WO2020098673A1 - Polymère et compositions associées - Google Patents

Polymère et compositions associées Download PDF

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WO2020098673A1
WO2020098673A1 PCT/CN2019/117874 CN2019117874W WO2020098673A1 WO 2020098673 A1 WO2020098673 A1 WO 2020098673A1 CN 2019117874 W CN2019117874 W CN 2019117874W WO 2020098673 A1 WO2020098673 A1 WO 2020098673A1
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polymer
group
alkyl
iodine
alkoxy
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PCT/CN2019/117874
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English (en)
Chinese (zh)
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黄建
祝令建
朱林桂
张玉成
李玲
Original Assignee
上海盛迪医药有限公司
上海森辉医药有限公司
江苏恒瑞医药股份有限公司
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Priority to CN201980072305.4A priority Critical patent/CN113348001B/zh
Publication of WO2020098673A1 publication Critical patent/WO2020098673A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • 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
    • 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
    • A61L31/18—Materials at least partially X-ray or laser opaque
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/18—Introducing halogen atoms or halogen-containing groups

Definitions

  • the present disclosure relates to a polymer and its composition, which can be used as an embolization material in medical treatment.
  • embolization is widely used for vascular malformations, such as aneurysms, arteriovenous malformations, fistulas, and tumors. It is to inject some artificial embolic material into the supply blood vessel or the diseased blood vessel of the lesion or organ in a controlled manner to cause occlusion and interrupt the blood supply, so as to achieve the functions of controlling bleeding, treating vascular disease, tumor and eliminating the diseased organ purpose.
  • Products including metal coils, polymer-metal hybrid coils, microparticles, and foam can be used to treat these vascular malformations.
  • US5580568 describes a blood vessel embolizing composition
  • cellulose diacetate polymer a biocompatible solvent (eg DMSO) and a water-insoluble contrast agent (eg tantalum, tantalum oxide and barium sulfate).
  • a biocompatible solvent eg DMSO
  • a water-insoluble contrast agent eg tantalum, tantalum oxide and barium sulfate.
  • US5851508 describes an embolization composition
  • an ethylene-vinyl alcohol copolymer eg DMSO
  • a biocompatible solvent eg DMSO
  • a water-insoluble contrast agent eg tantalum, tantalum oxide and barium sulfate
  • US5695480 describes the inclusion of cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, ethylene-vinyl alcohol copolymer, hydrogel, polyacrylonitrile, polyvinyl acetate, cellulose nitrate, urethane / Carbonate copolymers, biocompatible polymers of styrene / maleic acid copolymers and mixtures thereof, biocompatible solvents (e.g. DMSO, ethanol and acetone) and contrast agents (e.g. tantalum, tantalum oxide, tungsten and sulfuric acid) barium).
  • biocompatible solvents e.g. DMSO, ethanol and acetone
  • contrast agents e.g. tantalum, tantalum oxide, tungsten and sulfuric acid
  • these embolization compositions suspend the radiopaque contrast agent in the polymer solution, so that the contrast agent is dispersed in the polymer and is a heterogeneous dispersion. Therefore, these compositions may not guarantee the effect of a permanent contrast agent, and at the same time, the contrast agent dispersed in the polymer will gradually precipitate or aggregate over time, which may cause serious clinical toxic effects.
  • CN102781974A describes a class of iodobenzyl ether-PVA polymers that have improved stability, but also have a low viscosity but provide a higher concentration of embolic agent and show a clear contrast effect.
  • This class of iodobenzyl Ether-PVA polymers are not biodegradable.
  • CN104717983A describes an acrylic acid containing 2-oxo-2- (1-oxo-1- (1-oxo-1- (2,4,6-triiodophenoxy) propane-2-yloxy ) Liquid suppository polymer of the reaction product of propane-2-yloxy) ethoxy) ethyl ester, hydroxyethyl methacrylate and azobisisobutyronitrile.
  • X is the visualizer part
  • Y is the connecting part
  • Z is the ethylene-vinyl alcohol copolymer.
  • the polymer is soluble in non-physiological solutions and insoluble under physiological conditions.
  • the polymer described in the present disclosure contains an ethylene-vinyl alcohol copolymer part X and a visualizer part XY having a connection, and the ethylene-vinyl alcohol copolymer is connected to the visualizer through a connection part.
  • connection is capable of degrading, allowing separation of the visualization core from the polymer.
  • the linker sensitive to enzymatic hydrolysis may be an ester or an amino acid.
  • the connection sensitive to hydrolysis may be an ester, carbonate, polyester, acetal, or ketal.
