WO2021261444A1 - Ｔｌｒ４作動活性を有するアジュバント - Google Patents

Ｔｌｒ４作動活性を有するアジュバント Download PDF

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Publication number
WO2021261444A1
WO2021261444A1 PCT/JP2021/023402 JP2021023402W WO2021261444A1 WO 2021261444 A1 WO2021261444 A1 WO 2021261444A1 JP 2021023402 W JP2021023402 W JP 2021023402W WO 2021261444 A1 WO2021261444 A1 WO 2021261444A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
compound
oxy
tetradecanoyl
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PCT/JP2021/023402
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English (en)
French (fr)
Japanese (ja)
Inventor
仁志 坂
雄介 今▲崎▼
洋輔 ▲高▼梨
晃久 福島
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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Priority to AU2021295796A priority Critical patent/AU2021295796A1/en
Priority to IL299253A priority patent/IL299253A/en
Priority to CA3187828A priority patent/CA3187828A1/en
Priority to PE2022002961A priority patent/PE20230463A1/es
Priority to CN202180051288.3A priority patent/CN116056721A/zh
Priority to MX2022016181A priority patent/MX2022016181A/es
Priority to US18/011,586 priority patent/US20230287027A1/en
Priority to JP2022531976A priority patent/JPWO2021261444A1/ja
Priority to EP21829834.7A priority patent/EP4169527A4/en
Priority to PH1/2022/553464A priority patent/PH12022553464A1/en
Application filed by Sumitomo Dainippon Pharma Co Ltd filed Critical Sumitomo Dainippon Pharma Co Ltd
Priority to KR1020237001883A priority patent/KR20230026438A/ko
Priority to BR112022025969A priority patent/BR112022025969A2/pt
Publication of WO2021261444A1 publication Critical patent/WO2021261444A1/ja
Priority to SA522441781A priority patent/SA522441781B1/ar
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C07H5/06—Aminosugars
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/248—Colchicine radicals, e.g. colchicosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C07H1/08—Separation; Purification from natural products
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55572—Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a compound useful as a vaccine adjuvant, a method for producing the same, a pharmaceutical composition containing the compound, and use of the compound as a vaccine adjuvant.
  • Vaccines consisting of partial proteins or partial peptides derived from proteins produced by microorganisms can be produced by chemical synthesis or gene recombination technology, and are therefore excellent in terms of vaccine safety and production method.
  • a vaccine tends to have a weaker medicinal effect than a live vaccine or an inactivated vaccine produced from bacterial cells as a raw material, and an adjuvant may be added for the purpose of enhancing immunogenicity.
  • Alum has been widely used as an adjuvant for vaccines, but in recent years, 3-deacylated-4'-monophosphoryl lipid A (MPL), which is an agonist of Toll-like receptor 4 (TLR4), has been used as an adjuvant.
  • MPL 3-deacylated-4'-monophosphoryl lipid A
  • TLR4 Toll-like receptor 4
  • TLR4 forms a heterodimer with MD-2 (myeloid differentiation factor-2) and activates the TLR4 pathway.
  • LPS Lipid polysaccharide
  • Non-Patent Document 2 lipid A structure consisting of a phosphorylated disaccharide and a fatty acid side chain. It has been reported that it plays an important role in heterodimer formation by interacting with both TLR4 and MD-2 (Non-Patent Document 3).
  • the MPL is detoxified from LPS (Non-Patent Document 1), and MPL is a mixture of a plurality of compounds consisting of a phosphorylated disaccharide structure and a fatty acid side chain, similar to LPS (Non-Patent Document 4). .. It is known from the X-ray crystal structure that the phosphate group here interacts with both TLR4 and MD-2 (Non-Patent Document 3), and the activity is greatly attenuated when the phosphate group is removed from Lipid A. It is known to do so (Non-Patent Document 2). Further, the structure of the fatty acid here is also important for the TLR4 agonist activity, and it has been reported that it exhibits an antagonistic action depending on the structure of the fatty acid side chain (Non-Patent Document 2).
  • Patent Documents 1 and 2 Since compounds derived from biological components such as MPL have problems in terms of production, studies on synthetic TLR4 agonists that imitate MPL are being conducted.
  • AGP aminoalkylglucosamine phosphate
  • the phosphorylated disaccharide structure which is the central structure, is converted into a phosphorylated monosaccharide structure, and there is phosphoric acid in AGP.
  • the group is exemplified as an essential structure.
  • the fatty acid side chain structure of AGP has been studied in detail, and it has been reported that the TLR4 agonist activity is lost when the fatty acid is converted as in the case of Lipid A (Non-Patent Document 5).
  • TLR4 agonists having a structure containing a phosphate group such as AGP are considered to be disadvantageous in terms of production cost and stability during storage, but they have a central structure in various studies so far. There is no report of a vaccine adjuvant that does not contain a phosphate group and retains TLR4 agonist activity among TLR4 agonists having sugar and fatty acid side chains.
  • An object of the present invention is to provide a TLR4 agonist having high adjuvant activity even if it does not contain a phosphate group.
  • TLR4 agonist derivative represented by the following formula (1) (hereinafter, may be referred to as “compound of the present invention”) is provided.
  • the present invention is as follows.
  • Equation (1) [During the ceremony, A and A'independently represent hydrogen, hydroxy or-(CH 2 ) m- COOH, where at least one of A or A'represents-(CH 2 ) m- COOH.
  • R 1 represents -C (O) (CH 2 ) n -X or -CH 2- (CH 2 ) n -X.
  • R 2 represents -C (O) (CH 2 ) o -Y or -CH 2- (CH 2 ) o -Y.
  • R 3 represents -C (O) (CH 2 ) p -Z or -CH 2- (CH 2 ) p -Z.
  • X, Y, and Z are independent of methyl, C 6-10 aryl, respectively (the C 6-10 aryl is independent of hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 alkoxy. It may be substituted with 1-5 substituents of choice) or 5-10 membered heteroaryls (the 5-10 membered heteroaryls are hydroxy, C 1-6 alkyl, halogen, cyano, and Represents ( may be substituted with 1 to 4 substituents independently selected from C 1-6 alkoxy), provided that at least one of X, Y or Z is C 6-10 aryl (the said.
  • C 6-10 aryl may be substituted with 1-5 substituents independently selected from hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 alkoxy) or 5– 10-membered heteroaryl (the 5-10-membered heteroaryl is substituted with 1 to 4 substituents independently selected from hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 alkoxy.
  • A is -COOH and the stereochemistry of * is the S configuration
  • Y represents methyl
  • Y represents methyl.
  • R 4 , R 5 , and R 6 each independently represent C 10-20 alkyl.
  • m independently represents an integer of 0 to 6 and represents n, o, and p each independently represent an integer of 5 to 20] or a pharmaceutically acceptable salt thereof.
  • Item 2 The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein m is 0.
  • R 1 is -C (O) (CH 2 ) n -X
  • R 2 is -C (O) (CH 2 ) o -Y
  • R 3 is -C (O) (CH 2 ) p- Item 2.
  • Item 5 The compound according to any one of Items 1 to 3, wherein A is COOH, or a pharmaceutically acceptable salt thereof.
  • Item 5 The compound according to any one of Items 1 to 4, wherein A is COOH and A'is hydroxy, or a pharmaceutically acceptable salt thereof.
  • Item 5 The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 and R 6 are independently C 10-12 alkyl.
  • Equation (2) [During the ceremony, R 1 represents -C (O) (CH 2 ) n -X, R 2 represents -C (O) (CH 2 ) o -Y, R 3 represents -C (O) (CH 2 ) p -Z, X, Y, and Z each independently represent methyl, C 6-10 aryl or 5-10 membered heteroaryl, provided that at least one of X, Y, or Z is C 6-10 aryl or Represents a 5-10 member heteroaryl
  • Y represents methyl
  • R 4 , R 5 and R 6 each independently represent C 10-12 alkyl.
  • n, o, and p each independently represent an integer of 6 to 10], which is the compound according to Item 1 or a pharmaceutically acceptable salt thereof.
