WO2021060336A1 - 新規な架橋アルギン酸構造体 - Google Patents

新規な架橋アルギン酸構造体 Download PDF

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WO2021060336A1
WO2021060336A1 PCT/JP2020/035932 JP2020035932W WO2021060336A1 WO 2021060336 A1 WO2021060336 A1 WO 2021060336A1 JP 2020035932 W JP2020035932 W JP 2020035932W WO 2021060336 A1 WO2021060336 A1 WO 2021060336A1
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formula
group
alginic acid
alkyl group
alkyl
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French (fr)
Japanese (ja)
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古迫　正司
智裕 鳴海
佐藤　勉
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Mochida Pharmaceutical Co Ltd
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Mochida Pharmaceutical Co Ltd
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Priority to CN202080066960.1A priority Critical patent/CN114521199B/zh
Priority to US17/763,071 priority patent/US12479933B2/en
Priority to CN202510595751.0A priority patent/CN120463977A/zh
Priority to JP2021548963A priority patent/JP7692359B2/ja
Priority to EP20870420.5A priority patent/EP4035735A4/en
Publication of WO2021060336A1 publication Critical patent/WO2021060336A1/ja
Anticipated expiration legal-status Critical
Priority to JP2025091584A priority patent/JP2025131662A/ja
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    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
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    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
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    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/145—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M3/00—Tissue, human, animal or plant cell, or virus culture apparatus
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/04—Alginic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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    • C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
    • C08J2405/04—Alginic acid; Derivatives thereof

Definitions

  • the present invention relates to a novel crosslinked alginic acid, an alginic acid derivative for forming the crosslinked alginic acid, and the like.
  • Alginic acid is a bioabsorbable polysaccharide extracted from brown algae such as Lessonia, Macrocystis, Laminaria, Ascophyllum, Derbilia, Ecklonia cava, Arame, and Kombu, and is D-mannuronic acid (M) and L-glulon. It is a polymer in which two types of uronic acid called acid (G) are linearly polymerized. More specifically, the homopolymer fraction of D-mannuronic acid (MM fraction), the homopolymer fraction of L-glulonic acid (GG fraction), and D-mannuronic acid and L-gluuronic acid are randomly arranged. It is a block copolymer in which the obtained fractions (M / G fractions) are arbitrarily bonded. Alginic acid is used in a wide range of fields such as food, medicine, cosmetics, textiles, and papermaking.
  • Alginate alkali metal salts of alginate eg, sodium alginate, etc.
  • alginate alkaline earth metal salts of divalent salt eg, calcium alginate, etc.
  • Gels insolubilizes. That is, by adding an aqueous solution containing divalent metal ions (for example, calcium ion, barium ion, etc.) to an aqueous solution of alginic acid, an alginic acid gel (ion cross-linking) in which a three-dimensional network structure is formed through ionic cross-linking. Alginic acid) is obtained.
  • divalent metal ions for example, calcium ion, barium ion, etc.
  • the alginate gel has a gel structure easily because the divalent metal ions forming the ion crosslinks are captured in the gel by the presence of a chelating agent such as ethylenediaminetetraacetic acid (EDTA). Is known to break and return to alginic acid.
  • EDTA ethylenediaminetetraacetic acid
  • Non-Patent Documents 4 to 10 Non-Patent Documents 1 and 2.
  • alginic acid derivatives (alginic acid derivatives represented by the formulas (I) and (II) described later) into which a predetermined cross-linking group has been introduced.
  • Cross-linked alginic acid and cross-linked alginic acid structure (beads / dye-containing beads) were molded, and it was found that the beads had high stability and a gel having substance permeability, and the present invention was completed. I arrived. That is, the present invention is as follows.
  • the alginic acid derivative represented by the formula (I) and the alginic acid derivative represented by the formula (II) represented by the following embodiments a novel crosslinked alginic acid obtained by carrying out a Michael addition reaction using these, and the alginic acid.
  • a crosslinked alginic acid structure obtained by subjecting a gel obtained by dropping a derivative into a divalent metal ion-containing solution to a Michael addition reaction, and a method for producing the alginic acid derivative, the crosslinked alginic acid, and the crosslinked alginic acid structure.
  • an exemplary embodiment may be as follows [1] to [27].
  • the chemical crosslink is expressed by the following formula (LK-1): Wherein (LK-1), the ends -CONH- and -NHCO -, - L 1 -, and -L 2 - are as defined in the eighth aspect described below is a structure, The crosslinked alginic acid according to the above [1].
  • the crosslinked alginic acid according to the above [1] is produced, which comprises adding a solution of the alginic acid derivative represented by the formula (I) to the solution of the alginic acid derivative represented by the formula (II) and carrying out a cross-linking reaction.
  • the crosslinked alginic acid according to the above [1] is produced, which comprises adding a solution of the alginic acid derivative represented by the formula (II) to the solution of the alginic acid derivative represented by the formula (I) and carrying out a cross-linking reaction.
  • the chemical cross-linking formed by carrying out the Michael addition reaction using the alginic acid derivative represented by the formula (I) and the alginic acid derivative represented by the formula (II) is represented by the following formula (LK-1): Wherein (LK-1), the ends -CONH- and -NHCO -, - L 1 -, and -L 2 - are as defined in the aspects of the 11 described below is a structure, The method for producing crosslinked alginic acid according to the above [1].
  • a gel obtained by dropping a solution of an alginic acid derivative represented by the formula (I) into a solution containing divalent metal ions is subjected to a crosslinking reaction in a solution of the alginic acid derivative represented by the formula (II).
  • a crosslinked alginic acid structure comprising an ionic crosslink partially formed by divalent metal ions as a crosslink and a chemical crosslink formed by a Michael addition reaction.
  • a gel obtained by dropping a solution of an alginic acid derivative represented by the formula (II) into a solution containing divalent metal ions is subjected to a crosslinking reaction in a solution of the alginic acid derivative represented by the formula (I).
  • a crosslinked alginic acid structure comprising an ionic crosslink partially formed by divalent metal ions as a crosslink and a chemical crosslink formed by a Michael addition reaction.
  • a solution of a composition containing an alginic acid derivative represented by the formula (I) and an alginic acid derivative represented by the formula (II) is added dropwise into a solution containing a divalent metal ion, and is obtained as a divalent bridge.
  • a cross-linked alginic acid structure comprising an ionic cross-linking partially formed by metal ions and a chemical cross-linking formed by a Michael addition reaction.
  • the chemical cross-linking formed by carrying out the Michael addition reaction using the alginic acid derivative represented by the formula (I) and the alginic acid derivative represented by the formula (II) is represented by the following formula (LK-1): Wherein (LK-1), the ends -CONH- and -NHCO -, - L 1 -, and -L 2 - are as defined in the fifteenth aspect described below is a structure, The crosslinked alginic acid structure according to any one of the above [12] to [14].
  • the medical material according to [17] above which is a fibrous structure, fibers, beads, gel, or a substantially spherical gel.
  • a crosslinked alginic acid structure comprising dropping a solution of a composition containing an alginic acid derivative represented by the formula (I) and an alginic acid derivative represented by the formula (II) into a solution containing a divalent metal ion. How to manufacture.
  • a gel obtained by dropping a solution of an alginic acid derivative represented by the formula (I) into a solution containing divalent metal ions is subjected to a crosslinking reaction in a solution of the alginic acid derivative represented by the formula (II).
  • a method for producing a crosslinked alginic acid structure which comprises obtaining a crosslinked alginic acid structure, which comprises an ion crosslink partially formed by a divalent metal ion as a crosslink and a chemical crosslink formed by a Michael addition reaction.
  • a gel obtained by dropping a solution of an alginic acid derivative represented by the formula (II) into a solution containing divalent metal ions is subjected to a crosslinking reaction in a solution of the alginic acid derivative represented by the formula (I).
  • a method for producing a crosslinked alginic acid structure which comprises obtaining a crosslinked alginic acid structure, which comprises an ion crosslink partially formed by a divalent metal ion as a crosslink and a chemical crosslink formed by a Michael addition reaction.
  • the chemical cross-linking formed by carrying out the Michael addition reaction using the alginic acid derivative represented by the formula (I) and the alginic acid derivative represented by the formula (II) is represented by the following formula (LK-1): Wherein (LK-1), the ends -CONH- and -NHCO -, - L 1 -, and -L 2 - are as defined in the aspects of the 23 to be described later is a structure, The method for producing a crosslinked alginic acid structure according to any one of [20] to [22].
  • the alginic acid derivative represented by the formula (I) and the alginic acid derivative represented by the formula (II) are obtained by ionic cross-linking with a divalent metal ion and chemical cross-linking by a Michael addition reaction, and have a retention property of the contents.
  • Cross-linked alginate structure
  • the present invention comprises a novel cross-linked alginic acid, a cross-linked alginic acid structure, a novel alginic acid and a novel alginic acid derivative that can be used to form the cross-linked alginic acid structure, and an intermediate for producing the derivative (the present invention).
  • Amino compounds) and the like are provided.
  • the crosslinked alginic acid and the alginic acid derivative as a raw material are expected to be safe for living organisms.
  • the cross-linking reaction with the alginic acid derivative of the present invention is completed under mild conditions by the Michael addition reaction, so that it can be used safely and easily.
  • the cross-linked alginic acid of some embodiments is chemically cross-linked by the Michael addition reaction.
  • the cross-linked alginic acid of the present invention can be used in combination with a chemical cross-linking and further cross-linking methods, for example, cross-linking using divalent metal ions using calcium ions, and its stability is adjusted by adjusting the reaction conditions. Is improved as compared with non-crosslinked alginic acid (eg, monovalent sodium salt of alginic acid) or non-chemically crosslinked alginic acid (eg, calcium ion crosslinked crosslinked alginic acid). Further, in some embodiments, the gel physical properties of the crosslinked product can be adjusted, and the substance permeability can also be adjusted. The present invention has at least one or more of these effects.
  • a chemical cross-linking and further cross-linking methods for example, cross-linking using divalent metal ions using calcium ions, and its stability is adjusted by adjusting the reaction conditions. Is improved as compared with non-crosslinked alginic acid (eg, monovalent sodium salt of alginic acid) or non-chemically crosslinked al
  • the first aspect is as follows.
  • Alginic acid derivative represented by the formula (I) The following formula (I): (In formula (I), (ALG) represents alginic acid; -NHCO- represents an amide bond via any carboxyl group of alginic acid; -L 1- represents the following partial structural formula [both ends in each formula.
  • a and R b are each independently a hydrogen atom, C 1 ⁇ 6 alkyl group, a group selected from C 2 ⁇ 7 alkanoyl group, or a C 1 ⁇ 6 alkylsulfonyl group), guanidino C 1 ⁇ 6 alkyl group, C 7 ⁇ 16 aralkyl group, a hydroxy C 6 ⁇ 10 aryl C 1 ⁇ 6 alkyl group, or a plurality by a group selected from heteroaryl C 1 ⁇ 6 alkyl group (e.g., 1 to 10, or 1 ⁇ 5) may be replaced;
  • Formula (L1-1) the same methylene group in ⁇ formula (L1-4) (-CH 2 -) if the two hydrogen atoms is replaced by C 1 - 6 alkyl group bonded to the alkyl group to each other It may form a C 3 ⁇ 8 cycloalkyl ring;
  • the -NH- group in formulas (L1-3) and (L1-4) may form
  • a and R b are each independently a hydrogen atom, C 1 ⁇ 6 alkyl group, a group selected from C 2 ⁇ 7 alkanoyl group, or a C 1 ⁇ 6 alkylsulfonyl group), guanidino C 1 ⁇ 6 alkyl group, C 7 ⁇ 16 aralkyl group, a hydroxy C 6 ⁇ 10 aryl C 1 ⁇ 6 alkyl group, or a plurality by a group selected from heteroaryl C 1 ⁇ 6 alkyl group (e.g., 1 to 10, or 1 ⁇ 5) may be replaced;
  • Formula (L2-1) the same methylene group in ⁇ formula (L2-6) (-CH 2 -) if the two hydrogen atoms is replaced by C 1 - 6 alkyl group bonded to the alkyl group to each other It may form a C 3 ⁇ 8 cycloalkyl ring;
  • the -NH- group in formulas (L2-3) to (L2-6) may form a
  • an amide bond (-NH-CO- or -CO) that binds to (ALG) in the formula (-NH-CO- or -CO).
  • -CO- of -NH-) is a carbonyl group derived from carboxy of alginic acid.
  • each group in the sub-mode [1] shall be the same as the definition of each group in the mode [1].
  • C 6 ⁇ 10 aryl group for example, phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, or 1,2,3,4-tetrahydronaphthyl, Etc. can be mentioned.
  • heterocyclic group examples include a “heteroaryl group” and a “non-aromatic heterocyclic group”.
  • the "heteroaryl group” contains 1 to 5, preferably 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, sulfur atoms, and oxygen atoms. , 5-14 members, preferably 5-8 members, of monocyclic, polycyclic or fused ring type (however, in the case of polycyclic type or fused ring type, it may be partially hydrogenated). More preferably, it means a 5- to 7-membered heteroaryl ring.
  • heteroaryl group in the present specification includes, for example, a “monocyclic heteroaryl group”, a “condensed heteroaryl group”, and a “partially hydrogenated condensed ring”.
  • heteroaryl group and the like.
  • the "monocyclic heteroaryl group” is a monocyclic heteroaryl group described above, and has 5 to 8 ring members and 5 to 6 ring members. Is preferred (“5-6-membered heteroaryl group”).
  • the "5- to 6-membered heteroaryl group” is a 5- to 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • the term "5- to 6-membered heteroaryl group” means a monovalent group formed by removing an arbitrary hydrogen atom from the heteroaryl ring, unless otherwise specified.
  • the "5- to 6-membered heteroaryl group" in the present specification includes, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1, 2,3- Triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, frazayl, 1,2,3-thiadiazolyl, 1,2,4- Thiasiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazineyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 2H-1,2, 3-Thiadiazinyl, 4H-1,2,4-Th
  • the "5-membered heteroaryl group” is a 5-membered heteroaryl ring containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • the "5-membered heteroaryl group” means a monovalent group formed by removing an arbitrary hydrogen atom from the heteroaryl ring unless otherwise specified, and for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, and the like.
  • the "6-membered heteroaryl group” is a 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • the "6-membered heteroaryl group” means a monovalent group formed by removing an arbitrary hydrogen atom from the heteroaryl ring unless otherwise specified.
  • pyridyl (pyridinyl), pyridadinyl, pyrimidinyl, pyrazineyl, 1 , 2,3-Triazinyl, 1,2,4-Triazinyl, 1,3,5-Triazinyl, 2H-1,2,3-Thiadiadinyl, 4H-1,2,4-Thiadiadinyl, 6H-1,3,4 Groups such as-thiadiazinyl, pyridazine-3 (2H) -one, pyrimidine-2 (1H) -one, pyrazine-2 (1H) -one, or pyridine-2 (1H) -one can be mentioned.
  • the "5- to 6-membered heteroaryl C 1 ⁇ 6 alkyl group”, the “5- to 6-membered heteroaryl group” is substituted with the "C 1 ⁇ 6 alkyl group” Means a group, eg, pyrrolylmethyl, furylmethyl, thienylmethyl, imidazolylmethyl, pyrazolylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, 1,2,3-triazolylmethyl, 1,2,4-triazolylmethyl, 1,2,3-oxadiazolylmethyl, 1,2,4-oxadiazolylmethyl, 1,3,4-oxadiazolylmethyl, frazaylmethyl, 1,2, 3-Thiadiazolylmethyl, 1,2,4-thiadiazolylmethyl, 1,3,4-thiadiazolylmethyl, tetrazolylmethyl, pyridylmethyl, pyridadinylmethyl, pyr
  • the "partially hydrogenated fused heteroaryl group” is a condensation formed by condensing a "heterocyclic group” and an "aryl group” or a “heterocyclic group” and a “heteroaryl group”.
