituted with a heteroatom.
  • substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively.
  • heterocyclyls include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. it can.
  • heterocyclylene means a divalent group in which one hydrogen atom of the heterocyclyl is removed.
  • aryl means an aromatic ring group having 6 to 15 carbon atoms. Suitable aryls include, but are not limited to, phenyl, biphenyl, naphthyl, anthryl (anthracenyl), and the like.
  • arylene means a divalent group in which one hydrogen atom of the aryl is removed.
  • arylalkyl means a group in which one of the hydrogen atoms of the alkyl is substituted with the aryl.
  • Suitable arylalkyls include, but are not limited to, benzyl, 1-phenethyl, 2-phenethyl, and the like.
  • arylalkenyl means a group in which one of the alkenyl hydrogen atoms is substituted with the aryl.
  • Suitable arylalkenyls include, but are not limited to, styryl and the like.
  • heteroaryl refers to a heteroatom in which one or more carbon atoms of the aryl are each independently selected from a nitrogen atom (N), a sulfur atom (S), and an oxygen atom (O). Means a substituted group.
  • substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively.
  • heteroaryl include, but are not limited to, furanyl, thienyl (thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, Examples include pyrimidinyl, quinolinyl, isoquinolinyl and indolyl.
  • heteroarylene means a divalent group in which one hydrogen atom of the heteroaryl is removed.
  • heteroarylalkyl means a group in which one of the hydrogen atoms of the alkyl is substituted with the heteroaryl.
  • acyl means a group in which a monovalent group selected from the groups described above and carbonyl are linked. Suitable acyls include, but are not limited to, acetyl, propionyl, benzoyl, and the like.
  • alkoxy means a group in which one or more hydrogen atoms of the alkyl, alkenyl or alkynyl are substituted with oxygen atoms.
  • aminoalkoxy means a group in which one or more hydrogen atoms of the alkoxy are substituted with an amino group.
  • Suitable linear or branched amino C 1 -C 6 alkoxy may include aminomethoxy, 2-aminoethoxy, 3-aminopropoxy and the like.
  • halogen means fluorine, bromine, iodine or chlorine. Suitable halogens include, for example, fluorine, bromine or iodine.
  • heteroatom means an oxygen atom (O), a nitrogen atom (N), a sulfur atom (S), a silicon atom (Si), or a phosphorus atom (P).
  • the groups described above are each independently unsubstituted or one or more halogen, OH, NQ 1 Q 2 (Q 1 and Q 2 are each independently hydrogen, hydroxyl, alkyl , alkenyl or alkynyl), NO 2, C (O ) Q 3 (Q 3 is a monovalent group selected from hydrogen, hydroxyl, a group described in the NH 2 or above), or a group described in the It can be further substituted with a monovalent group selected from
  • a “protecting group” is a group that is introduced into a specific functional group in order to prevent an undesired reaction from progressing, and is quantitatively removed under specific reaction conditions. It means a group that is substantially stable under reaction conditions, that is, reaction inactive.
  • “protection (formation)” and “deprotection (formation)” mean introducing a protecting group into a functional group and removing the protecting group quantitatively, respectively.
  • “protected form” means a form in which a protective group is introduced into one or more functional groups, and “protected derivative” means one or more functional groups in a specific compound.
  • Means a derivative in which a protecting group is introduced that is, a derivative of the compound having a protected form of the group.
  • the protected derivative may be prepared by carrying out the protection described below, or a commercially available protected derivative into which a desired protecting group has been introduced in advance may be used.
  • the protection with the protecting group can be carried out, for example, by reacting with a protecting reagent such as acetic anhydride, benzoyl chloride or silane chloride in the presence of an organic base such as triethylamine or pyridine.
  • the deprotection of the protecting group can be carried out by treatment with an alkali such as sodium hydroxide, potassium hydroxide or ammonia in a solvent such as methanol or water.
  • protecting groups for terminal alkynes that are stable under acidic conditions and deprotected under desilylation conditions include, but are not limited to, for example, trimethylsilyl (TMS) and triisopropylsilyl (TIPS) ) And the like.
  • TMS trimethylsilyl
  • TIPS triisopropylsilyl
  • the deprotection of the protecting group can be carried out by reacting with a reagent such as tetrabutylammonium fluoride or a strong base in an aprotic polar solvent such as tetrahydrofuran (THF).