  • Equation (3) [During the ceremony, R 1 represents -C (O) (CH 2 ) n -X, R 2 represents -C (O) (CH 2 ) o -Y, R 3 represents -C (O) (CH 2 ) p -Z, X, Y, and Z each independently represent methyl, C 6-10 aryl or 5-10 membered heteroaryl, provided that at least one of X, Y, or Z is C 6-10 aryl or Represents a 5-10 member heteroaryl
  • Y represents methyl
  • n, o, and p each independently represent an integer of 6 to 10]
  • Equation (4) or Equation (5) [During the ceremony, R 1 represents -C (O) (CH 2 ) n -X, R 2 represents -C (O) (CH 2 ) o -Y, R 3 represents -C (O) (CH 2 ) p -Z, R 2 'represents -C (O) (CH 2) o -CH 3, X, Y, and Z each independently represent methyl, C 6-10 aryl or 5-10 membered heteroaryl, provided that, in formula (4), at least one of X, Y, or Z.
  • n, o, and p each independently represent an integer of 7 to 9], which is the compound according to Item 1 or a pharmaceutically acceptable salt thereof.
  • X, Y, and Z are each independently methyl or phenyl, provided that at least one of X, Y, or Z is phenyl, where A is -COOH and * the stereochemistry.
  • Y represents methyl, the compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.
  • Item 11 The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the following compound group: (2R) -2- ⁇ [(3R) -3- (decanoyloxy) tetradecanoyl] amino ⁇ -3- ⁇ [3- ⁇ [(3R) -3- (decanoyloxy) tetradecanoyl] amino ⁇ -5 Hydroxy-6- (hydroxymethyl) -4-( ⁇ (3R) -3-[(9-phenylnonanoyl) oxy] tetradecanoyl ⁇ oxy) oxane-2-yl] oxy ⁇ propanoic acid (Example 1) , (2S) -2- ⁇ [(3R) -3- (decanoyloxy) tetradecanoyl] amino ⁇ -3- ⁇ [3- ⁇ [(3R) -3- (decanoyloxy) tetradecanoyl] amino ⁇ -5 Hydroxy-6- (hydroxymethyl)
  • Item 13 The pharmaceutical composition according to Item 12, which is a lipid preparation.
  • Item 14 The pharmaceutical composition according to Item 12 or 13, wherein the lipid preparation is a liposome preparation containing a phospholipid.
  • Item 12 The pharmaceutical composition according to Item 14, wherein the phospholipid is 1,2-dimyristyl-sn-glycero-3-phosphocholine and egg yolk phosphatidylglycerol.
  • Item 14 or 15 which is a liposome preparation containing one or more additives selected from the group consisting of inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers.
  • additives selected from the group consisting of inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers. The pharmaceutical composition described.
  • Item 17 The pharmaceutical composition according to Item 17, wherein the antigen is a pathogen-derived antigen.
  • a vaccine adjuvant comprising the compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
  • Item 19 The vaccine adjuvant according to Item 19, which is an adjuvant for an infectious disease vaccine.
  • a therapeutic or prophylactic agent for an infectious disease which comprises a compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof, which is used in combination with a pathogen-derived antigen.
  • Item 5 The compound according to any one of Items 1 to 11, or a pharmaceutically acceptable salt thereof, which is used as a vaccine adjuvant.
  • [Item 23] A method for enhancing a specific immune response against an antigen in a mammal, comprising administering to the mammal the compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
  • [Item 25] a) A pharmaceutical composition containing the compound represented by the formula (1) of Item 1 or a pharmaceutically acceptable salt thereof, or the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof; and b) an antigen.
  • Item 25 The kit according to Item 25, wherein the antigen is a pathogen-derived antigen.
  • the compound of the present invention is a compound having TLR4 agonistic activity without introducing a phosphate group on the sugar skeleton by conversion of side chain fatty acid, and is a compound having high adjuvant activity. Since it does not contain a phosphate group on the sugar skeleton, it is highly stable during storage, and since the introduction step of the phosphate group can be omitted, the production cost can be suppressed, which is very useful as a vaccine adjuvant.
  • FIG. 1 is a graph showing the results of ELISA measurement of OVA-specific IgG2c in the serum of immune mice in mice intramuscularly administered with the formulations of Example 6 and Example 7 in Test Example 3.
  • the vertical axis shows the antibody titer of serum OVA-specific IgG2c.
  • the horizontal axis shows the sample administered (the dose in parentheses is the dose administered).
  • FIG. 2 is a graph showing the results of ELISA-measurement of OVA-specific IgG2c in the serum of immune mice in mice intramuscularly administered with the formulations of Reference Example 16 and Example 6 in Test Example 3. The vertical axis shows the antibody titer of serum OVA-specific IgG2c.
  • FIG. 3 is a graph showing the proportion of type 1 helper T cells in the spleen cells of mice intramuscularly administered with the formulations of Example 6 and Example 7 as a result of the evaluation carried out in Test Example 4.
  • the horizontal axis is the same as in FIG. FIG.
  • FIG. 4 is a graph showing the proportion of type 1 helper T cells in the spleen cells of mice intramuscularly administered with the formulations of Reference Example 16 and Example 6 as a result of the evaluation carried out in Test Example 4.
  • the horizontal axis is the same as in FIG.
  • FIG. 5 is a graph showing the ratio of OVA tetramer-positive CD8 T cells in the spleen cells of mice intramuscularly administered with the formulations of Example 6 and Example 7 as a result of the evaluation carried out in Test Example 4.
  • the horizontal axis is the same as in FIG. FIG.
  • FIG. 6 is a graph showing the ratio of OVA tetramer-positive CD8 T cells in the spleen cells of mice intramuscularly administered with the preparations of Reference Example 16 and Example 6 as a result of the evaluation carried out in Test Example 4.
  • the horizontal axis is the same as in FIG.
  • FIG. 7 is a graph showing the ratio of effector memory CD8T cells in the spleen cells of mice intramuscularly administered with the formulations of Example 6 and Example 7 as a result of the evaluation carried out in Test Example 4.
  • the horizontal axis is the same as in FIG. FIG.
  • FIG. 8 is a graph showing the ratio of effector memory CD8T cells in the spleen cells of mice intramuscularly administered with the formulations of Reference Example 16 and Example 6 as a result of the evaluation carried out in Test Example 4.
  • the horizontal axis is the same as in FIG.
  • the number of substituents in the group defined as “may be substituted” or “substituted” is not particularly limited as long as it can be substituted. Unless otherwise indicated, the description of each group also applies when the group is part of another group or a substituent.
  • halogen examples include fluorine, chlorine, bromine, and iodine. Fluorine or chlorine is preferable, and fluorine is more preferable.
  • C 1-6 alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
  • C 1-4 alkyl is preferable, and "C 1-3 alkyl” is more preferable.
  • Specific examples of “C 1-6 alkyl” include, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, 3-methylbutyl, Examples thereof include 2-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl and 1-methylpentyl, and "C.
  • 1-4 alkyl include examples of “C 1-6 alkyl” having 1 to 4 carbon atoms.
  • C 1-3 alkyl include examples of the specific example of “C 1-6 alkyl” having 1 to 3 carbon atoms.
  • C 1-6 alkoxy means “C 1-6 alkyloxy”, and the “C 1-6 alkyl” moiety is synonymous with the above “C 1-6 alkyl”.
  • the "C 1-6 alkoxy” is preferably “C 1-4 alkoxy”, and more preferably “C 1-3 alkoxy”. Specific examples of "C 1-6 alkoxy” include, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, 1-methylpropoxy, 1,1-dimethylethoxy, pentyroxy, 3-methyl.
  • C 10-20 alkyl means a linear or branched saturated hydrocarbon group having 10 to 20 carbon atoms.
  • “C 10-15 alkyl” is preferable, and “C 10-12 alkyl” is more preferable. Even more preferably, linear “C 10-12 alkyl” can be mentioned.