  • a ring it means a monovalent group formed by removing an arbitrary hydrogen atom from a partially hydrogenated fused ring.
  • the arbitrary hydrogen atom is excluded from either the hydrogen atom of the "heterocyclic group", the "aryl group” or the “heteroaryl group” in the fused ring, or the hydrogen atom of the hydrogenated ring portion.
  • the quinoline is a partially hydrogenated tetrahydroquinolyl, 5,6,7,8-tetrahydroquinolyl, 1,2,3,4-tetrahydroquinolyl and the like can be mentioned.
  • These groups are -2-yl, -3-yl, -4-yl, -5-yl, depending on the position except for any hydrogen atom, for example, 5,6,7,8-tetrahydroquinolyl. , -6-yl, -7-yl, -8-yl, etc., and 1,2,3,4-tetrahydroquinolyl, for example, -1-yl, -2-yl, -3-yl, etc.
  • Il, -4-il, -5-il, -6-il, -7-il, -8-il and the like are exemplified.
  • the "partially hydrogenated fused ring heteroaryl group” preferably has 8 to 12 ring members, that is, as a “partially hydrogenated 8- to 12-membered condensed heteroaryl group".
  • non-aromatic heterocyclic group means a “3 to 14-membered saturated or unsaturated non-aromatic heterocyclic group”.
  • 3 to 14-membered saturated or unsaturated non-aromatic heterocyclic group refers to 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom. It means a monovalent group formed by removing an arbitrary hydrogen atom from a saturated or unsaturated heterocycle containing 3 to 14 members.
  • non-aromatic heterocyclic group in the present specification includes, for example, aziridinyl, azetidinyl, oxylanyl, thiyranyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, thiolanyl, pyrazolinyl, pyrazoridinyl, and the like.
  • Imidazolidinyl piperidinyl, dihydropyranyl, tetrahydropyranyl (2-tetrahydro-2H-pyranyl, 3-tetrahydro-2H-pyranyl, 4-tetrahydro-2H-pyranyl (4-tetrahydro-2H-pyran-4-yl group)) , Tetrahydrothiopyranyl, piperazinyl, dioxanyl, oxazolidinyl, isoxazolinyl, 1,3-oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, 1,3-thiazolidinyl, isothiazolidinyl, oxadiazolinyl, 1,3 Groups such as 4-oxadiazolidinyl, morpholinyl, thiomorpholinyl, quinucridinyl, azepanyl, diazepinyl, oxepanyl and
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • halogenation in “halogenated C 1 to 6 alkyl groups” and the like means several, preferably 1 to 5 "halogen atoms" as substituents. Means to have.
  • C 1-6 alkyl groups in the present specification include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and the like. Alternatively, a group such as hexyl, etc. can be mentioned.
  • halogenated C 1 to 6 alkyl group is optionally substituted with the above “C 1 to 6 alkyl” with several, preferably 1 to 5 halogen atoms.
  • Groups such as fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, or pentafluoroethyl, etc. Can be mentioned.
  • the "C 1 to 6 alkoxy group” represents an alkoxy in which the "C 1 to 6 alkyl” is bonded to an oxygen atom, and for example, methoxy, ethoxy, propoxy, and isopropoxy. , Butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, or hexyloxy, and the like.
  • the "-NR a R b group” means a group in which two hydrogen atoms on the nitrogen atom of the "amino group" are substituted with -R a and -R b. To do.
  • Ra and R b are independently selected from a hydrogen atom, a C 1 to 6 alkyl group, a C 2 to 7 alkanoyl group, or a C 1 to 6 alkyl sulfonyl group, respectively.
  • the "C 2 to 7 alkanoyl group” means a “C 1 to 6 alkyl carbonyl group” in which a carbonyl group is bonded to the "C 1 to 6 alkyl group”.
  • groups such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyle, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropylmethylcarbonyl, or 2-methylcyclopropylcarbonyl.
  • groups such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyle, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopent
  • C 1 ⁇ 6 alkylsulfonyl group means a group substituted in,
  • groups such as methyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl and the like can be mentioned.
  • cyclic ether refers to a cyclic hydrocarbon (for example, a cyclic hydrocarbon having 3 to 8 carbon atoms among monocyclic or polycyclic saturated hydrocarbon ring groups.
  • a (C 3 ⁇ 8 cycloalkyl ring) means cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentane, ethers carbon has a structure substituted with an oxygen cyclooctane etc.), for example, epoxides, oxetanes , Tetrahydrofuran, tetrahydropyran, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, 1,3-dioxepan, 1,4-dioxepan, 1,4-dioxocan, or 1,5-dioxocan, etc. Cyclic ether can be mentioned.
  • the term "3-N- (C 2 ⁇ 7 alkanoyl) oxazolidine ring" a hydrogen atom of the NH group of the oxazolidine ring is replaced with the "C 2 ⁇ 7 alkanoyl group” It means a ring, and examples thereof include a 3-N-acetyl-oxazolidine ring, a 3-N-ethylcarbonyl-oxazolidine ring, and the like.
  • the term "4-N- (C 2 ⁇ 7 alkanoyl) morpholine ring” is a hydrogen atom NH groups morpholine ring substituted on the "C 2 ⁇ 7 alkanoyl group" It means a ring, and examples thereof include a 4-N-acetyl-morpholine ring, a 4-N-ethylcarbonyl-morpholine ring, and the like.
  • 4-N- (C 2 to 7 alkanoyl) -1,4-oxazepan ring means that the hydrogen atom of the NH group of the 1,4-oxazepan ring is the above-mentioned "C”. It means a ring substituted with "2 to 7 alkanoyl group”, and examples thereof include a 4-N-acetyl-1,4-oxazepan ring, a 4-N-ethylcarbonyl-1,4-oxazepan ring, and the like. ..
  • the "3-N- (C 1 to 6 alkyl sulfonyl) oxazolidine ring” means that the hydrogen atom of the NH group of the oxazolidine ring becomes the "C 1 to 6 alkyl sulfonyl group". It means a substituted ring, and means a substituted group, and examples thereof include a 3-N-methanesulfonyl-oxazolidine ring, a 3-N-ethylsulfonyl-oxazolidine ring, and the like.
  • the "4-N- (C 1 to 6 alkyl sulfonyl) morpholine ring” means that the hydrogen atom of the NH group of the morpholine ring becomes the "C 1 to 6 alkyl sulfonyl group". It means a substituted ring, and examples thereof include a 4-N-methanesulfonyl-morpholine ring, a 4-N-ethylsulfonyl-morpholine ring, and the like.
  • 4-N- (C 2 to 7 alkanoyl) -1,4-oxazepan ring means that the hydrogen atom of the NH group of the 1,4-oxazepan ring is the above-mentioned "C”. It means a ring substituted with "1 to 6 alkylsulfonyl groups", for example, a ring such as 4-N-methanesulfonyl-1,4-oxazepan ring, 4-N-ethylsulfonyl-1,4-oxazepan ring, etc. Can be mentioned.
  • hydroxy C 1 to 6 alkyl group means that any hydrogen atom of the "C 1 to 6 alkyl” is optionally substituted with 1 to 5 hydroxyl groups.
  • the "thiol C 1 to 6 alkyl group” is a thiol group (-SH group) in which the above “C 1 to 6 alkyl” is several, preferably 1 to 5 thiol groups. It means a group arbitrarily substituted with, and examples thereof include groups such as thiolmethyl, 2-thiolethyl, or 3-thiolpropyl.
  • C 1 to 6 alkylthio C 1 to 6 alkyl group refers to the hydrogen atom of the thiol group (-SH group) of the "thiol C 1 to 6 alkyl group”.
  • C 1 to 6 alkyl groups and examples thereof include groups such as methyl thiomethyl, methyl thioethyl, ethyl thiomethyl, or ethyl thioethyl.
  • the "-COO (C 1 to 6 alkyl) group” is a group in which the hydrogen atom of the “carboxy group” is substituted with the C 1 to 6 alkyl group.
  • R a R b N C 1 to 6 alkyl group
  • the "C 7 to 16 aralkyl group” means that any hydrogen atom of the "C 1 to 6 alkyl group” is replaced with the "C 6 to 10 aryl group”.
  • Group means, for example, benzyl group, phenethyl group, diphenylmethyl group, trityl group, biphenylmethyl group, naphthylmethyl group, indanylmethyl group, or 1,2,3,4-tetrahydronaphthalene-1-ylmethyl group, Etc. can be mentioned.
  • hydroxy C 6 to 10 aryl C 1 to 6 alkyl group refers to the hydrogen atom of the "C 6 to 10 aryl group” of the "C 7 to 16 aralkyl group”. It means a group arbitrarily substituted with several, preferably 1 to 5 hydroxyl groups, and examples thereof include groups such as a 2-hydroxybenzyl group, a 3-hydroxybenzyl group, or a 4-hydroxybenzyl group. Be done.
  • the "heteroaryl C 1 to 6 alkyl group” is a group in which any hydrogen atom of the “heteroaryl group” is substituted with the "C 1 to 6 alkyl group”.
  • a group such as a 2-pyridylmethyl group, a 4-imidazolylmethyl group, or a 3-indrylmethyl group can be mentioned.
  • non-aromatic heterocycle means a “3 to 14-membered saturated or unsaturated non-aromatic heterocycle”.
  • the "3 to 14-membered saturated or unsaturated non-aromatic heterocycle” contains 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms. It means a saturated or unsaturated heterocycle having 3 to 14 members.
  • non-aromatic heterocycle in the present specification includes, for example, aziridine, azetidine, pyrrolidine, pyrazolidine, oxazolidine, thiazolidine isooxazolidine, isothiazolidine, imidazolidine, piperidine, piperidine, morpholine, thio. Rings such as morpholine, oxazepan, diazepan, thiazepan, oxazocan, diazocan, thiazocan, or oxazine can be mentioned.
  • C3 to 8 cycloalkyl ring means a cyclic saturated hydrocarbon ring (including monocyclic or polycyclic) having 3 to 8 carbon atoms.
  • cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentane, or cyclooctane, isocycles can be mentioned.
  • a and R b are each independently a hydrogen atom, C 1 ⁇ 6 alkyl group, a group selected from C 2 ⁇ 7 alkanoyl group, or a C 1 ⁇ 6 alkylsulfonyl group), guanidino C 1 ⁇ 6 alkyl group, C 7 ⁇ 16 aralkyl group, a hydroxy C 6 ⁇ 10 aryl C 1 ⁇ 6 alkyl group, or a plurality by a group selected from heteroaryl C 1 ⁇ 6 alkyl group (e.g., 1 to 10, or 1 ⁇ 5) may be replaced;
  • Formula (L1-1) the same methylene group in ⁇ formula (L1-3) (-CH 2 -) if the two hydrogen atoms is replaced by C 1 - 6 alkyl group bonded to the alkyl group to each other It may form a C 3 ⁇ 8 cycloalkyl ring;
  • the -NH- group in formula (L1-3) may form a non-aromatic
  • -L 1- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]:
  • a and R b are each independently a hydrogen atom, C 1 ⁇ 6 alkyl group, a group selected from C 2 ⁇ 7 alkanoyl group, or a C 1 ⁇ 6 alkylsulfonyl group), guanidino C 1 ⁇ 6 alkyl group, C 7 ⁇ 16 aralkyl group, a hydroxy C 6 ⁇ 10 aryl C 1 ⁇ 6 alkyl group, or a plurality by a group selected from heteroaryl C 1 ⁇ 6 alkyl group (e.g., 1-5) is replaced May; n is an integer from 1 to 9; m is an integer from 1 to 5; j is a linker selected from the group consisting of (integer 0-5);
  • -L 1- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: (Methylene group in the formula (L1-1) ⁇ formula (L1-3) (-CH 2 - hydrogen atoms) include a halogen atom, a hydroxyl group, C 1 ⁇ 6 alkyl group, hydroxy C 1 ⁇ 6 alkyl group, - COOH group, -COOM group (M is, Li, Na, K, or 1 / 2Ca), - COO ( C 1 ⁇ 6 alkyl) group, or more groups selected from C 7 ⁇ 16 aralkyl group May be replaced (eg 1-3); n is an integer of 1 to 3; m is an integer of 1 to 3; j is a linker selected from the group consisting of (integer 0-2);
  • -L 1- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: A linker selected from the group consisting of;
  • -L 1- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: It is a linker selected from the group consisting of.
  • -L 2- is preferably the following partial structural formula [in each formula, the outside of the broken lines at both ends is not included]:
  • 1 to 10 or 1 to 5) may be replaced;
  • the -NH- group in formulas (L2-3), formula (L2-5) and formula (L2-6) may form a non-aromatic heterocycle with a substituent attached to an adjacent carbon atom.
  • n2 is an integer from 1 to 18
  • m3 is an integer from 1 to 10
  • n3 is an integer from 1 to 10
  • j2 is a linker selected from the group consisting of (integer
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]:
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken lines at both ends is not included]:
  • the RA groups are independently hydrogen atom, halogen atom, hydroxyl group, C 1 to 6 alkyl group, and hydroxy C 1 to 6.
  • n2 is an integer from 1 to 5
  • m3 is an integer from 1 to 3
  • n3 is an integer from 1 to 4
  • j2 is a linker selected from the group consisting of (integer 0 to 3);
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: A linker selected from the group consisting of;
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]:
  • the -NH- group in formula (L2-3), formula (L2-4), formula (L2-5) and formula (L2-6) is a non-aromatic heterocycle with a substituent attached to an adjacent carbon atom. Rings may be formed; n2 is an integer from 1 to 18; m3 is an integer from 1 to 10; n3 is an integer
  • R a and R b are independently selected from hydrogen atom, C 1 to 6 alkyl group, C 2 to 7 alkanoyl group, or C 1 to 6 alkyl sulfonyl group), guanidino C 1 to 6 alkyl group, C 7 ⁇ 16 aralkyl group, a hydroxy C 6 ⁇ 10 aryl C 1 ⁇ 6 alkyl group, or a plurality by a group selected from heteroaryl C 1 ⁇ 6 alkyl group (e.g., 1 to 10, or 1-5) may be replaced; n2 is an integer from 1 to 9; m3 is an integer from 1 to 6; n3 is an integer from 1 to 6; j2 is a linker selected from the group consisting of (integer 0-6);
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken lines at both ends is not included]:
  • the RA groups are independently hydrogen atom, halogen atom, hydroxyl group, C 1 to 6 alkyl group, and hydroxy C 1 to 6.
  • n2 is an integer from 1 to 5
  • m3 is an integer from 1 to 3
  • n3 is an integer from 1 to 4
  • j2 is a linker selected from the group consisting of (integer 0 to 3);
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: A linker selected from the group consisting of;
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: It is a linker selected from the group consisting of.
  • -L 2- is preferably the following partial structural formula [in each formula, the outside of the broken lines at both ends is not included]:
  • the -NH- group in formula (L2-3), formula (L2-4), formula (L2-5) and formula (L2-6) is a non-aromatic heterocycle with a substituent attached to an adjacent carbon atom. Rings may be formed; n2 is an integer from 1 to 18; m3 is an integer from 1 to 10; n3 is an integer
  • the -NH- group in formula (L2-3), formula (L2-4), formula (L2-5) and formula (L2-6) is a non-aromatic heterocycle with a substituent attached to an adjacent carbon atom. Rings may be formed; n2 is an integer from 1 to 9; m3 is an integer from 1 to 6; n3 is an integer from 1 to 6; j2 is a linker selected from the group consisting of (integer 0-6);
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken lines at both ends is not included]: (In the formula (L2-3-1), the formula (L2-4-1), the formula (L2-5-1) and the formula (L2-6-1), the RA groups are independently hydrogen atoms.
