WO2020098673A1

WO2020098673A1 - A polymer and compositions thereof

Info

Publication number: WO2020098673A1
Application number: PCT/CN2019/117874
Authority: WO
Inventors: 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
Priority date: 2018-11-13
Filing date: 2019-11-13
Publication date: 2020-05-22
Also published as: TW202031299A; CN113348001B; CN113348001A

Abstract

A polymer, as shown in Formula I as X—Y—Z I, wherein Z is an ethylene-vinyl alcohol copolymer, Y is a linkage, and X is a visualization agent. The polymer is soluble in a non-physiological solution and insoluble under physiological conditions.

Description

A polymer and its composition

Technical field

The present disclosure relates to a polymer and its composition, which can be used as an embolization material in medical treatment.

Background technique

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 comprising cellulose diacetate polymer, a biocompatible solvent (eg DMSO) and a water-insoluble contrast agent (eg tantalum, tantalum oxide and barium sulfate).

US5851508 describes an embolization composition comprising an ethylene-vinyl alcohol copolymer, a biocompatible solvent (eg DMSO) and 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).

However, 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.

Recently, US5695480 describes a class of I-PVA polymers that lack stability in terms of hydrolysis.

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.

Summary of the invention

The disclosure provides a polymer as shown in Formula I:

Among them, X is the visualizer part, Y is the connecting part, and 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.

In an alternative embodiment, the connection is capable of degrading, allowing separation of the visualization core from the polymer. Based on this, there are two types of linking parts, including those sensitive to hydrolysis and those sensitive to enzymatic hydrolysis.

In alternative embodiments, 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.

In other embodiments, the connecting portion is an ether or polyether and is not degradable.

In some embodiments, the linker is a bond (covalent bond).

Further, the 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.

In some embodiments, 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. When using fluorescence detection or 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).

When the polymer is grafted with the same iodide compound, the following formula can be used to calculate the polymer iodine content (I%):

Among them, 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.

In some embodiments, 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.

In some embodiments, the repeating unit of the polymer may be:

Among them, x = 5 to 94 mol%, y + z = 6 to 95 mol%, z = 2 to 40 mol%, and x + y + z = 100 mol%, R is a graft unit having a visualizer portion and a connecting portion.

In other embodiments, 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%. In some embodiments, the molar content of vinyl groups (X) in the repeating units of the polymer is 37 mol%.

In other embodiments, 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%.

On the other hand, 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:

In the present disclosure, the polymer represented by X-Y-Z does not mean that the ratio of X, Y, and Z is 1: 1: 1. Depending on the nature of the ethylene-vinyl alcohol copolymer, the number of hydroxyl groups in the copolymer, and the reaction feed ratio, 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.

In some embodiments, the hydroxyl substitution degree (DS) of the polymer is 3% -50%.

The degree of substitution (DS) is defined as:

DS = z / (y + z),

Where z represents the number of vinyl alcohol grafted repeating units, and y + z represents the total number of vinyl alcohol repeating units (vinyl alcohol grafted repeating units and vinyl alcohol ungrafted repeating units), DS can be obtained through the The peak area integral of each peak of NMR is calculated.

On the other hand, the polymer represented by Formula I in this disclosure is:

Wherein 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, cyclohexyl), heterocyclyl (preferably C _3-6 heterocyclyl), alkoxy (Preferably C _1-6 alkoxy), hydroxyalkyl (preferably C _1-6 hydroxyalkyl), alkenyl (preferably C _2-6 alkenyl), alkynyl (preferably C _2-6 alkynyl), aromatic Group, heteroaryl, nitro, nitrile, SR ', S (O) R', SO ₂ R ', P (O) R' (R "), NR '(R"), COOR', CONR ' (R ") is substituted, further, the alkyl group, cycloalkyl group, alkoxy group, hydroxyalkyl group, alkenyl group, aryl group, heteroaryl group may be optionally one or more selected from deuterium, hydroxy, halogen , SR ', NR' (R "), COOR ', CONR'(R"), the R 'or R "is independently selected from hydrogen, alkyl (preferably C _1-6 alkyl), cycloalkane Group (preferably C _3-6 cycloalkyl), heterocyclic group (preferably C _3-6 heterocyclyl), alkoxy (preferably C _1-6 alkoxy), hydroxyalkyl (preferably C _1-6 hydroxy) Alkyl), alkenyl (preferably C _2-6 alkenyl), acyl (e.g. C _1-6 alkanoyl, benzoyl, p-toluoyl); A, 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);

B is selected from alkylene (preferably C _1-6 alkylene, such as methylene, ethylene, propylene or n-butylene), poly (ethylene), poly (propylene), poly (Ethyleneoxy)

Oxyoxy (-O-), imino (-NR′-), thionylene (-S-), carbonyl

Sulfone group

Sulfoxide

Ester group

Amido

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, alkenyl, aryl, heteroaryl are optionally substituted by one or a plurality selected from hydroxy, halo, SR ', NR' (R "), COOR ', CONR'(R") are substituted, the R 'or R "are independently 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);

m = 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);

p = 0, 1, 2, 3, 4 or 5; and

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);

Z is as defined in formula I.

In an alternative embodiment of the present disclosure, 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.

In an alternative embodiment, the pyridyl group includes 3 iodine atoms at the C-3, C-4, and C-5 positions.

In an alternative embodiment of the present disclosure, the compound represented by formula I, wherein R ¹ is an aryl group, preferably a benzene ring, the benzene ring contains multiple iodine atoms, which may be 1 iodine atom, 2 iodine atoms, 3 Iodine atoms, 4 iodine atoms or 5 iodine atoms.

In an alternative embodiment, the benzene ring includes 3 iodine atoms at the C-2, C-3, and C-5 positions.

In an alternative embodiment, the benzene ring includes 3 iodine atoms at the C-2, C-4, and C-6 positions.

In an alternative embodiment, the benzene ring includes 2 iodine atoms at the C-3 and C-5 positions.

In other embodiments of the present disclosure, the polymer represented by formula II is:

Wherein, A, B, C, m, n, p are as defined in formula II, Z is as defined in formula I; 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 "is independently selected from hydrogen, alkyl (preferably C _1-6 alkyl), alkoxy (preferably C _{1 -6} alkoxy), cycloalkyl (preferably C _3-6 cycloalkyl), heterocyclic group (preferably C _3-6 heterocyclyl), hydroxyalkyl (preferably C _1-6 hydroxyalkyl), alkene Group (preferably C _2-6 alkenyl), acyl group (eg C _1-6 alkanoyl group, benzoyl group, p-toluoyl group);

r = 0, 1, 2, 3 or 4; q = 1, 2, 3 or 4.