  • Specific examples of the linear “C 10-20 alkyl” include decyl, undecylic, dodecyl, tridecylic, tetradecyl, pentadecylic, hexadecyl, heptadecyl, octadecyl, nonadecyl, and eicocil, and "C 10-15 alkyl".
  • Specific examples of the above include examples of the specific example of "C 10-20 alkyl” having 10 to 15 carbon atoms.
  • Specific examples of "C 10-12 alkyl” include examples of the specific example of "C 10-20 alkyl” having 10 to 12 carbon atoms.
  • C 6-10 aryl means an aromatic hydrocarbon having 6 to 10 carbon atoms. Specific examples of “C 6-10 aryl” include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like. More preferably, phenyl is mentioned.
  • the "5- to 10-membered heteroaryl” is a monocyclic 5- to 7-membered aromatic heterocycle containing 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms. Examples include groups and 2-ring 8- to 10-membered aromatic heterocyclic groups.
  • the "5- to 10-membered heteroaryl” is preferably a "5- to 7-membered heteroaryl", more preferably a 5- to 7-membered aromatic heterocycle having one or more nitrogen atoms in the ring (5-7 membered heteroaryl). "5-7 member nitrogen-containing heteroaryl").
  • pyridyl pyridazinyl, isothiazolyl, pyrrolyl, frill, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl.
  • Specific examples of the "5- to 7-membered heteroaryl” include examples of a single ring in the above-mentioned specific example of the "5- to 10-membered heteroaryl".
  • Specific examples of the "5- to 7-membered nitrogen-containing heteroaryl” include examples of the nitrogen-containing monocycle in the above-mentioned specific example of the "5- to 10-membered heteroaryl”.
  • the C 6-10 aryl in the present invention may be substituted with 1-5 substituents independently selected from hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 alkoxy.
  • the 5- to 10-membered heteroaryl may be substituted with 1 to 4 substituents independently selected from hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 alkoxy.
  • the number of substituents that may be substituted on the C 6-10 aryl and the 5-10 membered heteroaryl is preferably 1 to 3, more preferably 1 to 2, and even more preferably 1. It is one.
  • A, A', R 1 , R 2 , R 2' , R 3 , X, Y, Z, R 4 , R 5 , R. 6 , m, n, o, p, which are preferable, are as follows, but the technical scope of the present invention is not limited to the range of the compounds listed below.
  • Preferred A is hydrogen, hydroxy or-(CH 2 ) m- COOH.
  • A is hydrogen, hydroxy or-(CH 2 ) m- COOH.
  • -(CH 2 ) m -COOH is more preferable, and -COOH is more preferable.
  • Preferred A's include hydrogen, hydroxy or-(CH 2 ) m- COOH. Hydroxy is more preferably mentioned as A'.
  • the combination of A and A' is preferably a combination in which at least one of A or A'is-(CH 2 ) m- COOH. More preferably, the combination of A and A'includes a combination in which A is- (CH 2 ) m-COOH and A'is hydroxy. More preferably, the combination of A and A'includes a combination in which A is -COOH and A'is hydroxy.
  • R 1 examples include -C (O) (CH 2 ) n- X or -CH 2- (CH 2 ) n-X. More preferably, R 1 includes -C (O) (CH 2 ) n- X.
  • R 2 examples include -C (O) (CH 2 ) o- Y or -CH 2- (CH 2 ) o-Y. More preferably, R 2 includes -C (O) (CH 2 ) o- Y.
  • R 2' -C (O) (CH 2 ) o -CH 3 is preferable.
  • R 3 examples include -C (O) (CH 2 ) p- Z or -CH 2- (CH 2 ) p-Z. More preferably, R 3 is -C (O) (CH 2 ) p- Z.
  • X is preferably methyl, C 6-10 aryl (said C 6-10 aryl, hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 1 ⁇ 5 one independently selected from alkoxy It may be substituted with a substituent) or 5-10 membered heteroaryl (the 5-10 membered heteroaryl is independent of hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 alkoxy. It may be substituted with 1 to 4 substituents selected in the above).
  • the X is more preferably methyl or C 6-10aryl , even more preferably methyl or phenyl, and even more preferably phenyl.
  • Y is preferably methyl, C 6-10 aryl (where C 6-10 aryl is 1-5 independently selected from hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 alkoxy. It may be substituted with a substituent) or 5-10 membered heteroaryl (the 5-10 membered heteroaryl is independent of hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 alkoxy. It may be substituted with 1 to 4 substituents selected in the above).
  • Y is more preferably methyl or C 6-10 aryl, even more preferably methyl or phenyl, and even more preferably methyl.
  • Z is preferably methyl, C 6-10 aryl (said C 6-10 aryl, hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 1 ⁇ 5 one independently selected from alkoxy It may be substituted with a substituent) or 5-10 membered heteroaryl (the 5-10 membered heteroaryl is independent of hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 alkoxy. It may be substituted with 1 to 4 substituents selected in the above).
  • Z is more preferably methyl or C 6-10aryl , even more preferably methyl or phenyl, and even more preferably methyl.
  • the combination of X, Y, and Z is preferably at least one of X, Y, or Z with C 6-10 aryl (where C 6-10 aryl is hydroxy, C 1-6 alkyl, halogen, cyano, and C).
  • 1-6 Alkoxy may be substituted with 1-5 substituents independently selected) or 5-10 membered heteroaryls (the 5-10 membered heteroaryls are hydroxy, C1- 6 alkyl, halogen, cyano, and a C 1-6 optionally substituted with 1-4 substituents independently selected from alkoxy), provided that, a is located at a -COOH * stereochemistry
  • Y represents methyl and at least one of X or Z is C 6-10 aryl (the C 6-10 aryl is hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-.
  • 6 Alkoxy may be substituted with 1-5 substituents independently selected) or 5-10 membered heteroaryls (the 5-10 membered heteroaryls are hydroxy, C 1-6 alkyl. , Halogen, cyano, and C 1-6 alkoxy may be substituted with 1 to 4 substituents independently selected). More preferably, as a combination of X, Y, and Z, at least one of X, Y, or Z is a C 6-10 aryl or a 5-10 membered heteroaryl, where A is -COOH *. Examples include combinations in which when the chemistry is in the S configuration, Y represents methyl and at least one of X or Z is a C 6-10 aryl or a 5-10 membered heteroaryl.
  • Y represents methyl when at least one of X, Y, or Z is phenyl, where A is -COOH and the stereochemistry of * is the S configuration.
  • X or Z in which at least one is phenyl.
  • the combination of X, Y, and Z includes a combination in which X is phenyl and Y and Z are methyl.
  • R 4 , R 5 and R 6 are preferably independently C 10-20 alkyl, more preferably C 10-15 alkyl , and even more preferably C 10-12 alkyl. And even more preferably, C 11 alkyl.
  • the m is preferably an integer of 0 to 6, more preferably an integer of 0 to 1, and even more preferably 0.
  • n, o and p are preferably an integer of 5 to 20 independently of each other, more preferably an integer of 6 to 10, still more preferably 7 to 9, and even more preferably. , 8.
  • preferred embodiments of the compound include the following compounds or pharmaceutically acceptable salts thereof.
  • A is hydrogen, hydroxy or-(CH 2 ) m- COOH;
  • A' is hydrogen, hydroxy or-(CH 2 ) m- COOH;
  • R 1 is -C (O) (CH 2 ) n -X or -CH 2- (CH 2 ) n -X;
  • R 2 is -C (O) (CH 2 ) o -Y or -CH 2- (CH 2 ) o -Y;
  • R 3 is -C (O) (CH 2 ) p -Z or -CH 2- (CH 2 ) p -Z;
  • X, Y, and Z are independent of methyl, C 6-10 aryl, respectively (the C 6-10 aryl is independent of hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 alkoxy.
  • C 1-6 alkoxy may be substituted with 1 to 4 substituents independently selected); However, at least one of X, Y or Z is selected independently of C 6-10 aryl (the C 6-10 aryl is selected independently of hydroxy, C 1-6 alkyl, halogen, cyano, and C 1-6 alkoxy.
