TW202031299A - A polymer and compositons thereof - Google Patents

Abstract

The disclosure relates to a polymer and compositions thereof. In particular, the disclosure relates to a polymer, as shown in Formula I X-Y-Z I Wherein Z is an ethylene-vinyl alcohol copolymer, Y is a linkage, X is a visualization agent. The polymer is soluble in the non-physiological solution and insoluble in a physiological solution.

Description

A polymer and its composition

The present disclosure relates to a polymer and a composition thereof. The polymer can be used as an embolic material in medical treatment.

In medical treatment, embolization is widely used for vascular malformations, such as aneurysms, arteriovenous malformations, fistulas and tumors. It is to controlly inject some artificial embolic materials into the supply vessels of the diseased or organ or into the diseased blood vessel to make it occluded and interrupt the blood supply to achieve the purpose of controlling bleeding, treating vascular diseases, tumors and eliminating the function of the diseased organs . Products including metal coils, polymer-metal hybrid coils, particles and foams can be used to treat these vascular malformations.

US5580568 describes a composition for embolizing blood vessels, including a cellulose diacetate polymer, a biocompatible solvent (such as DMSO), and a water-insoluble contrast agent (such as tantalum, tantalum oxide, and barium sulfate).

US5851508 describes embolic compositions including ethylene-vinyl alcohol copolymers, biocompatible solvents (such as DMSO) and water-insoluble contrast agents (such as 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, nitrocellulose, urethane/ Biocompatible polymers of carbonate copolymers, styrene/maleic acid copolymers and their mixtures, biocompatible solvents (such as DMSO, ethanol and acetone) and contrast agents (such as tantalum, tantalum oxide, tungsten, and sulfuric acid) barium).

However, these embolic compositions suspend the radiopaque contrast agent in a polymer solution, so that the contrast agent is dispersed in the polymer, which is a heterogeneous dispersion. Therefore, these compositions may not guarantee the effect of a permanent contrast agent. At the same time, the contrast agent dispersed in the polymer will slowly precipitate or aggregate over time, which may cause serious clinically 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, which have improved stability, and also have low viscosity but provide a higher concentration of embolic agents and show clear contrast effects. This type of iodobenzyl ether- PVA polymers are not biodegradable.

CN104717983A describes a kind of acrylic acid containing 2-oxo-2-(1-oxo-1-(1-oxo-1-(2,4,6-triiodophenoxy)propan-2-yloxy) Liquid suppository polymer of the reaction product of propan-2-yloxy)ethoxy)ethyl, hydroxyethyl methacrylate and azobisisobutyronitrile.

The disclosure provides a polymer as shown in general formula I:

XYZ 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 X-Y having a connection, and the ethylene-vinyl alcohol copolymer is connected to the visualizer through a connection part.

In an alternative embodiment, the link is capable of degradation, allowing the visualization core to be separated from the polymer. Based on this, there are two types of connecting parts, including those that are sensitive to hydrolysis and those that are sensitive to enzymatic hydrolysis.

In an alternative embodiment, the linker that is sensitive to enzymatic hydrolysis may be an ester or an amino acid. The connecting part that is sensitive to hydrolysis can 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 connecting portion Y described in the present disclosure can be introduced by reacting an ethylene-vinyl alcohol copolymer with a visualization agent. Choosing or inserting different types of connecting parts (such as the length or number of the connecting parts) can change the physical and chemical properties of the polymer, such as the adhesion of the polymer in physiological saline, and the precipitation rate.

In some embodiments, the visualization agent may be an iodine compound (a compound containing an iodine structure), especially an aryl or heteroaryl group having multiple iodines to impart visualization of the polymer under fluorescence detection and CT imaging. When using fluorescence detection or CT imaging, the iodine concentration (content) that makes the liquid embolic agent visible is at least about 10% (w/w), at least about 20% (w/w), 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 iodinated compound, the following formula can be used to calculate the polymer iodine content (I%):

Among them, M _iodine represents the molecular weight of iodine atoms (ie 126.90), n represents the number of iodine atoms on each aromatic ring (ie 1 to 5), M _vinyl represents the molar mass of vinyl repeating units, and M _{vinyl alcohol} represents ethylene The molar mass of the alcohol repeating unit, M _{vinyl alcohol graft} means the molar mass of the vinyl alcohol graft repeating unit.

In some embodiments, the iodine content in the polymer in the present disclosure can be determined by the oxygen bomb combustion-potentiometric titration method or the 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%, and R is a graft unit having a visualizer part and a connecting part.

In other embodiments, the vinyl mol content (X) in the repeating unit of the polymer is 5-94%, preferably 10-60%, more preferably 20-50%, including but limited to 20mol%, 21mol% , 23mol%, 25mol%, 27mol%, 29mol%, 31mol%, 33mol%, 35mol%, 37mol%, 39mol%, 41mol%, 43mol%, 45mol%, 47mol%, 49mol%, 50mol%. In some embodiments, the vinyl mol content (X) in the repeating unit of the polymer is 37 mol%.

In other embodiments, the molar content of the graft unit (z) having the visualizer part and the connecting part in the repeating unit of the polymer is 2-40 mol%, including but limited to 2 mol%, 3 mol%, 4 mol%, 5 mol %, 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 the present disclosure only represents the schematic diagram of the polymer. R is a graft unit with a visualizer part and a connecting part, which represents a situation where the hydroxyl group in the polymer is substituted, as follows but not limited to:

或

或

。

or

or

.

The polymer represented by X-Y-Z in this disclosure 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 hydroxyl substitution of the polymer.

The degree of substitution ( DS ) of hydroxyl (-OH) of the polymer described in the present disclosure is not limited.

In some embodiments, the degree of hydroxyl substitution ( 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 determined by the polymer in the present disclosure The peak area of each peak of NMR is integrated and calculated.

On the other hand, the polymer represented by formula I in the present disclosure is:

R ¹ -(A) _m -(B) _n -(C) _p -Z II

)、碸基(

)、亞碸基(

)、磷醯基(

)、酯基(

或

)、醯胺基(

或

)，該R'選自氫、烷基(較佳C_1-6烷基)、烷氧基(較佳C_1-6烷氧基)、烯基(較佳C_2-6烯基)、醯基(例如C_1-6烷醯基、苯甲醯基、對甲苯醯基)； Among them, 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 Group, cyclohexyl group), heterocyclic group (preferably C _3-6 heterocyclic group), aryl group or heteroaryl group. The alkyl group, cycloalkyl group, aryl group or heteroaryl group contains multiple iodine atoms and may be 1 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), aryl, heteroaryl, nitro, nitrile, SR', S(O)R', SO ₂ R', P(O)R'(R"), NR'( R"), COOR', CONR'(R"), and further, the alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, aryl, and heteroaryl groups are optionally substituted by one or more One is selected from deuterium, hydroxyl, halogen, SR', NR'(R"), COOR', CONR'(R"), the R'or R" is independently selected from hydrogen, alkyl (preferably C _1-6 alkyl), cycloalkyl (preferably C _3-6 cycloalkyl), 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 (e.g. C _1-6 alkanoyl, benzyl, p-toluene Group); A and C are each independently selected from the group consisting of alkylene, oxy (-O-), amino (-NR'-), thio (-S-), carbonyl (