In an alternative embodiment of the present disclosure, the polymer represented by formula III, wherein m = 0 and p = 0.

In an alternative embodiment of the present disclosure, 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

The R ′ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy), C _2-6 alkenyl), C _1-6 alkanoyl, _{benzenesulfonyl} , p-toluenesulfonyl, p = 1 or 2.

In an alternative embodiment of the present disclosure, the polymer represented by formula III, wherein n = 0.

In an alternative embodiment of the present disclosure, C in the polymer represented by formula III is selected from C _1-6 alkylene, carbonyl

Sulfone group

Sulfoxide

Ester group

Amido

The R ′ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 alkanoyl, benzoyl, p-toluoyl, p = 1 or 2 .

In an alternative embodiment of the present disclosure, 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.

In a preferred embodiment of the present disclosure, the polymer represented by formula II is:

Among them, B, C, n, p, r, q, Z are as defined in formula III.

In an alternative embodiment of the present disclosure, the polymer represented by formula IV, wherein p = 0.

In an alternative embodiment of the present disclosure, 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 R ′ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy), C _2-6 alkenyl), C _1-6 alkanoyl, benzoyl, p-toluoyl, p = 1 Or 2.

In an alternative embodiment of the present disclosure, 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 as defined in formula II.

Among them, B, C, R ³ , m, n, p, r, q, Z are as defined in formula II.

In an alternative embodiment of the present disclosure, the polymer represented by formula V, wherein p = 0.

In an alternative embodiment of the present disclosure, 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

In an alternative embodiment of the present disclosure, 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.

Among them, B, C, R ³ , n, p, r, q, Z are as defined in formula II.

In an alternative embodiment of the present disclosure, the polymer represented by formula VI, wherein p = 0.

In an alternative embodiment of the present disclosure, the polymer represented by formula VI wherein C is independently selected from C _1-6 alkylene, oxyalkylene (-O-), imino (-NR′-), Sulfur (-S-), carbonyl

Ester group

Amido

In an alternative embodiment of the present disclosure, 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.

Wherein, B, C, n, p, r, q, R ', Z are as defined in formula II.

In an alternative embodiment of the present disclosure, the polymer represented by formula VII, wherein p = 0.

In an alternative embodiment of the present disclosure, 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

In an alternative embodiment of the present disclosure, the polymer represented by formula VII, wherein 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.

Wherein, B, C, R ³ , n, p, r, q, R ′ and Z are as defined in formula II.

In an alternative embodiment of the present disclosure, the polymer represented by formula VIII, wherein p = 0.

In an alternative embodiment of the present disclosure, 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

In an alternative embodiment of the present disclosure, the polymer represented by formula VIII, wherein B is selected from preferably C _1-6 alkylene, poly (ethyleneoxy)

o as defined in formula II.

Wherein, B, C, m, n, p, r, q, R ² and Z are as defined in formula II.

In an alternative embodiment of the present disclosure, the polymer represented by formula IX, wherein p = 0.

In an alternative embodiment of the present disclosure, 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

In an alternative embodiment of the present disclosure, the polymer represented by formula IX, wherein B is selected from preferably C _1-6 alkylene, poly (ethyleneoxy)

o as defined in formula II.

In the present disclosure, 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 YR ³ . The number introduced can be expressed by the degree of substitution of hydroxyl groups in the polymer.

Typical polymers represented by formula I include but are not limited to:

Where Z is as defined in formula II.

On the other hand, in some embodiments, 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.

In other embodiments, 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.

In some embodiments, 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, 310KDa, 320KDa, 330KDa, 340KDa, 350KDa, 360KDa, 370KDa, 380KDa, 390KDa, 400KDa, 410KDa, 420KDa, 430KDa, 440KDa, 450KDa, 460KDa, 470KDa, 480KDa 490KD or 500Kda.

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 ratio of ethylene to vinyl alcohol in the copolymer will affect the total lipophilicity / hydrophilicity of the composition and the rate of precipitation of the copolymer in an aqueous solution (such as blood).

In some embodiments, 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. When 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. When 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.

In an alternative embodiment, 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). Add any suitable accelerator of alkali, acid or condensing agent to promote the smooth progress of the reaction and obtain a product of high quality and high yield.

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).

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-azobenzotriazole (HOAt) and 3-hydroxy-1,2,3-benzotriazine-4 (3H) -one (HOOBt) Other urea positive ion type condensing agents such as O- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethylurea tetrafluoroborate (TBTU), benzotriazide Azole-N, N, N ′, N′-tetramethylureonium hexafluorophosphate (HBTU), O- (benzotriazol-1-yl) -N, N, N ′, N′-dipyrrole Urea hexafluorophosphate (HBPyU), (benzotriazol-1-yloxy) dipiperidine carbonium hexafluorophosphate (HBPipU).

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.

In an alternative embodiment, 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. Under physiological conditions, the solubility of the polymer in the composition decreases, causing the polymer to precipitate out of the non-physiological solvent and precipitate.

In some embodiments, 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%, 79%, 80%, preferably from 10 to 70%.

In an alternative embodiment, for example, a microcatheter is used to deliver the composition to a selected location. When the composition encounters blood in the blood vessel, 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.

In an alternative embodiment, 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.

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.

In alternative embodiments, the diseases in the present disclosure are selected from, but not limited to, vascular diseases, tumor diseases, and the like.

Explanation of terms:

"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. 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 With 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). In addition, by cutting off the blood supply, 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. For example, "C _2-6 alkenyl" means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms. Examples of 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.

The term "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. 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, oxo, carboxyl or carboxylate groups.

The term "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:

Wait.

The heterocyclic group may be optionally substituted or unsubstituted. 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, 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.

The term "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 π-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. When substituted, 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.

The term "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 term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. 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 term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted by halogen, wherein alkyl is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with a deuterium atom, where alkyl is as defined above.

The term "hydroxyl" refers to the -OH group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" means -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "alkylene" refers to an alkyl group substituted at both ends, where alkyl is as defined above. In some embodiments, 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.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "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). The NMR shift (δ) 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.