  • Halogen atom hydroxyl group, C 1-6 alkyl group, hydroxy C 1-6 alkyl group, -COOH group, -COOM group (M is Li, Na, K, or 1 / 2Ca), -COO (C 1-6 alkyl) group, or a group selected from C 7 ⁇ 16 aralkyl group;
  • M is Li, Na, K, or 1 / 2Ca
  • -COO (C 1-6 alkyl) group or a group selected from C 7 ⁇ 16 aralkyl group
  • the -NH- group in the formula (L2-3-1), the formula (L2-4-1), the formula (L2-5-1) and the formula (L2-6-1) is bonded to an adjacent carbon atom.
  • a non-aromatic heterocycle may be formed with the substituents to be used; n2 is an integer from 1 to 5; m3 is an integer from 1 to 3; n3 is an integer from 1 to 4; j2 is a linker selected from the group consisting of (integer 0 to 3);
  • the RA groups are independently hydrogen atom, halogen atom, hydroxyl group and C. 1 to 6 alkyl groups, hydroxy C 1 to 6 alkyl groups, -COOH groups, -COOM groups (M is Li, Na, K, or 1 / 2Ca), -COO (C 1 to 6 alkyl) groups, or C 7 A group selected from ⁇ 16 aralkyl groups; n2 is an integer from 1 to 5; m3 is an integer from 1 to 3; n3 is an integer from 1 to 4; j2 is an integer from 0 to 3; k is an integer from 1 to 4) and is a linker selected from the group consisting of;
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: A linker selected from the group consisting of;
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: It is a linker selected from the group consisting of.
  • a and R b are each independently a hydrogen atom, C 1 ⁇ 6 alkyl group, a group selected from C 2 ⁇ 7 alkanoyl group, or a C 1 ⁇ 6 alkylsulfonyl group), guanidino C 1 ⁇ 6 alkyl group, C 7 ⁇ 16 aralkyl group, a hydroxy C 6 ⁇ 10 aryl C 1 ⁇ 6 alkyl group, or a plurality by a group selected from heteroaryl C 1 ⁇ 6 alkyl group (e.g., 1 to 10, or 1 ⁇ 5) may be replaced;
  • Formula (L1-1) the same methylene group in ⁇ formula (L1-4) (-CH 2 -) if the two hydrogen atoms is replaced by C 1 - 6 alkyl group bonded to the alkyl group to each other It may form a C 3 ⁇ 8 cycloalkyl ring;
  • the -NH- group in formulas (L1-3) and (L1-4) may form
  • a and R b are each independently a hydrogen atom, C 1 ⁇ 6 alkyl group, a group selected from C 2 ⁇ 7 alkanoyl group, or a C 1 ⁇ 6 alkylsulfonyl group), guanidino C 1 ⁇ 6 alkyl group, C 7 ⁇ 16 aralkyl group, a hydroxy C 6 ⁇ 10 aryl C 1 ⁇ 6 alkyl group, or a plurality by a group selected from heteroaryl C 1 ⁇ 6 alkyl group (e.g., 1 to 10, or 1 ⁇ 5) may be replaced;
  • Formula (L1-1) the same methylene group in ⁇ formula (L1-3) (-CH 2 -) if the two hydrogen atoms is replaced by C 1 - 6 alkyl group bonded to the alkyl group to each other It may form a C 3 ⁇ 8 cycloalkyl ring;
  • the -NH- group in formula (L1-3) may form a non-aromatic
  • -L 1- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]:
  • a and R b are each independently a hydrogen atom, C 1 ⁇ 6 alkyl group, a group selected from C 2 ⁇ 7 alkanoyl group, or a C 1 ⁇ 6 alkylsulfonyl group), guanidino C 1 ⁇ 6 alkyl group, C 7 ⁇ 16 aralkyl group, a hydroxy C 6 ⁇ 10 aryl C 1 ⁇ 6 alkyl group, or a plurality by a group selected from heteroaryl C 1 ⁇ 6 alkyl group (e.g., 1-5) is replaced May; n is an integer from 1 to 9; m is an integer from 1 to 5; j is a linker selected from the group consisting of (integer 0-5);
  • -L 1- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: (Methylene group in the formula (L1-1) ⁇ formula (L1-3) (-CH 2 - hydrogen atoms) include a halogen atom, a hydroxyl group, C 1 ⁇ 6 alkyl group, hydroxy C 1 ⁇ 6 alkyl group, - COOH group, -COOM group (M is, Li, Na, K, or 1 / 2Ca), - COO ( C 1 ⁇ 6 alkyl) group, or more groups selected from C 7 ⁇ 16 aralkyl group May be replaced (eg 1-3); n is an integer of 1 to 3; m is an integer of 1 to 3; j is a linker selected from the group consisting of (integer 0-2);
  • -L 1- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: A linker selected from the group consisting of;
  • -L 1- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: It is a linker selected from the group consisting of.
  • Equation (BR-1) (In the formula (BR-1), -L 1- is the same as the definition in the above aspect [1] or [2]), the introduction rate of the group represented by the above is 1% to 30%.
  • the fourth aspect is as follows.
  • the alginic acid derivative according to the above [2], wherein the weight average molecular weight of the alginic acid derivative represented by the formula (I) is 100,000 Da to 3 million Da measured by a gel filtration chromatography method.
  • the fifth aspect is as follows.
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken lines at both ends is not included]:
  • a and R b are each independently a hydrogen atom, C 1 ⁇ 6 alkyl group, a group selected from C 2 ⁇ 7 alkanoyl group, or a C 1 ⁇ 6 alkylsulfonyl group), guanidino C 1 ⁇ 6 alkyl group, C 7 ⁇ 16 aralkyl group, a hydroxy C 6 ⁇ 10 aryl C 1 ⁇ 6 alkyl group, or a plurality by a group selected from heteroaryl C 1 ⁇ 6 alkyl group (e.g., 1 to 10, or 1 ⁇ 5) may be replaced;
  • Formula (L2-1) the same methylene group in ⁇ formula (L2-6) (-CH 2 -) if the two hydrogen atoms is replaced by C 1 - 6 alkyl group bonded to the alkyl group to each other It may form a C 3 ⁇ 8 cycloalkyl ring;
  • the -NH- group in formulas (L2-3) to (L2-6) may form a
  • -L 2 - is represented by the following partial structural formula [in each formula does not include the dashed outer ends:
  • 1 to 10 or 1 to 5) may be replaced;
  • the -NH- group in formulas (L2-3), formula (L2-5) and formula (L2-6) may form a non-aromatic heterocycle with a substituent attached to an adjacent carbon atom.
  • n2 is an integer from 1 to 18
  • m3 is an integer from 1 to 10
  • n3 is an integer from 1 to 10
  • j2 is a linker selected from the group consisting of (integer
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]:
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken lines at both ends is not included]:
  • the RA groups are independently hydrogen atom, halogen atom, hydroxyl group, C 1 to 6 alkyl group, and hydroxy C 1 to 6.
  • n2 is an integer from 1 to 5
  • m3 is an integer from 1 to 3
  • n3 is an integer from 1 to 4
  • j2 is a linker selected from the group consisting of (integer 0 to 3);
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: A linker selected from the group consisting of;
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: It is a linker selected from the group consisting of.
  • the -NH- group in formula (L2-3), formula (L2-4), formula (L2-5) and formula (L2-6) is a non-aromatic heterocycle with a substituent attached to an adjacent carbon atom. Rings may be formed; n2 is an integer from 1 to 18; m3 is an integer from 1 to 10; n3 is an integer
  • a and R b are each independently a hydrogen atom, C 1 ⁇ 6 alkyl group, a group selected from C 2 ⁇ 7 alkanoyl group, or a C 1 ⁇ 6 alkylsulfonyl group), guanidino C 1 ⁇ 6 alkyl group, C 7 ⁇ 16 aralkyl group, a hydroxy C 6 ⁇ 10 aryl C 1 ⁇ 6 alkyl group, or a plurality by a group selected from heteroaryl C 1 ⁇ 6 alkyl group (e.g., 1 to 10, or 1 ⁇ 5) may be replaced; n2 is an integer from 1 to 9; m3 is an integer from 1 to 6; n3 is an integer from 1 to 6; j2 is a linker selected from the group consisting of (integer 0-6);
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken lines at both ends is not included]:
  • the RA groups are independently hydrogen atom, halogen atom, hydroxyl group, C 1 to 6 alkyl group, and hydroxy C 1 to 6.
  • n2 is an integer from 1 to 5
  • m3 is an integer from 1 to 3
  • n3 is an integer from 1 to 4
  • j2 is a linker selected from the group consisting of (integer 0 to 3);
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: A linker selected from the group consisting of;
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: It is a linker selected from the group consisting of.
  • the -NH- group in formula (L2-3), formula (L2-4), formula (L2-5) and formula (L2-6) is a non-aromatic heterocycle with a substituent attached to an adjacent carbon atom. Rings may be formed; n2 is an integer from 1 to 18; m3 is an integer from 1 to 10; n3 is an integer
  • the -NH- group in formula (L2-3), formula (L2-4), formula (L2-5) and formula (L2-6) is a non-aromatic heterocycle with a substituent attached to an adjacent carbon atom. Rings may be formed; n2 is an integer from 1 to 9; m3 is an integer from 1 to 6; n3 is an integer from 1 to 6; j2 is a linker selected from the group consisting of (integer 0-6);
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken lines at both ends is not included]: (In the formula (L2-3-1), the formula (L2-4-1), the formula (L2-5-1) and the formula (L2-6-1), the RA groups are independently hydrogen atoms.
  • Halogen atom hydroxyl group, C 1-6 alkyl group, hydroxy C 1-6 alkyl group, -COOH group, -COOM group (M is Li, Na, K, or 1 / 2Ca), -COO (C 1-6 alkyl) group, or a group selected from C 7 ⁇ 16 aralkyl group;
  • M is Li, Na, K, or 1 / 2Ca
  • -COO (C 1-6 alkyl) group or a group selected from C 7 ⁇ 16 aralkyl group
  • the -NH- group in the formula (L2-3-1), the formula (L2-4-1), the formula (L2-5-1) and the formula (L2-6-1) is bonded to an adjacent carbon atom.
  • a non-aromatic heterocycle may be formed with the substituents to be used; n2 is an integer from 1 to 5; m3 is an integer from 1 to 3; n3 is an integer from 1 to 4; j2 is a linker selected from the group consisting of (integer 0 to 3);
  • the RA groups are independently hydrogen atom, halogen atom, hydroxyl group and C. 1 to 6 alkyl groups, hydroxy C 1 to 6 alkyl groups, -COOH groups, -COOM groups (M is Li, Na, K, or 1 / 2Ca), -COO (C 1 to 6 alkyl) groups, or C 7 A group selected from ⁇ 16 aralkyl groups; n2 is an integer from 1 to 5; m3 is an integer from 1 to 3; n3 is an integer from 1 to 4; j2 is an integer from 0 to 3; k is an integer from 1 to 4) and is a linker selected from the group consisting of;
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: A linker selected from the group consisting of;
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: It is a linker selected from the group consisting of.
  • P 1 is preferably a hydrogen atom, an acetyl group or a benzoyl group.
  • P 1 is preferably a hydrogen atom, an acetyl group or a benzoyl group, and more preferably a hydrogen atom or a benzoyl group.
  • the 6-1 aspect is as follows.
  • the sixth-2 aspect is as follows.
  • the 7-1th aspect is as follows.
  • the seventh-second aspect is as follows.
  • the eighth aspect is as follows.
  • the chemical crosslink is expressed by the following formula (LK-1): [In the formula (LK-1), -CONH- and -NHCO- at both ends represent amide bonds via any carboxyl group of alginic acid; -L 1- and -L 2- are the above-mentioned embodiments [1]. ]
  • the crosslinked alginic acid according to the above [1] which has the same structure as the definition in [1].
  • the 8-2 aspect is as follows.
  • preferred, more preferred, more preferred, particularly preferred or most preferred linker -L 2 - are as defined in the aspect [5-1].
  • the eighth-third aspect is as follows.
  • preferred, more preferred, more preferred, particularly preferred or most preferred linker -L 2 - are as defined in the aspects [5-1a].
  • the eighth-4th aspect is as follows.
  • preferred, more preferred, more preferred, particularly preferred, most preferred or even most preferred linker -L 2 - are as defined in the aspects [5-1b].
  • the eighth aspect is as follows.
  • the ninth aspect is as follows.
  • the tenth aspect is as follows.
  • the eleventh aspect is as follows.
  • the chemical cross-linking formed by carrying out the Michael addition reaction using the alginic acid derivative represented by the formula (I) and the alginic acid derivative represented by the formula (II) is represented by the following formula (LK-1): [In the formula (LK-1), -CONH- and -NHCO- at both ends represent an amide bond via any carboxyl group of alginic acid; -L 1- and -L 2- are the above-mentioned embodiments [1]. ]
  • the method for producing the crosslinked alginic acid according to the above [1] which has the same structure as the definition in [1].
  • the twelfth aspect is as follows.
  • a gel obtained by dropping a solution of an alginic acid derivative represented by the formula (I) into a solution containing divalent metal ions is subjected to a crosslinking reaction in a solution of the alginic acid derivative represented by the formula (II).
  • a cross-linked alginic acid structure comprising an ion cross-link formed partially by divalent metal ions as a cross-link and a chemical cross-link formed by a Michael addition reaction.
  • the thirteenth aspect is as follows.
  • a gel obtained by dropping a solution of an alginic acid derivative represented by the formula (II) into a solution containing divalent metal ions is subjected to a crosslinking reaction in a solution of the alginic acid derivative represented by the formula (I).
  • a cross-linked alginic acid structure comprising an ion cross-link formed partially by divalent metal ions as a cross-link and a chemical cross-link formed by a Michael addition reaction.
  • the fourteenth aspect is as follows.
  • a solution of a composition containing an alginic acid derivative represented by the formula (I) and an alginic acid derivative represented by the formula (II) is added dropwise into a solution containing divalent metal ions, which is obtained by divalent metal ions as a bridge.
  • a cross-linked alginic acid structure comprising a partially formed ionic cross-link and a chemical cross-linking formed by a Michael addition reaction.
  • the fifteenth aspect is as follows.
  • the chemical cross-linking formed by carrying out the Michael addition reaction using the alginic acid derivative represented by the formula (I) and the alginic acid derivative represented by the formula (II) is represented by the following formula (LK-1): [In the formula (LK-1), -CONH- and -NHCO- at both ends represent an amide bond via any carboxyl group of alginic acid; -L 1- and -L 2- are the above-mentioned embodiments [1]. ]
  • the crosslinked alginic acid structure according to any one of [12] to [14], which has the same structure as the definition in [12].
  • the 15-1 aspect is as follows.
  • preferred, more preferred, more preferred, particularly preferred or most preferred linker -L 1 - is the same as the definition of the aspect [2-1].
  • the aspect of the first 15-2 is as follows.
  • preferred, more preferred, more preferred, particularly preferred or most preferred linker -L 2 - are as defined in the aspect [5-1].
  • the sixteenth aspect is as follows.
  • the seventeenth aspect is as follows. A medical material containing the crosslinked alginic acid structure according to any one of the aspects [12] to [16].
  • the eighteenth aspect is as follows.
  • the medical material according to aspect [17] above which is a fibrous structure, a fiber, beads, a gel, or a substantially spherical gel.
  • the 19th aspect is as follows.
  • the 19-1 aspect is as follows. A composition containing an alginic acid derivative represented by the formula (I) and an alginic acid derivative represented by the formula (II-P).
  • the 19-2 aspect is as follows.
  • a crosslinked alginic acid structure is produced, which comprises dropping a solution of a composition containing an alginic acid derivative represented by the formula (I) and an alginic acid derivative represented by the formula (II) into a solution containing a divalent metal ion. Method.
  • the 21st aspect is as follows.