), 碸基(

), subunit (

), phosphoryl (

), ester group (

or

), amide group (

or

), the R'is selected from hydrogen, alkyl (preferably C _1-6 alkyl), alkoxy (preferably C _1-6 alkoxy), alkenyl (preferably C _2-6 alkenyl), An acyl group (for example C _1-6 alkyl acyl group, benzyl acyl group, p-tolyl acyl group);

)、氧基(-O-)、伸胺基(-NR'-)、硫基(-S-)、羰基(

)、碸基(

)、亞碸基(

)、酯基(

或

)、醯胺基(

或

)，該伸烷基視需要被一個或多個選自烷基(較佳C_1-6烷基，如甲基、乙基、丙基)、烷氧基(較佳C_1-6烷氧基，如甲氧基、乙氧基、丙氧基)、烯基(較佳C_2-6烯基)、炔基(較佳C_2-6炔基)、芳基、雜芳基、硝基、腈基、羥基、SR'、NR'(R")、COOR'、CONR'(R")所取代，進一步地，該烷基、烷氧基、烯基、芳基、雜芳基視需要被一個或多個選自羥基、鹵素、SR'、NR'(R")、COOR'、CONR'(R")所取代，該R'或R"獨立地選自氫、烷基(較佳C_1-6烷基)、烷氧基(較佳C_1-6烷氧基)、烯基(較佳C_2-6烯基)、醯基(例如C_1-6烷醯基、苯甲醯基、對甲苯醯基)； B is selected from alkylene (preferably C _1-6 alkylene, such as methylene, ethylene, propylene or n-butyl), poly(ethylene), poly(propylene), poly (Ethoxy)(

), oxy (-O-), amine extension (-NR'-), thio (-S-), carbonyl (

), 碸基(

), subunit (

), ester group (

or

), amide group (

or

), the alkylene group is optionally selected by one or more selected from alkyl (preferably C _1-6 alkyl, such as methyl, ethyl, propyl), alkoxy (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 Group, nitrile group, hydroxyl, SR', NR'(R"), COOR', CONR'(R"), and further, the alkyl, alkoxy, alkenyl, aryl, heteroaryl group Need to be substituted by one or more selected from hydroxyl, halogen, SR', NR'(R"), COOR', CONR'(R"), the R'or R" is independently selected from hydrogen, alkyl (more Preferably C _1-6 alkyl), alkoxy (preferably C _1-6 alkoxy), alkenyl (preferably C _2-6 alkenyl), alkynyl (e.g. C _1-6 alkanoyl, benzene Formaldehyde, p-toluene);

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 (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);

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, and the pyridyl group contains a plurality of iodine atoms, which may be 1 iodine atom or 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 can be 1 iodine atom, 2 iodine atoms, 3 One iodine atom, four iodine atoms, or five 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 (more (Preferably C _1-6 alkoxy), cycloalkyl (preferably C _3-6 cycloalkyl), heterocyclyl (preferably C _3-6 heterocyclyl), alkenyl (preferably C _2-6 alkene) Group), 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 and heteroaryl group are optionally selected from one or more hydroxy groups, Halogen, SR', NR'(R"), COOR', CONR'(R"), the R'or R" is independently selected from hydrogen, alkyl (preferably C _1-6 alkyl), alkane Oxy group (preferably C _1-6 alkoxy), cycloalkyl (preferably C _3-6 cycloalkyl), heterocyclic group (preferably C _3-6 heterocyclyl), hydroxyalkyl (preferably C _1-6 hydroxyalkyl), alkenyl (preferably C _2-6 alkenyl), alkynyl (e.g. C _1-6 alkanoyl, benzyl, p-tolyl);

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.

)、碸基(

)、磷醯基(

)、亞碸基(

)、酯基(

或

)、醯胺基(

或

)，該R'選自氫、C_1-6烷基、C_1-6烷氧基)、C_2-6烯基)、C_1-6烷醯基、苯甲磺醯基、對甲苯磺醯基，p=1或2。 In an alternative embodiment of the present disclosure, the polymer represented by formula III, wherein A and C are each independently selected from alkylene, oxy (-O-), amine (-NR'-), thio (-S-), carbonyl (

), 碸基(

), phosphoryl (

), subunit (

), ester group (

or

), amide group (

or

), the R'is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy), C _2-6 alkenyl), C _1-6 alkyl, toluenesulfonyl, p-toluenesulfonyl醯基, p=1 or 2.

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

)、碸基(

)、亞碸基(

)、酯基 (

或

)、醯胺基(

或

)，該R'選自氫、C_1-6烷基、C_1-6烷氧基、C_2-6烯基、C_1-6烷醯基、苯甲醯基、對甲苯醯基，p=1或2。 In an alternative embodiment of the present disclosure, C in the polymer represented by formula III is selected from C _1-6 alkylene, carbonyl (

), 碸基(

), subunit (

), ester group (

or

), amide group (

or

), the R'is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 alkanoyl, benzyl, p-tolyl, p =1 or 2.

)、氧基(-O-)、伸胺基(-NR'-)、硫基(-S-)、羰基(

)、碸基(

)、亞碸基(

)、酯基(

或

)、醯胺基(

或

)，o、Z如式II中所定義。 In an alternative embodiment of the present disclosure, the polymer represented by formula III, wherein B is selected from the preferred C _1-6 alkylene, poly(ethylene), poly(propylene), poly(ethylene oxide) base)(

), oxy (-O-), amine extension (-NR'-), thio (-S-), carbonyl (

), 碸基(

), subunit (

), ester group (

or

), amide group (

or

), o and Z are as defined in formula II.

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

Wherein, B, C, n, p, r, q, and Z are as defined in formula III.

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

)、碸基(

)、亞碸基(

)、酯基(

或

)、醯胺基(

或

)，該R'選自氫、C_1-6烷基、C_1-6烷氧基)、C_2-6烯基)、C_1-6烷醯基、苯甲醯基、對甲苯醯基，p=1或2。 In an alternative embodiment of the present disclosure, the polymer represented by formula IV wherein C is each independently selected from C _1-6 alkylene, oxy (-O-), amino (-NR'-), sulfur Group (-S-), carbonyl group (

), 碸基(

), subunit (

), ester group (

or

), amide group (

or

), the R'is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy), C _2-6 alkenyl), C _1-6 alkanoyl, benzyl and p-tolyl , P=1 or 2.

)、、氧基(-O-)、伸胺基(-NR'-)、硫基(-S-)、羰基(

)、碸基(

)、亞碸基(

)、酯基(

或

)、醯胺基(

或

)，o如式II中所定義。 In an alternative embodiment of the present disclosure, the polymer represented by formula III, wherein B is selected from the group of preferred C _1-6 alkylene, poly(ethylene), poly(propylene) poly(ethyleneoxy) )(

),, oxy (-O-), amine extension (-NR'-), thio (-S-), carbonyl (

), 碸基(

), subunit (

), ester group (

or

), amide group (

or

), o is as defined in formula II.

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

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

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

)、酯基(

或

)、醯胺基(

或

)，該R'選自氫、C_1-6烷基、C_1-6烷氧基)、C_2-6烯基)、C_1-6烷醯基、苯甲醯基、對甲苯醯基，p=1或2。 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-), amino (-NR'-), Thio (-S-), carbonyl (

), ester group (

or

), amide group (

or

), the R'is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy), C _2-6 alkenyl), C _1-6 alkanoyl, benzyl and p-tolyl , P=1 or 2.