BRIEF DESCRIPTION

Figure 1: Sample 4 morphology after curing in normal saline;

Figure 2: Sample 13 morphology after curing in physiological saline.

detailed description

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example 1

(1) Add 1.485g of ethylene-vinyl alcohol copolymer (EVOH) particles and 15ml of N, N'-dimethylformamide (DMF) to the reaction bottle, and heat to dissolve.

(2) Take another reaction flask and mix 1.0g 2,3,5-triiodobenzoic acid, 0.86g O- (7-benzotriazole) -N, N, N ', N'-tetramethyl Add urea hexafluorophosphate (HATU) and 5ml DMF to it. After stirring at 0 ℃ for 1 hour, add dropwise to the EVOH / DMF solution of (1) above, then add 0.85ml N, N-diisopropylethyl The amine was stirred at 50 ° C for 24 hours and then cooled to room temperature. After adding 200ml of acetone and 200ml of water to the reaction solution, it was filtered, washed with water, and the solid was collected and dried to obtain 2.2g of a yellow solid, which was an iodine-containing graft polymer EVOH). The iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 15%.

Remarks:

It only shows the schematic diagram of the polymer, where x = 37mol%, y + z = 63mol%, and the values of y and z can be calculated according to the substitution degree of the hydroxyl monomer and the iodine content in EVOH.

Example 2

1.49g of 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). The iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 23%.

Example 3

(1) 1.10g of ethylene-vinyl alcohol copolymer (EVOH) particles and 15ml of N, N'-dimethylformamide (DMF) are added to the reaction bottle and heated to dissolve.

(2) Take another reaction bottle and mix 5.65g pantothenic acid, 4.2g O- (7-oxidized benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate ( HATU) and 15ml DMF are added to it, after stirring well, dropwise add to the EVOH / DMF solution of (1) above, then add 3.80ml N, N-diisopropylethylamine, stir at 50 ° C for 24 hours and then cool At room temperature, 200 ml of acetone and 200 ml of water were added to quench the reaction, filtered, washed with water, and the solid was collected and dried to obtain 1.56 g of light yellow solid, which was an iodine-containing graft polymer (Ig-EVOH). . The iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 20%.

Example 4

(1) 9.58g 2,4,6-triiodophenol, 4.21g potassium carbonate, 70ml DMF and 3.90ml tert-butyl bromoacetate were stirred and reacted overnight. Then, 100 ml of tert-butyl methyl ether and 60 ml of water were added to the reaction solution, and the mixture was stirred for 5 min. The liquid was left to stand for separation. The aqueous phase was extracted three times with 210 ml of tert-butyl methyl ether, and the organic phases were combined. The organic phase was washed with 70 ml of saturated brine, dried over sodium sulfate, filtered, and concentrated to obtain crude 2- (2,4,6-triiodophenoxy) acetic acid tert-butyl ester. It was used in the next reaction without purification.

(2) Dissolve 12.71g of crude 2- (2,4,6-triiodophenoxy) acetic acid tert-butyl acetate in 60ml of dichloromethane, add 30ml of trifluoroacetic acid to the solution, stir at room temperature for 1 hour, and concentrate Crude 2- (2,4,6-triiodophenoxy) acetic acid was obtained. Add 50 ml of ethanol to the crude product, stir overnight at room temperature, filter, wash with 10 ml of ethanol, and dry to obtain 8.96 g of white solid, that is, 2- (2,4,6-triiodophenoxy) acetic acid.

(3) 1.14g of ethylene-vinyl alcohol copolymer (EVOH) particles and 15ml of N, N'-dimethylformamide (DMF) are added to the reaction bottle, and dissolved by heating.

(4) Take another reaction flask and combine 4.87g 2- (2,4,6-triiodophenoxy) acetic acid and 4.2g O- (7-benzotriazole) -N, N, N ' , N'-tetramethylurea hexafluorophosphate (HATU) and 15ml DMF were added to the reaction bottle, and stirred at 0 ℃ for 1 hour. The resulting solution was added to the above EVOH / DMF solution, then 3.80 ml of N, N'-diisopropylethylamine was added, and the reaction was stirred at 50 ° C for 24 hours and then cooled to room temperature. After adding 250 ml of methylene chloride and 250 ml of water to the reaction solution , Filter, wash with water, collect the solid, and dry to obtain 2.65g yellow solid, which is iodine-containing graft polymer (Ig-EVOH). The iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 48%.

Example 5

(1) Add 1.91g of p-toluenesulfonyl chloride and 2.1ml of dry triethylamine to a solution of 19.4g of tetraethylene glycol in dichloromethane (20ml), stir the reaction at room temperature overnight, add 20ml of dichloromethane to dilute, Washed with water (3 × 20 ml), washed with saturated brine (1 × 10 ml), dried over sodium sulfate, filtered, and concentrated. The resulting liquid was subjected to flash column chromatography (ethyl acetate: petroleum ether = 0-40%) to obtain a pale yellow oil 2.49g (yield 71%) is ethyl 2- (2- (2- (2- (2-hydroxyethyl) ethoxy) ethoxy) p-toluenesulfonate.

(2) Add 6ml DMF to 2.01g of 2- (2- (2- (2-hydroxyethyl) ethoxy) ethoxy) ethyl p-toluenesulfonate, 97mg of potassium iodide, 1.66g of potassium carbonate In the reaction flask, the resulting mixture was stirred at 90 ° C overnight. After TLC tracking showed that the raw materials disappeared, it was cooled to room temperature, 20 ml of saturated saline was added to the reaction mixture, and extracted with tert-butyl methyl ether (3 × 30 ml). The organic phases were combined And dried with sodium sulfate. After filtration, the solvent was removed, and the resulting liquid was subjected to flash column chromatography (ethyl acetate: petroleum ether = 0 to 150%) to obtain 3.6 g of light yellow oil (yield 96%), that is, 2- (2- (2- (2 -(2,4,6-triiodophenoxy) ethoxy) ethoxy) ethoxy) ethanol.