  • the connecting portion is an ether or polyether and is not degradable.
  • the linker is a bond (covalent bond).
  • connection part Y of the present disclosure can be introduced by reacting an ethylene-vinyl alcohol copolymer with a visualization agent. Selecting or inserting different kinds of connecting parts (such as the length or number of chains of the connecting parts) can change the physical and chemical properties of the polymer, such as the cohesiveness and precipitation speed of the polymer in physiological saline.
  • the visualization agent may be an iodine compound (a compound containing an iodine structure), especially an aryl group or a heteroaryl group having multiple iodine to impart visualization of the polymer under fluorescence detection and CT imaging.
  • the iodine concentration (content) of the liquid embolization agent is at least about 10% (w / w), at least about 20% (w / w), and at least about 30% (w / w) ), At least about 40% (w / w), at least about 50% (w / w), at least about 60% (w / w).
  • M iodine represents the molecular weight of the iodine atom (ie 126.90)
  • n represents the number of iodine atoms on each aromatic ring (ie 1 to 5)
  • M vinyl means the molar mass of the vinyl repeating unit
  • M vinyl alcohol means vinyl alcohol Molar mass of repeating unit
  • M vinyl alcohol grafting represents the molar mass of vinyl alcohol grafting repeating unit.
  • the iodine content of the polymer in the present disclosure can be determined by an oxygen bomb combustion-potential titration method or inductively coupled plasma-mass spectrometry (ICP-MS) technique.
  • ICP-MS inductively coupled plasma-mass spectrometry
  • the repeating unit of the polymer may be:
  • R is a graft unit having a visualizer portion and a connecting portion.
  • the molar content of vinyl groups (X) in the repeating units of the polymer is 5-94%, preferably 10-60%, more preferably 20-50%, including but not limited to 20mol%, 21mol%, 23mol%, 25mol%, 27mol%, 29mol%, 31mol%, 33mol%, 35mol%, 37mol%, 39mol%, 41mol%, 43mol%, 45mol%, 47mol%, 49mol%, 50mol%.
  • the molar content of vinyl groups (X) in the repeating units of the polymer is 37 mol%.
  • the molar content of the graft unit (z) having a visualizer portion and a connecting portion in the repeating unit of the polymer is 2-40mol%, including but not limited to 2mol%, 3mol%, 4mol%, 5mol %, 7mol%, 9mol%, 11mol%, 13mol%, 15mol%, 17mol%, 19mol%, 21mol%, 23mol%, 25mol%, 27mol%, 29mol%, 31mol%, 33mol%, 35mol%, 37mol%, 39mol%, 40mol%, preferably 5-20mol%.
  • the polymer repeating unit in this disclosure only represents a schematic diagram of the polymer, and R is a graft unit having a visualizer portion and a connecting portion, which represents a case where the hydroxyl group in the polymer is substituted, as follows but not limited to:
  • the polymer represented by X-Y-Z does not mean that the ratio of X, Y, and Z is 1: 1: 1.
  • the ratio of X, Y, and Z is not fixed.
  • the X-Y / Z ratio can be characterized by the degree of hydroxy substitution of the polymer.
  • the degree of substitution (DS) of hydroxyl (-OH) of the polymer described in this disclosure is not limited.
  • the hydroxyl substitution degree (DS) of the polymer is 3% -50%.
  • the degree of substitution (DS) is defined as:
  • DS can be obtained through the The peak area integral of each peak of NMR is calculated.
  • R 1 is selected from alkyl (preferably C 1-6 alkyl, such as methyl, ethyl, propyl), cycloalkyl (preferably C 3-6 cycloalkyl, such as cyclopropyl, cyclopentyl, Cyclohexyl), heterocyclyl (preferably C 3-6 heterocyclyl), aryl or heteroaryl, the alkyl, cycloalkyl, aryl or heteroaryl contains multiple iodine atoms, which may be one Iodine atom, 2 iodine atoms, 3 iodine atoms, 4 iodine atoms or 5 iodine atoms, and optionally one or more selected from deuterium, alkyl (preferably C 1-6 alkyl, such as methyl, Ethyl, propyl), cycloalkyl (preferably C 3-6 cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohex
  • C are each independently selected from alkylene, oxyoxy ( -O-), imino (-NR′-), thionyl (-S-), carbonyl Sulfone group Sulfoxide Phosphoryl Ester group Amido
  • the R ' is selected from hydrogen, alkyl (preferably C 1-6 alkyl), alkoxy (preferably C 1-6 alkoxy), alkenyl (preferably C 2-6 alkenyl), acyl (e.g. C 1-6 alkanoyl, benzoyl, p-toluoyl);
  • alkylene preferably C 1-6 alkylene, such as methylene, ethylene, propylene or n-butylene
  • the alkylene group is optionally selected from one or more alkyl groups (preferably C 1-6 alkyl groups such as methyl, ethyl, propyl) and alkoxy groups (preferably C 1-6 alkoxy groups such as Methoxy, ethoxy, propoxy), alkenyl (preferably C 2-6 alkenyl), alkynyl (preferably C 2-6 alkynyl), aryl, heteroaryl, nitro, nitrile, Hydroxy, SR ', NR' (R "), COOR ', CONR'(R”) are substituted, further, the alkyl, alkoxy,
  • n 0, 1, 2, 3, 4 or 5;
  • n 1 ⁇ 30 (can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29 or 30);
  • o 0 ⁇ 30 (may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29 or 30);
  • R 1 in the polymer represented by formula II is a heteroaryl group, preferably a pyridyl group, the pyridyl group contains a plurality of iodine atoms, which may be 1 iodine atom, 2 iodine atoms , 3 iodine atoms, 4 iodine atoms or 5 iodine atoms.