)、氧基(-O-)、伸胺基(-NR'-)、硫基(-S-)、羰基 (

)、碸基(

)、亞碸基(

)、酯基(

或

)、醯胺基(

或

)，o如式II中所定義。 In an alternative embodiment of the present disclosure, the polymer represented by formula V, wherein B is selected from the group of preferred C _1-6 alkylene, poly(ethylene), poly(propylene), poly(ethylene oxide) base)

), oxy (-O-), amine extension (-NR'-), thio (-S-), carbonyl (

), 碸基(

), subunit (

), ester group (

or

), amide group (

or

), o is as defined in formula II.

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

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

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

)、酯基(

或

)、醯胺基(

或

)，該R'選自氫、C_1-6烷基、C_1-6烷氧基)、C_2-6烯基)、C_1-6烷醯基、苯甲醯基、對甲苯醯基，p=1或2。 In an alternative embodiment of the present disclosure, the polymer represented by formula VI, wherein C is each independently selected from C _1-6 alkylene, oxy (-O-), amino (-NR'-), Thio (-S-), carbonyl (

), ester group (

or

), amide group (

or

), the R'is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy), C _2-6 alkenyl), C _1-6 alkanoyl, benzyl and p-tolyl , P=1 or 2.

)、聚(氧基伸乙氧基)(

)、氧基(-O-)、伸胺基(-NR'-)、硫基(-S-)、羰基(

)、碸基(

)、亞碸基(

)、酯基(

或

)、醯胺基(

或

)，o如式II中所定義。 In an alternative embodiment of the present disclosure, the compound represented by formula VI, wherein B is selected from the preferred C _1-6 alkylene, poly(ethylene), poly(propylene), poly(ethylene oxide) base)(

), poly(oxyethylene ethoxylate) (

), oxy (-O-), amine extension (-NR'-), thio (-S-), carbonyl (

), 碸基(

), subunit (

), ester group (

or

), amide group (

or

), o is as defined in formula II.

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

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.

)、酯基(

或

)、醯胺基(

或

)，該R'選自氫、C_1-6烷基、C_1-6烷氧基)、C_2-6烯基)、C_1-6烷醯基、苯甲醯基、對甲苯醯基，p=1或2。 In an alternative embodiment of the present disclosure, the polymer represented by formula VII, wherein C is each independently selected from C _1-6 alkylene, oxy (-O-), amino (-NR'-), Thio (-S-), carbonyl (

), ester group (

or

), amide group (

or

), the R'is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy), C _2-6 alkenyl), C _1-6 alkanoyl, benzyl and p-tolyl , P=1 or 2.

)、o如式II中所定義。 In an alternative embodiment of the present disclosure, the polymer represented by formula VII, wherein B is selected from the preferred C _1-6 alkylene (such as methylene, ethylene, propylene or n-butyl), poly (Ethoxy)(

), o are as defined in formula II.

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

Wherein, B, C, R ³ , 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 VIII, wherein p=0.

)、酯基(

或

)、醯胺基(

或

)，該R'選自氫、C_1-6烷基、C_1-6烷氧基)、C_2-6烯基)、C_1-6烷醯基、苯甲醯基、對甲苯醯基，p=1或2。 In an alternative embodiment of the present disclosure, the polymer represented by formula VIII, wherein C is each independently selected from C _1-6 alkylene, oxy (-O-), amino (-NR'-), Thio (-S-), carbonyl (

), ester group (

or

), amide group (

or

), the R'is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy), C _2-6 alkenyl), C _1-6 alkanoyl, benzyl and p-tolyl , P=1 or 2.

)，o如式II中所定義。 In an alternative embodiment of the present disclosure, the polymer represented by formula VIII, wherein B is selected from the group consisting of preferably C _1-6 alkylene, poly(ethoxy) (

), o is as defined in formula II.

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

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 of formula IX, wherein p=0.

)、酯基(

或

)、醯胺基(

或

)，該R'選自氫、C_1-6烷基、C_1-6烷氧基)、C_2-6烯基)、C_1-6烷醯基、苯甲醯基、對甲苯醯基，p=1或2。 In an alternative embodiment of the present disclosure, the polymer represented by formula IX, wherein C is each independently selected from C _1-6 alkylene, oxy (-O-), amino (-NR'-), Thio (-S-), carbonyl (

), ester group (

or

), amide group (

or

), the R'is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy), C _2-6 alkenyl), C _1-6 alkanoyl, benzyl and p-tolyl , P=1 or 2.

)，o如式II中所定義。 In an alternative embodiment of the present disclosure, the polymer represented by formula IX, wherein B is selected from the group of preferred C _1-6 alkylene, poly(ethoxylate) (

), o is as defined in formula II.

In the present disclosure, the XY-part of the polymer is introduced by reacting an ethylene-ethylene copolymer with XYR ³ having XY, wherein R ³ is hydrogen, alkyl (preferably C _1-6 alkyl), cycloalkyl (more Preferably C _1-6 cycloalkyl) or a leaving group, the leaving group is selected from halogen (fluorine, chlorine, bromine or iodine), sulfonate group (including but not limited to triflate, methyl Sulfonate group, p-toluenesulfonate group, benzenesulfonate group), or introduced by reacting ethylene-ethylene copolymer with XR ³ , YR ³ , or, vinyl alcohol ester monomer (not limited to methyl Ester or ethyl ester)/ethylene monomer is introduced by reacting with XYR ³ having XY moiety or reacting with XR ³ and YR ³ . The number of introductions 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:

和

，其中，Z如式II中所定義。

with

, Where Z is as defined in formula II.

On the other hand, in some embodiments, the visualizer part of the polymer represented by formula I is introduced by an iodine compound selected from but not limited to 2,3,5-triiodobenzoic acid, 2,3,5 -Sodium triiodobenzoate, iodotitanic acid, methodic acid, iodotic acid, iohexol. The iodine compound provides a carboxyl group to be combined with a hydroxyl group. The introduction of iodine compounds makes the polymer visible when using fluorescence detection or CT imaging.

In other embodiments, the visualization agent part of the polymer represented by formula I is introduced by gadolinium-based compounds (contrast agents), which include but are not limited to gammapentetate meglumineaminoethyl Acrylic acid ester, meglumine gadoterate, barium gamma meglumine. The gadolinium compound (contrast agent) provides carboxyl group and 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 gamma concentration of the gamma-type contrast agent can be about 0.1~1% (w/w), which can be 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9 %, 1.0%(w/w).

In the present disclosure, the average molecular weight of the ethylene-vinyl alcohol copolymer is not limited. In the relevant experimental scheme, using an ethylene-vinyl alcohol copolymer of too high molecular weight or too low molecular weight will not obtain an embolic agent with suitable viscosity.

In some embodiments, the average molecular weight of the ethylene-vinyl alcohol copolymer is 5000 to 500000 Daltons (or 5KDa to 500KDa), which can 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, 220KDa, 230KDa , 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 a starting material in the present disclosure can be obtained outsourcing, 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, benzyl peroxide, etc.), vinyl alcohol ester monomers (not limited to methyl and ethyl) are polymerized with ethylene to form ethylene-vinyl alcohol ester, followed by a step of hydrolysis. The vinyl (molar) content in the ethylene-vinyl alcohol is 5 to 94 mol%, and can 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 10-60mol%. The ratio of ethylene to vinyl alcohol in the copolymer will affect the total lipophilic/hydrophilicity of the composition and the precipitation rate of the copolymer in an aqueous solution (such as blood).