(3) Dissolve 2.00g of 2- (2- (2- (2- (2- (2,4,6-triiodophenoxy) ethoxy) ethoxy) ethoxy) ethanol in 12ml of dichloromethane Then, 12ml of 35% aqueous sodium hydroxide solution, 1.80ml of tert-butyl bromoacetate and 892mg of tetrabutylammonium chloride were added in sequence, and the resulting mixture was stirred overnight at room temperature. After TLC tracking showed that the raw material disappeared, the liquid was separated. The aqueous phase was extracted with ethyl acetate (3 × 20 ml), the organic phases were combined, washed with saturated brine (1 × 15 ml), and dried over sodium sulfate. It was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The resulting liquid was subjected to flash column chromatography (ethyl acetate: petroleum ether = 0 to 35%) to obtain 2.49 g of colorless oil (yield 66%), which is 14- (2 , 4,6-triiodophenoxy) -3,6,9,12-tetraoxomyristic acid tert-butyl ester.

(4) Dissolve 1.53g of 14- (2,4,6-triiodophenoxy) -3,6,9,12-tetraoxomyristic acid tert-butyl ester in 5ml of dichloromethane, then add 2ml of three Fluoroacetic acid, after stirring at room temperature for 1.5 hours, the raw material disappeared and was concentrated under reduced pressure. The obtained oily crude product was subjected to flash column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain 0.94 g of white solid (yield 67%), that is, 14- (2,4,6-triiodophenoxy) -3,6,9,12-tetraoxomyristic acid.

(5) Add 258 mg of ethylene-vinyl alcohol copolymer (EVOH) particles and 2 ml of DMF to the reaction bottle, and dissolve by heating. Take another reaction bottle, dissolve 715mg 14- (2,4,6-triiodophenoxy) -3,6,9,12-tetraoxomyristic acid in 2ml DMF, and bath with ice water under nitrogen atmosphere Next, the resulting mixture of 463 mg of O- (7-oxidized benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate (HATU) was stirred at 0 ° C for 1.5 hours. 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 iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 25%.

Example 6

(1) Add 2.36g of 2,4,6-triiodophenol, 1.39g of potassium carbonate and 50ml of acetone to the reaction bottle, and stir at room temperature. Add 2.16ml of 1,2-dibromoethane, stir the reaction to completion, then cool to room temperature, filter, concentrate the filtrate and add 20ml of ethanol, stir, filter, and rinse with ethanol to obtain 1.70g of off-white solid, which is 2- ( 2,4,6-triiodophenoxy) bromoethane.

(2) Dissolve 1.36g of ethylene-vinyl alcohol copolymer (EVOH) particles and 15ml of dimethyl sulfoxide (DMSO) in a reaction bottle, and heat to dissolve.

(3) Take another reaction bottle, add 150 mg of sodium hydride to the reaction bottle, add 8 ml of DMSO to the reaction bottle under nitrogen atmosphere and ice water bath, stir the reaction at 90 ° C for 1 hour and then cool to room temperature. The resulting solution was added to the above EVOH / DMSO solution, and after stirring for 1 hour, 7ml of 2- (2,4,6-triiodophenoxy) bromide (1.09g) / DMSO solution was added to the reaction solution, and continued at 50 The reaction was stirred at ℃ for 24 hours and then cooled to room temperature. 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 iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 3%.

Example 7

(1) Under a nitrogen atmosphere and an ice water bath, slowly add 42ml of 1.0M borane tetrahydrofuran solution to 3.00g of 2,3,5-triiodobenzoic acid in tetrahydrofuran solution (5ml). After the addition, continue under ice water bath After stirring for 1.5 hours, it was raised to room temperature and stirred for 1 hour. Under an ice-water bath, 16 ml of wet tetrahydrofuran (containing 2.5 ml of water) was slowly added dropwise to the reaction solution, and then 60 ml of ice-cold saturated sodium bicarbonate solution was added to continue stirring for 1 hour. After filtering, washing with water and ethanol successively, the collected white solid was dissolved in dichloromethane, dried over sodium sulfate, filtered and concentrated to obtain 2.85 g of solid, namely 2,3,5-triiodobenzyl alcohol.

(2) Under nitrogen atmosphere and ice-water bath, slowly add 0.76ml of phosphorus tribromide dropwise to 1.95g of 2,3,5-triiodobenzyl alcohol in tetrahydrofuran solution (12ml), and stir in ice-water bath for 5 minutes Warm to room temperature and stir for 25 minutes. After adding 15ml of dichloromethane to dilute, the reaction was quenched with 15ml of ice-cold water. After separation, the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed sequentially with saturated sodium bicarbonate and water, dried over sodium sulfate, filtered and concentrated to obtain 1.90g white solid, that is 2,3,5-triiodobenzyl bromide.

(3) Add 1.27g of ethylene-vinyl alcohol copolymer (EVOH) particles and 15ml of dimethyl sulfoxide (DMSO) to the reaction bottle, and dissolve by heating.

(4) Take another reaction bottle and add 84mg of sodium hydride to the reaction bottle under nitrogen atmosphere and ice water bath, then add 5ml of DMSO, stir the reaction at 90 ° C for 1.5 hours and then cool to room temperature, the resulting solution is added to the above EVOH / DMSO solution, stirring for 1 hour. Add 5ml 2,4,6-triiodobenzyl bromide (0.95g) / DMSO solution to the reaction solution, continue to stir the reaction at 80 ° C for 24 hours, then cool to room temperature, pour the reaction solution into 200ml acetone and 200ml water, and filter, Wash with water and dry to obtain 1.04g of light yellow solid, which is iodine-containing graft polymer (Ig-EVOH). The iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 18%.

Example 8

(1) Add 262 mg of solid sodium hydroxide to a mixture of 2.36 g of 2,4,6-triiodophenol and 20 ml of ethanol. After stirring at room temperature for 45 minutes, add 1.2 ml of epichlorohydrin to the reaction solution and stir at room temperature overnight , A large amount of white precipitates out, add 10ml of ethanol, continue stirring for 2 hours, and then filter to obtain the crude product. The crude product and 30 ml of ethanol were stirred for 2 hours, filtered, rinsed with 5 ml of ethanol, and dried to obtain 1.52 g of white solid powder, that is, 3- (2,4,6-triiodophenoxy) propylene oxide.

(2) 1.20 g of ethylene-vinyl alcohol copolymer (EVOH) particles and 15 ml of dimethyl sulfoxide (DMSO) are added to the reaction bottle, and dissolved by heating.