  • (B) is -COOH; A'is hydroxy; R 1 is -C (O) (CH 2 ) n -X; R 2 is -C (O) (CH 2 ) o -Y; R 3 is -C (O) (CH 2 ) p -Z; X, Y, and Z are each independently methyl, C 6-10 aryl, or 5-10 membered heteroaryl; However, at least one of X, Y or Z is a C 6-10 aryl, or a 5-10 membered heteroaryl, where Y represents methyl when the stereochemistry of * is the S configuration; R 4 , R 5 , or R 6 are each independently an alkyl of C 10-12; n, o and p are each independently an integer of 6-10.
  • a compound or pharmaceutically acceptable salt is
  • One embodiment of the compound represented by the formula (1) includes the following (C).
  • (C) A is -COOH; A'is hydroxy;
  • R 1 is -C (O) (CH 2 ) n -X;
  • R 2 is -C (O) (CH 2 ) o -Y;
  • R 3 is -C (O) (CH 2 ) p -Z;
  • X, Y, and Z are each independently methyl, C 6-10 aryl, or 5-10 membered heteroaryl;
  • at least one of X, Y or Z is a C 6-10 aryl, or a 5-10 membered heteroaryl, where Y represents methyl when the stereochemistry of * is the S configuration;
  • R 4, R 5 or R 6, are each independently a undecyl;
  • n, o and p are each independently an integer of 6-10.
  • a compound or pharmaceutically acceptable salt is
  • (D) is -COOH; A'is hydroxy; R 1 is -C (O) (CH 2 ) n -X; R 2 is -C (O) (CH 2 ) o -Y; R 3 is -C (O) (CH 2 ) p -Z; X, Y, and Z are each independently methyl, C 6-10 aryl, or 5-10 membered heteroaryl; However, at least one of X, Y or Z is a C 6-10 aryl, or a 5-10 membered heteroaryl, where Y represents methyl when the stereochemistry of * is the S configuration; R 4, R 5 or R 6, are each independently a undecyl; n, o and p are each independently an integer of 7-9, A compound or pharmaceutically acceptable salt.
  • One embodiment of the compound represented by the formula (1) includes the following compound group or a pharmaceutically acceptable salt thereof.
  • the method for producing the compound of the present invention will be described below, but the method for producing the compound of the present invention is not limited thereto.
  • the compound of the present invention represented by the formula (1) can be produced, for example, by the following production methods 1 to 3.
  • the compound represented by the formula (1) can be produced, for example, by the following production method.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, A', m are synonymous with item 1, and PA and PA'are independent of hydrogen, respectively.
  • Hydroxy, O-PG 4 or (CH 2 ) m- C (O) O-PG 5 , PG 1 and PG 2 each independently represent an amino protecting group, and PG 3 and PG 4 , Each independently represents a hydroxyl-protecting group, and PG 5 represents a carboxylic acid protecting group.
  • the protecting groups represented by PG 1 , PG 2 , PG 3 , PG 4 , or PG 5 are Protective Groups in Organic Synthesis (by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc.). The protecting group described in 1999) can be used.
  • Compound a1 can be produced, for example, by the method described in WO98 / 50399 and the like.
  • Compounds a2, a5, and a8 can be produced by the production methods 2 and 3 described later.
  • Step 1-1 Compound a3 is produced by reacting compound a1 with compound a2 in the presence of an appropriate condensing agent in an appropriate solvent.
  • the condensing agent is appropriately selected from the reagents exemplified below, and preferably carbodiimides, more preferably 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimidemethiodide. It is preferably used in combination with N, N-dimethyl-4-aminopyridine (DMAP) or 4-pyrrolidinopyridine as an accelerator for the condensation reaction.
  • the solvent used is appropriately selected from the solvents exemplified below, and preferably chloroform and dichloromethane.
  • the reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
  • Step 1-2 Compound a4 is produced by deprotecting the amino protecting group PG 1 of compound a3. This step can be performed according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
  • Step 1-3 Compound a6 is produced by reacting compound a4 with compound a5 in the presence of an appropriate condensing agent in an appropriate solvent.
  • the condensing agent is appropriately selected from the reagents exemplified below, and preferably 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.
  • the solvent used is appropriately selected from the solvents exemplified below, and preferably chloroform and dichloromethane.
  • the reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
  • Step 1-4 Compound a7 is produced by deprotecting the amino protecting group PG 2 of compound a6. This step can be performed according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
  • Step 1-5 Compound a9 is produced by reacting compound a7 with compound a8 by a method according to steps 1-3 described above.
  • Step 1-6 When the compound represented by formula (1) is a protective group PG 3 of the compound a9, comprising OPG 4 and / or C (O) OPG 5 to PA and PA 'are further PG 4 and / or PG 5 Manufactured by deprotecting.
  • This step can be performed according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
  • the condensation with the compounds a2, a5 and a8 may be carried out simultaneously depending on the substituents, or the order may be changed.
  • R 2 and R 3 are the same and R 5 and R 6 are the same
  • the same protecting group can be used for PG 1 and PG 2
  • steps 1-2 as shown below, can be used.
  • Compound a9 can be produced from compound a3 by the two steps of Steps 1-3.
  • the compound a2 described in the production method 1 can be produced, for example, by the following production method when R 1 is ⁇ C (O) (CH 2 ) n ⁇ X in the compound of the formula (1).
  • the compound a5 when R 2 is -C (O) (CH 2 ) o -Y and the compound a8 when R 3 is -C (O) (CH 2 ) p -Z are also manufactured by the same manufacturing method. It is possible.
  • X, R 4, n has the same meaning as in claim 1, j is an integer of 0 ⁇ 18, k is the n-j-2, PG 6 represents a protecting group of a carboxylic acid.
  • Steps 2-1 to 2-3 are methods according to the manufacturing method described in, for example, US2008 / 0188566. Further, steps 2-4 and 2-5 are methods according to, for example, the manufacturing method described in WO2004 / 062599.
  • the compound a2 described in the production method 1 can be produced, for example, by the following production method when R 1 is ⁇ CH 2- (CH 2 ) n ⁇ X in the compound of the formula (1).
  • the compound a5 when R 2 is -CH 2 (CH 2 ) o- Y and the compound a8 when R 3 is -CH 2 (CH 2 ) p- Z can be produced by the same production method.
  • PG 6 represents a protecting group of a carboxylic acid
  • Step 3-1 is a reaction of reducing carboxylic acid to alcohol, and can be produced according to the method described in, for example, Experimental Chemistry Course, Vol. 5, Vol. 14, p11-p16 (edited by The Chemical Society of Japan, 2005). Further, steps 3-2 to 3-4 are methods according to the manufacturing method described in, for example, WO01 / 36433.
  • Compound a2 can also be produced by the method described in Bioorg Med Chem Lett. 2015 Feb 1; 25 (3): 547-53.
  • the base used in each step of each of the above production methods should be selected in a timely manner depending on the reaction, the type of the raw material compound, etc., for example, sodium bicarbonate, alkali bicarbonate such as potassium bicarbonate, sodium carbonate.
  • Alkali carbonates such as potassium carbonate, sodium hydride, metal hydrides such as potassium hydride, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium methoxydo, sodium t-butoxide
  • Alkali metal alkoxides such as, butyl lithium, organic metal bases such as lithium diisopropylamide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0]-.
  • Examples include organic bases such as 7-Undecene (DBU).
  • the condensing agent used in each step of each of the above production methods should be selected in a timely manner depending on the type of the raw material compound and the like, and for example, phosphate esters such as diethyl cyanophosphate and diphenylphosphoryl azide; 1-ethyl-.
  • phosphate esters such as diethyl cyanophosphate and diphenylphosphoryl azide; 1-ethyl-.