In some embodiments, the ethylene-vinyl alcohol copolymer contains about 25-60 mol% vinyl repeating units and about 40-75 mol% vinyl alcohol repeating units, and the polymer has a precipitation rate suitable for embolizing blood vessels.

The present disclosure also provides a method for preparing the aforementioned polymer, the method comprising: a step of reacting an ethylene-vinyl alcohol copolymer with XYR ³ , wherein R ³ is hydrogen or a leaving group, and the leaving group is 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, toluenesulfonyl, p-toluenesulfonyl, benzenesulfonyl). The two types of reaction can be condensation reaction (unlimited ester condensation, amination) 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 XY- is an aldehyde compound, XY- and ethylene-vinyl alcohol copolymer undergo acetal or hemiacetal reaction to form an acetal or hemiacetal structure, and R ³ forms part of Y to obtain the corresponding Of polymers.

The present disclosure also provides a method for preparing the aforementioned polymer, the method comprising: a step of reacting an ethylene-vinyl alcohol copolymer with XR ³ and YR ³ , wherein R ³ is hydrogen or a leaving group, and the leaving group 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 ring Alkyl), sulfonyl (including but not limited to trifluoromethanesulfonyl, toluenesulfonyl, p-toluenesulfonyl, benzenesulfonyl). The two types of reaction can be condensation reaction (unlimited ester condensation, amination) or nucleophilic substitution. The ethylene-vinyl alcohol copolymer increases the hydroxyl group's participation 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, dimethylsulfide (DMSO), N -methylpyrrolidone (NMP), N , N' -dimethylformamide (DMF), N , N' -dimethylacetamide Amine (DMAc) or tetrahydrofuran (THF). The addition of appropriate alkali, acid or condensing agent to promote the smooth progress of the reaction, to obtain high-quality, high-yield products.

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 -di Isopropylethylamine (DIPEA) or N,N -dimethylaminopyridine (DMAP).

The acid in the present disclosure can 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 ether.

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 cation type condensing agent such as 7-azabenzotria Azol-1-yloxy tris (dimethylamino) phosphine hexafluorophosphate (AOP), (7-azabenzotriazole-1-oxo) tripyrrophos hexafluorophosphate (PyAOP), bromide (Dimethylamino) phosphorus hexafluorophosphate (BrOP), chlorotripyrrolidinyl hexafluorophosphate (PyClOP), tripyrrolidinyl phosphonium bromide hexafluorophosphate (PyBrOP), etc., and based on 1-hydroxy Benzotriazole (HOBt), 1-hydroxy-7-azobenzotriazole (HOAt) and 3-hydroxy-1,2,3-benzotriazine-4(3 H )-one (HOOBt) Iso-urea positive ion condensing agent such as O -(1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), benzotriazide Azole- N , N , N ′, N ′-Tetramethyluronium hexafluorophosphate (HBTU), O -(benzotriazol-1-yl) -N , N , N ′, N ′-dipyrrole Hydroxyuronium hexafluorophosphate (HBPyU), (benzotriazol-1-yloxy)dipiperidine carbonium hexafluorophosphate (HBPipU).

The method for preparing the polymer in the present disclosure further includes the steps of washing, filtering, washing or drying as necessary.

The present disclosure also provides a composition, which includes 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. The non-physiological solvent is preferably water-soluble, more preferably selected from methanol, ethanol, dimethylformamide, N-methylpyrrolidone, and 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 non-physiological solvents and precipitate.

In some embodiments, the concentration of the polymer in the non-physiological solution is 1 to 80%, and 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 a blood vessel, the non-physiological solvent in the composition will quickly diffuse into the blood, and precipitate the polymer in the blood vessel. And embolize the lesion site.

The present disclosure also provides an application for preparing embolism in a physiological environment. The composition is injected into the physiological environment by 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 by 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 be precipitated in the blood vessel. Precipitation and embolization of the lesion site.

The present disclosure also provides a method for treating diseases, 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 an alternative embodiment, the disease in the present disclosure is selected from but not limited to vascular disease, tumor disease and the like.

Term explanation:

"Biocompatibility" refers to substances that are non-toxic, chemically inert, and substantially non-immunogenic in the patient's body and are substantially insoluble in blood within the dosage range.

"Embolic" 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 the blood flow to the aneurysm, and for arteriovenous malformations and Arteriovenous fistulas can produce blockages or clots 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 caused by injury (such as organ bleeding, gastrointestinal bleeding, vascular bleeding, and bleeding associated with aneurysm). In addition, by cutting off the blood supply, embolization can be used to remove diseased tissues (such as tumors, etc.).

"Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, and an alkyl group having 1 to 6 carbon atoms is more preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second butyl, n-pentyl, 1,1-dimethylpropyl Group, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and various branched isomers Body etc. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point, preferably one or more of the following groups, independently selected from aryl, heteroaryl Group, halogen substituted. "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 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, 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, tetrahydronaphthyl , Benzocycloheptanyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are 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, cycloalkane Thio group, heterocycloalkylthio group, pendant oxy group, carboxyl group or carboxylate group.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 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 and pyrrolidinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

和

等。

with

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, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, oxo, carboxy, or carboxylate.

"Alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or alkene containing aliphatic hydrocarbon groups, or if the number of carbon atoms is specified, it means that specific number. For example, ethynyl, propynyl (e.g. 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 (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated π-electron system, preferably 6 to 10 members, for example Phenyl 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, non-limiting examples thereof include:

Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxyl or carboxylate, preferably phenyl.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is 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, etc., preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl 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 Group, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, Cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

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, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

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

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

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

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

The term "amino" refers to -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, wherein the alkyl group 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, hydroxyl, SR ', NR'(R"), COOR', CONR'(R"), and further, the alkyl group, alkoxy group, alkenyl group, aryl group and heteroaryl group are optionally selected from one or more Deuterium, hydroxyl, halogen, SR', NR'(R"), COOR', CONR'(R"), the R'or R" is independently selected from hydrogen, alkyl, alkoxy, alkenyl,醯基.

"As needed" or "as needed" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group substituted by an alkyl group as required" means that an alkyl group may but does not have to be present. The description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, and 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 in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.

In the present disclosure "average molecular weight" With a number average molecular weight, it is a statistical average molecular weight of all the polymer chains in a sample, which is defined as a single chain wherein the molecular weight M _i the representative, the representative of the respective N _i having a number molecular weight of the chain. M _n can be predicted by the polymerization mechanism and determined by measuring the number of molecules in a given mass sample; for example, end group analysis and other colligative methods. If M _n to characterize the molecular weight distribution, M _n sides of the distribution of the same number of molecules.

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 15-0 (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 Methyl Silane (TMS); ESI-MS is measured with FINNIGAN L CQ Ad (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan L CQ advantage MAX), LC-MS uses high performance liquid chromatography (manufacturer: Agilent , Model: 1200) Carry out gradient elution, scan in positive ion mode, and the mass scan range is 100~1500.

Figure 1 shows the shape of sample 4 after solidification in saline;

Figure 2 shows the shape of sample 13 after solidification in physiological saline.

