WO2017191827A1 - Polyrotaxane dégradable intérieurement et son procédé de synthèse - Google Patents

Polyrotaxane dégradable intérieurement et son procédé de synthèse Download PDF

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WO2017191827A1
WO2017191827A1 PCT/JP2017/017133 JP2017017133W WO2017191827A1 WO 2017191827 A1 WO2017191827 A1 WO 2017191827A1 JP 2017017133 W JP2017017133 W JP 2017017133W WO 2017191827 A1 WO2017191827 A1 WO 2017191827A1
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group
linear polymer
polyrotaxane
degradable
linear
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PCT/JP2017/017133
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Japanese (ja)
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由井　伸彦
篤志 田村
慶紀 有坂
麻由 伏見
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国立大学法人 東京医科歯科大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D171/00—Coating compositions based on polyethers obtained by reactions forming an ether link in the main chain; Coating compositions based on derivatives of such polymers
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J201/00—Adhesives based on unspecified macromolecular compounds

Definitions

  • the present invention relates to a degradable polyrotaxane compound having at least one degradable bond inside a linear polymer, and a synthesis method thereof.
  • Polyrotaxane is a supramolecule having a skeleton in which a linear polymer penetrates a plurality of cyclic molecular cavities.
  • PEG polyethylene glycol
  • CD cyclodextrin
  • a polyrotaxane can be prepared by modifying a bulky functional group (blocking group) at the end of the linear polymer of the inclusion complex.
  • Patent Document 1 a polyrotaxane in which a functional group containing a biodegradable bond is arranged between both ends of a linear polymer and a blocking group is synthesized. It has been shown that the degradation of the entire polyrotaxane is induced with dissociation.
  • Conventional degradable polymers have the property that only a part modified with a degradable group is sequentially decomposed to lower the molecular weight over time (Non-patent Documents 1 and 2), but degradable polyrotaxanes are produced by dissociation of blocking groups.
  • An object of the present invention is to provide a degradable polyrotaxane compound having at least one decomposable bond inside a linear polymer.
  • Another object of the present invention is to provide a method for producing a degradable polyrotaxane compound having at least one degradable bond inside a linear polymer. All of the degradable polyrotaxane compounds reported so far have degradable bonds at both ends of the linear polymer chain, and two degradable bonds must be arranged for one molecule of polyrotaxane. Therefore, the synthesis method required 6 to 7 steps or more.
  • Another object of the present invention is to provide a composition for various uses, which contains a degradable polyrotaxane compound having at least one degradable bond inside a linear polymer.
  • the present inventors have synthesized a linear polymer in which a functional group containing a bond that can be decomposed in an in vivo environment is arranged in the main chain away from the terminal site, and this linear polymer is a large number of cyclic molecules.
  • polyrotaxane a supramolecule penetrating through the cavity of (for example, cyclodextrin) with high purity and high yield.
  • This polyrotaxane has a new dissociation mechanism in which all cyclic molecules are released from the linear polymer as the degradable part (degradable bond) in the linear polymer is decomposed by an external stimulus.
  • the type of degradable bond can be selected to be decomposed as needed for treatment or diagnosis at any site / environment such as tissue or intracellular location, various stimuli in specific organelles (specific enzymes, etc.) It is possible to precisely prepare an intracellular degradable polyrotaxane that dissociates in response to.
  • a wide variety of biodegradable three-dimensional cross-linked bodies having a polyrotaxane skeleton can be prepared based on modifications such as polymerizable groups to cyclodextrin (CD), so that they can be cross-linked when applied to tissue regeneration or dental treatment. Physical properties of the body (mechanical strength, tissue adhesion, cell differentiation / proliferation, etc.) can be freely reduced according to the healing process and therapeutic purpose of the application site.
  • the linear polymer has the following formula: X 1 -Y 0 (-Z i -Y i) i -X 2 Wherein X 1 and X 2 are the same or different end groups, Y 0 and Y i are the same or different linear polymer moieties, and Z i is a degradable moiety , (-Z i -Y i ) i indicates that there are i repeating units composed of a degradable portion Y and a linear polymer portion Z, and each Z i and Y i in the linear polymer is the same However, the polyrotaxane compound according to [1], wherein i is an integer of 1 to 500.
  • the linear polymer has the following formula: X 1 -Y 0 -Z 1 -Y 1 -X 2 Has a structure shown in, wherein, X 1 and X 2 are the same or different terminal group, Y 0 and Y 1 are identical or different linear polymeric moiety, Z 1 is a degradable moiety
  • the decomposable moiety includes at least one decomposable group, and the decomposable group includes a p-methoxyphenacyl group, a 2-nitrobenzyl group, a 2-nitrobenzyloxycarbonyl group, and 2-nitrophenylethylene.
  • Glycol group benzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, ⁇ , ⁇ -dimethyl-3,5-dimethoxybenzyloxycarbonyl group, 3-nitrophenyl group, 3-nitrophenoxy group, 3,5- Dinitrophenoxy group, 3-nitrophenoxycarbonyl group, phenacyl group, 4-methoxyphenacyl group, ⁇ -methylphenacyl group, 3,5-dimethoxybenzoinyl group, 2,4-dinitrobenzenesulfenyl group, (coumarin -4-yl) methyl group, 7-nitroindolinyl group, arylazophosphate, [1] to [5] selected from the group consisting of a tellurium bond, a Schiff base bond, a carbamate bond, a peptide bond, an ether bond, an acetal bond, a hemiacetal bond, a disulfide bond, an organic peroxide, and an acylhydrazine
  • the polyrotaxane compound according to any one of the above [7] The polyrotaxane compound according to any one of [1] to [6], wherein the cyclic molecule is selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin. [8] The polyrotaxane compound according to any one of [1] to [7], wherein the cyclic molecule has one or more substituents.
  • the substituent is 2-hydroxyethoxyethyl (HEE), hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyethoxyethyl, N, N-dimethylaminoethyl, carboxyl, methyl, sulfo Group, primary amino group, polyethylene glycol, collagen, transferrin, RGD peptide, oligoarginine, (meth) acryloyl group, (meth) acryloyloxy group, (meth) acryloylamino group, (meth) acryloylthio group, vinyl group, aryl group
  • the polyrotaxane compound according to [8] which is selected from the group consisting of a group, a styryl group, and a (meth) acrylamide group.