  • the pyridyl group includes 3 iodine atoms at the C-3, C-4, and C-5 positions.
  • the benzene ring includes 3 iodine atoms at the C-2, C-3, and C-5 positions.
  • the benzene ring includes 3 iodine atoms at the C-2, C-4, and C-6 positions.
  • the benzene ring includes 2 iodine atoms at the C-3 and C-5 positions.
  • the polymer represented by formula II is:
  • R 2 is selected from alkyl (preferably C 1-6 alkyl), alkoxy (preferably C 1-6 alkoxy), cycloalkyl (preferably C 3-6 cycloalkyl), heterocyclyl (preferably C 3-6 heterocyclyl), alkenyl (preferably C 2-6 alkenyl), alkynyl (Preferably C 2-6 alkynyl), hydroxyalkyl (preferably C 1-6 hydroxyalkyl), aryl, heteroaryl, nitro, nitrile, SR ', NR' (R “), COOR ', CONR '(R “), the alkyl group, cycloalkyl group, alkoxy group, hydroxyalkyl group, alkenyl group, aryl group, heteroaryl group is optionally Substituted by '(R "), COOR', CONR '(R"), said R' or R
  • the polymer represented by formula III wherein A and C are each independently selected from alkylene, oxyalkylene (-O-), imino (-NR′-), sulfenyl (-S-), carbonyl Sulfone group Phosphoryl Sulfoxide Ester group Amido
  • C in the polymer represented by formula III is selected from C 1-6 alkylene, carbonyl Sulfone group Sulfoxide Ester group Amido
  • the polymer represented by formula III, wherein B is selected from preferably C 1-6 alkylene, poly (ethylene), poly (propylene), poly (ethyleneoxy) ) Oxyoxy (-O-), imino (-NR'-), sulfinyl (-S-), carbonyl Sulfone group Sulfoxide Ester group Amido o, Z is as defined in formula II.
  • the polymer represented by formula II is:
  • B, C, n, p, r, q, Z are as defined in formula III.
  • the polymer of formula IV wherein C is independently selected from C 1-6 alkylene, oxyalkylene (-O-), imino (-NR′-), thionylene Group (-S-), carbonyl Sulfone group Sulfoxide Ester group Amido
  • the polymer represented by formula II is:
  • B, C, R 3 , m, n, p, r, q, Z are as defined in formula II.
  • the polymer represented by formula V wherein C is each independently selected from C 1-6 alkylene, oxy (-O-), imino (-NR′-), Sulfur (-S-), carbonyl Ester group Amido
  • the polymer represented by formula V wherein B is selected from preferably C 1-6 alkylene, poly (ethylene), poly (propylene), poly (ethylene oxide) base) Oxyoxy (-O-), imino (-NR'-), sulfinyl (-S-), carbonyl Sulfone group Sulfoxide Ester group Amido o as defined in formula II.
  • the polymer represented by formula II is:
  • B, C, R 3 , n, p, r, q, Z are as defined in formula II.
  • the compound represented by formula VI wherein B is selected from preferably C 1-6 alkylene, poly (ethylene), poly (propylene), poly (ethyleneoxy) ) Poly (oxyethyleneoxy) Oxyoxy (-O-), imino (-NR'-), sulfinyl (-S-), carbonyl Sulfone group Sulfoxide Ester group Amido o as defined in formula II.
  • the polymer represented by formula II is:
  • B, C, n, p, r, q, R ', Z are as defined in formula II.