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

僅表示聚合物的示意圖，其中x=37mol%，y+z=63mol%，根據EVOH中羥基單體取代度和碘含量可計算獲得y和z值。 (2) Take another reaction flask, mix 1.0g 2,3,5-triiodobenzoic acid, 0.86g O -(7-benzotriazole oxide) -N , N , N ', N' -tetramethyl Hydroxyurea hexafluorophosphate (HATU) and 5ml DMF were added, after stirring for 1 hour at 0°C, added dropwise to the EVOH/DMF solution of (1) above, and then 0.85ml N , N -diisopropylethyl Amine, stirred and reacted at 50°C for 24 hours and then cooled to room temperature. After adding 200ml of acetone and 200ml of water, the reaction solution was filtered, washed with water, collected and dried to obtain 2.2g of yellow solid, which is an iodine-containing graft polymer (I -g -EVOH). The iodine content of the obtained iodine-containing graft polymer (I- g- EVOH) was analyzed by inductively coupled plasma-mass spectrometry (ICP-MS) technology to be 1%=15%. Remarks:

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

Example 2

1.49g of ethylene-vinyl alcohol copolymer (EVOH) particles and 10ml of dimethyl sulfide (DMSO) were added to the reaction flask and heated to dissolve. Then add 1.06g of 2,3,5-triiodobenzyl chloride in dimethyl sulfoxide solution and 2.1ml of triethylamine in sequence, stir the reaction at 50℃ for 24 hours, cool to room temperature, add 100ml of acetone and 100ml of water Then, filter, wash with water, collect the solid, and dry to obtain 2 g of yellow solid, which is the iodine-containing graft polymer (I- g- EVOH). Using inductively coupled plasma-mass spectrometry (ICP-MS) technology, the iodine content of the obtained iodine-containing graft polymer (I- g- EVOH) was I%=23%.

Example 3

(1) Add 1.10g of ethylene-vinyl alcohol copolymer (EVOH) particles and 15ml of N , N' -dimethylformamide (DMF) into the reaction flask and heat to dissolve.

(2) Take another reaction flask, add 5.65g diatrizoic acid, 4.2g O -(7-benzotriazole oxide) -N , N , N ', N' -tetramethylurea hexafluorophosphate ( Add HATU) and 15ml DMF. After stirring, add dropwise to the EVOH/DMF solution of (1) above, then add 3.80ml of N , N -diisopropylethylamine, stir and react at 50℃ 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, collected, and dried to obtain 1.56 g of light yellow solid, which is an iodine-containing graft polymer (I- g- EVOH). The iodine content of the obtained iodine-containing graft polymer (I- g- EVOH) was analyzed by inductively coupled plasma-mass spectrometry (ICP-MS) technology to be I%=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 tertiary butyl methyl ether and 60 ml of water were added to the reaction solution, and then stirred for 5 min, and allowed to stand for liquid separation. The aqueous phase was extracted three times with 210 ml of tertiary 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 the crude product of tert-butyl 2-(2,4,6-triiodophenoxy)acetate. It was used directly in the next reaction without purification.

(2) Dissolve 12.71g of crude 2-(2,4,6-triiodophenoxy)acetic acid tert-butyl ester in 60ml of dichloromethane, add 30ml of trifluoroacetic acid to the solution, stir and react at room temperature for 1 hour , Concentrated to obtain crude 2-(2,4,6-triiodophenoxy)acetic acid. 50ml of ethanol was added to the crude product, stirred overnight at room temperature, filtered, washed with 10ml of ethanol, and dried to obtain 8.96g of white solid, namely 2-(2,4,6-triiodophenoxy)acetic acid.

(3) Add 1.14g of ethylene-vinyl alcohol copolymer (EVOH) particles and 15ml of N,N'-dimethylformamide (DMF) into the reaction flask and heat to dissolve.

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

Example 5

(1) Add 1.91g of p-toluenesulfonyl chloride and 2.1ml of dry triethylamine to 19.4g of tetraethylene glycol in dichloromethane (20ml), stir and react overnight at room temperature, add 20ml of dichloromethane Dilute, wash with water (3×20ml), wash with saturated brine (1×10ml), dry with sodium sulfate, filter, concentrate, and subject the obtained liquid to flash column chromatography (ethyl acetate: petroleum ether=0~40%) to obtain 2.49g of light yellow oil (71% yield), which is 2-(2-(2-(2-hydroxyethyl)ethoxy)ethoxy)ethyl p-toluenesulfonic acid.

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

(3) Dissolve 2.00g of 2-(2-(2-(2-(2,4,6-triiodophenoxy)ethoxy)ethoxy)ethoxy)ethanol in 12ml of dichloromethane After adding 12ml of 35% aqueous sodium hydroxide solution, 1.80ml of tert-butyl bromoacetate and 892mg of tetrabutylammonium chloride, the resulting mixture was stirred at room temperature overnight. TLC tracking showed that the raw materials disappeared, and then the layers were separated. The aqueous phase was extracted with ethyl acetate (3× 20ml), combine the organic phases, wash with saturated brine (1×15ml), and dry with sodium sulfate. Filter under reduced pressure, and concentrate the filtrate under reduced pressure. The obtained liquid is subjected to fast column chromatography (ethyl acetate: petroleum ether=0~35%) to obtain 2.49g of colorless oil (yield 66%), which is 14-(2 ,4,6-Triiodophenoxy)-3,6,9,12-tetraoxomyristate.

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

(5) Add 258 mg of ethylene-vinyl alcohol copolymer (EVOH) particles and 2 ml of DMF to the reaction flask, and heat to dissolve. Take another reaction flask, dissolve 715mg of 14-(2,4,6-triiodophenoxy)-3,6,9,12-tetraoxa-myristic acid in 2ml DMF and place it in an ice-water bath under a nitrogen atmosphere Next, the resulting mixture of 463 mg of O- (7-benzotriazole oxide) -N , N , N ', N' -tetramethylurea hexafluorophosphate (HATU) was stirred at 0°C for 1.5 hours. The resulting solution was added to the above-mentioned EVOH/DMF solution, and then 0.42ml of N , N' -diisopropylethylamine was added, and the reaction was continued with stirring 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 yellow solid, which was an iodine-containing graft polymer (I- g- EVOH). The iodine content of the obtained iodine-containing graft polymer (I- g- EVOH) was analyzed by inductively coupled plasma-mass spectrometry (ICP-MS) technology to be I%=25%.

Example 6

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

(2) Heat 1.36g of ethylene-vinyl alcohol copolymer (EVOH) pellets and 15ml of dimethyl sulfide (DMSO) reaction flask to dissolve.

(3) Take another reaction flask, add 150mg sodium hydride into the reaction flask, add 8ml DMSO into the reaction flask under nitrogen atmosphere and ice water bath, stir and react at 90°C for 1 hour and then cool to room temperature. The resulting solution was added to the above EVOH/DMSO solution, stirred and reacted for 1 hour, then 7ml of 2-(2,4,6-triiodophenoxy) bromine (1.09g)/DMSO solution was added to the reaction solution, and continued The reaction was stirred at 50°C for 24 hours and then cooled to room temperature. The reaction solution was poured into 300 ml of water, filtered, washed with water, 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 obtained iodine-containing graft polymer (I- g- EVOH) was analyzed by inductively coupled plasma-mass spectrometry (ICP-MS) technology to be I%=3%.

Example 7

(1) Under nitrogen atmosphere and ice-water bath, slowly add 42ml 1.0M borane tetrahydrofuran solution dropwise to 3.00g 2,3,5-triiodobenzoic acid tetrahydrofuran solution (5ml), and continue in the ice-water bath after dropping. After stirring for 1.5 hours, warm to room temperature and stir for 1 hour. Under ice-water bath, slowly add 16ml of wet tetrahydrofuran (containing 2.5ml of water) to the reaction solution, and then add 60ml of ice-cold saturated sodium bicarbonate solution and continue to stir 1 After hours, filter, wash with water and ethanol successively, dissolve the collected white solid in dichloromethane, dry with sodium sulfate, filter and concentrate to obtain 2.85g solid, which is 2,3,5-triiodobenzyl alcohol.