  • Carbodiimides such as 3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (WSC ⁇ HCl), dicyclohexylcarbodiimide (DCC), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimidemethiodide; 2 , A combination of disulfides such as 2'-dipyridyl disulfide and phosphines such as triphenylphosphine; phosphorus halides such as N, N'-bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl); azo Combinations of azodicarboxylic acid diesters such as diethyl dicarboxylic acid and phosphine such as triphenylphosphine; 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide;
  • the solvent used in each step of each of the above production methods should be selected in a timely manner depending on the reaction, the type of raw material compound, etc., for example, alcohols such as methanol, ethanol and isopropanol, acetone, methyl ketone and the like. Ketones, halogenated hydrocarbons such as methylene chloride, chloroform, ethers such as tetrahydrofuran (THF), dioxane, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane.
  • alcohols such as methanol, ethanol and isopropanol
  • acetone methyl ketone
  • Ketones halogenated hydrocarbons
  • halogenated hydrocarbons such as methylene chloride, chloroform
  • ethers such as tetrahydrofuran (THF), dioxane
  • aromatic hydrocarbons such as toluene and
  • Esters such as ethyl acetate, propyl acetate, amides such as N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide (DMSO), acetonitrile.
  • DMF N, N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • Dimethyl sulfoxide can be mentioned, and these solvents can be used alone or in combination of two or more. Further, depending on the type of reaction, organic bases or organic acids may be used as a solvent.
  • the intermediate or final product in the above-mentioned production method appropriately converts its functional group, and in particular, extends various side chains from an amino group, a hydroxyl group, a carbonyl group, a halogen group, etc., and the same.
  • Functional group conversion and side chain extension can be performed by common methods commonly used (see, eg, Comprehensive Organic Transformations, R.C. Larock, John Wiley & Sons Inc. (1999), etc.).
  • Examples of the “pharmaceutically acceptable salt” include acid addition salts and base addition salts.
  • an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, or citrate, oxalate, phthalate, etc.
  • examples thereof include organic acid salts such as salts and camphor sulfonates
  • examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt and aluminum salt, or trimethylamine, triethylamine and pyridine.
  • Picolin 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, N, N-dibenzylethylamine and other organic bases.
  • Examples include salts, as well as amino acid salts such as basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.
  • Suitable and pharmaceutically acceptable salts of the starting and target compounds are conventional non-toxic salts, such as organic acid salts (eg, acetates, trifluoroacetates, maleates, fumarates).
  • inorganic acid salts eg hydrochloride, hydrobromide, hydroiodide, etc.
  • Acid addition salts such as sulfates, nitrates or phosphates), salts with amino acids (eg arginine, aspartic acid or glutamate), alkali metal salts (eg sodium or potassium salts) and alkaline earth metal salts.
  • Metallic salts such as (eg calcium salt or magnesium salt), ammonium salts, or organic base salts (eg trimethylamine salt, triethylamine salt, pyridine salt, picolin salt, dicyclohexylamine salt or N, N'-dibenzylethylenediamine salt, etc.) Others, such as, can be appropriately selected by those skilled in the art.
  • the compound of the present invention when it is desired to obtain a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it may be purified as it is, and if it is obtained in the form of a free form, it may be dissolved or suspended in a suitable organic solvent. It may be turbid and an acid or base may be added to form a salt by a usual method. Further, the compound of the present invention and a pharmaceutically acceptable salt thereof may exist in the form of a solvate with water or various solvents, and these adducts are also included in the present invention.
  • the temperature at which the salt is formed is selected from the range from ⁇ 50 ° C. to the boiling point of the solvent, preferably from 0 ° C. to the boiling point of the solvent, and more preferably from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature to near the boiling point of the solvent. When the precipitated salt is collected by filtration, it can be cooled if necessary to improve the yield.
  • the amount of the optically active acid or amine used is preferably in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent with respect to the substrate.
  • the crystals are placed in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, 2-propanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, acetonitrile and the like. It can also be recrystallized from the aproton solvent of No. 1 or a mixed solvent of two or more kinds selected from the above solvents) to obtain a highly pure optically active salt. Further, if necessary, the optically resolved salt can be treated with an acid or a base by a usual method to obtain a free form.
  • an inert solvent for example, an alcohol solvent such as methanol, ethanol, 2-propanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, acetonitrile and the like. It can also be recrystallized from the
  • a deuterium converter obtained by converting any one or two or more H of the compound represented by the formula (1) into 2 H (D) is also included in the compound represented by the formula (1).
  • the present invention includes a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof. Further, solvates such as these hydrates or ethanol solvates are also included. Further, the present invention includes all tautomers of the present invention compound (1), all existing stereoisomers, and crystalline forms of all modes.
  • the compounds (1) of the present invention are optical isomers based on optically active centers, atropisomers based on axial or planar clarities generated by the constraint of intramolecular rotation, other steric isomers, and tectonicity. All possible isomers and mixtures thereof, including these, are included within the scope of the invention, although some are possible, such as isomers and geometric isomers.
  • the mixture of optical isomers of the compound of the present invention can be produced according to a usual method.
  • the manufacturing method include a method using a raw material having an asymmetric point, or a method of introducing an asymmetry in an intermediate stage.
  • optical isomers can be obtained by using an optically active raw material or by performing optical resolution or the like at an appropriate stage in the manufacturing process.
  • an optical division method for example, when the compound represented by the formula (1) or an intermediate thereof has a basic functional group, it is contained in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, 2-propanol or the like).
  • Ether solvent such as diethyl ether, ester solvent such as ethyl acetate, hydrocarbon solvent such as toluene, aproton solvent such as acetonitrile, or a mixed solvent of two or more selected from the above solvents
  • Acids eg, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid, tartrate acid, diisopropyridene tartrate acid such as o-diisopropyridene tartrate acid, dicarboxylic acid such as malic acid, solvent acid such as solvent, solvent and solvent).
  • a diastereomer method for forming a salt using a solvent can be mentioned.
  • an optically active amine for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strikinone
  • optical resolution by forming a salt using an organic amine such as the above.
  • the compound of the present invention represented by the formula (1) or an intermediate thereof can be separated and purified by a method known to those skilled in the art. Examples include extraction, partitioning, reprecipitation, column chromatography (eg, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization. Examples of the recrystallized solvent include an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, an aromatic hydrocarbon solvent such as benzene or toluene, and acetone.
  • an alcohol solvent such as methanol, ethanol or 2-propanol
  • an ether solvent such as diethyl ether
  • an ester solvent such as ethyl acetate
  • aromatic hydrocarbon solvent such as benzene or toluene
  • acetone an aromatic hydrocarbon solvent
  • a ketone solvent, a halogen solvent such as dichloromethane or chloroform, a hydrocarbon solvent such as hexane, an aproton solvent such as dimethylformamide or acetonitrile, water, or a mixed solvent thereof can be used.
  • a halogen solvent such as dichloromethane or chloroform
  • a hydrocarbon solvent such as hexane
  • an aproton solvent such as dimethylformamide or acetonitrile
  • water or a mixed solvent thereof
  • the present invention provides a compound represented by the above-defined formula (1) or a pharmaceutically acceptable salt thereof, which is useful as a vaccine adjuvant, preferably a vaccine adjuvant for an infectious disease vaccine.
  • the present invention also combines a pharmaceutically acceptable diluent or carrier with a pharmaceutical composition comprising the compound represented by the formula (1) defined above or a pharmaceutically acceptable salt thereof (hereinafter referred to as pharmaceutically acceptable salt). ,
  • a pharmaceutical composition comprising the compound represented by the formula (1) defined above or a pharmaceutically acceptable salt thereof (hereinafter referred to as pharmaceutically acceptable salt).
  • pharmaceutically acceptable salt a pharmaceutically acceptable salt thereof
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be used as an adjuvant for maintaining or enhancing the immunostimulatory activity of an active ingredient having immunostimulatory activity. That is, the compound of the present invention or a pharmaceutically acceptable salt thereof has an activity of inducing or enhancing an antigen-specific antibody, specifically, an antigen-specific IgG, and more particularly, a Th1-type antigen-specific IgG (for example, IgG2c). In addition, the compound of the present invention or a pharmaceutically acceptable salt thereof has an activity of increasing cytotoxic T cells (CTL).
  • CTL cytotoxic T cells
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has an activity of inducing CTL in a mammal or an activity of enhancing CTL induction in a mammal.