  • the polymer represented by formula VII wherein C is independently selected from C 1-6 alkylene, oxy (-O-), imino (-NR′-), Sulfur (-S-), carbonyl Ester group Amido
  • B is selected from preferably C 1-6 alkylene (such as methylene, ethylene, propylene, or n-butylene), poly (Ethyleneoxy) o as defined in formula II.
  • the polymer represented by formula II is:
  • B, C, R 3 , n, p, r, q, R ′ and Z are as defined in formula II.
  • the polymer represented by formula VIII wherein C is independently selected from C 1-6 alkylene, oxy (-O-), imino (-NR′-), Sulfur (-S-), carbonyl Ester group Amido
  • the polymer represented by formula II is:
  • B, C, m, n, p, r, q, R 2 and Z are as defined in formula II.
  • the polymer represented by formula IX wherein C is independently selected from C 1-6 alkylene, oxyalkylene (-O-), imino (-NR′-), Sulfur (-S-), carbonyl Ester group Amido
  • the XY-moiety in the polymer is introduced by reacting an ethylene-ethylene copolymer with XYR 3 having XY, where R 3 is hydrogen, alkyl (preferably C 1-6 alkyl), cycloalkyl (preferably C 1 -6 cycloalkyl) or leaving group selected from halogen (fluorine, chlorine, bromine or iodine), sulfonate groups (including but not limited to trifluoromethanesulfonate, methanesulfonate (Ester group, p-toluenesulfonate group, benzenesulfonate group), or alternatively, introduced through the reaction of ethylene-ethylene copolymer with XR 3 and YR 3 , or alternatively, vinyl alcohol ester monomer (not limited to methyl ester or ethyl The ester) / vinyl monomer is reacted with XYR 3 having an XY part or introduced with XR 3 and Y
  • Typical polymers represented by formula I include but are not limited to:
  • the visualizer in the polymer of Formula I is partially introduced through an iodine compound selected from but not limited to 2,3,5-triiodobenzoic acid, 2,3,5 -Sodium triiodobenzoate, iodotitanic acid, formazan acid, iododonic acid, iohexol.
  • the iodine compound provides a combination of a carboxyl group and a hydroxyl group. The introduction of iodine compounds makes the polymer visible when using fluorescence detection or CT imaging.
  • the visualizer in the polymer of Formula I is partially introduced through a gadolinium compound (contrast agent), and the gadolinium compound (contrast agent) includes, but is not limited to, gadopentate meglumine aminoethylmethyl Acrylic esters, gadoterate meglumine, gadonium barium meglumine.
  • the gadolinium compound (contrast agent) provides a combination of a carboxyl group and a hydroxyl group.
  • the introduction of gadolinium compounds (contrast agents) makes the polymer visible when using nuclear magnetic resonance imaging. Visible during fluorescence detection or CT imaging.
  • the visible gadolinium concentration of the gadolinium-based contrast agent may be about 0.1 to 1% (w / w), and may be 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9 %, 1.0% (w / w).
  • the average molecular weight of the ethylene-vinyl alcohol copolymer in the present disclosure is not limited, and in the related experimental scheme, the use of an ethylene-vinyl alcohol copolymer of too high molecular weight or too low molecular weight will not result in an embolizing agent of suitable viscosity.
  • the average molecular weight of the ethylene-vinyl alcohol copolymer is 5000-500,000 Daltons (or 5KDa-500KDa), and may be selected from about 5KDa, 10KDa, 15KDa, 20KDa, 25KDa, 30KDa, 35KDa, 40KDa, 45KDa, 50KDa, 55KDa, 60KDa, 65KDa, 70KDa, 75KDa, 80KDa, 85KDa, 90KDa, 95KDa, 100KDa, 110KDa, 120KDa, 130KDa, 140KDa, 150KDa, 160KDa, 170KDa, 180KDa, 190KDa, 200KDa, 210KDa, 220KDa 240KDa, 250KDa, 260KDa, 270KDa, 280KDa, 290KDa, 300KDa, 310K
  • the ethylene-vinyl alcohol copolymer used as the starting material in the present disclosure can be obtained outsourced or can be prepared according to procedures recognized in the art, such as the free radical solvent method, that is, in azo or peroxy compounds (such as Under the conditions of azobisisobutyronitrile, benzoyl peroxide, etc.), vinyl alcohol ester monomers (not limited to methyl ester and ethyl ester) are polymerized with ethylene to produce ethylene-vinyl alcohol ester, followed by a step of hydrolysis.