  • a gel obtained by dropping a solution of an alginic acid derivative represented by the formula (I) into a solution containing divalent metal ions is subjected to a crosslinking reaction in a solution of the alginic acid derivative represented by the formula (II).
  • a method for producing a crosslinked alginic acid structure which comprises obtaining a crosslinked alginic acid structure comprising an ion crosslink partially formed by a divalent metal ion as a crosslink and a chemical crosslink formed by a Michael addition reaction.
  • the 22nd aspect is as follows.
  • a gel obtained by dropping a solution of an alginic acid derivative represented by the formula (II) into a solution containing divalent metal ions is subjected to a crosslinking reaction in a solution of the alginic acid derivative represented by the formula (I).
  • a method for producing a crosslinked alginic acid structure which comprises obtaining a crosslinked alginic acid structure comprising an ion crosslink partially formed by a divalent metal ion as a crosslink and a chemical crosslink formed by a Michael addition reaction.
  • the 23rd aspect is as follows.
  • the chemical cross-linking formed by carrying out the Michael addition reaction using the alginic acid derivative represented by the formula (I) and the alginic acid derivative represented by the formula (II) is represented by the following formula (LK-1): [In the formula (LK-1), -CONH- and -NHCO- at both ends represent an amide bond via any carboxyl group of alginic acid; -L 1- and -L 2- are the above-mentioned aspects [1]. ]
  • the 24th aspect is as follows.
  • a crosslinked alginic acid structure having content retention obtained by ionic cross-linking with a divalent metal ion and chemical cross-linking by a Michael addition reaction between an alginic acid derivative represented by the formula (I) and an alginic acid derivative represented by the formula (II). body.
  • the 25th aspect is as follows.
  • the 26a aspect is as follows.
  • the 27th aspect is as follows.
  • a non-aromatic heterocycle may be formed with a substituent attached to a carbon atom; n2 is an integer from 1 to 9; m3 is an integer from 1 to 6; n3 is an integer from 1 to 6; j2 is a linker selected from the group consisting of (integer 0-6);
  • -L 2- is the following partial structural formula [in each formula, the outside of the broken lines at both ends is not included]: (In the formula (L2-3-1), the formula (L2-4-1), the formula (L2-5-1) and the formula (L2-6-1), the RA groups are independently hydrogen atoms.
  • halogen atom hydroxyl group, C 1 ⁇ 6 alkyl group, hydroxy C 1 ⁇ 6 alkyl group, -COOH group, -COOM group (M is Li, Na, K, or 1 / 2Ca), or C 7 ⁇ 16 aralkyl group Is a group selected from;
  • M is Li, Na, K, or 1 / 2Ca
  • the -NH- group in the formula (L2-3-1), the formula (L2-4-1), the formula (L2-5-1) and the formula (L2-6-1) is bonded to an adjacent carbon atom.
  • a non-aromatic heterocycle may be formed with the substituents to be used; n2 is an integer from 1 to 5; m3 is an integer from 1 to 3; n3 is an integer from 1 to 4; j2 is a linker selected from the group consisting of (integer 0 to 3);
  • the RA groups are independently hydrogen atom, halogen atom, hydroxyl group and C.
  • n2 is an integer from 1 to 5
  • m3 is an integer from 1 to 3
  • n3 is an integer from 1 to 4
  • j2 is an integer from 0 to 3
  • k is an integer of 1 to 4) and is a linker selected from the group.
  • P 1 is preferably an acetyl group or a benzoyl group, and more preferably a benzoyl group.
  • the 28th aspect is as follows.
  • R B is a hydrogen atom, a halogen atom, a hydroxyl group, C 1 ⁇ 6 alkyl group, hydroxy C 1 ⁇ 6 alkyl group, or a group selected from C 7 ⁇ 16 aralkyl group )
  • P 1 is a benzoyl group or an acetyl group (however, when -L 2- is the formula (L2-b), P 1 is a benzoyl group)], or an amino compound thereof, or a pharmaceutical drug thereof.
  • Tolerable salt is a hydrogen atom, a halogen atom, a hydroxyl group, C 1 ⁇ 6 alkyl group, hydroxy C 1 ⁇ 6 alkyl group, or a group selected from
  • -L 2- is preferably the following partial structural formula [in each formula, the outside of the broken lines at both ends is not included]: (In the formula (L2-a), R B is a hydrogen atom, C 1 ⁇ 6 alkyl group, or a C 7 ⁇ 16 aralkyl group is a) a linker selected from the group consisting of;
  • R B is a hydrogen atom, C 1 ⁇ 6 alkyl group, or a C 7 ⁇ 16 aralkyl group is a) a linker selected from the group consisting of;
  • R B is a hydrogen atom, C 1 ⁇ 6 alkyl group, or a C 7 ⁇ 16 aralkyl group is a) a linker selected from the group consisting of;
  • R B is a hydrogen atom, C 1 ⁇ 6 alkyl group, or a C 7 ⁇ 16 aralkyl group is a) a linker selected from the group consisting of;
  • the following partial structural formula [in each formula, the outside of the broken line at both ends is not included]: It is a linker selected from the group consisting of.
  • P 1 is preferably a benzoyl group.
  • the 29th aspect is as follows.
  • the following formula An amino compound selected from (where Bz is a benzoyl group in each formula), or a pharmaceutically acceptable salt thereof.
  • the amino compound of the above aspect [29] or a pharmaceutically acceptable salt thereof is preferably of the following formula. It is an amino compound selected from (in each formula, Bz is a benzoyl group).
  • alginic acid in the present specification, when referring to alginic acid, at least one alginic acid (sometimes referred to as "alginic acids") selected from the group consisting of alginic acid, alginic acid esters, and salts thereof (for example, sodium alginate) is referred to. means.
  • the alginic acid used may be of natural origin or synthetic, but is preferably of natural origin.
  • Preferred alginates are bioabsorbable polysaccharides extracted from brown algae such as Lessonia, Macrocystis, Laminaria, Ascophyllum, Derbilia, Kadika, Arame, and Kombu, D-mannuronic acid (M).
  • alginic acid may be referred to as (ALG) -COOH, with alginic acid as (ALG) and one of any carboxyl groups of alginic acid as -COOH.
  • the alginic acid is sodium alginate.
  • the sodium alginate a commercially available sodium alginate can be used.
  • alginic acid having the physical property values shown in Table 1 can be used.
  • the sodium alginate of A-2 shown in Table 1 (publisher: Mochida Pharmaceutical Co., Ltd.) is used as the sodium alginate.
  • Table 1 shows the viscosity, weight average molecular weight and M / G ratio of each 1 w / w% aqueous solution of sodium alginate.
  • ALG-2 distributedor, Kimika Co., Ltd.
  • the sodium alginate has the weight average molecular weight described in ⁇ Measurement of molecular weight> described later.
  • the physical property values of the sodium alginate A-1, A-2, A-3, B-1, B-2, and B-3 were measured by the following various methods.
  • the measuring method is not limited to the method, but each physical property value may differ from the above depending on the measuring method.
  • Da (Dalton) may be added as a unit in the molecular weights of alginic acid, alginic acid derivatives, crosslinked alginic acid, and crosslinked alginic acid.
  • the composition ratio (M / G ratio) of D-mannuronic acid and L-gluuronic acid of alginic acids differs mainly depending on the type of organism from which seaweeds are derived, and is also affected by the habitat and season of the organism. , From a high G type with an M / G ratio of about 0.2 to a high M type with an M / G ratio of about 5. It is known that the gelling ability of alginic acids and the properties of the produced gel are affected by the M / G ratio, and that the gel strength generally increases when the G ratio is high.
  • the M / G ratio also affects the hardness, brittleness, water absorption, flexibility, etc. of the gel.
  • the M / G ratio of the alginic acids and / or salts thereof used is usually 0.2 to 4.0, more preferably 0.4 to 3.0, still more preferably 0.5 to 3.0. is there.
  • the numerical range indicated by using “-” indicates a range including the numerical values before and after "-" as the minimum value and the maximum value, respectively.
  • alginate ester and “alginate” used are not particularly limited, but in order to react with a cross-linking agent, it is necessary that they do not have a functional group that inhibits the cross-linking reaction.
  • alginate ester propylene glycol alginate and the like are preferable.
  • examples of the alginate include a monovalent salt of alginic acid and a divalent salt of alginic acid.
  • the monovalent salt of alginic acid is preferably sodium alginate, potassium alginate, ammonium alginate, etc., more preferably sodium alginate or potassium alginate, and particularly preferably sodium alginate.
  • Preferred examples of the divalent salt of alginic acid include calcium alginate, magnesium alginate, barium alginate, strontium alginate, and the like.
  • Alginic acid is a high molecular weight polysaccharide and it is difficult to accurately determine its molecular weight, but it generally has a weight average molecular weight of 10 to 10 million, preferably 10,000 to 8 million, and more preferably 20,000 to 3 million. Is the range of. It is known that in the measurement of the molecular weight of a polymer substance derived from a natural product, the value may differ depending on the measurement method.
  • the weight average molecular weight measured by gel permeation chromatography (GPC) or gel filtration chromatography (collectively referred to as size exclusion chromatography) is preferably 100,000 or more, more preferably 500,000 or more, and also. It is preferably 5 million or less, more preferably 3 million or less. The preferred range is 100,000 to 5 million, more preferably 150,000 to 3 million.
  • the absolute weight average molecular weight can be measured.
  • the weight average molecular weight (absolute molecular weight) measured by the GPC-MALS method is preferably 10,000 or more, more preferably 50,000 or more, still more preferably 60,000 or more, and preferably 1 million or less, more preferably 80. It is 10,000 or less, more preferably 700,000 or less, and particularly preferably 500,000 or less.
  • the preferred range is 10,000 to 1,000,000, more preferably 50,000 to 800,000, still more preferably 60,000 to 700,000, and particularly preferably 60,000 to 500,000.
  • a measurement error of 10% to 20% can occur.
  • the value may fluctuate in the range of 320,000 to 480,000 for 400,000, 400,000 to 600,000 for 500,000, and 800,000 to 1.2 million for 1 million.
  • the molecular weight of alginic acids can be measured according to a conventional method.
  • Typical conditions when gel filtration chromatography is used for molecular weight measurement are as described in Examples of the present specification described later.
  • the column for example, Superose6 Increase 10/300 GL column (GE Healthcare Science Co., Ltd.) can be used, and as a developing solvent, for example, a 10 mmol / L phosphate buffer solution (pH 7.4) containing 0.15 mol / L NaCl.
  • bluedextran, tyroglobulin, ferritin, aldolase, conalbumin, ovalbumin, ribonuclease A and aprotinin can be used as molecular weight standards.
  • the viscosity of alginic acid used in the present specification is not particularly limited, but when the viscosity is measured as an aqueous solution of 1 w / w% alginic acid, it is preferably 10 mPa ⁇ s to 1000 mPa ⁇ s, more preferably 50 mPa ⁇ s. It is s to 800 mPa ⁇ s.
  • the viscosity of an aqueous solution of alginic acid can be measured according to a conventional method.
  • a co-axis double-cylindrical rotational viscometer, a single cylindrical rotational viscometer (Brookfield type viscometer), a cone-plate type rotational viscometer (cone plate type viscometer), etc. Can be measured.
  • Alginic acids initially have a large molecular weight and high viscosity when extracted from brown algae, but in the process of drying and purification by heat, the molecular weight becomes small and the viscosity becomes low.
  • Alginic acids having different molecular weights can be produced by methods such as controlling conditions such as temperature in the production process, selecting brown algae as a raw material, and fractionating the molecular weight in the production process. Further, by mixing with different lots of alginic acids having different molecular weights or viscosities, it is possible to obtain alginic acids having a desired molecular weight.
  • the alginic acid used herein is alginic acid that has not been treated with low endotoxin in some embodiments, or alginic acid that has been treated with low endotoxin in some other embodiments.
  • Low endotoxin means that the endotoxin level is low enough not to cause inflammation or fever. More preferably, it is alginates treated with low endotoxin.
  • the low endotoxin treatment can be performed by a known method or a method similar thereto.
  • William et al.'S method for purifying biopolymer salts such as alginate and gellan gum (see, eg, JP-A-2002-530440)
  • James et al.'S method for purifying polysaccharides eg, international publication.
  • Low endotoxin treatment is not limited to these, but uses cleaning, filtration with filters (endotoxin removal filter, charged filter, etc.), extrafiltration, and columns (endotoxin adsorption affinity column, gel filtration column, column with ion exchange resin, etc.).
  • the endotoxin level can be confirmed by a known method, for example, it can be measured by a method using Limulus reagent (LAL), a method using Endospecy (registered trademark) ES-24S set (Seikagaku Corporation), or the like. ..
  • LAL Limulus reagent
  • Endospecy registered trademark
  • ES-24S set Seikagaku Corporation
  • the method for treating endotoxin used is not particularly limited, but as a result, the endotoxin content of alginates should be 500 endotoxin units (EU) / g or less when endotoxin measurement with Limulus reagent (LAL) is performed. Is more preferable, and more preferably 100 EU / g or less, particularly preferably 50 EU / g or less, and particularly preferably 30 EU / g or less.
  • Sodium alginate treated with low endotoxin is available from commercial products such as Sea Matrix (registered trademark) (Mochida Pharmaceutical Co., Ltd.) and PRONOVA TM UP LVG (FMCBioPolymer).
  • alginic Acid Derivatives novel alginic acid derivatives are provided.
  • the alginic acid derivative is a reactive group in a Michael addition reaction or a complementary reactivity of the reactive group via an amide bond and a divalent linker to any one or more carboxyl groups of alginic acid. The group was introduced.
  • the reactive group of the alginic acid derivative represented by the formula (I) is an acrylic acid residue, and the reactive group of the alginic acid derivative represented by the formula (II) (reactivity of the alginic acid derivative represented by the formula (I)).
  • Complementary reactive groups of groups are thiol residues. Both reactive groups of acrylic acid residue and thiol residue can form covalent bonds more easily than the Michael addition reaction.
  • acrylic acid residue examples include residues capable of forming an adduct by a Michael addition reaction with a thiol residue, and specific examples thereof include an acryloyl group, an acrylic group, a maleyl group, a maleimide group, and a fumal group. It is preferably an acryloyl group or a maleimide group, and more preferably a maleimide group.
  • thiol residue examples include residues capable of forming an adduct by a Michael addition reaction with an acrylic acid residue, and specifically, a benzyl thiol group, a thiophenol group, and an alkyl thiol group (for example, methane thiol).
  • Residues such as residues, ethanethiol residues, cysteine residues, etc., in which the thiol group is replaced with a C1 to 6 alkyl group) and the like can be mentioned, preferably a benzylthiol group or an alkylthiol group. , More preferably an archiquilthiol group.
  • the divalent linker (-L 1- or -L 2- ) is a reactive group or a complementary reaction as long as it does not inhibit the reaction of the reactive group with the complementary reactive group of the reactive group. Any linear group can be used by keeping the sex group and alginic acid at a constant distance.
  • -L 1- is the divalent linker described in the above-mentioned aspect [1] or [2]
  • -L 2- is described in the above-mentioned aspect [1] or [5]. There is a divalent linker that is used.
  • -L 1- in the formula (I) is the following formula (L 1-3-1-a) (in the formula, both outer sides of the broken line are not included):
  • L1-3-1-aS in which the configuration of the carbon substituted by the benzyl group is the S form
  • L1-3 in which the configuration of the carbon substituted by the benzyl group is the R form.
  • -1-aR in any equation, both outer sides of the broken line are not included
  • -L 2- in the formula (II) or the formula (II-P) is the following formula (L2-6-1-a) (in the formula, both outer sides of the broken line are not included): If, the configuration of the carbon substituted by the benzyl group is the S form (L2-6-1-aS) and the configuration of the carbon substituted by the benzyl group is the R form (L2-6). -1-aR) (In any equation, both outer sides of the broken line are not included): It means that the linker represented by is included.