  • the linear polymer portion is selected from the group consisting of polyethylene glycol, polypropylene glycol, a copolymer of polyethylene glycol and polypropylene glycol, polyethyleneimine, polyamino acid, and polymethyl vinyl ether, [1] to [9] ]
  • the terminal groups are 2,4-dinitrophenyl group, 3,5-dinitrophenyl group, cyclodextrin, adamantane group, O-triphenylmethyl (O-Trt) group, S-triphenylmethyl (S-Trt) ) Group, N-triphenylmethyl (N-Trt) group, N-tritylglycine, benzyloxycarbonyl (Z) group, 9-fluorenylmethyloxycarbonyl (Fmoc) group, benzyl ester (OBz) group, third group Butylcarbonyl (Boc) group, amino acid tertiary butyl ester (OBu group), trityl group, fluorescein, pyrene, substituted benzene, optionally substituted polynuclear aromatic, MPC (2-methacryloyloxyethyl phosphorylcholine), BMA (n -Butyl methacrylate), a combination of
  • [12] comprising at least two linear polymer portions each including a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymers are linked via at least one degradable portion.
  • An adhesive composition containing a polyrotaxane compound. comprising at least two linear polymer portions each including a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymers are linked via at least one degradable portion.
  • [14] comprising at least two linear polymer portions each including a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymers are linked via at least one degradable portion.
  • a surface coating agent containing a polyrotaxane compound comprising at least two linear polymer portions each including a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymers are linked via at least one degradable portion.
  • An anti-adhesion agent comprising a polyrotaxane compound.
  • At least two linear polymer portions each including a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymers are linked via at least one degradable portion.
  • a body implant containing a polyrotaxane compound comprising at least two linear polymer portions each including a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymers are linked via at least one degradable portion.
  • At least two linear polymer portions each including a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymers are linked via at least one degradable portion.
  • a tissue regeneration device containing a polyrotaxane compound.
  • [18] comprising at least two linear polymer portions each including a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymers are linked via at least one degradable portion.
  • a pharmaceutical composition for use in treating or preventing a disease comprising a polyrotaxane compound.
  • a subject preferably for a human, comprising a plurality of cyclic molecules and one linear polymer having a terminal group, the linear polymer via at least one degradable moiety
  • a method for the treatment or prophylaxis of a disease comprising the step of administering a pharmaceutical composition comprising a polyrotaxane compound comprising at least two linear polymer moieties linked.
  • a pharmaceutical composition comprising a polyrotaxane compound comprising at least two linear polymer moieties linked.
  • the manufacture of a medicament for the treatment or prevention of a disease it comprises a plurality of cyclic molecules and one linear polymer having a terminal group, and the linear polymer passes through at least one degradable moiety.
  • a polyrotaxane compound comprising at least two linear polymer moieties linked together.
  • the pharmaceutical composition according to [18], wherein the disease is a disease caused by an abnormal cell metabolic function, a disease caused by intracellular cholesterol accumulation, or a disease caused by a dysfunction of autophagy, [19] Or the use according to [20].
  • the diseases are Gaucher disease (Gaucher disease), Niemann-Pick disease type A (Niemann-Pick disease type A), Niemann-Pick disease type B (Niemann-Pick disease type B), Niemann-Pick disease type C (Niemann-Pick disease type C), GM1 gangliosidosis, GM2 gangliosidosis, Krabbe disease (Krabbe disease), metachromatic leukodystrophy, multiple sulfatase deficiency, Farber disease (Farber disease) Disease), mucopolysaccharidosis type I, mucopolysaccharidosis type II, mucopolysaccharidosis type III, mucopolysaccharidosis type IV, mucopolysaccharidosis type VI, mucopolysaccharidosis type VII, mucopolysaccharidosis type IX, sialidosis, galactosialidosis , I-cell disease / mucolipidosis type III
  • At least two linear polymer portions each including a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymers are linked via at least one degradable portion.
  • a method for producing a polyrotaxane compound comprising: a) adding a reactive group to both ends of a linear polymer portion; b) decomposing a linear polymer portion having a reactive group added to both ends; A linear polymer comprising at least two linear polymer moieties linked via at least one degradable moiety, c) reacting the linear polymer with a cyclic molecule A process for obtaining a pseudopolyrotaxane, and d) a step of adding end groups to both ends of the pseudopolyrotaxane.
  • the reactive group added to both ends of the linear polymer portion is selected from the group consisting of an amino group, a carboxyl group, an aldehyde group, a sulfanyl group, an azide group, an alkynyl group, a tosyl group, and an active ester group.
  • At least two lines comprising a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymers are linked via at least one degradable moiety.
  • Polyrotaxane compound including a linear polymer portion in other words, a polyrotaxane compound including a plurality of cyclic molecules and one linear polymer having a terminal group, and having at least one decomposable portion inside the linear polymer Is provided.
  • the degradable polyrotaxane compound according to the present invention has a degradable portion inside the linear polymer main chain, it is decomposed compared to a conventional degradable polyrotaxane compound having degradable bonds at both ends. Larger changes in molecular weight can occur at times, which can dramatically change the basic physical properties of polymers such as viscosity, solubility, and glass transition point. In addition, it is fundamentally different from conventional double-end-decomposable polyrotaxanes, and molecules with a bulky structure such as enzymes are arranged because degradable bonds are placed inside the linear polymer main chain at the end away from the terminal site.
  • the degradable functional polyrotaxane introduces degradable bonds at both ends of the linear polymer chain, it is necessary to arrange two degradable bonds with respect to one molecule of polyrotaxane. Required more than 6-7 steps.
  • the degradable bond is arranged only near the center of the linear polymer, so that the synthesis method is simplified within 4 steps, and the production time is shortened. There is also an advantage that an improvement in the recovery amount can be achieved.
  • FIG. 3 is a diagram showing a 1 H-NMR spectrum of polyrotaxane A having a decomposable group. It is the figure which showed the GPC chart of the polyrotaxane A after ultraviolet irradiation.