  • the vinyl (mole) content in the ethylene-vinyl alcohol is 5 to 94 mol%, and may be 5 mol%, 7 mol%, 9 mol%, 11 mol%, 13 mol%, 15 mol%, 17 mol%, 19 mol%, 21 mol%, 23 mol% , 25mol%, 27mol%, 29mol%, 31mol%, 33mol%, 35mol%, 37mol%, 39mol%, 41mol%, 43mol%, 45mol%, 47mol%, 49mol%, 51mol%, 53mol%, 55mol%, 57mol %, 59mol%, 61mol%, 63mol%, 65mol%, 67mol%, 69mol%, 71mol%, 73mol%, 75mol%, 77mol%, 79mol%, 81mol%, 83mol%, 85mol%, 87mol%, 89mol%, 91mol%, 94mol%, preferably from 10 to 60mol%.
  • the ethylene-vinyl alcohol copolymer contains about 25 to 60 mol% vinyl repeating units and about 40 to 75 mol% vinyl alcohol repeating units, and the polymer has a precipitation rate necessary to embolize blood vessels.
  • the present disclosure also provides a method of preparing the aforementioned polymer, the method comprising: a step of reacting an ethylene-vinyl alcohol copolymer with X-Y-R 3 , wherein R 3 is hydrogen or a leaving group, and the leaving group Selected from alkyl (preferably C 1-6 alkyl), alkoxy (preferably C 1-6 alkoxy), cycloalkyl (preferably C 1-6 cycloalkyl), alkenyloxy (preferably C 2- 6 alkenyloxy), halogen (fluorine, chlorine, bromine or iodine), sulfonyl (including but not limited to trifluoromethanesulfonyl, mesyl, p-toluenesulfonyl, benzenesulfonyl)
  • the two types of reaction can be condensation reaction (unlimited ester condensation, amidation) or nucleophilic substitution.
  • the ethylene-vinyl alcohol copolymer provides hydroxyl groups to participate in the aforementioned condensation reaction or nucleophilic substitution reaction.
  • R 3 is hydrogen and X—Y—is an aldehyde compound, X—Y—and ethylene-vinyl alcohol copolymer undergo an acetal or hemiacetal reaction to form an acetal or hemiacetal structure, and R 3 constitutes Y In part, the corresponding polymer is obtained.
  • the present disclosure also provides a method of preparing the foregoing polymer, the method comprising: a step of reacting an ethylene-vinyl alcohol copolymer with X—R 3 and Y—R 3 , wherein R 3 is hydrogen or a leaving group.
  • the degroup is selected from halogen (fluorine, chlorine, bromine or iodine), alkyl (preferably C 1-6 alkyl), alkoxy (preferably C 1-6 alkoxy), cycloalkyl (preferably C 1- 6 cycloalkyl), sulfonyl (including but not limited to trifluoromethanesulfonyl, methanesulfonyl, p-toluenesulfonyl, benzenesulfonyl).
  • the two types of reaction can be condensation reaction (unlimited ester condensation, amidation) or nucleophilic substitution.
  • the ethylene-vinyl alcohol copolymer raises the hydroxyl group to participate in the aforementioned condensation reaction or nucleophilic substitution reaction.
  • R 3 is hydrogen and YR 3 is an aldehyde compound, YR 3 and the corresponding hydroxyl group are connected in an acetal or hemiacetal structure.
  • the aforementioned reaction is carried out in an aprotic solvent.
  • the aprotic solvent includes but is not limited to dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), N, N'-dimethylformamide (DMF), N, N'-dimethylethyl Amide (DMAc) or tetrahydrofuran (THF).
  • DMSO dimethyl sulfoxide
  • NMP N-methylpyrrolidone
  • DMF N, N'-dimethylformamide
  • DMAc N, N'-dimethylethyl Amide
  • THF tetrahydrofuran
  • the base in the present disclosure is an inorganic base or an organic base.
  • the inorganic base includes but is not limited to sodium hydroxide, potassium hydroxide, sodium hydride, and potassium carbonate;
  • the organic base includes but is not limited to triethylamine, N, N -Diisopropylethylamine (DIPEA) or N, N-dimethylaminopyridine (DMAP).
  • DIPEA N -Diisopropylethylamine
  • DMAP N-dimethylaminopyridine
  • the acid described in the present disclosure may be a conventional organic acid or inorganic acid, such as hydrochloric acid, phosphoric acid, formic acid, etc., or a Lewis acid, such as boron trifluoride etherate.