  • the racemate can be separated into each optically active substance by a usual optical resolution means (separation method), and the amine derivative (AM-1) corresponding to the formula (I) can be separated.
  • one of the optical isomers can be selectively synthesized by using asymmetric synthesis, and each optically active substance can be synthesized.
  • the (optically active) formula (II) or formula (II-P) having each optically active substance and asymmetric carbon is similar to the above-mentioned method. It is possible to synthesize alginic acid derivatives.
  • Fractional recrystallization method An optical resolution agent is ionically bonded to a racemate to obtain a crystalline diastereomer, and then the crystalline diastereomer is separated by a fractional recrystallization method and optically resolved if desired. It is a method of obtaining an optically pure compound through a step of removing the agent.
  • the optical resolution agent is, for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonidine. , (-)-Cinchonidine, brucine and the like.
  • Diastereomer method An optical resolution agent is covalently bonded to a mixture of racemates to obtain a mixture of diastereomers, which is then subjected to conventional separation means (eg, fractional recrystallization, silica gel column chromatography, HPLC, etc.). It is a reaction in which an optically pure diastereomer is separated, and then an optically pure optical isomer is obtained through a step of removing an optical resolution agent by a chemical reaction (hydrolysis reaction or the like).
  • the compound or intermediate compound in the present specification has a hydroxyl group or an amino group (primary or secondary)
  • the compound and an optically active organic acid for example, ⁇ -methoxy- ⁇ - (trifluoromethyl)
  • Phenylacetic acid, (-)-mentoxyacetic acid, etc. Phenylacetic acid, (-)-mentoxyacetic acid, etc.
  • ester or amide diastereomers from each.
  • an amide or ester diastereomer can be obtained from each of the compounds by a condensation reaction of the compound with an optically active amine or an optically active alcohol.
  • the diastereomers obtained by the condensation reaction are separated and each diastereomer is subjected to a hydrolysis reaction with an acid or a base to be converted into an optically pure optical isomer of the original compound.
  • Chiral column method A method of directly optical resolution by subjecting a racemate or a salt thereof to chromatography using a chiral column (column for separating optical isomers). For example, in the case of high performance liquid chromatography (HPLC), a mixture of optical isomers is added to a chiral column (for example, CHIRAL series manufactured by Daicel), and an elution solvent (water, various buffers (for example, phosphate buffer)) is added. Liquid) and a single solvent such as an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) or a mixed solvent thereof) to develop the optical isomer.
  • HPLC high performance liquid chromatography
  • a mixture of optical isomers is added to a chiral column (for example, CHIRAL series manufactured by Daicel), and an elution solvent (water, various buffers (for example, phosphate buffer
  • optical isomers can be separated by using a chiral column (for example, CP-Chirasil-DeX CB (manufactured by GL Sciences Co., Ltd.)).
  • a chiral column for example, CP-Chirasil-DeX CB (manufactured by GL Sciences Co., Ltd.)
  • SFC supercritical fluid chromatography
  • a mixture of optical isomers is added to a chiral column (for example, CHIRAL series manufactured by Daicel Co., Ltd.), and carbon dioxide and an appropriate organic solvent (for example, for example) are added to the elution solvent.
  • Methanol, ethanol, isopropanol, trifluoroacetic acid, diethylamine, etc. can be used to separate the optical isomers.
  • the asymmetric synthesis that selectively synthesizes one of the optical isomers includes (1) an asymmetric synthesis reaction in which a racemic compound is enantioselectively reacted to lead to an optically active compound, and (2) a naturally occurring optically active compound. Examples thereof include a method of diastereoselectively synthesizing from (sugar, amino acid, etc.).
  • alginic acid derivatives represented by the formulas (I) and (II), which are novel alginic acid derivatives in the present specification can be produced, for example, by the method of the following formula (for details, refer to the general production method described later). It is possible.
  • the weight average molecular weight of the alginic acid derivative represented by the formula (I), the formula (II) or the formula (II-P) of the present specification is 100,000 Da to 3 million Da, preferably 300,000 Da to 2.5 million Da. It is more preferably 500,000 Da to 2 million Da.
  • the molecular weight of both alginic acid derivatives can be determined by the method described later.
  • the group of the formula (BR-1) in the alginic acid derivative of the formula (I) is referred to as a reactive group
  • the group of the formula (BR-2) in the alginic acid derivative of the formula (II) is complementary. It becomes a reactive group.
  • the group of the formula (BR-2) in the alginic acid derivative of the formula (II) is referred to as a reactive group
  • the group of the formula (BR-1) in the alginic acid derivative of the formula (I) is complementary. It becomes a reactive group.
  • the introduction rate of the reactive group or the complementary reactive group is, for example, 0.1% to 30% or 1% to 30%, preferably 2% to 20%, respectively. More preferably, it is 3% to 10%.
  • the introduction rate of the reactive group or the complementary reactive group is expressed as a percentage of the number of uronic acid monosaccharide units into which each reactive group has been introduced among the uronic acid monosaccharide units which are repeating units of alginic acids. It is the value that was set.
  • % used for the introduction rate of a reactive group or a complementary reactive group in an alginic acid derivative means mol%.
  • the introduction rate of each reactive group or complementary reactive group can be determined by the method described in Examples described later.
  • Protecting group P 1 of the thiol groups in the alginic acid derivative represented by formula (II-P) may be protected and de-protected appropriately selecting the protecting group easily, for example, "Protective Groups in Protecting groups described in Organic Synthesis in Organic Synthesis 5th Edition, 5th Edition, 2014, John Willy & Sons, Greene et al., Etc., as appropriate. it can.
  • the protective group P 1, acetyl, ethylcarbonyl, C 2 ⁇ 6 alkanoyl group and the like; benzoyl group, naphthyl carbonyl group, C 6 ⁇ 10 aryl group and the like; trityl group (triphenylmethyl Groups), diphenylmethyl groups; protecting groups such as NC 1-6 alkyl-carbamoyl groups such as methylaminocarbonyl group, ethylaminocarbonyl group, etc., but are not limited thereto.
  • the maleimide group in the formula (BR-1) group in the alginic acid derivative in the formula (I) and the thiol (HS-) group in the alginic acid derivative of the formula (II) are covalently bonded by the Michael addition reaction. Is formed, thereby forming a crosslink.
  • alginic acid derivatives include derivatives of the formula (I) have the formula (AM-1) amine derivative represented by (wherein -L 1 - is the aspect [1] or [2] in It can be produced by a condensation reaction between a salt thereof and any carboxyl group of alginic acids.
  • the alginic acid derivative represented by the formula (II) is represented by the formula (AM-2) (in the formula-L 2- and P 1 are the same as the definitions in the above-mentioned embodiment [1] or [5]). It can be produced by deprotecting one protecting group P after obtaining an alginic acid derivative represented by the formula (II-P) by a condensation reaction of an amine derivative or a salt thereof with an arbitrary carboxyl group of an alginic acid.
  • DCC 1,3-Dicyclohexylcarbodiimide
  • WSC ⁇ HCl 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • benzotriazole-1-yloxytris dimethylamino
  • BOP reagent Phosphonium hexafluorophosphate
  • BOP-Cl bis (2-oxo-3-oxazolidinyl) phosphinic chloride
  • CIP 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate
  • DMT-MM 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride
  • Et al. Alcohol-based solvents such as methanol and ethanol, polar solvents such as N, N-dimethylformamide, or mixed solvents thereof (however, the mixed solvent is a mixed solvent to the extent that argylic acid does not precipitate).
  • an inorganic base such as sodium hydrogen carbonate or sodium carbonate or an organic base such as triethylamine or pyridine
  • an organic base such as triethylamine or pyridine
  • an alginic acid derivative represented by the formula (II) can be produced.
  • P 1 group of formula (II-P) is an acetyl group
  • a benzoyl group, C 2 ⁇ 6 alkanoyl group such as the protecting group for the benzoyl group system
  • the following formula (BR-2-P) introduced into an aqueous solution of an alginic acid derivative of formula (II-P) (for example, 0.5% by weight to 1% by weight):
  • an inorganic base such as sodium hydroxide or potassium hydroxide is added in an excessive amount and hydrolyzed at a reaction temperature of 0 ° C. to 30 ° C. to obtain a salt of the alginic acid derivative of the formula (II).
  • an inorganic base such as sodium hydroxide or potassium hydroxide
  • the introduction rate of the amine derivative of the formula (AM-1) or the formula (AM-2) is the property of the amine and the like.
  • ether-based solvents such as tetrahydrofuran, 1,4-dioxane, methylene chloride, 1, Among the solvents selected from halogen-based solvents such as 2-dichloroethane, polar solvents such as N, N-dimethylformamide, etc., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3'-dimethylamino) Propyl) carbodiimide hydrochloride (WSC ⁇ HCl), benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-) Cl), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), 4- (4,6-dime
  • the maleic anhydride and the amine represented by the formula (III) are mixed in a solvent such as an alcohol solvent such as methanol and ethanol in the presence or absence of a base such as triethylamine, N, N-diisopropylethylamine and pyridine.
  • a solvent such as an alcohol solvent such as methanol and ethanol
  • a base such as triethylamine, N, N-diisopropylethylamine and pyridine.
  • the compound of formula (IV) can be produced by reacting.
  • the compound of the formula (VI) is produced by carrying out a reaction in acetic anhydride using the crude compound of the formula (IV) obtained in [Production Method A] ⁇ Step 1> and a base such as sodium acetate. be able to.
  • the compound of formula (VI) can be produced by reacting at a temperature from 78 ° C. to the time during which the solvent is refluxed.
  • the compound represented by the formula (VI) can be expressed by a method known in the literature, for example, "Protective Groups in Organic Synthesis 5th Edition", 5th edition, 2014, John Willy and Sons ( john Wiley & Sons), as described in Green (Greene) et al ", etc., according to the deprotection method of the amino-protecting group, followed by deprotection according to the type of the protecting group P 2, the formula (AM The amine derivative of -1) can be produced.
  • the amine derivative of the formula (AM-1) can be obtained as a salt, if necessary, and examples thereof include salts such as hydrochloride and trifluoroacetic acid salt.
  • P 2 in represents a protecting group of the amine, for example, "Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis 5th Edition ) Fifth Edition, 2014, John Wiley & Protecting groups described in "John Wiley & Sons, Greene et al.” And the like can be appropriately selected.
  • P 2 is, for example, an -C (O) O-tertBu group
  • an acid hydrogen chloride (a solution of 1,4-dioxane containing hydrogen chloride, cyclopentyl methyl ether, ethyl acetate, etc.) may be used).
  • Trifluoroacetic acid, etc. can be used for deprotection. More specifically, for example, “Protective Groups in Organic Synthesis 5th Edition, 5th Edition, 2014, John Wiley &Sons," Green (Green), et al. It is possible to select a deprotection method according to the type of protecting group by referring to a method known in the literature such as.
  • P 1 is an acetyl group, acetyl chloride; if it is a benzoyl group, benzoyl chloride; if it is a trityl group, triphenylmethyl chloride; if it is an EtNHCO- group, use ethyl isocyanate to protect the protecting group. Can be introduced.
  • condensation reaction of the formula (IX) is carried out according to the method of [Production Method A] ⁇ Step 1> using the compound represented by the formula (VIII) and the carboxylic acid derivative such as acetic acid and benzoic acid. Compounds can be produced.
  • an acylthio derivative such as thiobenzoic acid, thioacetic acid, or potassium thioacetate, etc., in a solvent selected from acetonitrile, methylene chloride, N, N-dimethylformamide, etc., potassium carbonate, etc.
  • a solvent selected from acetonitrile, methylene chloride, N, N-dimethylformamide, etc., potassium carbonate, etc.
  • the compound of formula (IX) can be produced by carrying out the reaction in the presence or absence of a base.
  • the amine derivative of the formula (AM-2) can be obtained as a salt, if necessary, and examples thereof include salts such as hydrochloride and trifluoroacetic acid.
  • P 3 in represents a protecting group of the amine, for example, "Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis 5th Edition ) Fifth Edition, 2014, John Wiley & Protecting groups described in "John Wiley & Sons, Greene et al.” And the like can be appropriately selected.
  • Protecting groups such as groups, -C (O) CF 3 groups, -SO 2 Ph, -SO 2 PhMe groups, -SO 2 Ph (NO 2 ) groups, etc. are not limited thereto.
  • P 3 is, for example, an -C (O) O-tertBu group
  • an acid hydrogen chloride (a solution of 1,4-dioxane containing hydrogen chloride, cyclopentyl methyl ether, ethyl acetate, etc.) may be used).
  • Trifluoroacetic acid, etc. can be used for deprotection. More specifically, for example, Protective Groups in Organic Synthesis 5th Edition, 5th Edition, 2014, John Wiley & Sons, Green et al. It is possible to select a deprotection method according to the type of protecting group by referring to a method known in the literature such as.
  • the amine derivative (amino compound) represented by the formula (AM-1) or the formula (AM-2) (including the lower formula of each formula) is a pharmaceutically acceptable salt (for example, , Acid addition salt) may be formed.
  • the salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a salt with an inorganic acid, a salt with an organic acid, and a salt with an acidic amino acid.
  • Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid.
  • Salts with acids salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvate, oxylic acid, salicylic acid, N-acetylcysteine, etc.
  • examples thereof include salts with organic carboxylic acids, salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamate.
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Of these, pharmaceutically acceptable salts are preferable.
  • the carboxyl group is substituted in the amine derivative (amino compound) represented by the formula (AM-1) or the formula (AM-2) (including the lower formulas of each formula), pharmaceuticals are manufactured. It may form a generally acceptable salt (eg, a base addition salt).
  • the salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a metal salt, an ammonium salt, and a salt with an organic base.
  • the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, aluminum salt and the like. ..
  • salts with organic bases include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, tri.
  • the salt is separated and collected by filtration according to a conventional method, for example, by mixing a solution containing an appropriate amount of acid or base with the compound of the present invention to form a desired salt, or distilling off the mixed solvent.
  • a solution containing an appropriate amount of acid or base with the compound of the present invention to form a desired salt, or distilling off the mixed solvent.
  • the amine compound represented by the formula (AM-1) or the formula (AM-2) (including the formulas lower than each formula) or a salt thereof is solvated with a solvent such as water, ethanol or glycerol.
  • a solvent such as water, ethanol or glycerol.
  • Michael addition reaction is a carbon anion on an electron-deficient double bond (for example, an acryloyl group, a cinnamic acid group, a maleimide group, etc.) in which an electron-withdrawing group is conjugated as shown in the reaction formula below.
  • An organic metal compound, an amine, an alkoxide, and a thioalkoxide are subjected to a 1,4-addition (conjugate addition) reaction to form a covalent bond.
  • EWG represents an electron-withdrawing group (eg, COOR, CONHR, etc.);
  • Nu ⁇ is a carbon anion ( RM), R—NH 2 (or R—NH ⁇ ), R. -OH (or R-O -), R- SH ( or R-S -) represents a nucleophilic reagent selected from such;
  • R represents various substituents, such as C 1 ⁇ 6 alkyl group;
  • R x Alternatively, R y represents various substituents such as a hydrogen atom and a C1 to 6 alkyl group;
  • M represents a metal such as Li and Na).
  • the Michael addition reaction in the present specification is a reaction in which a thiol compound undergoes a 1,4-addition (conjugate addition) reaction with a maleimide compound represented by the following reaction formula to form a covalent bond.
  • R represents various substituents such as C1 to 6 alkyl groups
  • the Michael addition reaction does not produce unwanted by-products and is capable of forming covalently bonded crosslinks between alginate molecules in a short time, easily and efficiently.
  • an alginic acid derivative in a preferred embodiment, almost no undesired by-products are formed in the Michael addition reaction.