  • a reagent such as tetrabutylammonium fluoride or a strong base in an aprotic polar solvent such as tetrahydrofuran (THF).
  • aprotic polar solvent such as tetrahydrofuran (THF).
  • “desilylation conditions” means the reaction conditions for carrying out the deprotection of silyl as described above.
  • Examples of the hydroxyl protecting group that is stable under basic conditions and deprotected by acid treatment include, but are not limited to, acetonide, tert-butyl, and trityl.
  • the protection with the protecting group is carried out, for example, by reacting with acetone or isobutene in the presence of an acid such as sulfuric acid or hydrochloric acid, or by reacting with trityl chloride in the presence of an organic base such as triethylamine or pyridine. can do.
  • the deprotection of the protecting group can be carried out by reacting with an acid such as trifluoroacetic acid (TFA) in an aqueous solvent.
  • TFA trifluoroacetic acid
  • the linking group needs to contain a 1,2,3-triazole ring.
  • the 1,2,3-triazole ring may be arranged so as to be directly bonded to the sugar of the nucleoside moiety, and via a divalent hydrocarbon group which may have a hetero atom. You may arrange
  • an azide is substituted at the 3′-position, and a 5′-
  • the two nucleoside intermediates are composed of two linking groups containing a 1,2,3-triazole ring. It has been found that cyclic dinucleotide analogs having a linked structure are formed.
  • a nucleoside derivative having a structure in which two nucleoside intermediates are linked by a single linking group containing a 1,2,3-triazole ring has a rigid molecule, so that a distorted middle ring structure is formed. It was thought that it could not be formed stably.
  • a linear nucleoside derivative having a structure in which the nucleoside intermediate is linearly linked is preferentially formed (Patent Document 3). It is a novel finding that the present inventors have found that by optimizing the reaction conditions of the cycloaddition reaction, a cyclic dinucleotide analog having a strained medium ring structure can be formed.
  • Non-Patent Document 3 As an artificial cyclic nucleoside conjugate in which the phosphodiester bond portion of a natural cyclic dinucleotide is substituted with another linking group, the compound described in Non-Patent Document 3 is known. However, in the case of the method for producing a compound described in Non-Patent Document 3, the synthesis process is complicated and the production cost may increase. Monophosphorothioic acid diester bonds can also be hydrolyzed by hydrolases. For this reason, the c-di-GMP analog described in Non-Patent Document 3 may be less stable against hydrolase present in the living body. Furthermore, the monophosphorothioic acid diester bond has substantially the same polarity as the phosphodiester bond.
  • a linking group containing a 1,2,3-triazole ring contained in the cyclic dinucleotide analog of the present invention is not decomposed by a nucleic acid hydrolase, unlike a phosphodiester bond and a monophosphorothioate diester bond.
  • the cyclic dinucleotide analog of the present invention can improve in vivo stability as compared with a natural cyclic dinucleotide.
  • the 1,2,3-triazole ring is uncharged, the linking group containing the 1,2,3-triazole ring has not only high lipid solubility but also low electrostatic interaction. Therefore, the cyclic dinucleotide analog of the present invention can improve cell membrane permeability for binding into a target cell and binding force to a complementary strand, as compared with a natural cyclic dinucleotide.
  • cyclic dinucleotide analogs of the invention comprise Formula (I): It is represented by
  • X a and X b are each independently selected from purine bases and pyrimidine bases.
  • X a and X b are each independently selected from the group consisting of purine nucleobases such as adenine and guanine, and derivatives thereof, and pyrimidine nucleobases such as uracil, cytosine and thymine, and derivatives thereof It is preferable.
  • Y 1 and Y 2 are each independently a divalent group containing a 1,2,3-triazole ring.
  • Y 1 and Y 2 are substituted or unsubstituted linear or branched C 1 -C 6 alkylene, substituted, including 1,2,3-triazole-diyl or 1,2,3-triazole-diyl Or unsubstituted linear or branched C 2 -C 6 alkenylene, substituted or unsubstituted linear or branched C 2 -C 6 alkynylene, substituted or unsubstituted C 3 -C 6 cycloalkylene, Substituted or unsubstituted C 4 -C 6 cycloalkenylene (the alkylene, alkenylene, alkynylene, cycloalkylene and cycloalkenylene have 1 to 3 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom) May be substituted, unsubstituted C