  • the condensing agent described in the present disclosure is selected from but not limited to carbodiimide type condensing agents such as N, N'-dicyclohexylcarbodiimide (DCC), phosphorus positive ion type condensing agents such as 7-azabenzotris Azole-1-yloxytris (dimethylamino) phosphine hexafluorophosphate (AOP), (7-azabenzotriazole-1-oxo) tripyrrole hexafluorophosphate (PyAOP), bromo Tris (dimethylamino) phosphorus hexafluorophosphate (BrOP), chlorotripyrrolidinyl hexafluorophosphate (PyClOP), tripyrrolidinium phosphonium bromide hexafluorophosphate (PyBrOP), etc., and based on 1- Hydroxybenzotriazole (HOBt), 1-hydroxy-7-azo
  • the method for preparing a polymer in the present disclosure may optionally include steps of leaching, filtering, washing, or drying.
  • the present disclosure also provides a composition including the aforementioned polymer.
  • the polymer makes the composition visible when using fluorescence detection or CT imaging, or the polymer makes the composition visible when using nuclear magnetic resonance imaging.
  • the aforementioned composition further contains a non-physiological solvent, which is preferably water-soluble, more preferably from methanol, ethanol, dimethylformamide, N-methylpyrrolidone, isosorbide Dimethyl ether or dimethyl sulfoxide.
  • a non-physiological solvent which is preferably water-soluble, more preferably from methanol, ethanol, dimethylformamide, N-methylpyrrolidone, isosorbide Dimethyl ether or dimethyl sulfoxide.
  • the concentration of the polymer in the non-physiological solution is 1-80%, which may include 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% , 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26 %, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% , 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76 %, 77%, 78%,
  • a microcatheter is used to deliver the composition to a selected location.
  • the non-physiological solvent in the composition will quickly diffuse into the blood and precipitate the polymer in the blood vessel. Precipitate and embolize the lesion.
  • the present disclosure also provides a use for preparing an embolism in a physiological environment.
  • the composition is injected into the physiological environment through a delivery device, and the polymer in the composition precipitates and embolizes in the physiological environment.
  • the aforementioned composition is injected into the physiological environment through a delivery device (including but not limited to a syringe), the non-physiological solvent in the composition will quickly diffuse into the blood, and the polymer will precipitate out in the blood vessel, and the polymer will precipitate And embolize the lesion.
  • a delivery device including but not limited to a syringe
  • the present disclosure also provides a method of treating a disease, which includes the step of injecting the aforementioned composition into a physiological environment through a delivery device.
  • the polymer in the composition precipitates and embolizes in the physiological environment.
  • the diseases in the present disclosure are selected from, but not limited to, vascular diseases, tumor diseases, and the like.
  • Biocompatibility refers to a substance that is non-toxic, chemically inert, and substantially non-immunogenic in the patient's body and substantially insoluble in blood within the dosage range.
  • Embolism refers to the process of injecting a substance into a blood vessel.
  • a substance for example, in the case of an aneurysm, it can fill the aneurysm sac and / or promote clot formation to stop blood flow into the aneurysm, and for arteriovenous malformations
  • arteriovenous fistulas blockages or clots can be generated to control blood flow / change the direction of blood flow and ensure proper tissue perfusion. Therefore, vascular embolism is very important to prevent / control bleeding due to injury (eg, organ bleeding, gastrointestinal bleeding, vascular bleeding, and bleeding related to aneurysm).
  • embolism can be used to remove diseased tissues (eg, tumors, etc.).
  • Alkyl refers to a saturated aliphatic hydrocarbon group, including linear and branched groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 10 carbon atoms is preferable, and an alkyl group containing 1 to 6 carbon atoms is more preferable.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and its various branched isomers Wait.
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available connection point, preferably one or more of the following groups, independently selected from aryl, heteroaryl , Replaced by halogen.
  • alkenyl includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups.
  • C 2-6 alkenyl means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Radicals, cyclooctyl, etc .; polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls.
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl, etc.
  • the cycloalkyl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate groups.
  • heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) m (where m is an integer from 0 to 2), but does not include the ring portion of ⁇ O ⁇ O ⁇ , ⁇ O ⁇ S ⁇ or ⁇ S ⁇ S ⁇ , and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl, pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • the heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate groups.
  • Alkynyl includes branched and straight-chain alkynyl groups having 2 to 12 carbon atoms or an olefin containing an aliphatic hydrocarbon group, or if a specified number of carbon atoms is specified, it means the specific number. For example, ethynyl, propynyl (eg, 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene And naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle
  • the alkylthio group, carboxyl group or carboxylate group is preferably phenyl.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, Pyrimidinyl, thiadiazole, pyrazinyl and the like are preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate groups.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate groups.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted by halogen, wherein alkyl is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with a deuterium atom, where alkyl is as defined above.