  • FIG. 3 is a diagram showing a 1 H-NMR spectrum of polyrotaxane B having a methacryloyl group as a polymerizable group. It is the figure which showed the result of the tension test of the Bis-GMA containing hardening body which does not contain a polyrotaxane. It is the figure which showed the result of the tensile test of the hardening body containing polyrotaxane B.
  • Polyrotaxane, 2-dimethylaminoethyl methacrylate, camphorquinone, 2-hydroxyethyl methacrylate are mixed in a silicone mold (thickness 1 mm, length 15 mm, dumbbell shape with a center width 1 mm, end width 2 mm). It is the figure shown about producing a hardening body by adding the photopolymerization type adhesive agent prepared in this way. It is the graph which showed the micro tensile strength of the non-UV irradiation group and the UV irradiation group about the polyrotaxane of a different mass part.
  • One aspect of the present invention includes a plurality of cyclic molecules and one linear polymer having a terminal group, and the linear polymer is linked via at least one degradable moiety.
  • a polyrotaxane compound containing a linear polymer portion in other words, a plurality of cyclic molecules and one linear polymer having a terminal group, and at least one decomposable inside the linear polymer away from the terminal.
  • the present invention relates to a polyrotaxane compound having a moiety. The present invention is described in detail below.
  • Polyrotaxane (PRX) compound Rotaxane is a macromolecule that is penetrated by a macromolecule and bonds bulky sites to both ends of the macromolecule so that the ring cannot be removed from the shaft due to steric hindrance. .
  • PRX Polyrotaxane
  • one linear polymer penetrates the ring of a plurality of macrocyclic molecules.
  • known molecules can be used, and are not particularly limited.
  • the linear polymer contained in the polyrotaxane has a structure represented by the following formula: X 1 -Y 0 (-Z i -Y i ) i -X 2
  • X 1 and X 2 are the same or different terminal group
  • Y 0 and Y i are identical or different linear polymeric moiety
  • Z i is an exploded moiety
  • (- Z i -Y i I) i indicates that there are i repeating units composed of a decomposable portion Y and a linear polymer portion Z
  • each Z i and Y i in the linear polymer may be the same or different.
  • i is not particularly limited, i is preferably an integer of 1 to 500, more preferably 1 to 10, for example 1 or 2.
  • the linear polymer has a structure in which two linear polymer parts are linked via one degradable part as shown in the following formula: X 1 -Y 0 -Z 1 -Y 1 -X 2
  • X 1 and X 2 are the same or different end groups
  • Y 0 and Y 1 are the same or different linear polymer moieties
  • Z 1 is a degradable moiety.
  • the linear polymer has a structure in which three linear polymer parts are connected via two degradable parts as shown in the following formula: X 1 -Y 0 -Z 1 -Y 1 -Z 2 -Y 2 -X 2
  • X 1 and X 2 are the same or different end groups
  • Y 0 , Y 1 and Y 2 are the same or different linear polymer moieties
  • Z 1 and Z 2 are the same or different degradable moieties. is there.
  • a known polyrotaxane can be appropriately selected.
  • the average molecular weight of the linear polymer is not particularly limited, but is preferably 1000 to 100,000, particularly 2000 to 40000 or 5000 to 20000. Two or more linear polymer portions contained in one linear polymer may be the same as or different from each other.
  • the average molecular weight of the linear polymer portion is not particularly limited, but is preferably 100 to 100,000, particularly 200 to 40,000 or 500 to 20,000.
  • cyclic molecule a conventionally known cyclic molecule can be used.
  • ⁇ , ⁇ or ⁇ -cyclodextrin is preferred, but it may have a cyclic structure similar to this, and examples of such cyclic structure include cyclic polyether, cyclic polyester, cyclic polyetheramine, cyclic Polyamine, cyclophane, crown ether and the like can be mentioned.
  • a preferable cyclic molecule from the viewpoint of the ability to form pseudopolyrotaxane is ⁇ , ⁇ or ⁇ -cyclodextrin, and ⁇ -cyclodextrin is particularly preferable.
  • the cyclic molecule contained in the polyrotaxane according to the present invention may have one or a plurality of substituents.
  • a substituent can be introduced into the hydroxyl group of cyclodextrin.
  • the substituent include 2-hydroxyethoxyethyl (HEE) group, hydroxyethyl group, hydroxypropyl group, hydroxybutyl group, hydroxyethoxyethyl group, N, N-dimethylaminoethyl group (sometimes referred to as DMAE group).
  • the cyclic molecule may contain multiple types of substituents. Examples of the polymerizable group include (meth) acryloyl group, (meth) acryloyloxy group, (meth) acryloylamino group, (meth) acryloyl group derivative group such as (meth) acryloylthio group, vinyl group, aryl group, styryl.
  • the polyrotaxane compound according to the present invention may contain a plurality of types of polymerizable groups. These groups may be directly bonded to the cyclic molecule or may be bonded via a linker.
  • the linker is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the linker may be a carbamate ester bond (—O—CO—NH—), an ester bond (—O—CO—), a carbonate bond (— O-CO-O-), ether bond (-O-) and the like.
  • the combination of the linear polymer and the cyclic molecule a combination of ⁇ -cyclodextrin and polyethylene glycol, a combination of ⁇ -cyclodextrin and poloxamer, or the like is preferable.
  • the synthesis of polyrotaxane by a combination of ⁇ -cyclodextrin and poloxamer is also disclosed in Patent Document 1 described above, the contents of which are also incorporated herein by reference.
  • the ratio between the number of molecules of the linear polymer and the number of molecules of the cyclic molecule is not particularly limited, but is preferably 1: 1 to 1: 500, more preferably 1: 5 to 1: 200. A ratio of 1:10 to 1: 100 is used. That is, preferably 1 to 500 cyclic molecules are contained in one molecule of the linear polymer, more preferably 5 to 200 cyclic molecules, for example, 10 to 100 cyclic molecules may be contained.