  • the substituent is preferably selected from the substituents listed above.
  • Y 1 and Y 2 are substituted or unsubstituted linear or branched C 1 -C 6 alkylene, including 1,2,3-triazole-diyl, the cyclic dinucleotide analogs of the present invention
  • the distortion of the medium ring structure can be reduced.
  • R a1 and R b1 are each independently hydroxyl or a protected form thereof.
  • Preferred protected forms of hydroxyl are acetyl (Ac), benzoyl (Bz), or silyl such as tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS).
  • Y 1 and Y 2 are each independently the following formulas (YI) to (Y-IV): It is preferably selected from the group consisting of
  • * a shows the binding position of the nucleoside moiety including X a
  • * b shows binding position of a nucleoside moiety comprising X b.
  • Z a and Z b are each independently a divalent hydrocarbon group which may have a direct bond or a hetero atom.
  • Z a and Z b are each independently a direct bond, substituted or unsubstituted linear or branched C 1 -C 6 alkylene, substituted or unsubstituted linear or branched C 2 -C 6 alkenylene, substituted or unsubstituted linear or branched C 2 -C 6 alkynylene, substituted or unsubstituted C 3 -C 6 cycloalkylene, substituted or unsubstituted C 4 -C 6 cycloalkenylene (the above alkylene) , Alkenylene, alkynylene, cycloalkylene and cycloalkenylene may have 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur atoms), substituted or unsubstituted C 6 -C 15 Preferably it is a heterocyclylene, a substituted or
  • the substituent is preferably selected from the substituents listed above.
  • Z a and Z b are each independently a direct bond or a substituted or unsubstituted linear or branched C 1 -C 6 alkylene, the middle ring structure of the cyclic dinucleotide analog of the present invention Can reduce distortion.
  • Z a and Z b are a direct bond when bonded to a nitrogen atom of a 1,2,3-triazole ring, and when bonded to a carbon atom of a 1,2,3-triazole ring.
  • Particularly preferred is methylene. In this case, distortion of the membered ring structure of the cyclic dinucleotide analog of the present invention can be particularly reduced.
  • X a and X b are the same base, and Y 1 is formula (YI) or formula (Y-III) and Y 2 is formula (Y-II) or formula (Y-IV), Alternatively, Y 1 is preferably the formula (Y-II) or the formula (Y-IV) and Y 2 is preferably the formula (YI) or the formula (Y-III).
  • the cyclic dinucleotide analog represented by the formula (I) is a homodimer composed of the same nucleoside moiety.
  • the cyclic dinucleotide analog of the present invention is particularly preferably selected from compounds represented by the following formulae.
  • the cyclic dinucleotide analog of the present invention maintains the structural similarity with the corresponding natural cyclic dinucleotide, and is more stable in vivo than the natural cyclic dinucleotide. Cell membrane permeability and the ability to bind to complementary strands to migrate to can be significantly improved.
  • the cyclic dinucleotide analog of the present invention includes not only the compound itself but also a salt thereof.
  • the counter ion of the salt of the cyclic dinucleotide analog of the present invention is not limited, but includes, for example, cations such as sodium ion, potassium ion, calcium ion or magnesium ion, or chloride ion, bromide ion, formic acid.
  • the cyclic dinucleotide analog of the present invention is in the form of a salt with the counter ion, the stability in vivo, the permeability to the cell membrane for migration into the target cell, and the binding force to the complementary strand are substantially reduced.
  • the compound can be used without it.
  • the cyclic dinucleotide analog of the present invention includes not only the compound itself but also a solvate thereof.
  • Solvents that can form solvates with the cyclic dinucleotide analogs of the present invention are not limited and include, for example, methanol, ethanol, 2-propanol (isopropyl alcohol), dimethyl sulfoxide (DMSO), acetic acid, ethanol Organic solvents such as amines or ethyl acetate, or water are preferred.
  • the cyclic dinucleotide analog of the present invention is in the form of a solvate with the above-mentioned solvent, the stability in vivo, the permeability to the cell membrane for migration into the target cell, and the binding force to the complementary strand are substantially increased.
  • the compound can be used without lowering.
  • the cyclic dinucleotide analog of the present invention includes not only the compound itself but also a protected derivative thereof.