  • hydroxyl refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • alkylene refers to an alkyl group substituted at both ends, where alkyl is as defined above.
  • the alkylene group is optionally selected from one or more of deuterium, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, SR ', NR' (R “), COOR ', CONR' (R"), further, the alkyl, alkoxy, alkenyl, aryl, heteroaryl groups are optionally substituted by one or more Selected from deuterium, hydroxyl, halogen, SR ', NR' (R “), COOR ', CONR' (R”), the R 'or R "is independently selected from hydrogen, alkyl, alkoxy, Alkenyl, acyl.
  • heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino group or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
  • the "average molecular weight” in the present disclosure adopts the number average molecular weight of the polymer, which is a statistical average value of the molecular weights of all the polymer chains in the sample, which is defined as follows: M i represents the single-chain molecular weight, and N i represents the number of chains with corresponding molecular weights.
  • M n may be predicted by polymerization mechanism, and is determined by measuring the number of molecules of a given mass of a sample; for example, and several methods by end group analysis. If M n is used to characterize the molecular weight distribution, there are equal numbers of molecules distributed on both sides of M n .
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR shift ( ⁇ ) is given in units of 15 to 0 (ppm).
  • NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard was four Methylsilane (TMS); FINNIGAN L CQ Ad (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan L CQ advantage MAX) for the measurement of ESI-MS, LC-MS using high performance liquid chromatography (manufacturer: Agilent , Model: 1200) Gradient elution, scanning in positive ion mode, the mass scanning range is 100 ⁇ 1500.
  • Figure 1 Sample 4 morphology after curing in normal saline
  • Figure 2 Sample 13 morphology after curing in physiological saline.
  • ethylene-vinyl alcohol copolymer (EVOH) particles and 10ml of dimethyl sulfoxide (DMSO) were added to the reaction bottle, and dissolved by heating. Then add 1.06g of 2,3,5-triiodobenzoyl chloride in dimethyl sulfoxide and 2.1ml of triethylamine, stir the reaction at 50 ° C for 24 hours, cool to room temperature, add 100ml of acetone and 100ml of water, Filter, wash with water, collect the solid, and dry to obtain 2 g of a yellow solid, which is an iodine-containing graft polymer (Ig-EVOH).
  • Ig-EVOH iodine-containing graft polymer
  • ICP-MS inductively coupled plasma-mass spectrometry
  • EVOH ethylene-vinyl alcohol copolymer
  • DMF N, N'-dimethylformamide
  • Ig-EVOH iodine-containing graft polymer
  • the resulting solution was added to the above EVOH / DMF solution, and then 0.42 ml of N, N'-diisopropylethylamine was added, and the reaction was continued to be stirred at 50 ° C for 24 hours and then cooled to room temperature.
  • the reaction solution was poured into 50 ml of dichloromethane and 50 ml of water, filtered, washed with water, and dried to obtain 420 mg of a yellow solid, which was an iodine-containing graft polymer (I-g-EVOH).
  • the reaction solution was poured into 300 ml of water, filtered, washed with water, and the solid was collected and dried to obtain 1.10 g of a yellow solid, which was an iodine-containing graft polymer (I-g-EVOH).
  • the reaction solution was poured into 200 ml of acetone and 200 ml of water, filtered, washed with water, and the solid was collected to obtain 1.0 g of a light yellow solid, which was an iodine-containing graft polymer (I-g-EVOH).
  • the reaction solution was dropped into 200 ml of acetone and 200 ml of water, filtered, washed with water, and dried to obtain 5.25 g of light yellow solid, which was an iodine-containing graft polymer (I-g-EVOH). .
  • the resulting solution was added to the above EVOH / DMF solution, and then 0.83 ml of N, N'-diisopropylethylamine was added, and the reaction solution was further stirred at 50 ° C for 24 hours and then cooled to room temperature.
  • the reaction solution was poured into 150 ml of acetone and 150 ml of water, filtered, washed with water, and dried to obtain 1.18 g of a yellow solid, which is an iodine-containing graft polymer (I-g-EVOH).
  • the reaction solution was dropped into 200 ml of acetone and 200 ml of water, filtered, washed with water, and dried to obtain 0.93 g of a yellow solid, which was an iodine-containing graft polymer (I-g-EVOH).
  • the resulting solution was added to the above EVOH / DMF solution, then 1.23 ml of N, N-diisopropylethylamine was added, after stirring at 50 ° C for 24 hours, 140 ml of dichloromethane and 140 ml of water were added, filtered, washed with water and collected The solid was dried to obtain 2.57 g of a light yellow solid, which was an iodine-containing graft polymer (Ig-EVOH).