(3) Take another reaction bottle, add 80 mg of sodium hydride to the reaction bottle, add 8 ml of DMSO to the reaction bottle under nitrogen atmosphere and ice water bath, stir the reaction at 90 ° C for 1 hour and then cool to room temperature. The resulting solution was added to the above EVOH / DMSO solution, and the reaction was stirred for 1 hour, and then 5 ml of 3- (2,4,6-triiodophenoxy) propylene oxide (867mg) / DMSO solution was added to the reaction solution, and continued at 80 ° C After stirring for 24 hours, it was cooled to room temperature. 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 iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 26%.

Example 9

(1) Add 9.2g of 2- (2,4,6-triiodophenoxy) bromoethane prepared according to Example 6 to a 250ml reaction bottle, and under a nitrogen atmosphere, add 80ml of dimethyl sulfoxide in sequence And 2.7 mg of potassium tert-butoxide solid (in batches), and stirred at room temperature for 24 hours. After dilution with 80 ml of methyl tert-butyl ether, 40 ml of water was added to quench the reaction. The reaction was extracted three times with methyl tert-butyl ether, washed successively with saturated sodium bicarbonate and water, dried over sodium sulfate, filtered and concentrated. Analysis (petroleum ether / ethyl acetate = 100: 1) gave 6.04 g of white solid, namely 1,3,5-triiodostyryl ether.

(2) Add 1.59 g of ethylene-vinyl alcohol copolymer (EVOH) particles and 20 ml of dimethyl sulfoxide (DMSO) to the reaction bottle, and heat to dissolve. To the EVOH / DMSO solution, 10 ml of 1,3,5-triiodostyryl ether (5.98 g) / DMSO solution and 413 mg of p-toluenesulfonic acid were added, the reaction was stirred at 130 ° C. for 24 hours, and then cooled to room temperature. 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 iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 58%.

Example 10

(1) Add 90ml of water and 2.5ml of 9M sulfuric acid to a 250ml reaction bottle. Under stirring at room temperature, add 1.68g of aniline, 9.14g of iodine and 8.1ml of 30% hydrogen peroxide. Stir the reaction at 50 ° C for 24 hours and cool to room temperature , Adjust the pH to neutral with 5M aqueous sodium hydroxide solution, add 50ml of saturated sodium thiosulfate aqueous solution, stir to precipitate solid, filter, wash with water and ethanol in sequence to obtain a tan solid, the obtained solid is sublimated at 170 ° C (0.02mmHg) A yellow-brown solid of 5.93g is 2,4,6-triiodoaniline.

(2) Under nitrogen atmosphere and ice water bath, after mixing 2.49g of 2,4,6-triiodoaniline and 15ml of dichloromethane, add 0.85ml of concentrated sulfuric acid and 1.25ml of acetic anhydride in sequence, and stir at room temperature for 24 hours ， Add 25ml of dichloromethane to dilute the reaction solution, wash with water, saturated sodium bicarbonate aqueous solution and saturated brine successively, dry, and concentrate to obtain 2.44g brown yellow solid, which is N-acetyl-2,4,6-triiodoaniline .

(3) Under a nitrogen atmosphere, add 1.76g of sodium hydride in portions to 2.05g of N-acetyl-2,4,6-triiodoaniline in N, N'-dimethylformamide (DMF) solution (40ml ), Stirred at 70 ° C for 1 hour and cooled to room temperature. After adding 5.3 ml of ethyl bromoacetate dropwise to the reaction solution, stirring at 80 ° C overnight and then cooling to room temperature, the reaction was quenched by adding 40 ml of water, the reaction solution was extracted three times with 240 ml of ethyl acetate, washed three times with water, and washed with saturated brine , Dried with sodium sulfate, and concentrated to obtain a crude product. The crude product was dissolved in an aqueous ethanol solution (100 ml of ethanol and 50 ml of water) containing 2.4 g of sodium hydroxide. The mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed under reduced pressure and diluted with 60 ml of water , Washed twice with 120 ml of dichloromethane, adjusted to pH = 1 with concentrated hydrochloric acid, the precipitated tan solid was filtered, washed with water, and recrystallized with ethanol / water to obtain 1.37 g of tan solid, namely N-acetyl-N -(2,4,6-triiodobenzene) glycine.

(4) Add 503 mg of ethylene-vinyl alcohol copolymer (EVOH) particles and 10 ml of N, N′-dimethylformamide (DMF) to the reaction bottle, and dissolve by heating.

(5) Take another reaction flask and mix 1.16g N-acetyl-N- (2,4,6-triiodobenzene) glycine, 912mg O- (7-oxybenzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate (HATU) and 5ml DMF were added to the reaction flask, and the resulting mixture was stirred at 0 ° C for 1 hour. Add the resulting solution to the above EVOH / DMF solution, and then add 0.84 ml of N, N'-diisopropylethylamine, continue to stir the reaction solution at 50 ° C for 24 hours, then cool to room temperature, and pour the reaction solution into 150 ml of Chloromethane and 150ml of water, filtered, washed with water, and dried to obtain 1.00g of yellow solid, which is iodine-containing graft polymer (Ig-EVOH). The iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 41%.

Example 11

(1) Under a nitrogen atmosphere, add 2.82g of 2,4,6-triiodoaniline obtained in Example 9 and a stir bar to a 100ml reaction bottle, add 60ml of DMF and stir to dissolve, then add 1.02g of iodomethane and 1.66g Potassium carbonate, the mixture was stirred at 50 ° C and the reaction was completed (petroleum ether: ethyl acetate = 3: 1 shows the disappearance of raw materials), the reaction solution was poured into 200ml of cold water, filtered, and rinsed with ethanol to obtain a tan solid. The obtained tan solid and 40 ml of ethanol were stirred overnight, filtered, and rinsed with 5 ml of ethanol to obtain 2.42 g of tan solid, namely N-methyl-2,4,6 triiodoaniline.

(2) Add 2.42g of N-methyl-2,4,6 triiodoaniline, 0.55g of succinic anhydride and 40ml of toluene to a 100ml reaction bottle, then add a drop of 85% phosphoric acid, and the resulting mixture is heated to reflux for 12 hours Cool to room temperature. Dilute with 60ml of methyl tert-butyl ether, wash with 5% aqueous sodium hydroxide solution, wash the aqueous phase with dichloromethane and acidify with concentrated hydrochloric acid to precipitate a tan solid, filter, and dissolve the resulting solid in 50ml of methyl tert-butyl ether Medium, dried over sodium sulfate, concentrated, recrystallized with 1,2-dichloroethane and petroleum ether (3: 1) to obtain 1.40g brownish yellow solid, which is 4-carbonyl-4- [N-methyl- (2 , 4,6 triiodobenzene) amino] butyric acid.