  • Protecting groups that can form a protected derivative of the cyclic dinucleotide analog of the present invention include, but are not limited to, substituted carbamoyl (eg, diphenylcarbamoyl), acetyl (Ac), benzoyl (Bz), silyl ( For example, tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS) or triisopropylsilyl (TIPS)), acetonide, tert-butyl, or trityl are preferred.
  • the cyclic dinucleotide analog of the present invention is in the form of a protected derivative having the above-mentioned protecting group, it is possible to prevent an undesirable reaction from
  • the present invention also relates to a method for producing a cyclic dinucleotide analog.
  • X a , X b , R a1 and R b1 are as defined above.
  • X a , X b , R a1 and R b1 may each independently be a protected form having one or more protecting groups. That is, in the present invention, the compound represented by the formula (Ia) and the compound represented by (Ib) include not only the compound itself but also a protected derivative form thereof.
  • R a2 is an azide and R a3 is ethynyl, or R a2 is ethynyl and R a3 is an azide.
  • R b2 is an azide and R b3 is ethynyl, or R b2 is ethynyl and R b3 is an azide.
  • L a1 and La 2 and L b1 and L b2 are each independently a divalent hydrocarbon group which may have a direct bond or a hetero atom.
  • L a1 and L a2 and L b1 and L b2 are each independently a direct bond, substituted or unsubstituted linear or branched C 1 to C 6 alkylene, substituted or unsubstituted linear or branched.
  • C 2 ⁇ C 6 alkenylene Edakusari substituted or unsubstituted straight or branched C 2 ⁇ C 6 alkynylene, substituted or unsubstituted C 3 ⁇ C 6 cycloalkylene, substituted or unsubstituted C 4 ⁇ C 6 cycloalkenylene (wherein said alkylene, alkenylene, alkynylene, cycloalkylene and cycloalkenylene may have 1 to 3 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom), substituted or non-substituted Preferably it is a substituted C 6 -C 15 heterocyclylene, a substituted or unsubstituted C 6 -C 15 arylene, or a substituted or unsubstituted C 6 -C 15 heteroarylene, directly bonded or substituted or unsubstituted Linear or branched And more preferably of C 1 ⁇ C 6 alkylene.
  • the substituent is preferably selected from the substituents listed above.
  • L a1 and L a2 and L b1 and L b2 are each independently a direct bond or a substituted or unsubstituted linear or branched C 1 -C 6 alkylene, It is possible to reduce distortion of a reaction intermediate formed with a medium ring structure. For this reason, the yield of the resulting cyclic dinucleotide analog can be improved.
  • L a1 and L a2 and L b1 and L b2 are a direct bond when they are bonded to the nitrogen atom of azide contained in R a2 or R a3 or R b2 or R b3 , and the ethynyl carbon atom When it is bonded, methylene is particularly preferable. In this case, distortion of the intermediate intermediate structure reaction intermediate formed in the reaction process of this step can be reduced. For this reason, the yield of the resulting cyclic dinucleotide analog can be improved.
  • La1 is a direct bond
  • Ra2 is an azide
  • La2 is methylene
  • Ra3 is ethynyl
  • L b1 is a direct bond
  • R b2 is azido
  • L b2 is methylene
  • R b3 is ethynyl
  • a ligation reaction in a reaction system containing a compound represented by formula (Ia) and a compound represented by formula (Ib) at a concentration of 1 to 50 mM.
  • concentration of the compound represented by formula (Ia) and the compound represented by formula (Ib) in the reaction system is more preferably in the range of 1 to 25 ⁇ mM, and more preferably in the range of 1 to 10 ⁇ mM. Is particularly preferred, and it is particularly preferred that it is 10 ⁇ m.
  • the concentration means the concentration of the compound at the time when the ligation reaction of the compound represented by the formula (Ia) and the compound represented by the formula (Ib) is started.
  • the compound represented by formula (Ia) and the compound represented by formula (Ib) are preferably subjected to a ligation reaction in a reaction system in the presence of a catalyst.
  • a catalyst include a combination of divalent copper and a reducing agent, a combination of zerovalent copper and divalent copper, a monovalent copper complex, and a ruthenium complex.
  • Examples of combinations of divalent copper and a reducing agent include, for example, a combination of copper sulfate (II) anhydride or hydrate and sodium ascorbate, a combination of copper acetate (II) and sodium ascorbate, copper chloride (II ) And sodium ascorbate, and a combination of copper sulfate anhydride or hydrate and tri (carboxyethyl) phosphine.
  • divalent copper is reduced by the reducing agent to produce monovalent copper in the reaction solution.
  • Examples of monovalent copper complexes include copper halide dimethyl sulfide complexes such as copper bromide dimethyl sulfide complex, and copper halides (I) such as copper bromide (I) and copper iodide (I). it can.