  • the compounds of the invention or pharmaceutically acceptable salts thereof have the activity of increasing CD4 positive (ie, MHC class II binding) and / or CD8 positive (ie, MHC Class I binding) T cells.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has an activity of increasing antigen-specific T cells.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has an activity of increasing memory T cells, specifically CD8-positive effector memory T cells.
  • an adjuvant compound having a TLR4 agonist activity containing the same number of moles of phosphoric acid structure and having an action of increasing CTL is administered. It has the characteristic that it is about the same as the case where it is used.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has an activity of activating immunocompetent cells.
  • the pharmaceutical composition of the present invention may contain an antigen, and examples of the antigen include tumor antigens and pathogen-derived antigens.
  • the tumor antigen include a tumor antigen protein, a partial peptide derived from the tumor antigen protein, and the like, and a complex of these antigens and a carrier is also included in the category of antigens in the present specification.
  • the pathogen-derived antigen include a pathogen antigen protein such as a virus or a bacterium, a partial peptide derived from the pathogen antigen protein, and the like, and a complex of these antigens and a carrier is also an antigen in the present specification. Is included in the category of.
  • Such complexes include those in which an antigen (including, but not limited to, proteins and peptides) is chemically crosslinked with a protein as a carrier via a linker known to those skilled in the art, and the antigen is a virus-like particle. Examples include those included in (Virus-like Particle; VLP). Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof is useful as a drug for treating or preventing infectious diseases such as viruses or bacteria, or cancer when used in combination with the antigen. In addition, the compound of the present invention or a pharmaceutically acceptable salt thereof is useful as an adjuvant that enhances the therapeutic or preventive effect of an infectious disease such as a virus or a bacterium, or cancer when used in combination with the antigen.
  • an antigen including, but not limited to, proteins and peptides
  • VLP Virus-like Particle
  • the route of administration of the pharmaceutical composition of the present invention includes, for example, parenteral administration, specifically, intravascular (for example, intravenous), subcutaneous, intradermal, intramuscular, nasal, lymph node, and transdermal administration. ..
  • parenteral administration specifically, intravascular (for example, intravenous), subcutaneous, intradermal, intramuscular, nasal, lymph node, and transdermal administration. ..
  • the pharmaceutical composition of the present invention may contain a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
  • Examples of the form of the pharmaceutical composition of the present invention include liquid preparations and the like.
  • liquid preparation of the present invention examples include an aqueous solution preparation or an aqueous suspension, an oily solution preparation or an oily suspension, a lipid preparation, an emulsion preparation and the like.
  • an antigen tumor antigen or pathogen-derived antigen
  • a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is dissolved or dispersed in water. Examples include the above-mentioned preparations.
  • an antigen for example, an antigen (tumor antigen or pathogen-derived antigen) and / or a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is dissolved or dispersed in an oily component.
  • the prepared product can be mentioned.
  • the lipid preparation include a liposome preparation containing an antigen (tumor antigen or pathogen-derived antigen) and / or a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the emulsion preparation for example, a preparation containing an aqueous solution and an oily composition containing an antigen (tumor antigen or pathogen-derived antigen) and / or a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • Additives used in the aqueous solution preparation or aqueous suspension of the present invention include, for example, purified water, water for injection, buffer, pH adjuster, stabilizer, tonicity agent, solubilizer or lysis aid. And so on.
  • Additives used in the oily solution preparation or oily suspension of the present invention include, for example, buffers, pH adjusters, stabilizers, tonicity agents, animal and vegetable fats and oils, hydrocarbons, fatty acids, fatty acid esters. , Solubilizers, solubilizers and the like.
  • the emulsion preparation of the present invention includes an oil-in-water emulsion (also referred to as O / W emulsion), a water-in-oil emulsion (also referred to as W / O emulsion), and an oil-in-water emulsion (W / O / W emulsion). Also referred to as) or an oil-in-water emulsion (also referred to as O / W / O emulsion) in oil can be used.
  • the emulsion preparation of the present invention preferably includes a water-in-oil emulsion (W / O emulsion) or an oil-in-water emulsion (O / W emulsion).
  • an oil-in-water emulsion (O / W emulsion) can be mentioned.
  • the water-in-oil emulsion preparation of the present invention can be produced by emulsifying the aqueous phase and the oil phase by a known method.
  • the antigen (tumor antigen or pathogen-derived antigen) and / or the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is the oil phase and water in the emulsion. It may be contained in either one or both of the phases.
  • the oil-in-water emulsion preparation of the present invention can be produced by emulsifying the aqueous phase and the oil phase by a known method.
  • the antigen tumor antigen or pathogen-derived antigen
  • the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is the oil phase and the aqueous phase in the emulsion. It may be contained in either one or both of the above.
  • the liposome means a microvesicle having an internal phase composed of a lipid multilayer such as a bilayer of an amphipathic lipid molecule (lipid bilayer).
  • lipid bilayer lipid bilayer
  • the lipid multilayer is preferably a lipid bilayer.
  • the liposome preparation of the present invention contains an amphipathic lipid molecule.
  • Amphiphile Lipid Molecule The liposome preparation of the present invention preferably contains one or more "phospholipids".
  • the "phospholipid” include phosphatidylcholine, phosphatidylglycerol, phosphatidylate, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin and the like.
  • Preferred examples of the "phospholipid” include phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, sphingomyelin, and phosphatidylserine. More preferably, the "phospholipid” includes phosphatidylcholine, sphingomyelin, phosphatidylserine, and phosphatidylglycerol.
  • the liposome containing the compound of the present invention can contain sterols.
  • sterols include cholesterol, ⁇ -citosterol, stigmasterol, campesterol, brush castelloll, ergosterol, fucostelloll and the like.
  • Preferable examples of sterols include cholesterol.
  • the liposome containing the compound of the present invention can contain a pharmaceutically acceptable additive.
  • Additives include, for example, inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers.
  • the inorganic acid include phosphoric acid, hydrochloric acid, and sulfuric acid.
  • the inorganic acid salt include sodium hydrogen phosphate, sodium chloride, ammonium sulfate, and magnesium sulfate.
  • the organic acid include citric acid, acetic acid, succinic acid, and tartaric acid.
  • Examples of the organic acid salt include sodium citrate, sodium acetate, disodium succinate, and sodium tartrate.
  • saccharides include glucose, sucrose, mannitol, sorbitol, and trehalose.
  • buffer include L-arginine, L-histidine, tromethamole (trishydroxymethylaminomethane, Tris) and salts thereof.
  • Antioxidants include, for example, sodium sulfite, L-cysteine, sodium thioglycolate, sodium thiosulfate, ascorbic acid, and tocopherol.
  • the polymers include polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, and sodium carboxymethyl cellulose.
  • the compound represented by the formula (1) described in the present specification, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention may be combined with other drugs in addition to the above-mentioned pathogen-derived antigen. Can be used.
  • the pharmaceutical composition of the present invention may further contain other additives, and examples of the additives include surfactants, antioxidants, preservatives, and soothing agents.
  • the compound of formula (1) or a pharmaceutically acceptable salt thereof can be administered simultaneously with the antigenic substance (immunogen) or at a time lag, and the dose thereof is usually about 0.1 ng for warm-blooded animals.
  • Unit doses ranging from / kg to 100 mg / kg, which usually provide effective doses as vaccine adjuvants.
  • Unit dosage forms such as injectables usually contain, for example, 1 ng to 250 mg of active ingredient. Preferably, it is used at a dose in the range of 1 ng to 50 mg / kg per day. However, this daily dose may also need to vary depending on the host receiving treatment, the specific route of administration and the severity of the disease being treated. Therefore, the optimal dose can also be determined by the individual patient or the practitioner treating the warm-blooded animal.
  • treatment is used to include alleviating all or part of any, some or all of the symptoms of a disease, or blocking or delaying the progression of a condition. ..
  • prevention means primary prevention (preventing the onset of the disease) or secondary prevention (after the onset of the disease, preventing recurrence in patients whose symptoms have been alleviated or cured. , Prevention of recurrence).