  • terminal group also referred to as bulky substituent
  • examples of the terminal group (also referred to as bulky substituent) used in the present invention include 2,4-dinitrophenyl group, 3,5-dinitrophenyl group, cyclodextrin, adamantane group, O-triphenylmethyl (O— Trt) group, S-triphenylmethyl (S-Trt) group, N-triphenylmethyl (N-Trt) group, N-tritylglycine, benzyloxycarbonyl (Z) group, 9-fluorenylmethyloxycarbonyl ( Fmoc) group, benzyl ester (OBz) group, tertiary butylcarbonyl (Boc) group, amino acid tertiary butyl ester (OBu group), trityl group, fluorescein, pyrene, substituted benzene (as substituents, alkyl, alkyloxy, hydroxy) , Hal
  • a polynuclear aromatic which may be substituted (but not limited to these), and may be the same as those described above, but is not limited thereto.
  • One or more substituents may be present. May be selected from the group consisting of, but not limited to, MPC (2-methacryloyloxyethyl phosphorylcholine), BMA (n-butyl methacrylate), a combination of MPC and BMA, and steroids.
  • One preferred end group is an adamantane group.
  • the end group need not be directly linked to the linear polymer moiety, but via a linker moiety known to those skilled in the art (eg, a moiety containing a peptide bond, carbamate bond, ester bond, or ether bond). It may be connected.
  • the polyrotaxane compound according to the present invention includes a plurality of cyclic molecules and one linear polymer having a terminal group, and has at least one decomposable portion inside the linear polymer away from the terminal.
  • the degradable moiety of the polyrotaxane compound according to the present invention includes at least one degradable group.
  • decomposable group examples include p-methoxyphenacyl group, 2-nitrobenzyl group, 2-nitrobenzyloxycarbonyl group, 2-nitrophenylethylene glycol group, benzyloxycarbonyl group, 3,5-dimethoxybenzyloxy Carbonyl group, ⁇ , ⁇ -dimethyl-3,5-dimethoxybenzyloxycarbonyl group, 3-nitrophenyl group, 3-nitrophenoxy group, 3,5-dinitrophenoxy group, 3-nitrophenoxycarbonyl group, phenacyl group, 4 -Methoxyphenacyl group, ⁇ -methylphenacyl group, 3,5-dimethoxybenzoinyl group, 2,4-dinitrobenzenesulfenyl group, (coumarin-4-yl) methyl group, 7-nitroindolinyl group, Photocleavable groups such as arylazophosphate ester units; ester bonds, Schiff bases Various hydrolyzable bonds such as carbamate bonds, peptide bonds, ether bonds,
  • Preferable degradable groups include, for example, a photocleavable group, a disulfide group, and a peptide consisting of 2 to 30 amino acid residues.
  • Peptides may have specific sequences that are recognized and cleaved by enzymes such as specific proteases and peptidases.
  • the position is preferably near the center of the linear polymer, in other words, two linear shapes connected to the degradable portion.
  • the length ratio of the polymer portion is preferably 1: 1, but the position is not limited.
  • the ratio of the lengths of the two linear polymer portions linked to the degradable portion can be any ratio included, for example, from 1: 1 to 1: 4.
  • the degradable part is located in the center of the linear polymer, two linear polymer parts having a length half that of the linear polymer are generated along with the decomposition of the decomposable part. Cyclic molecules are released from the non-existing ends.
  • the ratio of the lengths of the linear polymer portions connected to each degradable portion is also preferably 1: 1, but there is no particular limitation. It can be any ratio comprised between 1: 1 and 1: 4.
  • the number average molecular weight of the polyrotaxane according to the present invention is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably about 10,000 to 500,000.
  • the polyrotaxane compound according to the present invention can be used as a dental adhesive. Since the photodegradable polyrotaxane having a polymerizable functional group introduced into a plurality of cyclodextrins (CD) functions as a crosslinking agent, a three-dimensional structure can be easily produced by copolymerizing with other monomers. Furthermore, the three-dimensional structure can be decomposed by irradiation with ultraviolet rays to reduce the mechanical strength.
  • CD cyclodextrins
  • a photodegradable polyrotaxane crosslinking agent when used as a resin monomer in a dental material, it can be developed into a dental adhesive that is cured by irradiation with visible light and decomposed by irradiation with ultraviolet light.
  • a photodegradable polyrotaxane crosslinking agent when used as a resin monomer in a dental material, it can be developed into a dental adhesive that is cured by irradiation with visible light and decomposed by irradiation with ultraviolet light.
  • Seo et al. Reported the construction of a three-dimensional structure using a photodegradable polyrotaxane in which nitrobenzyl, which is photolyzed by ultraviolet irradiation, is arranged between both ends of a linear polymer and a blocking group (Seo). et al., ACS Macro Lett., 4, 1154, 2015).
  • one embodiment of the present invention includes a plurality of cyclic molecules and one linear polymer having a terminal group, and the linear polymer is linked via at least one degradable moiety.
  • the present invention relates to an adhesive composition containing a polyrotaxane compound containing at least two linear polymer moieties.
  • Another embodiment of the present invention includes a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymer is linked via at least one degradable moiety.
  • the present invention relates to a dental material composition containing a polyrotaxane compound containing two linear polymer parts.
  • the above composition according to the present invention may further contain a polymerizable monomer.
  • the polyrotaxane compound contained in the composition according to the present invention is preferably soluble in a solution of a polymerizable monomer.
  • the polymerizable monomer for example, those having at least one polymerizable group in the molecule such as a polymerizable unsaturated group, a ring-opening polymerizable group, and a polycondensable group can be used.
  • Conventionally known polymerizable monomers used in known adhesive compositions can be used without limitation. These polymerizable monomers cause a polymerization initiation reaction by the action of heat, a polymerization initiator, gamma rays, electrolysis, plasma, and the like.
  • polymerizable monomer examples include 2-ethylhexyl (meth) acrylate, glycidyl (meth) acrylate, benzyl (meth) acrylate, ethylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, triethylene glycol di ( And (meth) acrylate, methyl (meth) acrylate, 4-methacryloxyethyl trimellitate anhydride and the like.
  • the composition according to the present invention may further contain a polymerization initiator.
  • a polymerization initiator conventionally known polymerization initiators used for conventionally known radical polymerization, anionic polymerization, cationic polymerization, polyaddition reaction, polycondensation reaction, coupling reaction, inorganic synthetic polymer synthesis and the like can be used.