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

(3) Add 1.27 g of ethylene-vinyl alcohol copolymer (EVOH) particles and 15 ml of dimethyl sulfide (DMSO) to the reaction flask, and heat to dissolve.

(4) Take another reaction flask, add 84mg sodium hydride to the reaction flask under nitrogen atmosphere and ice-water bath, then add 5ml DMSO, stir and react at 90℃ for 1.5 hours, then cool to room temperature, add the resulting solution to the above EVOH/DMSO solution, stir 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 , Washed with water, and dried to obtain 1.04 g of light yellow solid, which is an iodine-containing graft polymer (I- g- EVOH). Using inductively coupled plasma-mass spectrometry (ICP-MS) technology, the iodine content of the obtained iodine-containing graft polymer (I- g- EVOH) was I%=18%.

Example 8

(1) Add 262 mg of sodium hydroxide solid to a mixture of 2.36 g of 2,4,6-triiodophenol and 20 ml of ethanol, and after stirring for 45 minutes at room temperature, add 1.2 ml of epichlorohydrin to the reaction solution. After stirring overnight, a large amount of white precipitate was precipitated. 10ml of ethanol was added. After stirring for 2 hours, the crude product was filtered. The crude product was stirred with 30 ml of ethanol for 2 hours, filtered, rinsed with 5 ml of ethanol, and dried to obtain 1.52 g of white solid powder, namely 3-(2,4,6-triiodophenoxy)propylene oxide.

(2) Add 1.20 g of ethylene-vinyl alcohol copolymer (EVOH) particles and 15 ml of dimethyl sulfide (DMSO) into the reaction flask, and heat to dissolve.

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

Example 9

(1) Add 9.2g of 2-(2,4,6-triiodophenoxy) bromoethane prepared according to Example 6 into a 250ml reaction flask, and under nitrogen atmosphere, add 80ml of dimethyl sulfide sequentially And 2.7 mg solid potassium tert-butoxide (in batches), stirred at room temperature for 24 hours. After diluting with 80ml methyl tertiary butyl ether, add 40ml water to quench the reaction, extract three times with methyl tertiary butyl ether, wash with saturated sodium bicarbonate and water successively, dry with sodium sulfate, filter and concentrate. Column chromatography (petroleum ether/ethyl acetate=100:1) to obtain 6.04 g of white solid, which is 1,3,5-triiodo styryl ether.

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

Example 10

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

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

(3) Under nitrogen atmosphere, add 1.76 g of sodium hydride to 2.05 g of N -acetyl-2,4,6-triiodoaniline in N , N' -dimethylformamide (DMF) solution in batches (40ml), stirred at 70°C for 1 hour and then cooled to room temperature. After adding 5.3ml ethyl bromoacetate to the reaction solution dropwise, stirring overnight at 80°C and then cooling to room temperature, adding 40ml water to quench the reaction, the reaction solution was extracted three times with 240ml ethyl acetate, washed three times with water, saturated brine Wash, dry with sodium sulfate, and concentrate to obtain the crude product. The crude product is dissolved in ethanol aqueous solution (100ml ethanol and 50ml water) containing 2.4g sodium hydroxide. The mixture is heated to reflux for 3 hours and then cooled to room temperature. The solvent is removed under reduced pressure and 60ml is added. Dilute with water, wash twice with 120ml of dichloromethane, adjust the pH to 1 with concentrated hydrochloric acid, filter, wash with water, and recrystallize with ethanol/water to obtain 1.37g of brown solid, which is N -acetate Group- N- (2,4,6-triiodophenyl)glycine.

(4) Add 503 mg of ethylene-vinyl alcohol copolymer (EVOH) particles and 10 ml of N , N' -dimethylformamide (DMF) into the reaction flask, and heat to dissolve.

(5) Take another reaction flask, add 1.16g N -acetyl- N- (2,4,6-triiodophenyl)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 0.84ml of N , N' -diisopropylethylamine. The reaction solution was stirred at 50°C for 24 hours and then cooled to room temperature. The reaction solution was poured into 150ml Dichloromethane and 150 ml of water, filtered, washed with water, and dried to obtain 1.00 g of yellow solid, which is an iodine-containing graft polymer (I- g- EVOH). The iodine content of the obtained iodine-containing graft polymer (I- g- EVOH) was analyzed by inductively coupled plasma-mass spectrometry (ICP-MS) technology to be I%=41%.

Example 11

(1) Under nitrogen atmosphere, add 2.82g of 2,4,6-triiodoaniline obtained in Example 9 and a stir bar into a 100ml reaction flask, add 60ml DMF and stir to dissolve, then add 1.02g methyl iodide 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 the raw materials), the reaction solution was poured into 200 ml of cold water, filtered, and rinsed with ethanol to obtain a brown solid. The obtained tan solid was stirred overnight with 40 ml of ethanol, filtered, and rinsed with 5 ml of ethanol to obtain 2.42 g of a brown solid, which was 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 into a 100ml reaction flask, then add a drop of 85% phosphoric acid, and the resulting mixture is heated to reflux for 12 hours Cool to room temperature. Add 60ml methyl tertiary butyl ether to dilute, wash with 5% sodium hydroxide aqueous solution, wash the aqueous phase with dichloromethane and acidify with concentrated hydrochloric acid, precipitate a brown solid, filter, and dissolve the obtained solid in 50ml methyl tertiary butyl In the base ether, dried with sodium sulfate, concentrated, recrystallized with 1,2-dichloroethane and petroleum ether (3:1) to obtain 1.40g of a brown-yellow solid, which is 4-carbonyl-4-[ N -methyl- (2,4,6 triiodophenyl)amino]butyric acid.

(3) Add 623 mg of ethylene-vinyl alcohol copolymer (EVOH) particles and dimethyl sulfide (DMSO) into the reaction flask and heat to dissolve.

(4) Take another reaction flask, add 1.18g 4-carbonyl-4-[ N -methyl-(2,4,6 triiodophenyl) amino] butyric acid, 961mg O -(7-benzotrioxane) Nitrozole) -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 0.83 ml of N , N' -diisopropylethylamine was added. The reaction solution was stirred at 50°C for 24 hours and then cooled to room temperature. The reaction solution was poured into 150 ml of acetone to neutralize 150 ml of water, filtered, washed with water, and dried to obtain 1.18 g of a yellow solid, which was an iodine-containing graft polymer (I- g- EVOH). The iodine content of the obtained iodine-containing graft polymer (I- g- EVOH) was analyzed by inductively coupled plasma-mass spectrometry (ICP-MS) technology to be I%=37%.

Implementation column 12

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

(2) Add 2.12 g of 2-( N -methyl-2,4,6 triiodoanilino) ethanol obtained in the previous step into the reaction flask, add 40 ml of dichloromethane and 1.4 ml of triethylamine under a nitrogen atmosphere, and the mixture After stirring for 10 minutes at room temperature, it was cooled with an ice-water bath, 0.4ml of methanesulfonyl chloride was added dropwise, and stirring was continued for 2 hours in an ice-water bath. Add 20ml of dichloromethane to dilute, wash twice with 20ml of 2% hydrochloric acid, 10ml of water, 10ml of saturated brine, and dry with sodium sulfate. Filter and concentrate to obtain 2.19 g of brown solid. Beat with 20ml of ethanol and filter to obtain 2.02g of brown-yellow solid, which is methanesulfonic acid-2-( N -methyl-2,4,6-triiodoanilino)ethyl ester.