  • the I-g-EVOH obtained in the above Examples 1-13 is added to a water-soluble non-physiological solvent, and after stirring and dissolving, the liquid embolic agent is added to the vial and capped. Autoclave at 121 ° C for 15 minutes.
  • Example 1 300mg 5ml N-methylpyrrolidone 2
  • Example 2 500mg 5ml dimethyl sulfoxide 3
  • Example 3 1.2g 5ml dimethyl sulfoxide 4
  • Example 4 2.25g 5ml dimethyl sulfoxide 5
  • Example 5 300mg 5ml dimethyl sulfoxide 6
  • Example 6 600mg 5ml dimethyl sulfoxide 7
  • Example 7 600mg 2.4ml dimethyl sulfoxide
  • Example 8 800mg 2ml dimethyl sulfoxide 9
  • Example 9 4.2g 6ml dimethyl sulfoxide 10
  • Example 10 400mg 2ml dimethyl sulfoxide
  • Example 11 500mg 5ml dimethyl sulfoxide 12
  • Example 12 360mg 6ml dimethyl sulfoxide 13
  • Example 13 1.00g 4mL dimethyl sulfoxide
  • the liquid embolization agent samples 1, 4, 5 and 13 in Example 14 were respectively injected into physiological saline with an 18G needle.
  • the sample immediately precipitated a white precipitate in the water, and the precipitate gradually became firm and dense from the inside out.
  • the formed precipitates were rated from 1-10, with 1-2 being the worst and 9-10 being the best.
  • the liquid embolic formulation is delivered through a 2.6F (0.87mm) microcatheter.
  • the precipitation rate was rated as slow, medium and fast. All other properties are rated from 1 to 10, with 1-2 being the least desirable and 9-10 being the most desirable.
  • the sample was formulated into a DMSO solution at the corresponding concentration (Wt./V), and the solution was measured with a Brookfield DV2T LVTJ0 viscometer, and the temperature was 22 ° C during the measurement.
  • the density is calculated according to 1.153g / mL
  • kinematic viscosity dynamic viscosity / density
  • the volume of the column cavity is about 10mL.
  • the syringe needle needs to be vertically upward, and the volume of the embolization volume is about 6mL.
  • the samples were extracted with MEM culture medium containing 10% fetal bovine serum in an inert container, and the samples were extracted at 37 ° C and 60 rpm for 24 hours.
  • the cell density of the 96-well cell culture plate was 1.0 ⁇ 10 5 cells / mL, and 100 ⁇ L per well was inoculated.
  • the blank control, negative control, positive control and samples The extract was contacted with adherent L929 cells (mouse fibroblasts), and after 24 hours of culture, MTT solution was added and incubated for 2 hours. Discard the liquid in the well, add 100 ⁇ L of isopropanol solution, measure the absorbance at a wavelength of 570 nm (reference wavelength 650 nm) of the microplate reader, and calculate the survival rate of the cells.
  • the survival rate (Viab.%) Is defined as Among them, OD 570e is the average optical density of the 100% extract of the test sample, and OD 570b is the average optical density of the blank.
  • sample A Prepares the following polymer (sample A) according to the method in CN104717983, prepare the sample into a 20% dimethyl sulfoxide (DMSO) solution, and inject it into a silicone tube through a microcatheter for curing. After curing, test its tensile properties and apply it Ratings from 1 to 10, with 1-2 being brittle and brittle, and 9-10 being excellent in stretchability. The results are as follows:
  • x 48.4mol%
  • y 51.6mol%
  • the iodine content is 41.5%.
  • sequence sample condition A 1 Sample A 150mg 3% hydrogen peroxide, 70 °C Triiodophenol detected 2 Sample A 150mg 0.9% NaCl solution, 70 °C Triiodophenol detected 3 Sample 14 3% hydrogen peroxide, 70 °C No triiodophenol detected 4 Sample 14 0.9% NaCl solution, 70 °C No triiodophenol detected

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Abstract

La présente invention concerne un polymère, tel que représenté dans la formule I en tant que X—Y—Z I, dans laquelle Z représente un copolymère d'éthylène-alcool vinylique, Y représente une liaison et X représente un agent de visualisation. Le polymère est soluble dans une solution non physiologique et insoluble dans des conditions physiologiques.
PCT/CN2019/117874 2018-11-13 2019-11-13 Polymère et compositions associées WO2020098673A1 (fr)

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WO2023006679A1 (fr) * 2021-07-26 2023-02-02 Iberhospitex, S.A. Compositions pour embolisation

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