  • Examples of the ruthenium complex include divalent ruthenium complexes such as Ru (OAc) 2 (PPh 3 ) 2 , Cp * RuCl (PPh 3 ) 2 and Cp * RuCl (NBD).
  • a combination of divalent copper and a reducing agent is preferable, and a combination of copper (II) sulfate anhydride or hydrate and sodium ascorbate is more preferable.
  • the compound represented by the formula (Ia) and the compound represented by the formula (Ib) are preferably subjected to a ligation reaction in a reaction system in the presence of a solvent.
  • the solvent is a protic polar organic solvent such as tert-butanol, methanol or 2-propanol, an aprotic polar organic solvent such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile or pyridine, or their A combination is preferred.
  • a protic polar organic solvent such as tert-butanol, methanol or 2-propanol
  • an aprotic polar organic solvent such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile or pyridine, or their A combination is preferred.
  • the compound represented by the formula (Ia) and the compound represented by the formula (Ib) are preferably subjected to a ligation reaction in a reaction system in the presence of a base.
  • the base is preferably tris (benzyltriazolylmethyl) amine (TBTA) or tris (2-benzimidazolylmethyl) amine, more preferably TBTA.
  • the temperature for the ligation reaction between the compound represented by formula (Ia) and the compound represented by formula (Ib) is preferably in the range of 20 to 80 ° C., and in the range of 50 to 60 ° C. More preferably.
  • the reaction time is preferably in the range of 2 to 48 hours, more preferably in the range of 6 to 24 hours.
  • the cyclic dinucleotide analog of the present invention having a structure in which two nucleoside moieties are linked by two linking groups to form a cyclic structure is preferentially formed.
  • this step is performed at a temperature of 50 ° C. or higher, the catalyst described above can be substantially dissolved in the reaction system. For this reason, the yield of the cyclic dinucleotide analog obtained as a result can be improved by implementing this process on the said conditions.
  • the compound represented by the formula (Ia) and the compound represented by the formula (Ib) are the same compound.
  • the cyclic dinucleotide analog formed in this step is a homodimer composed of the same nucleoside moiety.
  • the compound represented by the formula (Ia) and the compound represented by the formula (Ib) used in this step may be prepared by purchasing a previously synthesized compound, for example, Patent Document 3 or You may prepare by synthesize
  • the cyclic dinucleotide analog of the present invention is more stable in vivo than the natural cyclic dinucleotide, while maintaining structural similarity with the corresponding natural cyclic dinucleotide.
  • the cell membrane permeability for transferring into the target cell and the binding force to the complementary strand can be remarkably improved. Therefore, by using the cyclic dinucleotide analog of the present invention and the method for producing the same, a bacterial infection preventive or therapeutic agent against bacteria such as plague, cholera, and salmonella, an immune response activator, an anticancer agent, etc. It becomes possible to provide a new medicine.
  • ⁇ II Synthesis of Triazole-Linked Cyclic Bis (3'-5 ') Diguanylate Derivatives (1)> Guanosine derivative (1) (49.5 mg, 124 ⁇ mol), copper (II) sulfate pentahydrate (3.13 mg, 12.5 ⁇ mol), sodium ascorbate (24.6 mg, 124 ⁇ mol) and tris (benzyltriazolylmethyl) amine (6.56) mg, 12.3 ⁇ mol) of tert-butanol / DMF (volume ratio 1: 2, 13 ml) was stirred at 50 ° C. for 21 hours. Thereafter, the solvent was distilled off from the reaction solution under reduced pressure.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un analogue de nucléotide cyclique artificiel consistant en un analogue d'un dinucléotide cyclique de forme naturelle, et fournit un moyen d'améliorer la stabilité chimique et la lipophilie de cet analogue tout en préservant une similitude de constitution avec sa forme naturelle. Plus précisément, l'invention concerne un analogue de dinucléotide cyclique qui possède : deux parties nucléotide contenant une base purique et une base pyrimidique ; et deux groupes de liaison qui contiennent un cycle 1, 2, 3-triazole, et qui forment une structure cyclique par liaison entre elles des deux parties nucléotide.
PCT/JP2013/085042 2013-01-09 2013-12-27 Analogue de dinucléotide cyclique lié à un triazol WO2014109256A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2014513396A JP6153116B2 (ja) 2013-01-09 2013-12-27 トリアゾール連結型環状ジヌクレオチド類縁体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2013001994 2013-01-09
JP2013-001994 2013-01-09