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

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

Example 13

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

The slurry was beaten with absolute ethanol overnight, filtered with suction, washed, and dried to obtain 3.15 g of 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 overnight at 65°C, concentrate, Add 2N hydrochloric acid to acidify, filter with suction, wash with water, and dry in vacuum to obtain 2.44g of white solid, namely 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) into the reaction flask, and heat to dissolve. Take another reaction flask, mix 2.0g 11-(2,4,6-triiodophenoxy)undecanoic acid, 1.36g O -(7-benzotriazole oxide) -N , N , N ', N' -tetramethyluronium hexafluorophosphate (HATU) and 7 mL DMF were added to the reaction flask and stirred at 0°C. The resulting solution was added to the above EVOH/DMF solution, then 1.23ml of N , N -diisopropylethylamine was added, and after stirring for 24 hours at 50°C, 140ml of dichloromethane and 140ml 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 (I- g- EVOH). Using inductively coupled plasma-mass spectrometry (ICP-MS) technology, the iodine content of the obtained iodine-containing graft polymer (I- g- EVOH) was I%=36%.

Example 14: Preparation of liquid embolic agents

Take the I- g- EVOH obtained in the foregoing Examples 1-13 and add it to a water-soluble non-physiological solvent, stir to dissolve, and then add the liquid embolic agent to the vial and cap it. Autoclave at 121°C for 15 minutes.

Example 15:

Samples 1, 4, 5, and 13 of the liquid embolic agent in Example 14 were 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 to the outside. The precipitates formed are rated from 1-10, with 1-2 being the worst adhesive and 9-10 being the best adhesive.

The following example shows that the adhesiveness can be changed by changing the formulation.

Example 16:

In the flow model, the liquid embolic preparation was delivered via a 2.6F (0.87mm) microcatheter. Visually evaluate the adhesion of the embolic agent, injection pressure, embolism formation and precipitation speed. The settling rate is rated as slow, medium and fast. Rate all other properties from 1 to 10, with 1-2 being the least expected and 9-10 being the most expected.

The following examples show that changes in fluidity can be achieved by changing the formulation.

Example 17: Arteriography (DSA) study

(樣品14)，其中x=37mol%；y=51.07mol%；z=11.93mol%，I%=45.79%。

(樣品15)，其中x=37mol%，y=49.54mol%，z=14.52mol%，I%=42.27%。 Refer to the method of Example 4 to prepare the following polymer

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

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

The sample was prepared into a DMSO solution according to the corresponding concentration (Wt./V), and the solution was measured with a Brookfield DV2T LVTJ0 viscometer at a temperature of 22°C. The density is calculated as 1.153g/mL

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

External embolization evaluation:

Prepare the relevant sample into a 20% DMSO solution. The column cavity volume is about 10 mL. When embolization, the syringe needle needs to be vertically upward, and the embolization volume consumed is less than 6 mL.

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

Example 18:

With reference to GB/T 16886.12-2017 based on different extraction ratios, the samples were extracted with MEM medium containing 10% fetal bovine serum in an inert container, and the sample extract was prepared by extraction at 37°C and 60rpm for 24 hours. Prepare blank control, negative control (high density polyethylene) and positive control sample (10% DMSO solution) in the same way. Under the condition of 37℃ and 5% CO ₂ , the density of inoculated cells in 96-well cell culture plate is 1.0×10 ⁵ cells/mL, and 100 μL per well is inoculated. After 24 hours of culture, the blank control, negative control, positive control and sample The extract was contacted with adherently grown L929 cells (mouse fibroblasts), 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 the wavelength of the microplate reader at 570nm (reference wavelength 650nm), and calculate the survival rate of the cells.

，其中OD570e是試驗樣品100%浸提液光密度平均值，OD570b是空白光密度平均值。 The survival rate (Viab.%) is defined as

, Where OD570e is the average value of the optical density of the test sample 100% extract, and OD570b is the average value of the blank optical density.

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

Comparative example 1:

，其中，x=48.4mol%，y=51.6mol%，碘含量為41.5%。 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 micropipette for curing, and test its tensile properties after curing. Rate it from 1 to 10, where 1-2 is brittle and breakable, and 9-10 is excellent stretchability. The results are as follows:

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

After the microcatheter was injected into the silicone tube to simulate the embolism in the body and solidified, the samples 4 and 13 had good appearance as shown in Figure 1 and Figure 2.

Place 150 mg of polymer (sample A) in 1.5 ml of 3% hydrogen peroxide or 0.9% NaCl solution, and place it at 70°C for 10 days (accelerate degradation), then take the aforementioned solid sample and dissolve in an appropriate amount of dimethyl sulfoxide solution to prepare To a 0.07%wt/v solution, HPLC detection, the results are as follows:

備註：HPLC條件Aglient色譜管柱C-18(2.7μm*4.6mm*50mm)，流動相0.05%三氟乙酸/乙腈0.05%三氟乙酸/水，梯度洗脫。

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

Result: 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 degrade into triiodophenol. Triiodophenol has very strong cytotoxicity and has potential medicinal safety problem.

Claims (44)

A polymer, as shown in general formula I: XYZ 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 the first item of the patent application, wherein the link Y is selected from bond, ester, carbonate, polyester, polyether, acetal, ketal or amino acid. For the polymer described in item 1 or 2 of the scope of patent application, the polymer represented by formula I is: R ¹ -(A) _m -(B) _n -(C) _p -Z II Wherein, R ^{1 is} selected from an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group. The alkyl group, cycloalkyl group, aryl group or heteroaryl group contains multiple iodine atoms, which may be one iodine atom , 2 iodine atoms, 3 iodine atoms or 4 iodine atoms, and optionally one or more selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aromatic Group, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', S(O)R', SO ₂ R', P(O)R'(R"), NR'(R"), COOR ', CONR'(R"), and further, the alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, aryl, and heteroaryl groups are optionally substituted by one or more selected from deuterium, Hydroxy, halogen, SR', NR'(R"), COOR', CONR'(R"), the R'or R" is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy Alkyl, alkenyl, acyl; A and C are each independently selected from alkylene, oxy (-O-), amino (-NR'-), thio (-S-), carbonyl (

), 碸基(

), subunit (

), phosphoryl (

), ester group (

or

), amide group (

or

), the R'is selected from hydrogen, alkyl, alkoxy, alkenyl, and acyl; B is selected from alkylene, poly(ethylene), poly(propylene), poly(ethyleneoxy) (