  • radical polymerization initiators used for photopolymerization include benzoin methyl ether, benzyl dimethyl ketal, benzophenone, 4,4′-dimethylbenzophenone, diacetyl, 2,3-pentadione benzyl, camphorquinone, 9,10-phenone. Examples thereof include nantraquinone and 9,10-anthraquinone.
  • the polyrotaxane compound according to the present invention can be used as a coating agent on the surface of a material.
  • a coating agent on the surface of a material.
  • various functional groups and cell-adhesive oligopeptides to CD
  • Seo et al. Can control protein-level and cell-level biointerfaces such as inactive surface adsorption of proteins and rapid cell adhesion. (J. Am. Chem. Soc., 2013, 135, 5513).
  • Seo et al. Analyzed, for example, the adsorption of fibrinogen that activates platelets using a polyrotaxane surface obtained by methylating CD.
  • fibrinogen adsorbed on the surface has a suppressed conformational change and is in an inactive state. It has also been reported (Soft Matter, 2012, 8, 5477). It is known that a three-dimensional structure produced using a polyrotaxane has mechanical properties such as collagen fibers constituting skin and blood vessels. That is, it exhibits flexibility for small deformations and high rigidity for large deformations (see, for example, Ito, Polym. J., 2007, 39, 489). Materials with such properties can follow the movements of the body, such as stretching and contracting of muscles and tendons, contraction of the stomach and heart beat, and adhere to tissue composed of cells and extracellular matrix.
  • one embodiment of the present invention includes a plurality of cyclic molecules and one linear polymer having a terminal group, and the linear polymer is linked via at least one degradable moiety.
  • the present invention relates to a surface coating agent containing a polyrotaxane compound containing at least two linear polymer moieties.
  • Another embodiment of the present invention includes a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymer is linked via at least one degradable moiety.
  • the present invention relates to an anti-adhesion agent containing a polyrotaxane compound containing two linear polymer moieties.
  • the polyrotaxane compound according to the present invention can be used as an in-vivo implant or tissue regenerative device by using a three-dimensional structure produced by crosslinking or the like.
  • Seo et al. Can regulate the formation of cytoskeletal proteins by controlling the number of cyclodextrin (CD) penetrations, and surface with low surface molecular mobility.
  • CD cyclodextrin
  • the upper mesenchymal stem cells promote the formation of actin fibers, which are cytoskeletal proteins, and differentiate into osteoblasts. On surfaces with high surface molecular mobility, the formation of actin fibers is inhibited and differentiates into adipocytes.
  • hESC human embryonic stem cells
  • pluripotent stem cells are cultured using incubators with polyrotaxane block copolymer surfaces with different molecular motility. It is possible to maintain the undifferentiated state by culturing or to induce differentiation into specific cells.
  • the implant material and cell culture device can be produced by crosslinking a degradable polyrotaxane.
  • a decomposable polyrotaxane is prepared by introducing a functional group that forms a crosslinking point into a linear polymer terminal or in the vicinity of the terminal, or in a cyclic molecule, and can be prepared by crosslinking it alone or with other reactive molecules.
  • the crosslinkable functional group include a vinyl group, an aldehyde group, and a carboxyl group.
  • the reactive molecule used for the crosslinking reaction include vinyl polymerizable monomers, polysaccharides, proteins (polypeptides) and the like.
  • Scaffolds composed of degradable polyrotaxanes are capable of degrading and disappearing after a certain period of time when cell differentiation and proliferation were promoted in vivo by the molecular mobility of polyrotaxanes, and cells or tissues can be integrated with surrounding tissues.
  • one embodiment of the present invention includes a plurality of cyclic molecules and one linear polymer having a terminal group, and the linear polymer is linked via at least one degradable moiety.
  • the present invention relates to an in vivo implant containing a polyrotaxane compound containing at least two linear polymer moieties.
  • Another embodiment of the present invention includes a plurality of cyclic molecules and one linear polymer having a terminal group, wherein the linear polymer is linked via at least one degradable moiety.
  • the present invention relates to a tissue regeneration device containing a polyrotaxane compound containing two linear polymer portions. These implants and tissue regenerators may contain other materials such as collagen and gelatin, preferably bioabsorbable materials.
  • the polyrotaxane compound according to the present invention is used for the treatment of diseases caused by abnormal cell metabolic functions such as lysosomal disease, diseases caused by intracellular cholesterol accumulation, or diseases caused by dysfunction of autophagy. It can be used as an active ingredient of a pharmaceutical composition.
  • a degradable portion of the polyrotaxane compound according to the present invention a degradable group capable of degrading in an acidic environment within a cell and in an acidic environment at pH 4.0 to 6.0 can be employed.
  • Such a polyrotaxane compound is decomposed in an acidic environment, the polyrotaxane skeleton is collapsed, and a cyclic molecule such as ⁇ -CD is released.
  • vesicles such as lysosomes and late endosomes exist in eukaryotic cells including humans, and the lumens of these vesicles are acidified.
  • the pH of the lysosomal lumen is around 5. Therefore, the polyrotaxane compound according to the present invention can be decomposed by being taken into these vesicles.
  • the polyrotaxane compound according to the present invention releases a cyclic molecule such as ⁇ -CD upon decomposition.
  • ⁇ -cyclodextrin when ⁇ -cyclodextrin is released in lysosomes, it can include cholesterol present in lysosomes, thereby causing Niemann-Pick disease type C, which is caused by excessive accumulation of cholesterol in lysosomes. Lysosomal disease can be treated or prevented (see, eg, Tamura and Yui, Sci. Rep., 2014, 4, 4356).
  • one embodiment of the present invention relates to a pharmaceutical composition for treating a disease caused by intracellular cholesterol accumulation.
  • one embodiment of the present invention relates to a method for treating or preventing Niemann-Pick disease type C (NPC).
  • one aspect of the present invention also relates to the use of a polyrotaxane compound in the manufacture of a medicament for treating or preventing Niemann-Pick disease type C (NPC).