Publications (1)

Publication Number Publication Date
WO2014109256A1 true WO2014109256A1 (fr) 2014-07-17

Family

ID=51166912

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2013/085042 WO2014109256A1 (fr) 2013-01-09 2013-12-27 Analogue de dinucléotide cyclique lié à un triazol

Country Status (2)

Country Link
JP (1) JP6153116B2 (fr)
WO (1) WO2014109256A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109843302A (zh) * 2016-07-06 2019-06-04 斯必乐维生物科学公司 用于治疗疾病的化合物、组合物和方法
US10519188B2 (en) 2016-03-18 2019-12-31 Immunesensor Therapeutics, Inc. Cyclic di-nucleotide compounds and methods of use
US10980825B2 (en) 2016-12-01 2021-04-20 Takeda Pharmaceutical Company Limited Cyclic dinucleotide
US11542293B2 (en) 2017-11-10 2023-01-03 Takeda Pharmaceutical Company Limited Sting modulator compounds, and methods of making and using
US11725024B2 (en) 2020-11-09 2023-08-15 Takeda Pharmaceutical Company Limited Antibody drug conjugates

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05186495A (ja) * 1991-07-18 1993-07-27 Farmitalia Carlo Erba Spa 環状オリゴヌクレオチドホスホロチオアート
WO2005005450A1 (fr) * 2003-07-15 2005-01-20 Mitsui Chemicals, Inc. Procede de synthese d'un bisdinucleoside cyclique
JP2007500697A (ja) * 2003-07-28 2007-01-18 デイビッド・ケイ・アール・カラオリス 微生物病原体の毒性を減弱させる方法、および微生物のバイオフィルム形成を阻害する方法
WO2008120016A1 (fr) * 2007-03-30 2008-10-09 University Of Southampton Acides nucléiques modifiés

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05186495A (ja) * 1991-07-18 1993-07-27 Farmitalia Carlo Erba Spa 環状オリゴヌクレオチドホスホロチオアート
WO2005005450A1 (fr) * 2003-07-15 2005-01-20 Mitsui Chemicals, Inc. Procede de synthese d'un bisdinucleoside cyclique
JP2007500697A (ja) * 2003-07-28 2007-01-18 デイビッド・ケイ・アール・カラオリス 微生物病原体の毒性を減弱させる方法、および微生物のバイオフィルム形成を阻害する方法
WO2008120016A1 (fr) * 2007-03-30 2008-10-09 University Of Southampton Acides nucléiques modifiés