  • various bioactive molecules are incorporated, and alginate hydrogel for reconstructive surgery or gene therapy is used. It becomes possible to take up cellular substances.
  • Cross-linked alginic acid is mediated by (i) a divalent metal ionic bond, (ii) a chemical bond, or (iii) a divalent metal ionic bond and a chemical bond. There is something. Any crosslinked alginic acid has the property of being able to form a gel-like to semi-solid, and in some cases sponge-like morphology.
  • Cross-linked alginic acid via a divalent metal ionic bond proceeds at an ultrafast speed and is reversible, whereas cross-linked alginic acid via a chemical bond proceeds slowly under relatively mild conditions. And it is irreversible.
  • the physical characteristics of the crosslinked alginic acid are adjusted by, for example, changing the concentration of the aqueous solution containing the divalent metal ion to be used (for example, an aqueous solution of calcium chloride) or the introduction rate of the reactive group introduced into alginic acid. Is possible.
  • a specific structure can be instantly formed from an alginic acid solution by an ionic cross-linking reaction, and a cross-linking reaction by a chemical bond is used to strengthen the structure of the structure (for example, to obtain long-term stability, etc.). It is possible to do. Further, for example, in a crosslinked alginic acid structure via both a divalent metal ionic bond and a chemical bond, the divalent metal ion incorporated by the ionic bonding was reversibly released, and only the crosslink by the chemical bond remained. It is also possible to create a structure.
  • the crosslinked alginic acid of a certain aspect can be obtained by mixing the alginic acid derivatives of the formula (I) and the alginic acid derivative of the formula (II) and carrying out a Michael addition reaction.
  • to carry out the cross-linking reaction means to carry out the Michael addition reaction using the alginic acid derivative represented by the formula (I) and the alginic acid derivative represented by the formula (II).
  • a chemical crosslink (chemical bond) is formed between the alginic acid derivative represented by the above formula (II) and the alginic acid derivative represented by the formula (II), or the alginic acid derivative represented by the above formula (I) and the above formula (II) are represented.
  • an ionic crosslink (ion bond) is formed between the alginic acid derivative represented by the formula (I) and / or the alginic acid derivative represented by the formula (II). This means that both chemical cross-linking by the Michael addition reaction and ion cross-linking by divalent metal ions are formed.
  • a mixed solution containing an alginic acid derivative of the formula (I) and an alginic acid derivative of the formula (II-P) (however, P 1 is not a hydrogen atom in the formula (II-P)), or a mixed solution of the formula ( A solution of the composition containing the alginic acid derivative of I) and the alginic acid derivative of formula (II-P) (where P 1 is not a hydrogen atom in formula (II-P)) of the formula (II-P).
  • a deprotecting agent for example, when P 1 is an acyl-based protecting group such as an acetyl group or a benzoyl group, a base such as an aqueous sodium hydroxide solution is used) so that the protecting group P 1 of the alginic acid derivative is deprotected. protecting agent by adding it) be appropriately selected depending on the protecting group P 1, capable of forming a chemical crosslinking (chemical bonding).
  • Cross-linked alginic acid of a certain aspect forms a three-dimensional network structure through chemical cross-linking (cross-linking by a covalent bond formed from a maleimide group and a thiol group).
  • a preferred alginic acid derivative is one in which the stability of the crosslinked alginic acid after cross-linking is improved.
  • the crosslinked alginic acid has the following formula (LK-1) between an arbitrary carboxyl group of the first alginic acid and an arbitrary carboxyl group of the second alginic acid.
  • LK-1 -CONH- and -NHCO- at both ends represent an amide bond via any carboxyl group of alginic acid; -L 1- and -L 2- are the above-mentioned embodiments [1].
  • the mixing ratio of the alginic acid derivative of formula (I) to the alginic acid derivative of formula (II) in preparing the crosslinked alginic acid is the weight of the derivative of formula (I) and the derivative of formula (II).
  • the ratio is, for example, 1 to 1.5: 1, preferably 1.2 to 1.5: 1, or 1 to 1.2: 1, more preferably 1: 1.
  • the mixing ratio of the alginic acid derivative of formula (II) to the alginic acid derivative of formula (I) in preparing the crosslinked alginic acid is the weight of the derivative of formula (II) and the derivative of formula (I).
  • ratio for example, 1 to 4.0: 1, preferably 1.5 to 4.0: 1, or 1.2 to 1.5: 1, or 1 to 1.2: 1, more preferably 1. It is 1.
  • the mixing ratio of the alginic acid derivative of the formula (I) to the alginic acid derivative of the formula (II) in preparing the crosslinked alginic acid is more preferably the alginic acid derivative of the formula (I) and the alginic acid derivative of the formula (II).
  • the introduction rate (mol%) ratio of the reactive group of the alginic acid derivative for example, 1 to 1.5: 1, preferably 1.2 to 1.5: 1, or 1 to 1.2: 1. , More preferably 1: 1.
  • the mixing ratio of the alginic acid derivative of the formula (II) to the alginic acid derivative of the formula (I) in preparing the crosslinked alginic acid is more preferably the alginic acid derivative of the formula (II) and the alginic acid derivative of the formula (I).
  • the introduction rate (mol%) ratio of the reactive group of the alginic acid derivative for example, 1 to 4.0: 1, preferably 1.5 to 4.0: 1, or 1.2 to 1.5 :. 1, or 1 to 1.2: 1, more preferably 1: 1.
  • the crosslinked alginic acid does not need to have all the carboxyl groups of the constituent units of alginic acid having the crosslink of the above formula (LK-1).
  • the introduction rate (also referred to as the crosslinking rate) of the crosslinking represented by the above formula (LK-1) is, for example, 0.1 to 80%, 0.3 to 60%, 0.5 to 30%, or It is in the range of 1.0 to 10%.
  • the concentration of the alginic acid derivative of the formula (I) or the formula (II) in the Michael addition reaction for obtaining the crosslinked alginic acid is usually 1 to 500 mg / mL, preferably in the range of 5 to 100 mg / mL.
  • the reaction temperature of the Michael addition reaction is usually an outside temperature of 4 to 60 ° C, preferably an outside temperature of 15 to 40 ° C.
  • the stirring time for forming the crosslinked alginic acid (hydrogel) is, for example, several seconds to 24 hours, several seconds to 12 hours, several seconds to 30 minutes, or several seconds to 10 minutes.
  • the reaction solvent or reaction solution used for the Michael addition reaction is not particularly limited, but for example, tap water, pure water (for example, distilled water, ion-exchanged water, RO water, RO-EDI water, etc.), ultrapure water, etc.
  • tap water pure water
  • pure water for example, distilled water, ion-exchanged water, RO water, RO-EDI water, etc.
  • ultrapure water etc.
  • cell culture medium phosphate buffered physiological saline (PBS), and physiological saline
  • PBS phosphate buffered physiological saline
  • ultrapure water is preferable.
  • Cross-linked alginic acids of some embodiments include cross-linked alginic acids, including covalently formed chemical cross-links formed by the Michael addition reaction as cross-links and ion cross-links partially formed by divalent metal ions (eg, calcium ions, etc.). Is.
  • composition A composition containing an alginic acid derivative represented by the formula (I) and an alginic acid derivative represented by the formula (II) is provided.
  • the weight ratio of the alginic acid derivative of formula (I) to the alginic acid derivative of formula (II) is, for example, 1: 1. It is 1 to 1.5, preferably 1: 1.2 to 1.5, or 1: 1 to 1.2, more preferably 1: 1.
  • the weight ratio of the alginic acid derivative of formula (II) to the alginic acid derivative of formula (I) is, for example, 1: It is 1 to 1.5, preferably 1: 1.2 to 1.5, or 1: 1 to 1.2, more preferably 1: 1.
  • the mixing ratio of the alginic acid derivative of the formula (I) to the alginic acid derivative of the formula (II) is the formula (BR-1) group and the formula (II) in the alginic acid derivative of the formula (I).
  • the introduction rate (mol%) ratio of the formula (BR-2) group in the alginic acid derivative of for example, 1: 1 to 1.5, preferably 1: 1.2 to 1.5, or 1: 1. It is 1 to 1.2, more preferably 1: 1.
  • the mixing ratio of the alginic acid derivative of the formula (II) to the alginic acid derivative of the formula (I) is the formula (BR-2) group and the formula (I) in the alginic acid derivative of the formula (II).
  • the introduction rate (mol%) ratio of the formula (BR-1) group in the alginic acid derivative of for example, 1: 1 to 1.5, preferably 1: 1.2 to 1.5, or 1: 1. It is 1 to 1.2, more preferably 1: 1.
  • a composition containing an alginic acid derivative represented by the formula (I) and an alginic acid derivative represented by the formula (II-P) is provided.
  • the weight ratio of the alginic acid derivative of formula (I) to the alginic acid derivative of formula (II-P) is.
  • 1: 1 to 1.5 preferably 1: 1.2 to 1.5, or 1: 1 to 1.2, more preferably 1: 1.
  • the weight ratio of the alginic acid derivative of formula (II-P) to the alginic acid derivative of formula (I) is.
  • 1: 1 to 1.5 preferably 1: 1.2 to 1.5, or 1: 1 to 1.2, more preferably 1: 1.
  • the mixing ratio of the alginic acid derivative of the formula (I) to the alginic acid derivative of the formula (II-P) is the formula (BR-1) group and the formula (BR-1) in the alginic acid derivative of the formula (I).
  • the introduction rate (mol%) ratio of the formula (BR-2-P) group in the alginic acid derivative of II-P) for example, 1: 1 to 1.5, preferably 1: 1.2 to 1. .5, or 1: 1 to 1.2, more preferably 1: 1.
  • the mixing ratio of the alginic acid derivative of formula (II-P) to the alginic acid derivative of formula (I) is the formula (BR-2-P) in the alginic acid derivative of formula (II-P).
  • the introduction rate (mol%) ratio of the group to the alginic acid derivative of the formula (I) for example, 1: 1 to 1.5, preferably 1: 1.2 to 1. .5, or 1: 1 to 1.2, more preferably 1: 1.
  • crosslinked alginic acid structure can be obtained by a method including subjecting the alginic acid derivative to a crosslinking reaction.
  • Specific cross-linked alginic acid structures include, for example, fibrous structures, fibers, beads, gels, substantially spherical gels, and the like.
  • a preferred crosslinked alginate structure is one with improved stability.
  • the crosslinked alginic acid structure may have an ability to retain the contents inside the crosslinked alginic acid structure (content retention).
  • the crosslinked alginic acid structure can be prepared by, for example, the following methods, but is not limited thereto.
  • deprotecting agent after the addition of appropriate can be selected) according to the protective group P 1, by dropping a solution containing divalent metal ions, it is formed by chemical crosslinking (Michael addition reaction It is possible to form a crosslinked alginic acid structure, which is a specific structure in which a cross-linking by a covalent bond) and an ionic cross-link (a cross-linking partially formed by a divalent metal ion) are formed.
  • a specific structure partially crosslinked can be obtained by dropping a solution containing the alginic acid derivative of the formula (I) into a solution containing divalent metal ions.
  • a further cross-linking reaction (Michael addition reaction) is carried out on the surface of the structure or the like. Therefore, a crosslinked alginic acid structure can be obtained. It is also possible to carry out this method by substituting the alginic acid derivative of the formula (I) with the alginic acid derivative of the formula (II) and the alginic acid derivative of the formula (II) with the alginic acid derivative of the formula (I). ..
  • a specific structure partially crosslinked can be obtained by dropping a solution containing the alginic acid derivative of the formula (I) into a solution containing divalent metal ions.
  • the structure obtained above such as a gel, is added to a solution containing the above-mentioned alkylate derivative of the formula (II-P) (where P 1 is not a hydrogen atom in the formula (II-P)).
  • a deprotecting agent for example, when P 1 is an acyl-based protecting group such as an acetyl group or a benzoyl group
  • the protecting group P 1 of the alginic acid derivative represented by the above formula (II-P) is deprotected.
  • deprotecting agent by adding a suitable can be selected) according to the protective group P 1, further crosslinking reactions on the surface and the like of the structure (Michael addition reaction) Can form a crosslinked alkylate structure.
  • a structure such as a gel or the like, is added to a solution containing alginic acid derivative of formula (I) described above, further wherein the protector group P 1 of the (II-P) alginic acid derivatives are deprotected
  • a deprotecting agent for example, when P 1 is an acyl-based protecting group such as an acetyl group or a benzoyl group, a base such as an aqueous sodium hydroxide solution can be mentioned.
  • the deprotecting agent is appropriately used according to the protecting group P 1.
  • a crosslinked alkylate structure can be formed by further subjecting the surface of the structure or the like to a cross-linking reaction (Michael addition reaction).
  • the divalent metal ion used in the above method is not particularly limited, and examples thereof include calcium ion, magnesium ion, barium ion, strontium ion, zinc ion and the like, and calcium ion is preferable.
  • the solution containing calcium ions used in the above method is not particularly limited, and examples thereof include aqueous solutions such as an aqueous solution of calcium chloride, an aqueous solution of calcium carbonate, and an aqueous solution of calcium gluconate, and an aqueous solution of calcium chloride is preferable.
  • the calcium ion concentration of the solution containing calcium ions used in the above method is not particularly limited, but examples thereof include 1 mM to 1 M, preferably 5 mM to 500 mM, and more preferably 10 mM to 300 mM.
  • the solvent or solution used in the above method is also not particularly limited, but for example, tap water, pure water (for example, distilled water, ion-exchanged water, RO water, RO-EDI water, etc.), ultrapure water, cell culture medium. , Phosphoric acid buffered physiological saline (PBS), physiological saline and the like, and ultrapure water is preferable.
  • the physical characteristics of the alginate gel can be adjusted by the physical characteristics such as hardness, elasticity, repulsive force, tearing force, and stress at break.
  • biocompatibility means a biocompatible material (here, an alginic acid derivative represented by the formula (I) or the formula (II), and a crosslinked alginic acid or a crosslinked alginic acid structure produced by using both alginic acid derivatives.
  • a biocompatible material here, an alginic acid derivative represented by the formula (I) or the formula (II)
  • a crosslinked alginic acid or a crosslinked alginic acid structure produced by using both alginic acid derivatives.
  • the property of not causing a reaction such as an interaction between a living body and a living body, a local reaction of a tissue adjacent to the biological material, or a systemic reaction is said to have biocompatibility.
  • the biocompatibility of the alginic acid derivative, the crosslinked alginic acid, or the crosslinked alginic acid structure can be confirmed in the examples of biocompatibility described later.
  • Stability of the crosslinked alginic acid structure The stability of the crosslinked alginic acid structure can be confirmed by, for example, measuring the gel stability, and the permeability can be confirmed by measuring the gel transmittance.
  • Phosphate buffered saline PBS
  • concentration of alginic acid leaked into PBS ⁇ g / mL
  • the value obtained by dividing the measured alginic acid concentration by the total alginic acid concentration obtained by decomposing the crosslinked alginic acid structure gel as a percentage is defined as the disintegration rate.
  • the gel stability can be determined by the method described in Examples described later.
  • the gel disintegration rate of the crosslinked alginic acid structure is preferably 0% to 90%, more preferably 0% to 70%, and further preferably 0% to 50%.
  • the stability of the crosslinked alginic acid structure means that the lower the concentration of alginic acid leaked into the aqueous solution, that is, the lower the gel disintegration rate, the higher the stability.
  • a crosslinked alginic acid structure gel containing fluorescein isothiocyanate-dextran is prepared, physiological saline is added to the gel in a container, and the concentration of dextran leaked into the physiological saline is measured.
  • the gel permeability is the value obtained by dividing the measured dextran concentration by the total dextran concentration obtained by decomposing the fluorescein isothiocyanate-dextran-encapsulating cross-linked alginic acid structure gel.
  • the gel transmittance can be determined by the method described in Examples described later.