  • an infectious disease has a stage of infection with a pathogen (bacteria, fungus, protozoan, virus, etc.) and a stage of onset, it includes both prevention of infection with the pathogen and prevention of onset after infection.
  • prevention also includes the meaning of preventing the transmission of pathogens from humans to other mediator organisms.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has an immunoadjugant activity in vitro or in vivo, it is intended to maintain or enhance the immunogenicity of a tumor antigen or a pathogen-derived antigen as a vaccine adjuvant. It is useful for.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has an adjuvant activity of cell-mediated immunity in vitro or in vivo, it maintains the immunogenicity of a tumor antigen or a pathogen-derived antigen as a vaccine adjuvant. Useful for augmentation.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof acts as an immunostimulatory substance (immune stimulator) which is a therapeutic or prophylactic agent for a disease, that is, a substance that induces a tumor antigen or a pathogen-derived antigen-specific immune response. It can be used to maintain or improve.
  • immunostimulatory substance immunostimulatory substance
  • the composition is also an aspect of the present invention.
  • the tumor antigen or pathogen-derived antigen is not particularly limited, but is derived from a tumor-derived antigen protein, a pathogen-derived antigen protein, a tumor-derived antigen peptide derived from the tumor-derived antigen protein, or a pathogen derived from the pathogen-derived antigen protein.
  • examples thereof include antigenic peptides (partial peptides) and complexes of these with carriers.
  • the compound of the invention or a pharmaceutically acceptable salt thereof is administered in combination with a pathogen-derived antigen protein or pathogen-derived antigen peptide for the prevention of an infectious disease to cause an infectious disease. Can be treated or prevented.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered in combination with a pathogen-derived antigen protein or a pathogen-derived antigen peptide for the treatment or prevention of infectious diseases to obtain a therapeutic or preventive effect on infectious diseases. Can be enhanced.
  • infectious disease is not particularly limited, but is, for example, genital tract, vulgaris vulgaris, sole vulgaris, hepatitis B, hepatitis C, simple herpesvirus, infectious soft genus tumor, natural pox, human immunodeficiency.
  • Viral diseases such as virus (HIV), human papillomavirus (HPV), RS virus, norovirus, cytomegalovirus (CMV), varicella herpes virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, parainfluenza; tuberculosis , Mycobacterium abium, bacterial diseases such as Hansen's disease; fungal disease, chlamydia, candida, aspergillus, cryptococcus meningitis, pneumocystis carini, cryptospolidium disease, histoplasmosis, toxoplasmosis, malaria, tripanosoma infection and leashmania It is possible to prevent infections such as diseases.
  • the active ingredient of the infectious disease preventive vaccine is not particularly limited, and examples thereof include substances derived from microorganisms / pathogens such as bacteria, fungi, protozoans, and viruses that cause infectious diseases, and examples thereof include antigen proteins and substances derived from the proteins. Examples thereof include antigenic peptides (partial peptides), polysaccharides, lipids, and combinations thereof, or combinations of substances and carriers derived from the above-mentioned microorganisms / pathogens.
  • the viral antigen peptide derived from the viral antigen is not particularly limited, but for example, influenza matrix protein peptide 58-66 (Jager E et al., Int. J. Cancer 67: 54 (1996)), HPV16 E7 peptide 86. -93 (van Driel WJ et al., Eur. J. Cancer 35: 946 (1999)), HPV E7 peptide 12-20 (Scheibenbogen C et al., J. Immunother 23: 275 (2000)), HPV16 E7 peptide 11-20 (Smith JWI et al., J. Clin. Oncol.
  • the compounds of the invention or pharmaceutically acceptable salts thereof are administered in combination with a tumor antigen protein or tumor antigen peptide for cancer immunotherapy to treat or prevent cancer.
  • a tumor antigen protein or tumor antigen peptide for cancer immunotherapy to treat or prevent cancer.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered in combination with a tumor antigen protein or a tumor antigen peptide for cancer immunotherapy to enhance the therapeutic or preventive effect of cancer.
  • cancer include leukemia, myelodystrophy syndrome, multiple myeloma, malignant lymphoma, gastric cancer, colon cancer, lung cancer, breast cancer, germ cell cancer, liver cancer, skin cancer, bladder cancer, prostate cancer, uterine cancer, and cervical cervix.
  • Cancer ovarian cancer, brain tumor, bone cancer, pancreatic cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, rectal cancer, anal cancer, testis cancer, oviductal carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, External pudendal carcinoma, Hodgkin's disease, non-Hojikin's lymphoma, esophageal cancer, small intestinal cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urinary tract cancer, penis cancer, acute myeloid leukemia, chronic myeloid leukemia , Acute lymphoblastic leukemia, Chronic or acute leukemia including chronic lymphocytic leukemia, Pediatric solid cancer, Lymphocytic lymphoma, Kidney or urinary tract cancer, Renal calcinoma, Central nervous system (CNS) tumor, Primary CNS Lymphoma, tumor neovascularization, spinal tumor, brain stem gliome, pituitary
  • the carrier used in the present invention is a substance that chemically and / or physically binds an antigen protein or an antigen peptide, and examples thereof include proteins and lipids.
  • the carrier is not particularly limited, but is, for example, CRM197 (Vaccine. 2013). Oct 1; 31 (42): 4827-33), KLH (Cancer Immunol Immunother. 2003 Oct; 52 (10): 608-16), virus-like particles (PLoS ONE 5 (3): e9809) and liposomes (J Liposome) Res. 2004; 14 (3-4): 175-89).
  • the antigen protein can be prepared by cloning the cDNA encoding the antigen protein and expressing it in a host cell according to a basic book such as Molecular Cloning 2nd Edt., Cold Spring Harbor Laboratoy Press (1989).
  • the synthesis of the antigenic peptide can be performed according to the method used in ordinary peptide chemistry.
  • the synthesis method is described in the literature (Peptide Synthesis, Interscience, New York, 1966; The Proteins, Vol. 2, Academic Press Inc., New York, 1976) and the like. The method is mentioned.
  • the antigen is not particularly limited as long as it is an antigen that can be used as an active ingredient of a vaccine, but the above-mentioned antigen protein, an antigen peptide (partial peptide) derived from the antigen protein, or the like, and further, these and a carrier. Examples include a complex and the like.
  • a compound represented by the formula (1) for the production of a vaccine vaccine adjuvant, or a pharmaceutically acceptable salt thereof.
  • the use of the compound represented by the above-defined formula (I) or a pharmaceutically acceptable salt thereof as a vaccine adjuvant in the production of a vaccine for the treatment of infectious diseases is used. offer.
  • a step of administering to a patient a compound represented by the above-defined formula (I) or a pharmaceutically acceptable salt thereof together with a tumor-derived antigen or a pathogen-derived antigen is included.
  • it provides a method for treating, preventing or preventing the progression of an infectious disease.
  • treatment and progression of an infectious disease which comprises a step of administering to a patient a compound represented by the above-defined formula (I) or a pharmaceutically acceptable salt thereof together with a pathogen-derived antigen.
  • prevention or preventive measures are provided.
  • Troc 2,2,2-trichloroethoxycarbonyl group
  • TBS tert-butyldimethylsilyl group
  • Bn benzyl group
  • Fmoc 9-fluorenylmethyloxycarbonyl
  • Boc tert-butoxycarbonyl
  • Alko p -Alkoxybenzyl alcohol
  • PEG polyethylene glycol tBu: tert-butyl HBTU: O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphart
  • DIPEA N, N- Diisopropylethylamine
  • DMF N, N-dimethylformamide
  • TFA Trifluoroacetate
  • TIS Triisopropylsilane
  • LCMS liquid chromatographic mass spectrometry
  • reaction solution was extracted with water / ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by concentration was purified by silica gel column chromatography (eluting solvent; hexane: ethyl acetate) to purify the compound (676 mg). ) Was obtained.