(3) Add 623 mg of ethylene-vinyl alcohol copolymer (EVOH) particles and dimethyl sulfoxide (DMSO) to the reaction bottle, and dissolve by heating.

(4) Take another reaction flask and combine 1.18g 4-carbonyl-4- [N-methyl- (2,4,6 triiodobenzene) amino] butyric acid, 961mg O- (7-benzotriazine Azole) -N, N, N ', N'-tetramethylurea hexafluorophosphate (HATU) and 5ml DMF were added to the reaction flask, and the resulting mixture was stirred at 0 ° C for 1 hour. 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 iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 37%.

Implementation column 12

(1) 2.91g Add the N-methyl-2,4,6 triiodoaniline obtained in Example 10 to a 50ml reaction bottle, then add 20ml toluene, 1.4ml triethylamine and 0.65ml 2-bromoethanol in sequence to obtain The mixture was heated to reflux for 3 hours and then cooled to room temperature. The reaction was quenched by the addition of saturated ammonium chloride, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to give 2.12 g of a brown solid, that is 2- (N-methyl-2,4,6 triiodophenylamino) ethanol. Can be directly invested in the next reaction.

(2) Add 2.12g of 2- (N-methyl-2,4,6triiodophenylamino) ethanol obtained in the previous step to the reaction bottle, add 40ml of dichloromethane and 1.4ml of triethylamine under a nitrogen atmosphere, the mixture After stirring at room temperature for 10 minutes, it was cooled in an ice water bath. After adding 0.4 ml of methanesulfonyl chloride dropwise, stirring was continued for 2 hours in an ice water bath. Diluted with 20 ml of dichloromethane, washed twice with 20 ml of 2% hydrochloric acid, 10 ml of water, 10 ml of saturated brine, and dried over sodium sulfate. Filtration and concentration gave 2.19 g of brown solid. Beat with 20ml of ethanol and filter to obtain 2.02g of brownish yellow solid, which is ethyl 2- (N-methyl-2,4,6triiodophenylamino) methanesulfonate.

(3) Add 0.545 mg of ethylene-vinyl alcohol copolymer (EVOH) particles and 10 ml of dimethyl sulfoxide (DMSO) to the reaction bottle, and heat to dissolve.

(4) Take another reaction bottle and add 170 mg of sodium hydride to the reaction bottle. Under a nitrogen atmosphere and an ice water bath, 5 ml of DMSO was added to the reaction bottle, and the resulting mixture was stirred at 90 ° C for 1.5 hours and then cooled to room temperature. The resulting solution was added to the above EVOH / DMSO solution and stirred for 1 hour. 5 ml of 2,4,6-triiodobenzyl bromide (1.33g) / DMSO solution was added to the reaction solution. The reaction solution was stirred at 80 ° C for 24 hours and then cooled To room temperature. 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 iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 39%.

Example 13

1) 2.36g 2,4,6-triiodophenol, 1.04g potassium carbonate, 8ml DMF and 1.6111-bromoundecanoic acid ethyl ester were stirred and reacted overnight. Pour 80ml of water, stir, and filter with suction to obtain 3.4g of crude product.

Pulp with absolute ethanol overnight, suction filtration, washing and drying to obtain 3.15g white solid, ethyl 11- (2,4,6-triiodophenoxy) undecanoate.

(2) Dissolve 3.15g of ethyl 11- (2,4,6-triiodophenoxy) undecanoate in 15mL of tetrahydrofuran, add 5mL of ethanol and 5mL of NaOH solution to the solution, stir at 65 ° C overnight, concentrate, Add 2N hydrochloric acid to acidify, filter with suction, wash with water, and dry in vacuo to obtain 2.44g of white solid, ie 11- (2,4,6-triiodophenoxy) undecanoic acid.

(3) Add 710 mg of ethylene-vinyl alcohol copolymer (EVOH) and 7.2 ml of N, N-dimethylformamide (DMF) to the reaction bottle, and dissolve by heating. Take another reaction flask and combine 2.0g 11- (2,4,6-triiodophenoxy) undecanoic acid, 1.36g O- (7-benzotriazole) -N, N, N ', N'-Tetramethylureaium hexafluorophosphate (HATU) and 7mL DMF were added to the reaction flask and stirred at 0 ° C. 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 iodine content of the iodine-containing graft polymer (I-g-EVOH) obtained by inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 1% = 36%.

Example 14: Preparation of liquid embolic agent

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.

样品sample	I-g-EVOH来源I-g-EVOH source	I-g-EVOH用量I-g-EVOH dosage	非生理溶液Non-physiological solution
11	实施例1Example 1	300mg300mg	5ml N-甲基吡咯烷酮5ml N-methylpyrrolidone
22	实施例2Example 2	500mg500mg	5ml二甲亚砜5ml dimethyl sulfoxide
33	实施例3Example 3	1.2g1.2g	5ml二甲亚砜5ml dimethyl sulfoxide
44	实施例4Example 4	2.25g2.25g	5ml二甲亚砜5ml dimethyl sulfoxide
55	实施例5Example 5	300mg300mg	5ml二甲亚砜5ml dimethyl sulfoxide
66	实施例6Example 6	600mg600mg	5ml二甲亚砜5ml dimethyl sulfoxide
77	实施例7Example 7	600mg600mg	2.4ml二甲亚砜2.4ml dimethyl sulfoxide
88	实施例8Example 8	800mg800mg	2ml二甲亚砜2ml dimethyl sulfoxide
99	实施例9Example 9	4.2g4.2g	6ml二甲亚砜6ml dimethyl sulfoxide
1010	实施例10Example 10	400mg400mg	2ml二甲亚砜2ml dimethyl sulfoxide

1111	实施例11Example 11	500mg500mg	5ml二甲亚砜5ml dimethyl sulfoxide
1212	实施例12Example 12	360mg360mg	6ml二甲亚砜6ml dimethyl sulfoxide
1313	实施例13Example 13	1.00g1.00g	4mL二甲亚砜4mL dimethyl sulfoxide

Example 15:

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 following examples show that the change in adhesion can be achieved by changing the formulation.