  • Preferred acid-decomposable polyrotaxane compounds as pharmaceutical compositions include, for example, compounds having a disulfide bond in the interior of the linear polymer, preferably the central portion, and an N-triphenylmethyl (N-Trt) group at the terminal. included.
  • lysosomal disease more specifically Gaucher disease (Gaucher disease), Neimann-Pick disease type A (Niemann-Pick disease type A), Neiman-Pick disease. B type (Niemann-Pick disease type B), Niemann-Pick disease type C (Niemann-Pick disease type C), GM1 gangliosidosis, GM2 gangliosidosis ("Tay-Sachs Sandhoff type AB").
  • one embodiment of the present invention relates to a pharmaceutical composition for treating or preventing Niemann-Pick disease type C (NPC).
  • one embodiment of the present invention relates to a method for treating or preventing Niemann-Pick disease type C (NPC).
  • one aspect of the present invention also relates to the use of a polyrotaxane compound in the manufacture of a medicament for treating or preventing Niemann-Pick disease type C (NPC).
  • the polyrotaxane compound according to the present invention can be used as an active ingredient of a composition for use in inducing autophagy in cells. Accordingly, one embodiment of the present invention relates to a composition for inducing autophagy in a cell. In another aspect, one embodiment of the present invention relates to a method for inducing autophagy in a cell. Furthermore, one aspect of the present invention also relates to the use of a polyrotaxane compound in the manufacture of a medicament for inducing autophagy in a cell.
  • the methylated polyrotaxane according to the present invention can induce autophagic cell death in cells. It is known to those skilled in the art that autophagic cell death can be used to induce cell death in cancer cells.
  • one aspect of the present invention relates to a pharmaceutical composition for treating cancer, preferably a pharmaceutical composition for treating cancer resistant to apoptosis.
  • one embodiment of the present invention relates to a method for treating cancer, particularly for treating cancer resistant to apoptosis.
  • one aspect of the present invention pertains to the use of polyrotaxane compounds in the manufacture of a medicament for treating cancer.
  • one embodiment of the present invention relates to a pharmaceutical composition for treating or preventing a disease caused by autophagy dysfunction.
  • one embodiment of the present invention relates to a method for treating or preventing a disease caused by a dysfunction of autophagy.
  • one aspect of the present invention also relates to the use of a polyrotaxane compound in the manufacture of a medicament for treating or preventing a disease resulting from autophagy dysfunction.
  • diseases caused by autophagy dysfunction include the above-mentioned lysosomal diseases, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.
  • the polyrotaxane compound according to the present invention can be used as an active ingredient in a pharmaceutical composition used for the treatment or prevention of the above-mentioned diseases. Therefore, one embodiment of the present invention relates to a pharmaceutical composition used for treatment or prevention of diseases.
  • the other components in the pharmaceutical composition according to the present invention are not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include pharmaceutically acceptable carriers. There is no restriction
  • the pharmaceutical composition according to the present invention is water-soluble at around body temperature, for example, 34 ° C to 42 ° C, more preferably 35 ° C to 38 ° C or 37 ° C.
  • an injection Solution, suspension, solid agent for use, etc.
  • inhaled powders for example, a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. are added to the polyrotaxane compound according to the present invention, and subcutaneous, intramuscular, intravenous, etc. are added by a conventional method.
  • An injection for internal use can be produced.
  • the pH adjusting agent and the buffering agent include sodium citrate, sodium acetate, sodium phosphate and the like.
  • Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
  • Examples of the isotonic agent include sodium chloride and glucose.
  • Examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride.
  • the administration method of the pharmaceutical composition according to the present invention is not particularly limited, and for example, either local administration or systemic administration can be selected according to the dosage form of the pharmaceutical composition, the patient's condition, and the like.
  • local administration includes intracerebroventricular administration.
  • the subject of administration of the pharmaceutical composition according to the present invention is not particularly limited and may be appropriately selected depending on the purpose. Examples thereof include humans, mice, rats, cows, pigs, monkeys, dogs, cats and the like. However, it is preferably a human.
  • the dosage of the pharmaceutical composition according to the present invention is not particularly limited, and can be appropriately selected depending on the dosage form, the age and weight of the administration subject, the degree of desired effect, and the like.
  • the administration time of the pharmaceutical composition according to the present invention is not particularly limited and may be appropriately selected depending on the purpose. For example, it may be administered prophylactically to a patient susceptible to the above-mentioned diseases, It may be administered therapeutically to patients presenting with symptoms. Moreover, there is no restriction
  • the degradable polyrotaxane compound according to the present invention can be synthesized more easily and in a shorter time than a conventional degradable polyrotaxane compound having degradable groups at both ends.
  • One embodiment of the present invention includes a plurality of cyclic molecules and one linear polymer having a terminal group, and the linear polymer is connected via at least one degradable moiety.
  • a method for producing a polyrotaxane compound comprising a polymer portion wherein a) a step of adding a reactive group to both ends of the linear polymer portion, b) a linear polymer portion having reactive groups added to both ends To obtain a linear polymer comprising at least two linear polymer moieties linked via at least one degradable moiety, and c) the linear polymer as a cyclic molecule. To a pseudopolyrotaxane, and d) adding a terminal group to both ends of the pseudopolyrotaxane.
  • the reactive group added to both ends of the linear polymer portion is, for example, a leaving group such as an amino group, a carboxyl group, an aldehyde group, a sulfanyl group, an azido group, an alkynyl group, a tosyl group, It may be an active ester group such as a carboxylic acid succinimide ester.
  • the linear polymer may be selected based on the length of the linear polymer.
  • a linear polymer in which two linear polymer parts are connected via one degradable part is selected.
  • reaction solution was dropped into diethyl ether, and the precipitate was collected.
  • the resulting precipitate was dialyzed against ultrapure water using a dialysis membrane (fractionated molecular weight 3,500) for 5 days, and then freeze-dried and recovered as a solid (recovered amount 7.4 g).
  • a solution obtained by dissolving 4.0 g of BOP reagent, 2.2 g of 1-adamantanecarboxylic acid and 2.1 mL of N, N-diisopropylethylamine in 120 mL of N, N-dimethylformamide and the recovered inclusion complex were mixed at room temperature. The reaction was performed for 24 hours.