  • Reference example 2 (3R) -3-[(9-Phenylnonanoyl) oxy] tetradecanoic acid
  • Zinc powder (672 mg) was added to a solution of the compound (676 mg) of Reference Example 1 in acetic acid (15 mL), and the mixture was stirred at 60 ° C. for 4 hours.
  • the reaction solution was filtered through Celite, and the residue obtained by concentration was purified by silica gel column chromatography (eluting solvent; chloroform: methanol) to obtain the compound (451 mg) of the subject.
  • reaction solution was stirred at room temperature for 18 hours and then extracted with water / chloroform.
  • organic layer was dried over anhydrous magnesium sulfate, and the concentrated residue was purified by silica gel column chromatography (eluting solvent; hexane: ethyl acetate) to obtain the compound Q1 (1.62 g) of the subject.
  • reaction solution was filtered through Celite and extracted with water / ethyl acetate.
  • organic layer was dried over anhydrous magnesium sulfate and concentrated, and the obtained residue was purified by silica gel column chromatography (eluting solvent; hexane: ethyl acetate) to obtain the compound Q3 (114 mg) of the subject.
  • Reference example 5-8 The compounds shown in Table 1 were obtained by reacting and treating with the corresponding raw materials in the same manner as in Reference Example 3 or 4.
  • Example 1 (2R) -2- ⁇ [(3R) -3- (decanoyloxy) tetradecanoyl] amino ⁇ -3- ⁇ [3- ⁇ [(3R) -3- (decanoyloxy) tetradecanoyl] amino ⁇ -5 Hydroxy-6- (hydroxymethyl) -4-( ⁇ (3R) -3-[(9-phenylnonanoyl) oxy] tetradecanoyl ⁇ oxy) oxane-2-yl] oxy ⁇ propanoic acid THF (2 mL) was added to the compound of Reference Example 3 (33 mg) and 10% palladium carbon (25.9 mg), and the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere at 1 atm.
  • reaction mixture was filtered through Celite and concentrated, then THF (1 mL) and TFA (0.1 mL) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was neutralized with an aqueous sodium hydrogen carbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (eluting solvent; chloroform: methanol) to obtain the compound of the subject (5.1 mg).
  • the human TLR4 reporter gene assay HEK-Blue TM hTLR4 cell line (Invivogen) is a stable expression of human TLR4, MD2, CD14 and secretory alkaline phosphatase (SEAP) reporter genes under transcriptional control of NF- ⁇ B response elements. It is a co-transfected cell line. TLR4 expression in this cell line has been tested by RT-PCR, flow cytometry. Stable expression transformants were selected using the antibiotic HEK-Blue TM Selection. TLR signaling leads to NF- ⁇ B translocation and promoter activation results in SEAP gene expression. The cells were incubated with the compounds synthesized in Examples and References at 37 ° C.
  • Mouse TLR4 reporter gene assay HEK-Blue TM mTLR4 cell line (Invivogen) is a stable co-transfected cell line expressing mouse TLR4, MD2, CD14 and secretory SEAP reporter genes under transcriptional control of NF- ⁇ B response elements. It is a stock. TLR4 expression in this cell line has been tested by RT-PCR, flow cytometry. Stable expression transformants were selected using the antibiotic HEK-Blue TM Selection. TLR signaling leads to NF- ⁇ B translocation and promoter activation results in SEAP gene expression. The cells were incubated with the compounds synthesized in Examples and References at 37 ° C.
  • TLR4 specific activation was evaluated.
  • the degree of mouse TLR4 activation of the compounds of the invention was assessed using the mouse TLR4 reporter gene assay to determine the concentration of the compound resulting in half the maximum level of LPS-induced SEAP (EC 50 ).
  • Test Examples 1 and 2 are shown in Tables 5 and 6.
  • the compound of Reference Example 10 was not detected.
  • the compound of Reference Example 10 was not liposomalized and was considered to have been trapped in the extruder membrane.
  • the liposome was diluted 10-fold with purified water, and the average particle size, polydispersity index and zeta potential were measured by a dynamic light scattering method (ZETASIZER Nano-ZS, manufactured by Malvern).
  • ZETASIZER Nano-ZS manufactured by Malvern
  • the formulations of Examples 6 and 7 and Reference Example 16 were quantified by high performance liquid chromatography (HPLC).
  • Ovalbumin (OVA) (2 mg / mL) as an antigen and the preparation prepared in Example 6, Example 7, or Reference 16 in 7-week-old C57BL / 6 male mice (Example 1, Example).
  • An equal volume mixture (100 ⁇ L / mouse) containing 0.2 or 2 mg / mL of the compound of Reference Example 9 was intramuscularly administered to the gastrocnemius muscle for initial immunization.
  • an equal amount of the same mixture was intramuscularly administered to the gastrocnemius muscle for booster immunization.
  • cardiac blood was collected under maintenance of isoflurane inhalation anesthesia, and serum was collected by centrifugation.
  • OVA-specific IgG2c levels in serum were quantified by the following ELISA method. That is, after adding OVA solution (SIGMA) to a 96-well plate, blocking with 1% skim milk (Wako), adding a serum sample diluted with phosphate buffer, and then adding a secondary antibody, goat anti-mouse. After IgG2c (Southern Bio) was added and SureBlue® TMB Micrewell Peroxidase Substrate (KPL) was added, the product of the enzymatic reaction was measured and quantified with a microplate reader. The results are shown in FIGS. 1 and 2. In Example 1, Example 2 and Reference Example 9, significantly stronger OVA-specific IgG2c induction was shown compared to the negative control group.
  • SIGMA OVA solution
  • Wako skim milk
  • KPL SureBlue® TMB Micrewell Peroxidase Substrate
  • Test Example 4 Ovalbumin (OVA) (2 mg / mL) prepared in Test Example 3 and the preparation prepared in Example 6, Example 7, or Reference Example 16 (compounds of Example 1, Example 2 or Reference Example 9 are 0.2. Or, an equal volume mixture (containing 2 mg / mL) (100 ⁇ L / mouse) was administered to the mice to prepare their spleen cells, and OVA and Breferdin A (eBioscience) were added and then cultured overnight.
  • OVA Ovalbumin
  • Cells were harvested, stained with APC-labeled anti-mouse CD3e antibody (invitrogen), PerCP-labeled anti-mouse CD4 antibody (BioLegend) and Fixable Viability Dye eFluor TM 520 (invitorgen), and then fixed with Fixation / Permeabilization buffer (invitrogen). Cells were treated with Permeabilization buffer (invitrogen) and then stained with antibody cocktail BV421-labeled anti-IFN- ⁇ antibody (BioLegend), PE-Cy7-labeled anti-IL-2 antibody (eBioscience) and PE-labeled TNF- ⁇ (BioLegend).
  • the above spleen cells were subjected to V450-labeled anti-mouse CD3e antibody (invitrogen), Alexa Fluor® 647-labeled anti-mouse CD8 antibody (MBL), PE-Cy7-labeled anti-mouse CD44 antibody (invitrogen), PerCP-Cy5. Stained with 5-labeled anti-mouse CD62L antibody (invitrogen) and Fixable Viability dye eFluor 520 (invitrogen). Data acquisition and analysis were performed using FACS Cant II (BD Biosciences) and FLOWJO software (TreeStar). The results are shown in FIGS. 7 and 8.
  • Example 1 The compounds of Example 1, Example 2 and Reference Example 9 were OVA-specific type 1 helper T cells, especially the proportion of OVA-specific multifunctional CD4-positive T lymphocytes and MHC-restricted OVA-specific CD8-positive T lymphocytes ( The proportion of OVA tetramer-positive CD8 T cells in FIGS. 5 and 6 and the proportion of CD8-positive effector memory T lymphocytes were significantly increased compared to the negative control group.
  • the compound of the present invention is useful as an adjuvant that enhances the immunostimulatory action of a vaccine preparation.

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CA3187828A1 (en) 2021-12-30
US20230287027A1 (en) 2023-09-14
JPWO2021261444A1 (https=) 2021-12-30
IL299253A (en) 2023-02-01
EP4169527A1 (en) 2023-04-26
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