  • the gel permeability of the crosslinked alginic acid 24 hours after the addition of the physiological saline is preferably 0% to 90%, more preferably 0% to 70%, and further preferably 0% to 70% when dextran having a molecular weight of 2 million is included. It is preferably 0% to 50%.
  • dextran having a molecular weight of 150,000 is included, for example, if the purpose of use of the crosslinked alginic acid structure gel is to release / produce a protein or antibody, it is preferably 1% to 100%, more preferably 10. It is% to 100%, more preferably 30% to 100%. If the purpose of use is an immune septum, it is preferably 0% to 90%, more preferably 0% to 70%, and even more preferably 0% to 50%.
  • the permeability of the crosslinked alginic acid structure means that the lower the transmittance, the lower the permeability of the contents and extragel substances, and the higher the transmittance, the higher the permeability of the contents and extragel substances. means.
  • the transmittance of the gel can be adjusted by the molecular weight and concentration of alginic acid used, the type and introduction rate of cross-linking groups to be introduced into alginic acid, the type and concentration of divalent metal ions used for gelation, or a combination thereof. is there.
  • a crosslinked alginic acid structure gel containing fluorescein isothiocyanate-dextran as a content can be prepared by the following method.
  • the solution of the alginic acid derivative represented by the formula (I) and the fluorescein isothiocyanate-dextran solution are mixed.
  • (2) The mixed solution obtained in (1) is mixed with the solution of the alginic acid derivative represented by the formula (II).
  • the formula (II) of (2) is changed to the formula (I)
  • (3) The mixed solution obtained in (2) is dropped into a solution containing calcium ions, and the obtained gel forms chemical crosslinks and ion crosslinks in the solution to form fluorescein isothiocyanate-dextran.
  • An encapsulated crosslinked alginic acid structure gel is obtained.
  • Alginic acid derivatives can be used in place of conventional alginic acid in a wide range of fields such as food, medical care, cosmetics, textiles, and papermaking.
  • Preferred uses of the alginic acid derivative or the crosslinked alginic acid structure are specifically for medical use such as a wound dressing, a postoperative adhesion preventive material, a substrate for sustained release of a drug, a substrate for cell culture, and a substrate for cell transplantation. Materials can be mentioned.
  • Diseases to be treated by cell transplantation include diabetes, Parkinson's disease, hemophilia and the like.
  • Examples of the shape of the crosslinked alginic acid structure when used as a medical material include fibrous structures, fibers, beads, gels, substantially spherical gels, etc., and beads, gels or substantially spherical gels are preferable. It is more preferable to use a substantially spherical gel.
  • JEOL JNM-ECX400 FT-NMR (JEOL Ltd.) was used for the measurement of the nuclear magnetic resonance spectrum (NMR).
  • Root temperature in the examples usually indicates a temperature of about 0 ° C to about 35 ° C.
  • Example 1 To the compound (500 mg) obtained in ⁇ Step 1>, a 4N-hydrogen chloride ethyl acetate solution (5.0 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. After adding ethyl acetate (5.0 mL), the precipitate was collected by filtration and washed with ethyl acetate. The obtained hygroscopic solid was suspended in ethyl acetate, ethyl acetate was distilled off under reduced pressure, and the mixture was dried under reduced pressure to give the title compound (328 mg) as a white solid.
  • Example 2 Trifluoroacetic acid (2.3 mL) was added to the compound (0.5 g) obtained in ⁇ Step 1> under ice-water cooling, and the mixture was stirred at room temperature for 1 hour. Diisopropyl ether (11.3 mL) was added, and the mixture was stirred at room temperature for 30 minutes, and the precipitated solid was collected by filtration and washed with diisopropyl ether. The obtained hygroscopic solid was suspended in diisopropyl ether, the solvent was distilled off, and the mixture was dried under reduced pressure to give the title compound (0.3 g) as a pale yellow solid.
  • Example 3 The compound (500 mg) and maleic anhydride (217 mg) obtained in ⁇ Step 1> were suspended in ethanol (5.0 mL) and stirred at room temperature for 30 minutes. Ethanol was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (heptane to ethyl acetate) to obtain an amide compound (423 mg). Acetic anhydride (4.2 mL) is added to the obtained colorless oil and sodium acetate (100 mg), and after stirring at 40 ° C. for 1 hour, 60 ° C. for 1 hour, 80 ° C. for 1.5 hours, and 100 ° C. The mixture was stirred for 2 hours.
  • Example 3 Trifluoroacetic acid (1.9 mL) was added to the compound (275 mg) obtained in ⁇ Step 2> under ice-water cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate to 30% methanol / ethyl acetate) to give the title compound (231 mg) as a colorless oil.
  • Step 4 2- (2- (2- (2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) ethoxy) ethoxy) ethylamino group-introduced alginic acid (AL-EX-3) synthesis
  • Example 4 Trifluoroacetic acid (0.52 mL) was added to the mixture of the compound (0.074 g) and dichloromethane (0.22 mL) obtained in ⁇ Step 1> under ice-cooled stirring. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated and diisopropyl ether (20 mL) was added. Since the gum-like compound was formed, the mixture was concentrated under reduced pressure and dried to obtain the title crude compound (0.097 g) as a pale yellow gum-like compound.
  • Example 5 Trifluoroacetic acid (0.7 mL) was added to the mixture of the compound (0.1 g) and dichloromethane (1.3 mL) obtained in ⁇ Step 1> under ice-cooled stirring. , Stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and diisopropyl ether (20 mL) was added. The suspension was filtered to give the title compound (0.12 g) as a white solid.
  • Example 5 Using an aqueous solution (29.7 mL) of sodium alginate (manufactured by Kimika Co., Ltd., ALG-2) prepared to 1% by weight and the compound (27.5 mg) obtained in (Example 5) ⁇ Step 2>, ( Example 4) The same operation as in ⁇ Step 3> was carried out to obtain the title compound (264.8 mg) as a white cotton-like compound.
  • the crude product was purified by silica gel column chromatography (25% ethyl acetate / heptane-100% ethyl acetate, ethyl acetate-20% methanol / ethyl acetate) to give the title compound (0.21 g) as a white amorphous substance. ..
  • the crude product was purified by silica gel column chromatography (25% ethyl acetate / heptane-100% ethyl acetate, ethyl acetate-20% methanol / ethyl acetate).
  • the recovered fraction was concentrated under reduced pressure and dissolved in tert-butyl methyl ether (20 mL). This solution was washed twice with saturated aqueous sodium hydrogen carbonate (5 mL) and water (5 mL), sequentially with saturated brine (5 mL), and dried over anhydrous sodium sulfate.
  • the organic layer was concentrated under reduced pressure to give the title compound (220 mg) as a white amorphous substance.
  • Example 6 Using the compound (0.22 g) obtained in ⁇ Step 2>, the same operation as in (Example 5) ⁇ Step 2> was carried out to obtain the title compound (0.25 g) as a white solid. Got as.
  • Example 4 Using an aqueous solution (49.4 mL) of sodium alginate (manufactured by Kimika Co., Ltd., ALG-2) prepared in 1% by weight and the compound (52.4 mg) obtained in (Example 6) ⁇ Step 3>, ( Example 4) The same operation as in ⁇ Step 3> was carried out to obtain the title compound (485 mg) as a white cotton-like compound.
  • Example 7 The compound (1.20 g) obtained in ⁇ Step 1> was suspended in acetonitrile (24.0 mL). Potassium thioacetate (0.53 g) was added, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (50 mL) and water (20 mL) were added to the reaction solution, and the layers were separated. The organic layer was washed successively with water (20 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with tert-butyl methyl ether, and the solid was collected by filtration and washed with tert-butyl methyl ether. The obtained solid was dried under reduced pressure at 40 ° C. to obtain the title compound (1.27 g) as a white solid.
  • Example 7 To the compound (0.60 g) obtained in ⁇ Step 2>, 4N-hydrogen chloride / 1,4-dioxane (4.2 mL) was added under ice-water cooling to 30 at room temperature. Stir for minutes. 4-Hydrogen chloride / 1,4-dioxane (2.1 mL) was added, and the mixture was stirred at room temperature for an additional 30 minutes. Diisopropyl ether (12.6 mL) was added to the reaction solution, and the obtained precipitate was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give the title compound (0.46 g) as a white solid.
  • Example 7 The compound (160 mg) obtained in ⁇ Step 4> was dissolved in water (8.0 mL), 1N-sodium hydroxide aqueous solution (112 ⁇ L) was added, and the temperature was 25 ° C. for 2 hours. Stirring prepared a 2 wt% solution of the title compound. When the ethanol was precipitated, it became a gel, so the solution as it was was used for the test. Partially treated with ethanol, and the disappearance of the acetyl group was confirmed by NMR.
  • Example 8 The compound (560 mg) obtained in ⁇ Step 1> was dissolved in tetrahydrofuran (11.2 mL). Lithium aluminum hydride (146 mg) was added over 5 minutes, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium sulfate solution (50 drops) was added under ice-water cooling, and the mixture was stirred at the same temperature for 1 hour. The precipitated insoluble material was removed by filtration and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure to give the title compound (569 mg) as a colorless oil.
  • Example 8 The compound (400 mg) obtained in ⁇ Step 2> was dissolved in tetrahydrofuran (8.0 mL). p-Toluenesulfonyl chloride (272 mg), N, N-dimethyl-4-aminopyridine (15 mg) and triethylamine (0.33 mL) were added, and the mixture was stirred at 70 ° C. for 6 hours. Ethyl acetate (25 mL) and water (10 mL) were added to the reaction solution, the mixture was separated, and the aqueous layer was extracted with ethyl acetate (5 mL).
  • Example 8 The compound (224 mg) obtained in ⁇ Step 3> was suspended in acetonitrile (4.5 mL). Potassium thioacetate (87 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (20 mL) and water (10 mL) were added to the reaction solution, and the layers were separated. The organic layer was washed successively with water (10 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / heptane to ethyl acetate) to give the title compound (189 mg) as a white solid.
  • Step 1 Synthesis of S-(2-((tert-butoxycarbonyl) amino) ethyl) benzothioate (EX9-IM-1) 2-aminoethane-1-thiol hydrochloride (3.0 g) and triethylamine (4.1 mL) ) was suspended in methylene chloride (20 mL). A solution of ditert-butyl dicarbonate (6.3 g) in methylene chloride (10 mL) was added under ice-water cooling, and the mixture was stirred at room temperature for 2 hours.
  • EX9-IM-1 2-aminoethane-1-thiol hydrochloride
  • Triethylamine (4.4 mL) and benzoyl chloride (3.7 mL) were added under ice-water cooling, and the mixture was stirred at room temperature for 1 hour.
  • tert-butyl methyl ether (100 mL) and water (50 mL) were added, the mixture was separated, and the aqueous layer was extracted with tert-butyl methyl ether (50 mL).
  • the organic layers were combined, washed successively with water (50 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (heptane-30% ethyl acetate / heptane) to give the title compound (5.2 g) as a colorless oil.
  • Step 3 Synthesis of S- (2- (4-((tert-butoxycarbonyl) amino) butanamide) ethyl) benzothioate (EX9-IM-3) 4-((tert-butoxycarbonyl) amino) butanoic acid (0.50) g), triethylamine (0.36 mL) was dissolved in tetrahydrofuran (10.0 mL). Isobutyl chlorocarbonate (0.34 mL) was added under ice-water cooling, and the mixture was stirred at the same temperature for 20 minutes.
  • Example 9 The compound (0.64 g) and triethylamine (0.75 mL) obtained in ⁇ Step 2> were added at the same temperature, and the mixture was stirred at the same temperature for 1.5 hours. Ethyl acetate (20 mL) and water (10 mL) were added to the reaction solution, and the layers were separated. The organic layer was washed successively with semi-saturated aqueous sodium hydrogen carbonate (10 mL), water (10 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-80% ethyl acetate / heptane) to give the title compound (0.74 g) as a white solid.
  • ⁇ Step 5> Synthesis of S- (2- (4-aminobutanamid) ethyl) benzothioate group-introduced alginic acid (AL-EX-9) Sodium alginate (manufactured by Kimika Co., Ltd., ALG-2) aqueous solution (20 mL) prepared in 1% by weight. And (Example 9) using the compound (61 mg) obtained in ⁇ Step 4>, the same operation as in (Example 1) ⁇ Step 3> was carried out to obtain the title compound (198 mg) as a white solid. ..
  • Example 9 The compound (25 mg) obtained in ⁇ Step 5> was dissolved in water (2.48 mL), 1N-sodium hydroxide aqueous solution (17 ⁇ L) was added, and the temperature was 25 ° C. for 2 hours. Stirring prepared a 1 wt% solution of the title compound.
  • the crude product was purified by silica gel column chromatography (25% ethyl acetate / heptane-100% ethyl acetate, ethyl acetate-20% methanol / ethyl acetate) to give a fraction containing the title compound (124 mg).
  • Step 6> Synthesis of methyl S-benzoyl-N-glycyl-L-cystine group-introduced alginate (AL-EX-10) Sodium alginate (manufactured by Mochida Pharmaceutical Co., Ltd., A-2) aqueous solution (19.78 mL) prepared in 1% by weight. In contrast, at room temperature, 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (45.76 mg), 1 molar concentration-sodium alginate (45). 8.8 ⁇ L) was added.
  • Example 10 The compound (50 mg) obtained in ⁇ Step 6> was dissolved in water (2.48 mL), 1N-sodium hydroxide aqueous solution (21.2 ⁇ L) was added, and 2 at room temperature. Stir for hours to prepare a 2 wt% solution of the title compound.
  • Step 1 Synthesis of N-((tert-butoxycarbonyl) -L-phenylalanine) -S-trityl-L-cysteine (EX11-IM-1) (tert-butoxycarbonyl) -L-phenylalanine [CAS: 13734-34- 4]
  • EX11-IM-1 tert-butoxycarbonyl
  • N-methylmorpholine 82.9 ⁇ L
  • isobutyl chlorophosphate 99 ⁇ L
  • Step 3> An aqueous solution (19.78 mL) of sodium alginate (manufactured by Mochida Pharmaceutical Co., Ltd., A-2) prepared to 1% by weight and the compound EX10-IM-5 (15.23) obtained in (Example 11) ⁇ Step 2>.
  • the title compound (179 mg) was obtained as a white solid by performing the same operation as in ⁇ Step 6> of (Example 10) using (mg).
  • Example 11 The compound AL-EX-11 (50 mg) obtained in ⁇ Step 3> was dissolved in water (2.48 mL) to provide 1N-sodium hydroxide aqueous solution (18.2 ⁇ L). In addition, the mixture was stirred at room temperature for 2 hours to prepare a 2 wt% solution of the title compound.
  • the crude product was purified by silica gel column chromatography (25% ethyl acetate / heptane-100% ethyl acetate, ethyl acetate-20% methanol / ethyl acetate) to give the title compound (0.581 g) as a white amorphous substance.
  • Step 3 Synthesis of S-benzoyl-N-glycylglycyl-L-cysteine group-introduced alginic acid (AL-EX-12) In an aqueous solution (49.44 mL) of sodium alginate (manufactured by Mochida Pharmaceutical Co., Ltd., A-2) prepared in 1% by weight. In contrast, at room temperature, 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (114.4 mg), 1 molar concentration-alginate aqueous solution (114. 4 ⁇ L) was added.
  • A-EX-12 S-benzoyl-N-glycylglycyl-L-cysteine group-introduced alginic acid
  • Example 12 The compound AL-EX-12 (50 mg) obtained in ⁇ Step 3> was dissolved in water (2.48 mL) to provide 1N-sodium hydroxide aqueous solution (19.4 ⁇ L). In addition, the mixture was stirred at room temperature for 2 hours to prepare a 2 wt% solution of the title compound.