样品sample	粘结性Cohesiveness
11	77
44	99
55	44
77	77
1313	88

Example 16:

In the flow model, the liquid embolic formulation is delivered through a 2.6F (0.87mm) microcatheter. Visually assess embolic agent adhesion, injection pressure, plug formation, and precipitation rate. 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 following examples show that the fluidity can be changed by changing the formulation.

样品sample	沉淀速度Settling speed	粘结性Cohesiveness	注射压力Injection pressure	栓形成Plug formation
11	中等medium	88	88	88
44	快速fast	88	88	1010
55	缓慢slow	66	66	44
1313	快速fast	88	88	1010

Example 17: Arteriography (DSA) study

The following polymer was prepared according to the method of Example 4

(Sample 14), where x = 37 mol%; y = 51.07 mol%; z = 11.93 mol%, I% = 45.79%.

(Sample 15), where x = 37 mol%, y = 49.54 mol%, z = 14.52 mol%, I% = 42.27%.

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

Remarks: a temperature is 37 ℃ during measurement; kinematic viscosity = dynamic viscosity / density

In vitro embolization assessment:

Relevant samples are prepared into 20% DMSO solution, the volume of the column cavity is about 10mL. During embolization, the syringe needle needs to be vertically upward, and the volume of the embolization volume is about 6mL.

Conclusion: In the in vitro simulation test, the viscosity of sample 14 and sample 15 is suitable, easy to inject, and the precipitation state is good, the state of embolization is more suitable, and the effect of developing embolization is better.

Example 18:

According to GB / T 16886.12-2017, based on different extraction ratios, 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. Prepare blank control, negative control (high density polyethylene) and positive control samples (10% DMSO solution) in the same way. Under the condition of 37 ° C and 5% CO ₂ , the cell density of the 96-well cell culture plate was 1.0 × 10 ⁵ cells / mL, and 100 μL per well was inoculated. After 24 hours of culture, 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 μL 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.

样品来源Sample source	检测结果Test results
空白对照Blank control	100％100%
阴性对照(EVOH)Negative control (EVOH)	106.4％106.4%
阳性对照(三碘苯酚)Positive control (triiodophenol)	1.4％1.4%
实施例4Example 4	90.6％90.6%
实施例13Example 13	76.3％76.3%

Note: If the survival rate drops to <70% of the blank, the sample has potential cytotoxicity.

Comparative example 1:

Prepare 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:

Among them, x = 48.4mol%, y = 51.6mol%, and the iodine content is 41.5%.

样品sample	固体形态Solid form	固化后评价Evaluation after curing
11	韧性固体Ductile solid	88
44	韧性固体Ductile solid	9-109-10
1313	韧性固体Ductile solid	88
样品ASample A	颗粒状粉末Granular powder	22

After being injected into the silicone tube through the microcatheter and simulating in vivo embolization for curing, samples 4 and 13 are shown in Figs.

Place 150mg of polymer (Sample A) in 1.5ml of 3% hydrogen peroxide or 0.9% NaCl solution. After 10 days at 70 ° C (accelerated degradation), take the aforementioned solid sample and dissolve it in the appropriate amount of dimethyl sulfoxide solution. 0.07% wt / v solution, HPLC detection, the results are as follows:

序列sequence	样品sample	条件condition	A
11	样品A 150mgSample A 150mg	3％双氧水，70℃3% hydrogen peroxide, 70 ℃	检测到三碘苯酚Triiodophenol detected
22	样品A 150mgSample A 150mg	0.9％ NaCl溶液，70℃0.9% NaCl solution, 70 ℃	检测到三碘苯酚Triiodophenol detected
33	样品14Sample 14	3％双氧水，70℃3% hydrogen peroxide, 70 ℃	未检测到三碘苯酚No triiodophenol detected
44	样品14Sample 14	0.9％ NaCl溶液，70℃0.9% NaCl solution, 70 ℃	未检测到三碘苯酚No triiodophenol detected

Remarks: HPLC condition Aglient column C-18 (2.7μm * 4.6mm * 50mm), mobile phase 0.05% trifluoroacetic acid / acetonitrile 0.05% trifluoroacetic acid / water, gradient elution.

Results: Compared with the polymer in CN104717983, it is not easy to degrade during the placement process, only less than 5% degradation, even if it is degraded, it will not be degraded into triiodophenol, triiodophenol has very strong cytotoxicity, and has potential medicinal safety problem.

Claims

A polymer is shown in Formula I:

Among them, X is the visualizer part, Y is the connecting part, and Z is the ethylene-vinyl alcohol copolymer.
The polymer according to claim 1, wherein the connecting part Y is selected from a bond, an ester, a carbonate, a polyester, a polyether, an acetal, a ketal, or an amino acid.
The polymer according to claim 1 or 2, the polymer represented by formula I is:

Wherein, R 1 is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the alkyl, cycloalkyl, aryl or heteroaryl contains multiple iodine atoms, which may be one iodine Atoms, 2 iodine atoms, 3 iodine atoms or 4 iodine atoms, and optionally one or more selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, Aryl, heteroaryl, nitro, nitrile, hydroxy, halogen, SR ', S (O) R', SO 2 R ', P (O) R' (R "), NR '(R"), COOR ', CONR' (R ") is substituted, further, the alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, aryl, heteroaryl is optionally selected from one or more Deuterium, hydroxyl, halogen, SR ', NR' (R "), COOR ', CONR'(R") are substituted, the R 'or R "is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy Group, hydroxyalkyl, alkenyl, acyl;

A and C are each independently selected from alkylene, oxy (-O-), imino (-NR′-), sulfinyl (-S-), carbonyl
Sulfone group
Sulfoxide
Phosphoryl
Ester group
Amido
The R 'is selected from hydrogen, alkyl, alkoxy, alkenyl, acyl;

B is selected from alkylene, poly (ethylene), poly (propylene), poly (ethyleneoxy)
Oxyoxy (-O-), imino (-NR′-), thionyl (-S-), carbonyl
Sulfone group
Sulfoxide
Ester group
Amido

The alkylene group is optionally selected from one or more of 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 selected from one or more selected from hydroxyl, halogen, SR , NR '(R "), COOR', CONR '(R"), the R' or R "is independently selected from hydrogen, alkyl, alkoxy, alkenyl, acyl;

m = 0, 1, 2, 3, 4 or 5;

n = 1 ~ 30;

p = 0, 1, 2, 3, 4 or 5; and

o = 0 ～ 30;