), oxy (-O-), amine extension (-NR'-), thio (-S-), carbonyl (

), 碸基(

), subunit (

), ester group (

or

), amide group (

or

), the alkylene group is optionally selected from one or more alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, SR', NR'(R "), COOR', CONR'(R"), and further, the alkyl group, alkoxy group, alkenyl group, aryl group, and heteroaryl group are optionally substituted by 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, and 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 item 1 of the scope of patent application The polymer described in item 3 of the scope of patent application, wherein R ¹ in the polymer represented by formula II is an aryl group or a heteroaryl group. The polymer according to item 4 of the scope of patent application, wherein R ¹ in the polymer represented by formula II is a benzene ring, and the benzene ring contains multiple iodine atoms, which can be 1 iodine atom, 2 iodine atoms, 3 One iodine atom, four iodine atoms, or five iodine atoms. The polymer according to item 5 of the scope of patent application, wherein R ¹ in the polymer represented by formula II is a benzene ring, and the benzene ring includes positions C-2, C-3 and C-5 or C- 2. Three iodine atoms on the C-4 and C-6 positions or two iodine atoms on the C-3 and C-5 positions. The polymer described in item 4 of the scope of patent application, wherein R ¹ in the polymer represented by formula II is a pyridyl group, and the pyridyl group contains multiple iodine atoms, which can be 1 iodine atom, 2 iodine atoms, 3 One iodine atom or four iodine atoms. The polymer according to any one of items 3 to 7 in the scope of patent application, wherein the polymer represented by formula II is:

Among them, A, B, C, m, n, p, Z are as defined in item 3 of the scope of the patent application; 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, The alkoxy group, hydroxyalkyl group, alkenyl group, aryl group and heteroaryl group are optionally selected from deuterium, hydroxyl, halogen, SR', NR'(R"), COOR', CONR'(R" ), the 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 described in item 8 of the scope of patent application, wherein A and C in the polymer represented by formula III are each independently selected from C _1-6 alkylene, oxy (-O-), amino (-) NR'-), thio (-S-), carbonyl (

), 碸基(

), subunit (

), ester group (

or

), amide group (

or

), the R'is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 alkanoyl, benzyl, p-tolyl, p =1 or 2. The polymer described in item 8 or 9 of the scope of patent application, wherein C in the polymer represented by formula III is selected from C _1-6 alkylene, carbonyl (

), 碸基(

), subunit (

), ester group (

or

), amide group (

or

), R'is as defined in item 9 of the scope of patent application. The polymer according to any one of items 8 to 10 in the scope of the patent application, wherein B in the polymer represented by formula III is selected from C _1-6 alkylene, poly(ethyleneoxy) (

),, o as defined in item 3 of the scope of patent application. The polymer described in item 11 of the scope of the patent application, wherein B in the polymer represented by formula III is selected from C _1-6 alkylene. The polymer described in item 12 of the scope of patent application, wherein B in the polymer represented by formula III is selected from methylene, ethylene, propylene or n-butyl. The polymer according to any one of items 1 to 13 in the scope of the patent application, which is selected from:

with

, Where Z is as defined in item 1 of the scope of patent application. Such as the polymer described in item 1 or 2 of the scope of patent application, wherein the visualizer is partly introduced by an iodine compound or a gadolinium compound. Such as the polymer described in item 15 of the scope of patent application, wherein the iodine compound is selected from 2,3,5-triiodobenzoic acid, sodium 2,3,5-triiodobenzoate, iodotitanic acid, mepanic acid, iodine Da acid, iohexol. As described in item 15 of the patent application, the gadolinium compound is selected from the group consisting of gadopentetate meglumine aminoethyl methacrylate, gadoterate meglumine, and barium barium meglumine. The polymer according to any one of items 1 to 14 in the scope of the patent application, wherein the average molecular weight of the ethylene-vinyl alcohol copolymer is 5KD~500KD. The polymer according to any one of items 1 to 18 in the scope of the patent application, wherein the repeating unit of the polymer is:

or

or

Among them, x = 5 to 94 mol%, y + z = 6 to 95 mol%, z = 2 to 40 mol%, and x + y + z = 100 mol%, and R is a graft unit having a visualizer part and a connecting part. The polymer according to any one of items 1 to 19 in the scope of the patent application, wherein the vinyl content in the ethylene-vinyl alcohol copolymer is 5-94 mol%. The polymer according to item 20 of the scope of patent application, wherein the vinyl content in the ethylene-vinyl alcohol copolymer is 10-60 mol%. The polymer according to item 21 of the scope of patent application, wherein the vinyl content in the ethylene-vinyl alcohol copolymer is 20-50 mol%. The polymer described in any one of items 1 to 22 in the scope of the patent application has an iodine content of at least 10% (w/w). The polymer described in item 23 of the scope of patent application has an iodine content of at least 20% (w/w). The polymer described in item 24 of the scope of patent application has an iodine content of at least 40% (w/w). The polymer according to any one of items 1 to 25 in the scope of patent application, wherein the polymer is soluble in the non-physiological solution and insoluble in the physiological solution. The polymer according to any one of items 1 to 26 in the scope of patent application, wherein the connecting part Y is degradable. A method for preparing the polymer described in any one of items 1 to 7 in the scope of patent application, comprising: a step of reacting an ethylene-vinyl alcohol copolymer with XYR ³ , wherein R ³ is hydrogen or a leaving group, and The leaving group is selected from halogen, alkyl, alkoxy, cycloalkyl, sulfonyl, and X and Y are as defined in item 1 of the scope of the patent application. A method for preparing the polymer described in any one of items 1 to 27 in the scope of patent application, comprising: a step of reacting an ethylene-vinyl alcohol copolymer with XR ³ and YR ³ , wherein R ³ is hydrogen or a leaving group , The leaving group is selected from halogen, alkyl, alkoxy, cycloalkyl, sulfonyl; X and Y are as defined in item 1 of the scope of patent application. The method described in item 28 or 29 of the scope of the patent application, wherein the reaction is carried out in an aprotic solvent. The method according to item 30 of the scope of patent application, wherein the aprotic solvent is selected from the group consisting of dimethyl sulfoxide, N-methylpyrrolidone, N,N'-dimethylformamide, and N,N'-dimethyl Acetamide or tetrahydrofuran. The method according to any one of items 28 to 31 in the scope of the patent application, wherein the reaction further includes an accelerator, and the accelerator is selected from any one of alkali, acid, or condensation agent. The method according to item 32 of the scope of patent application, wherein the base is selected from an organic base or an inorganic base. The method according to item 33 of the scope of patent application, wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium hydride, and potassium carbonate. The method according to item 33 of the scope of patent application, wherein the organic base is selected from triethylamine, N,N-diisopropylethylamine or N,N-dimethylaminopyridine. The method according to any one of the 32 to 35 patents, wherein the condensing agent is selected from N , N' -dicyclohexylcarbodiimide, O- (7-azabenzotriazole-1 -Radical) -N , N , N ′, N ′-tetramethyluronium hexafluorophosphate. A composition comprising the polymer described in any one of items 1 to 27 in the scope of the patent application. The composition described in item 37 of the scope of the patent application further contains a non-physiological solvent. The composition according to item 38 of the scope of patent application, wherein the non-physiological solvent is water-soluble. The composition according to item 39 of the patent application, wherein the non-physiological solvent is selected from methanol, ethanol, dimethylformamide, N-methylpyrrolidone, isosorbide dimethyl ether or dimethylsulfide. The composition according to any one of items 37 to 40 in the scope of the patent application, wherein the concentration of the polymer is 1 to 80%. The composition described in item 41 of the scope of patent application, wherein the concentration of the polymer is 10 to 70%. A method for preparing an embolism in a physiological environment, which comprises using a delivery device to transfer the composition described in any one of the 37 to 42 patents or to any one of the 1 to 27 patents. The polymer is injected into the physiological environment, and the polymer or polymer in the composition precipitates and embolizes in the physiological environment. A method for treating diseases, which comprises: injecting the composition described in any one of the 37th to 42nd patent applications or the polymer described in any one of the 1st to 27th patent applications through a delivery device Steps in the physiological environment.

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