  • ⁇ Step 3> Synthesis of S-benzoyl-N-glycyl-L-cysteine group-introduced alginic acid (AL-EX-13) Sodium alginate (manufactured by Mochida Pharmaceutical Co., Ltd., A-2) aqueous solution (49.44 mL) prepared to 1% by weight and (Example 13) Using the compound EX13-IM-5 (45.33 mg) obtained in ⁇ Step 2>, the same operation as in (Example 12) ⁇ Step 3> was carried out to obtain the title compound (Example 12). 468 mg) was obtained as a white solid.
  • Example 13 The compound AL-EX-13 (50 mg) obtained in ⁇ Step 3> was dissolved in water (2.478 mL), and 1N-sodium hydroxide aqueous solution (21.8 ⁇ L) was added. In addition, the mixture was stirred at room temperature for 2 hours to prepare a 2 wt% solution of the title compound.
  • Step 1 Synthesis of N-((tert-butoxycarbonyl) L-alanine) -S-trityl-L-cysteine (EX14-IM-1) (tert-butoxycarbonyl) -L-alanine [CAS: 15761-38-3] ( 260.5 mg) was dissolved in tetrahydrofuran (20 mL). N-Methylmorpholine (151 ⁇ L) and isobutyl chloroformate (181 ⁇ L) were gradually added to this solution under ice-cooled stirring. The mixture was stirred at the same temperature for 25 minutes.
  • benzoyl chloride (0.335 mL) was added dropwise under ice-cooled stirring, and the mixture was stirred at room temperature for 17 hours. Further, benzoyl chloride (0.335 mL) was added under ice-cooled stirring, and the mixture was stirred at room temperature for 3 hours. Diisopropyl ether (80 mL) was added, the suspension was stirred at room temperature overnight, filtered and dried under reduced pressure to give the title compound (0.271 g) as a beige solid.
  • Step 3 Synthesis of N- (L-alanyl) -S-benzoyl-L-cysteine group-introduced alginic acid (AL-EX-14) Sodium alginate (manufactured by Mochida Pharmaceutical Co., Ltd., A-2) aqueous solution (39. 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (121.8 mg), 1 molar concentration- Alginate aqueous solution (91 ⁇ L) was added.
  • Example 14 The compound AL-EX-14 (100 mg) obtained in ⁇ Step 3> was dissolved in water (4957 ⁇ L), 1N-sodium hydroxide aqueous solution (42 ⁇ L) was added, and the mixture was added at room temperature. Stirring for 2 hours prepared a 2 wt% solution of the title compound.
  • benzoyl chloride (0.19 mL) was added at room temperature, and the mixture was stirred at room temperature for 17 hours and 50 minutes. Further, benzoyl chloride (0.095 mL) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours, the same amount of benzoyl chloride was added, and the mixture was stirred at room temperature for 18 hours. Then, benzoyl chloride (0.19 mL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours and 40 minutes.
  • Step 3> Synthesis of N- (3-aminopropanol) -S-benzoyl-L-cysteine group-introduced alginic acid (AL-EX-15) Sodium alginate (manufactured by Mochida Pharmaceutical Co., Ltd., A-2) aqueous solution prepared in 1% by weight (A-2) Using the compound EX15-IM-2 (37.5 mg) obtained in (39.5 mL) and (Example 15) ⁇ Step 3>, the same operation as in (Example 14) ⁇ Step 3> is performed. As a result, the title compound (0.348 g) was obtained as a white solid.
  • Example 15 The compound AL-EX-15 (100 mg) obtained in ⁇ Step 3> was dissolved in water (4957 ⁇ L), 1N-sodium hydroxide aqueous solution (42 ⁇ L) was added, and the mixture was added at room temperature. Stirring for 2 hours prepared a 2 wt% solution of the title compound.
  • Step 3> Synthesis of S-benzoyl-N-glycyl-L-prolyl-L-cysteine group-introduced alginic acid (AL-EX-16) 1% by weight of sodium alginate (manufactured by Mochida Pharmaceutical Co., Ltd., A-2) aqueous solution (39.
  • A-EX-16 S-benzoyl-N-glycyl-L-prolyl-L-cysteine group-introduced alginic acid
  • A-2 sodium alginate
  • Example 16 The compound AL-EX-16 (30 mg) obtained in ⁇ Step 3> was dissolved in water (1484 ⁇ L), 1N-sodium hydroxide aqueous solution (16 ⁇ L) was added, and the mixture was added at room temperature. Stirring for 2 hours prepared a 2 wt% solution of the title compound.
  • the introduction rate of the reactive group means a value obtained by expressing the number of the reactive groups introduced per uronic acid monosaccharide unit, which is a repeating unit of alginic acid, as a percentage.
  • the reactive group or complementary reactive group introduction rate (mol%) was calculated by 1 H-NMR integration ratio.
  • the amount of alginic acid required to calculate the introduction rate is measured by the carbazole sulfate method using a calibration curve, and the amount of reactive groups or complementary reactive groups is measured by an absorbance measurement method using a calibration curve. You can also do it.
  • the gel was filtered.
  • AKTA Explorer 10S was used as a chromatograph device, and a 10 mmol / L phosphate buffer solution (pH 7.4) containing 0.15 mol / L NaCl was used as a developing solvent, and the flow rate was 0.8 mL / min at room temperature. It was carried out in. Chromatograms of each sample were prepared by monitoring absorption at 220 nm, 240 nm or 235 nm. Alternatively, absorption at 215 nm was monitored. The peak analysis of the obtained chromatogram was performed by Unicorn 5.31 software (GE Healthcare Science Co., Ltd.).
  • the molecular weight of the cross-linking group-introduced alginic acid is bluedextran (molecular weight 2 million Da, SIGMA), tyroglobulin (molecular weight 669000 Da, GE Healthcare Science), ferritin (molecular weight 440,000 Da, GE Healthcare Science).
  • the molecular weight (Mi) at the elution time i of the previously obtained chromatogram was calculated.
  • the absorbance at the elution time i was read as Hi, and the weight average molecular weight (Mw) was calculated from these data from the following formula.
  • the molecular weight of sodium alginate before the introduction of the reactive group was determined as follows. That is, each alginic acid was weighed in consideration of drying weight loss, and ultrapure water was added to prepare a 1% aqueous solution. Then, it was diluted to a 10 mmol / L phosphate buffer solution (pH 7.4) containing NaCl having an alginic acid concentration of 0.2% and a solution composition of 0.15 mol / L.
  • the weight average molecular weight of sodium alginate before the introduction of the cross-linking group was determined by the same method as the calculation method of the molecular weight of the cross-linking group-introduced alginic acid.
  • Hi was calculated from the data of the differential refractometer.
  • the molecular weight of sodium alginate (manufactured by Kimika Co., Ltd., ALG-2) before the introduction of the cross-linking group used in (Example 1) to (Example 3) and (Example 7) to (Example 9) is It was eluted broadly from 2.6 million Da to 145,000 Da, and the weight average molecular weight was calculated to be 1.46 million Da.
  • the molecular weight of sodium alginate (ALG-2 manufactured by Kimika Co., Ltd.) before the introduction of the cross-linking group used in Examples 4 to 6 was eluted broadly from 9600 Da to 2.51 million Da, and the weight average. The molecular weight was calculated to be 1.38 million Da.
  • the molecular weights of sodium alginate (manufactured by Mochida Pharmaceutical Co., Ltd., A-2) before the introduction of the cross-linking group used in Examples 10 to 16.1 are the molecular weights shown in Table 1 above.
  • Example 2 An alginic acid aqueous solution (2-1) is obtained by dissolving an alginic acid derivative (AL-EX-2) produced in the same manner as in ⁇ Step 3> in water so as to have a concentration of 0.5% by weight. It was. Further, 2% by weight of an alginic acid derivative (AL-EX-7.) Produced in the same manner as in (Example 7), (Example 10), (Example 11), (Example 12) and (Example 13).
  • Alginic acid aqueous solution (2-1) and alginic acid aqueous solution (7-1), (10-1), (11-1), (12-1) or (13-1) are mixed in equal amounts of 250 ⁇ L each, and the concentration is 30.
  • 40 mL of an mmol / L calcium chloride solution was added, and the mixture was stirred for 5 minutes to obtain an alginate gel.
  • This gel was washed once with 10 mL of PBS to obtain a chemically crosslinked alginate gel. 19.5 mL of PBS was added to this gel, and the mixture was shaken at 37 ° C. to recover the aqueous solution over time, and the same amount of PBS as the recovered amount was replenished.
  • Fig. 1 The result shown in Fig. 1 was obtained.
  • the crosslinked alginate gel (beads) had a disintegration rate of 1% or less after 24 hours and a disintegration rate of 40% or less after 96 hours, so that the stability of the gel could be confirmed. That is, it was suggested that the produced (bead) structure maintained its structure for a long period of time due to the formation of chemical crosslinks by the Michael reaction.
  • the alginic acid concentration in the recovered aqueous solution was measured by the carbazole sulfate method, and the value obtained by correcting the amount of alginic acid in the aqueous solution at each time point with the already recovered amount of alginic acid was calculated from the alginic acid concentration at all time points and the alginic acid concentration after the test was completed.
  • the value divided by the amount of alginic acid divided by the amount of alginic acid was expressed as a percentage, and the disintegration rate was used as an index of gel stability.
  • the result shown in Fig. 2 was obtained.
  • the crosslinked alginate gel (beads) had a disintegration rate of about 40% even after 24 hours, confirming the stability of the gel. That is, it was suggested that the structure is maintained for a long period of time even in the (bead) structure produced by EDTA treatment.
  • Example 5 An alginic acid aqueous solution (5-1) is obtained by dissolving an alginic acid derivative (AL-EX-5) produced in the same manner as in ⁇ Step 3> in water so as to have a concentration of 1.0% by weight. It was. Further, a 2 wt% alginic acid derivative (AL-EX-7.1) solution produced in the same manner as in (Example 7) and (Example 10), (Example 11), (Example 12) and (Example).
  • Alginic acid aqueous solution (5-1) and alginic acid aqueous solution (7-2), (10-2), (11-2), (12-2) or (13-2) are mixed in equal amounts of 250 ⁇ L each, and the concentration is 30.
  • 40 mL of an mmol / L calcium chloride solution was added, and the mixture was stirred for 5 minutes to obtain an alginate gel.
  • This gel was washed once with 10 mL of PBS to obtain a chemically crosslinked alginate gel. 19.5 mL of PBS was added to this gel, and the mixture was shaken at 37 ° C. to recover the aqueous solution over time, and the same amount of PBS as the recovered amount was replenished.
  • the alginic acid concentration in the recovered aqueous solution was measured by the carbazole sulfate method, and the value obtained by correcting the amount of alginic acid in the aqueous solution at each time point with the already recovered amount of alginic acid was calculated from the alginic acid concentration at all time points and the alginic acid concentration after the test was completed.
  • the value divided by the amount of alginic acid divided by the amount of alginic acid was expressed as a percentage, and the disintegration rate was used as an index of gel stability.
  • the results shown in Fig. 4 were obtained.
  • the crosslinked alginate gel (beads) had a disintegration rate of about 30% even after 24 hours, confirming the stability of the gel. That is, it was suggested that the structure is maintained for a long period of time even in the (bead) structure produced by EDTA treatment.
  • Example 2 An alginic acid aqueous solution (2-3) is obtained by dissolving an alginic acid derivative (AL-EX-2) produced in the same manner as in ⁇ Step 3> in water so as to have a concentration of 1.0% by weight. It was. Further, an equal amount of PBS was added to the 2% by weight alginic acid derivative (AL-EX-7.1) solution and the (AL-EX-16.1) solution produced by the same method as in (Example 7) to 1.0. Alginic acid aqueous solution (7-2) and (16-1) were obtained in% by weight.
  • the result shown in Fig. 8 was obtained.
  • the crosslinked alginate gel (beads) had a disintegration rate of 15% or less after 24 hours and a disintegration rate of 20% or less after 96 hours, so that the stability of the gel could be confirmed. That is, it was suggested that the produced (bead) structure maintained its structure for a long period of time due to the formation of chemical crosslinks by the Michael reaction.
  • a calcium chloride solution (3.5 mL) having the same concentration was added, and the mixture was allowed to stand for 5 minutes.
  • the gel was washed twice with 5 mL of saline to give a chemically crosslinked alginate gel.
  • 19.5 mL of 5 mM ethylenediaminetetraacetic acid dipotassium dihydrate (EDTA.2K) / physiological saline aqueous solution was added, and the mixture was shaken at 37 ° C. and the aqueous solution was recovered 24 hours later.
  • the same amount of 5 mM EDTA ⁇ 2K / physiological saline solution was replenished.
  • the result shown in Fig. 9 was obtained.
  • the crosslinked alginate gel (beads) had a disintegration rate of about 40% even after 24 hours, confirming the stability of the gel. That is, it was suggested that the structure is maintained for a long period of time even in the (bead) structure produced by EDTA treatment.
  • alginic acid aqueous solution (2-2) or (5-2) and alginic acid aqueous solution (7-1), (10-1), (11-1), (12-1) or (13-1) Equal amounts were mixed one by one, 40 mL of a calcium chloride solution having a concentration of 30 mmol / L was added, and the mixture was stirred for 5 minutes to obtain an alginate gel.
  • This gel was washed once with 10 mL of physiological saline to obtain a chemically crosslinked alginate gel containing fluorescein isothiocyanate-dextran. 19.5 mL of physiological saline was added to this gel, and the mixture was shaken at 37 ° C.
  • the result shown in Fig. 5 was obtained.
  • the transmittance after 3 hours was about 14 to about 20%.
  • the transmittance after 24 hours was about 30 to about 37%.
  • the transmittance after 3 hours was about 17 to about 27%.
  • the transmittance after 24 hours was about 31 to about 42%.
  • Example 2 An alginic acid aqueous solution was prepared by dissolving an alginic acid derivative (AL-EX-2) produced in the same manner as in ⁇ Step 3> in water so as to have a concentration of 2.0% by weight. To this alginic acid aqueous solution (1.0 mL) was added fluorescein isothiocyanate-dextran (Sigma Aldrich, FD150S) (0.4 mL) and PBS (0.6 mL) having a molecular weight of 150,000 prepared at 1 mg / mL.
  • fluorescein isothiocyanate-dextran Sigma Aldrich, FD150S
  • PBS 0.6 mL having a molecular weight of 150,000 prepared at 1 mg / mL.
  • a 1.0% alginic acid aqueous solution (2-4) containing 0.2 mg / mL fluorescein isothiocyanate-dextran was obtained. Further, an equal amount of PBS was added to the 2% alginic acid derivative (AL-EX-7.1) solution and the (AL-EX-16.1) solution prepared in the same manner as in (Example 7) and (Example 16). In addition, the content was adjusted to 1.0% by weight to obtain aqueous alginic acid solutions (7-2) and (16-1).
  • the alginic acid aqueous solution (2-4) and the alginic acid aqueous solution (7-2) or (16-1) were mixed in equal amounts of 300 ⁇ L each, and pipetting was performed three times. 500 ⁇ L of this solution was dispensed into a calcium chloride solution (2.5 mL) having a concentration of 55 mmol / L, shaken lightly, and then allowed to stand for 5 minutes. Further, a calcium chloride solution (3.5 mL) having the same concentration was added, and the mixture was allowed to stand for 5 minutes. This gel was washed twice with 5 mL of physiological saline to obtain a chemically crosslinked alginate gel containing fluorescein isothiocyanate-dextran.
  • the dextran concentration in the recovered aqueous solution was measured by a fluorescence quantification method (excitation light: 485 nm, fluorescence: 535 nm), and the value obtained by dividing the dextran amount at each time point by the dextran amount after the test was completed is the transmittance. And said.
  • the result shown in Fig. 10 was obtained.
  • the transmittance after 3 hours was about 5 to about 10%.
  • the transmittance after 24 hours was about 26 to about 37%.

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