Z is as defined in claim 1.
The polymer according to claim 3, wherein R 1 in the polymer represented by formula II is an aryl group or a heteroaryl group, the aryl group is preferably a benzene ring, and the benzene ring contains a plurality of iodine atoms, which can be Is 1 iodine atom, 2 iodine atoms, 3 iodine atoms, 4 iodine atoms or 5 iodine atoms, more preferably the benzene ring is included in the C-2, C-3 and C-5 positions -3, three iodine atoms at the C-4 and C-6 positions or two iodine atoms at the C-3 and C-5 positions; the heteroaryl group is preferably a pyridyl group, the pyridyl group contains multiple One iodine atom can be 1 iodine atom, 2 iodine atoms, 3 iodine atoms or 4 iodine atoms.
The polymer according to claim 3 or 4, wherein the polymer represented by formula II is:

Where A, B, C, m, n, p, Z are as defined in claim 3; R 2 is selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, alkenyl, alkynyl, hydroxyalkyl , Aryl, heteroaryl, nitro, nitrile, halogen, hydroxyl, SR ', NR' (R "), COOR ', CONR'(R"), the alkyl, cycloalkyl, alkoxy , Hydroxyalkyl, alkenyl, aryl, heteroaryl are optionally substituted by one or more selected from deuterium, hydroxyl, halogen, SR ', NR' (R "), COOR ', CONR'(R") , Said R 'or R "is independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, hydroxyalkyl, alkenyl, acyl; r = 0, 1, 2, 3 or 4; q = 1 2, 3, 4 or 5.
The polymer according to claim 5, wherein A and C in the polymer represented by formula III are each independently selected from C 1-6 alkylene, oxyalkylene (-O-), and imino (-NR ' -), Thionylene (-S-), carbonyl
Sulfone group
Sulfoxide
Ester group
Amido
The R ′ is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 1-6 alkanoyl, benzoyl, p-toluoyl, p = 1 or 2 .
The polymer according to claim 5 or 6, wherein C in the polymer represented by formula III is selected from C 1-6 alkylene and carbonyl
Sulfone group
Sulfoxide
Ester group
Amido
R 'is as defined in claim 6.
The polymer according to any one of claims 5 to 7, wherein B in the polymer represented by formula III is selected from C 1-6 alkylene and poly (ethyleneoxy)
A C 1-6 alkylene group is preferred, and methylene, ethylene, propylene, or n-butylene is more preferred, as defined in claim 3.
The polymer according to claims 1-8, selected from:

Here, Z is as defined in claim 1.
The polymer according to claim 1 or 2, wherein the visualizer is partially introduced through an iodine compound or a gadolinium compound, and the iodine compound is preferably selected from 2,3,5-triiodobenzoic acid, 2,3,5-tris Sodium iodobenzoate, iodotitanic acid, formazan acid, iododaconic acid, iohexol; the gadolinium compounds are preferably selected from the group consisting of gadopentate meglumine aminoethyl methacrylate, gadoterate meglumine, and gadolinium barium Meglumine.
The polymer according to any one of claims 1 to 9, wherein the ethylene-vinyl alcohol copolymer has an average molecular weight of 5KD to 500KD.
The polymer according to any one of claims 1 to 11, wherein the repeating unit of the polymer is:

Among them, x = 5 to 94 mol%, y + z = 6 to 95 mol%, z = 2 to 40 mol%, and x + y + z = 100 mol%, R is a graft unit having a visualizer portion and a connecting portion.
The polymer according to any one of claims 1 to 12, wherein the ethylene-vinyl alcohol copolymer has a vinyl content of 5 to 94 mol%, preferably 10 to 60 mol%, more preferably 20 to 50 mol%.
The polymer according to any one of claims 1-13, having an iodine content of at least 10% (w / w), preferably from an iodine content of at least 20% (w / w), more preferably at least 40% (w / w) the iodine content.
The polymer according to any one of claims 1 to 14, wherein the polymer is soluble in the non-physiological solution and insoluble in physiological solution.
The polymer according to any one of claims 1 to 15, wherein the connecting portion Y is degradable.
A method for preparing the polymer according to any one of claims 1-4, comprising: a step of reacting an ethylene-vinyl alcohol copolymer with X-Y-R 3 , wherein R 3 is hydrogen or a leaving group, said The leaving group is selected from halogen, alkyl, alkoxy, cycloalkyl, sulfonyl, and X and Y are as defined in claim 1.
The method for preparing the polymer according to any one of claims 1-16, 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 leaving group is selected from halogen, alkyl, alkoxy, cycloalkyl, sulfonyl; X, Y are as defined in claim 1.
The method according to claim 17 or 18, wherein the reaction is carried out in an aprotic solvent, preferably the aprotic solvent is selected from dimethyl sulfoxide, N-methylpyrrolidone, N, N'-dimethyl Formamide, N, N'-dimethylacetamide or tetrahydrofuran.
The method according to any one of claims 17 to 19, wherein the reaction further includes an accelerator, and the accelerator is selected from any one of a base, an acid, and a condensation agent.
The method according to claim 20, wherein the base is selected from an organic base or an inorganic base, the inorganic base is preferably selected from sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate; the organic base is preferably selected from triethylamine , N, N-diisopropylethylamine or N, N-dimethylaminopyridine.
The method of claim 21, wherein the condensing agent is selected from N, N'-dicyclohexylcarbodiimide, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethylureonium hexafluorophosphate.
A composition comprising the polymer of any one of claims 1-16.
The composition according to claim 23, further comprising a non-physiological solvent, the non-physiological solvent is preferably water-soluble, more preferably from methanol, ethanol, dimethylformamide, N-methylpyrrolidone, isosorbide Dimethyl ether or dimethyl sulfoxide.
The composition according to claim 23 or 24, wherein the concentration of the polymer is 1 to 80%, preferably from 10 to 70%.
Use for preparing an embolism in a physiological environment, which comprises injecting the composition according to any one of claims 23-25 or the polymer according to any one of claims 1-16 into a physiological environment through a delivery device, which The polymer or polymer in the composition precipitates and embolizes in the physiological environment.
A method for treating a disease, comprising the step of injecting the composition of any one of claims 23-25 or the polymer of any one of claims 1-16 into a physiological environment through a delivery device.