  • the precipitate formed by dropping the reaction solution into methanol was collected by centrifugation.
  • the operation of dissolving the collected precipitate in dimethyl sulfoxide and precipitating with methanol was repeated several times.
  • the operation of dissolving the collected precipitate in dimethyl sulfoxide and precipitating with water was repeated several times.
  • lyophilization yielded a purified polyrotaxane (polyrotaxane A having a degradable group) (recovery amount 9.2 g).
  • polyrotaxane A having a decomposable group was identified by 1 H-NMR and GPC, and it was confirmed that unencapsulated CD was not contained.
  • FIG. 1 shows the 1 H-NMR spectrum of Polyrotaxane A. Further, when the number of penetrations of ⁇ -CD with respect to PEG was calculated, the number of penetrations of ⁇ -CD was 28.1 molecules.
  • FIG. 2 shows a GPC chart of Polyrotaxane A after ultraviolet irradiation. This result indicates that the axial polymer chain is cleaved by cleavage of nitrobenzene having photodegradability, and a part or all of ⁇ -CD is released from the inclusion state to the non-inclusion state. That is, it was confirmed that the supramolecular structure of polyrotaxane A was decomposed and collapsed by irradiation with ultraviolet rays (254 nm, 2.5 mW / cm 2 ).
  • 1,4-diazabicyclo [2.2.2] octane 500 mg was added, and the mixture was reacted at room temperature for 24 hours. After the reaction, dialysis was carried out for 2 days against dimethyl sulfoxide using a dialysis membrane (fraction molecular weight 3,500). Subsequently, dialysis was performed for 2 days against water using the same dialysis membrane (fraction molecular weight 3,500).
  • FIG. 3 shows the 1H-NMR spectrum of Polyrotaxane B. The molecular weight was confirmed by GPC. Moreover, as a result of confirming an absorption spectrum, it confirmed that polyrotaxane B had the absorption derived from a nitrobenzyl group.
  • polyrotaxane B was a predetermined polyrotaxane B having a nitrobenzyl group as a photocleavable group as a decomposable group and a methacryloyl group as a polymerizable group.
  • a solution obtained by dissolving 4.0 g of BOP reagent, 2.2 g of 1-adamantanecarboxylic acid and 2.1 mL of N, N-diisopropylethylamine in 120 mL of N, N-dimethylformamide and the recovered inclusion complex were mixed at room temperature. The reaction was performed for 24 hours.
  • a precipitate formed by dropping the reaction solution into methanol was collected by centrifugation.
  • the operation of dissolving the collected precipitate in dimethyl sulfoxide and precipitating with methanol was repeated several times.
  • the operation of dissolving the collected precipitate in dimethyl sulfoxide and precipitating with water was repeated several times.
  • lyophilization yielded a purified polyrotaxane (polyrotaxane X having no degradable group) (recovered amount 10.1 g).
  • the obtained polyrotaxane (polyrotaxane X having no decomposable group) was identified by 1 H-NMR and GPC, and it was confirmed that unencapsulated CD was not contained.
  • the number of penetrating ⁇ -CD to PEG was 28.8 molecules.
  • Polyrotaxane X was dissolved in 1 mL of dimethyl sulfoxide. Thereafter, ultraviolet rays (254 nm, 2.5 mW / cm 2 ) were irradiated for 1, 5 and 10 minutes, and it was confirmed by gel permeation chromatography (GPC) that there was no change in molecular weight. This result indicates that the axial polymer chain not containing photodegradable nitrobenzene did not respond to ultraviolet irradiation, and ⁇ -CD maintained the inclusion state.
  • GPC gel permeation chromatography
  • 1,4-diazabicyclo [2.2.2] octane 500 mg was added, and the mixture was reacted at room temperature for 24 hours. After the reaction, dialysis was carried out for 2 days against dimethyl sulfoxide using a dialysis membrane (fraction molecular weight 3,500). Subsequently, dialysis was performed for 2 days against water using the same dialysis membrane (fraction molecular weight 3,500).
  • Example 2 Effect of Reducing Maximum Tensile Strength on Photoinduced Degradation of Cured Product Prepared Using Polyrotaxane B Having Hydrophobic and Polymerizable Groups 29.5 parts by mass of polyrotaxane B synthesized in Synthesis Example 2, 2-hydroxy 69.5 parts by mass of ethyl methacrylate, 0.3 part by mass of 2-dimethylaminoethyl methacrylate, and 0.7 parts by mass of camphorquinone were mixed and used as a solution-type photopolymerizable adhesive B.
  • Photopolymerizable adhesive B was added to a dumbbell mold made of silicone, and light was irradiated for 180 seconds with a dental visible light irradiator (700 mW / cm 2 ) to prepare a cured body.
  • the cured product is obtained by adding a photopolymerizable adhesive B to a silicone mold (thickness 1 mm, length 15 mm, center width 1 mm, end width 2 mm) and then applying a visible light irradiator (wavelength (400 to 450 nm, 700 mW / cm 2 ) for 180 minutes to produce a cured product.
  • a comparative cured product was prepared using the same method as described above. 29.5 parts by mass of polyrotaxane Y synthesized in Comparative Synthesis Example 2, 69.5 parts by mass of 2-hydroxyethyl methacrylate, 0.3 parts by mass of 2-dimethylaminoethyl methacrylate, 0.7 parts by mass of camphorquinone These were mixed and used as a solution-type photopolymerizable adhesive Y.
  • the photopolymerizable adhesive Y was added to a silicone dumbbell mold, and light was irradiated for 180 seconds with a dental visible light irradiator (700 mW / cm 2 ) to prepare a cured body.
  • the cured product was obtained by adding a photopolymerizable adhesive Y to a silicone mold (dumb shape having a thickness of 1 mm, a length of 15 mm, a center width of 1 mm, and an end width of 2 mm), and then a visible light irradiator (wavelength). (400 to 450 nm, 700 mW / cm 2 ) for 180 minutes to produce a cured product.
  • the micro tensile strength of the non-UV irradiation group was 45.7 MPa (standard deviation 2.4 MPa), whereas the micro tensile strength of the UV irradiation group was 24.1 MPa.