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
GRAJKOWSKI A. ET AL.: "Convenient Synthesis of a Propargylated Cyclic (3'-5') Diguanylic Acid and Its ''Click'' Conjugation to a Biotinylated Azide", BIOCONJUGATE CHEMISTRY, vol. 21, no. 11, 2010, pages 2147 - 2152 *
HIROYUKI ISOBE ET AL.: "Chemistry of Triazole- Linked Analogue of Nucleic Acids", JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY, vol. 70, no. 8, 2012, JAPAN, pages 821 - 830 *
LIETARD, J. ET AL.: "New Strategies for Cyclization and Bicyclization of Oligonucleotides by Click Chemistry Assisted by Microwaves", JOURNAL OF ORGANIC CHEMISTRY, vol. 73, no. 1, 2008, pages 191 - 200 *
LUO, Y. ET AL.: "Differential binding of 2'- biotinylated analogs of c-di-GMP with c-di-GMP riboswitches and binding proteins", MOLECULAR BIOSYSTEMS, vol. 8, no. 3, 2012, pages 772 - 778 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10519188B2 (en) 2016-03-18 2019-12-31 Immunesensor Therapeutics, Inc. Cyclic di-nucleotide compounds and methods of use
US11299512B2 (en) 2016-03-18 2022-04-12 Immunesensor Therapeutics, Inc. Cyclic di-nucleotide compounds and methods of use
CN109843302A (zh) * 2016-07-06 2019-06-04 斯必乐维生物科学公司 用于治疗疾病的化合物、组合物和方法
US11744845B2 (en) 2016-07-06 2023-09-05 F-star Therapeutics, Inc. Compounds,compositions, and methods for the treatment of disease
US10980825B2 (en) 2016-12-01 2021-04-20 Takeda Pharmaceutical Company Limited Cyclic dinucleotide
US11666594B2 (en) 2016-12-01 2023-06-06 Takeda Pharmaceutical Company Limited Antibody-drug conjugates comprising a cyclic dinucleotide
US12171777B2 (en) 2016-12-01 2024-12-24 Takeda Pharmaceutical Company Limited Methods of making a cyclic dinucleotide
US11542293B2 (en) 2017-11-10 2023-01-03 Takeda Pharmaceutical Company Limited Sting modulator compounds, and methods of making and using
US12054512B2 (en) 2017-11-10 2024-08-06 Takeda Pharmaceutical Company Limited Sting modulator compounds, and methods of making and using
US11725024B2 (en) 2020-11-09 2023-08-15 Takeda Pharmaceutical Company Limited Antibody drug conjugates
US12221460B2 (en) 2020-11-09 2025-02-11 Takeda Pharmaceutical Company Limited Antibody drug conjugates

Also Published As

Publication number Publication date
JPWO2014109256A1 (ja) 2017-01-19
JP6153116B2 (ja) 2017-06-28

Similar Documents

Publication Publication Date Title
JP4923216B2 (ja) 化合物
CN112004928A (zh) 寡核苷酸组合物及其使用方法
JP6153116B2 (ja) トリアゾール連結型環状ジヌクレオチド類縁体
JP2017521398A (ja) 多環式カルバモイルピリドン化合物の合成
JP4966186B2 (ja) 新規ピリミジンヌクレオシド化合物又はその塩
CN101967105A (zh) 具有抗癌活性的β-羟基保护的双癸基季铵盐及制备方法
JP6767011B2 (ja) 抗ｄｎａウィルス活性などの生理活性を有するヌクレオシド誘導体
US11214590B2 (en) Photoresponsive nucleotide analog capable of photocrosslinking in visible light region
WO2022174779A1 (fr) Dérivé nucléotidique ayant une activité antitumorale, composition pharmaceutique et utilisation associée
KR102606167B1 (ko) 불소 함유 치환 벤조티오펜 화합물, 그의 약학적 조성물 및 응용
EP2045258B1 (fr) Dérivé de 3'-éthynylcytidine
JP5075340B2 (ja) ヌクレオシド誘導体
JPH0517920B2 (fr)
CN113563502B (zh) 固载苯醌氧化剂及其制备方法、合成烟酰胺核糖有机酸盐的用途
CN116003394A (zh) 一种酰胺化合物的盐酸盐晶型、药物组合物及用途
CN106336443B (zh) 一类核苷类化合物的合成方法
JP2014189499A (ja) 新規なピリミジンヌクレオシドのシリル誘導体
JP6983814B2 (ja) 抗ウイルス活性を示すヌクレオシド誘導体
JPS6310957B2 (fr)
JP2016135748A (ja) トリアゾール連結型オリゴリボヌクレオチドを含むオリゴリボヌクレオチド類縁体を用いるポリペプチドの製造方法
TWI642680B (zh) 基因表現造影劑前驅物之製造方法
WO2024234619A1 (fr) Forme cristalline d'un composé, composition pharmaceutique et utilisation de celles-ci
WO2010028781A1 (fr) 2'-désoxyguanosines 8- et 6,8-substituées et utilisations de celles-ci
CN118440132A (zh) 一种乳酰化修饰胞苷及其制备方法与应用
CN111153946A (zh) N-叠氮基乙酰-d-甘露糖胺衍生物及其制备方法和在检测硝基还原酶中的应用

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref document number: 2014513396

Country of ref document: JP

Kind code of ref document: A

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13870747

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13870747

Country of ref document: EP

Kind code of ref document: A1