  • the standard deviation was as low as 4.7 MPa (FIG. 5).
  • the microtensile strength was significantly reduced by the decomposition of polyrotaxane B accompanying the cleavage of the photocleavable group (nitrobenzyl group) by UV irradiation.
  • the micro tensile strength could be greatly reduced by a simple treatment of UV irradiation for a relatively short time.
  • the micro tensile strength of the non-UV irradiation group was 41.3 MPa (standard deviation 4.6 MPa), whereas the micro tensile strength of the UV irradiation group was 38. .2 MPa (standard deviation 4.9 MPa).
  • the photopolymerizable adhesive B prepared using a polyrotaxane B having a nitrobenzyl group that is a photocleavable group as a decomposable group and a methacryloyl group as a polymerizable group It was confirmed that the effect of greatly reducing the micro tensile strength of the prepared cured product was obtained by applying a specific wavelength UV light that acts to cleave a certain nitrobenzyl. For example, it is shown that the adhesiveness can be greatly lowered even in a short operation time by performing a simple operation of irradiating the cured product of the photopolymerizable adhesive B with light that acts to break the degradable bond of polyrotaxane B. It was done.
  • Example 3 Maximum Tensile Strength Reduction Effect on Photo-Induced Decomposition of Cured Product Made by Changing Content of Polyrotaxane B
  • the mass part of polyrotaxane B synthesized in Synthesis Example 2 and polyrotaxane Y synthesized in Comparative Synthesis Example 2 is 9. 5, 29.5, 49.5, 0.3 parts by mass of 2-dimethylaminoethyl methacrylate and 0.7 parts by mass of camphorquinone were fixed, and the total of parts by mass of 2-hydroxyethyl methacrylate was 100 parts by mass. It mixed so that it might become, and was used as a photopolymerization type adhesive agent (FIG. 6).
  • Example 2 is a case where the mass part of the polyrotaxane Y is 29.5, and is described together with Example 3.
  • a photopolymerization adhesive was added to a silicone mold (dumb shape having a thickness of 1 mm, a length of 15 mm, a center width of 1 mm, and an end width of 2 mm), and then a visible light irradiator ( A cured product was produced by irradiation with light at a wavelength of 400 to 450 nm, 700 mW / cm 2 ) for 180 minutes.
  • the photopolymerizable adhesive B prepared using polyrotaxane B having a nitrobenzyl group which is a UV-cleavable group has a small amount of cured product prepared by applying UV light. It was confirmed that the effect of greatly reducing the tensile strength was obtained. It is shown that the adhesiveness can be greatly reduced even in a short working time by a simple operation of irradiating the cured product of the photopolymerizable adhesive B with light that acts to break the degradable bond of polyrotaxane B. It was.
  • the centrally decomposable functional polyrotaxane according to the present invention can be used in various applications by replacing a conventional polyrotaxane having degradable linkers at both ends.
  • Such centrally-resolved functional polyrotaxane has fewer synthetic steps than both-end-resolved type, so there are advantages in manufacturing, and it is also possible to use functional molecules such as peptides that are difficult to introduce at both ends. It becomes.
  • Possible uses include use as a resin monomer in dental materials and use as a therapeutic agent for Niemann-Pick disease type C (NPC), as described above.
  • NPC Niemann-Pick disease type C

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Abstract

La présente invention concerne un composé de polyrotaxane dégradable qui est facilement produit et qui présente de grandes modifications des propriétés physiques pendant la dégradation. Plus spécifiquement, ledit composé de polyrotaxane est obtenu grâce à la synthèse d'un composé de polyrotaxane comprenant au moins deux fractions polymères linéaires dans lesquelles des polymères linéaires sont liés par l'intermédiaire d'au moins une section dégradable. Ce type de composé de polyrotaxane a une section dégradable à l'intérieur d'une chaîne principale de polymère linéaire et, en conséquence, est capable d'avoir un plus grand changement de poids moléculaire pendant la dégradation, par rapport aux composés de polyrotaxane dégradables classiques ayant des liaisons dégradables aux deux extrémités de ceux-ci, et est capable de modifier considérablement les propriétés physiques de base du polymère telles que la viscosité, la solubilité et le point de transition vitreuse.
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WO2023100864A1 (fr) * 2021-11-30 2023-06-08 日東電工株式会社 Couche d'agent collant et/ou couche d'adhésif
WO2023100862A1 (fr) * 2021-11-30 2023-06-08 日東電工株式会社 Adhésif autocollant et/ou adhésif
CN116239708A (zh) * 2023-03-20 2023-06-09 山东滨州智源生物科技有限公司 一种封端聚轮烷及其制备方法和应用
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EP4253446A4 (fr) * 2020-11-26 2024-05-15 Denka Company Ltd Polyrotaxane possédant un groupe amino

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EP4253535A4 (fr) * 2020-11-26 2024-05-15 Denka Company Ltd Polyrotaxane possédant un groupe hydroxy ou un groupe sulfo
EP4253446A4 (fr) * 2020-11-26 2024-05-15 Denka Company Ltd Polyrotaxane possédant un groupe amino
WO2022176887A1 (fr) * 2021-02-18 2022-08-25 国立大学法人九州大学 Matériau de liaison facile à désassembler, corps lié et procédé de désassemblage
JP2022126154A (ja) * 2021-02-18 2022-08-30 国立大学法人九州大学 易解体性接着材料、接合体および解体方法
JP7248328B2 (ja) 2021-02-18 2023-03-29 国立大学法人九州大学 易解体性接着材料、接合体および解体方法
WO2023100863A1 (fr) * 2021-11-30 2023-06-08 日東電工株式会社 Couche d'agent collant et/ou couche d'adhésif
WO2023100864A1 (fr) * 2021-11-30 2023-06-08 日東電工株式会社 Couche d'agent collant et/ou couche d'adhésif
WO2023100862A1 (fr) * 2021-11-30 2023-06-08 日東電工株式会社 Adhésif autocollant et/ou adhésif
CN116239708A (zh) * 2023-03-20 2023-06-09 山东滨州智源生物科技有限公司 一种封端聚轮烷及其制备方法和应用

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