Iodine compounds having radiocontrast properties

Abstract

Organoiodine compounds are provided that contain a radiopaque moiety, such as iodine, and an additional chemical group that increases solubilization, mixing, and / or compatibilization with various materials with which the compounds are mixed.SOLUTION: The present invention relates to an iodine compound comprising at least one 2,4,6 - triiodobenzene moiety, wherein at least one of the hydrogens in position 1, 3 and 5 of the 2,4,6 - triiodobenzene moiety is substituted by an iodinated substituent comprising one or more iodophenyl-containing groups. It also relates to compositions containing such iodine compounds and methods of making such iodine compounds.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] Among other aspects, the present disclosure relates to iodine compounds having radioimaging properties, methods of making such iodine compounds, and medical products containing such iodine compounds. [Background technology]

[0002] There is a continuing need for new types of radiopaque enhancing agents that can be added to medical products, including medical devices and implants, that can replace the use of metallic materials as radiopaque enhancing agents. As a specific example, metallic radiopaque additives, such as tantalum, used in liquid embolic formulations suffer from beam hardening limitations, which create streak artifacts and severely hinder the resolution and structural details of adjacent tissues or organs. Compounds that can be added to medical polymers to make them radiopaque under X-ray imaging are highly desirable if they (i) do not significantly adversely affect the material properties of the polymer, (ii) do not cause undesirable imaging artifacts, (iii) can be dissolved in solvents or mixed into polymer melts for ease of processing, and / or (iv) do not leach from the polymer or undergo significant degradation during use. Summary of the Invention

[0003] The present disclosure relates to a family of organic iodine compounds that contain a radiopaque moiety, such as iodine, and additional chemical groups that increase solubilization, mixing, and / or compatibilization with various materials with which the compounds are mixed. In various embodiments, the iodine compounds contain hydroxyl groups that enhance interactions with hydrophilic groups in other materials with which they are mixed. This can aid in compatibility between the compound and the material, resulting in improved performance. These compounds also have the potential to be used in place of metals when some applications require minimizing and / or eliminating electrical and / or ferromagnetic conductivity.

[0004] In various aspects, the present disclosure relates to iodo compounds comprising at least one 2,4,6-triiodobenzene moiety, wherein at least one of the hydrogens at the 1-, 3-, and 5-positions of the 2,4,6-triiodobenzene moiety is replaced by an iodine substituent comprising one, two, three, four, or more iodophenyl-containing groups (an iodophenyl-containing group includes only iodine atom substitutions on the phenyl group and may have one, two, three, four, or five iodine atoms replacing the phenyl hydrogen atoms).

[0005] In some embodiments, the iodophenyl-containing group can be selected from one or more of a mono-iodophenyl-containing group, a di-iodophenyl-containing group, a tri-iodophenyl-containing group, a tetra-iodophenyl-containing group, or a penta-iodophenyl-containing group.

[0006] In some embodiments that can be used in conjunction with the above aspects and embodiments, the iodophenyl-containing group can be selected from an iodophenyloxy group, an iodophenylcarbonyloxy group, or an iodophenyl group attached via a cyclic acetal or carbamate group.

[0007] In some embodiments that can be used in conjunction with the above aspects and embodiments, the iodinated substituent comprises a C2-C6 alkyl-amino group or a C2-C6 alkyl-carbonyl group in which the C2-C6 alkyl hydrogen is replaced by (a) one or more iodophenyl-containing groups and (b) zero, one, or more hydroxyl groups. In more particular embodiments, the iodinated substituent comprises a C2-C6 alkyl-aminocarbonyl group or a C2-C6 alkyl-carbonylamino group in which the C2-C6 alkyl hydrogen is replaced by (a) one or more iodophenyl-containing groups and (b) zero, one, or more hydroxyl groups. In particular embodiments, the C2-C6 alkyl is a C3 alkyl.

[0008] In some embodiments, the present disclosure provides a compound of formula I:

[0009] [ka]

[0010] In the formula, R 20 , R 21 , R 22 , R 23 , R 24 , and R 25 Each of R 20 , R 21 , R 22 , R 23 , R 24 , and R 25 At least one of Formula II, Formula III, Formula X:

[0011] [ka]

[0012] wherein m is 0, 1, 2, 3, 4, 5, 6, or more; n is 1, 2, 3, 4, or 5; and R 70 is selected from the group consisting of H or C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, butyl, hexyl), preferably H or C1-C4 alkyl). 30 H and R, provided that 30 are independently selected from, or In the formula, R 20 +R 21 , R 22 +R 23 , and R 24 +R 25 taken together, at least one of the groups represented by formula IV:

[0013] [ka]

[0014] where n is 1, 2, 3, 4, or 5, and any non-cyclizing substituent R 20 , R 21 , R 22, R 23 , R 24 , and R 25 is H, in which case

[0015] [ka]

[0016] The compound of Formula I may be any of the following: (a) 1, 2, 3, 4, 5, or 6 iodophenyl-containing -OR groups attached to at least one of the nitrogen atoms; 30 Note that the hydroxyl group (a) contains two C3 alkyl-aminocarbonyl groups and one C3 alkyl-amino group, which may collectively contain 0, 1, 2, 3, 4, or 5 hydroxyl groups.

[0017] In some embodiments, the present disclosure provides a compound of formula V:

[0018] [ka]

[0019] In the formula, R 31 , R 32 , R 33 , R 34 , and R 35 Each of R 31 , R 32 , R 33 , R 34 , and R 35 At least one of R is defined above. 30 H and R, provided that 30 are independently selected from, or In the formula, R 31 +R 32 and R 34 +R 35 taken together, at least one of the groups represented by formula IV:

[0020] [ka]

[0021] where n is 1, 2, 3, 4, or 5, and any non-cyclizing substituent R 31 , R 32 , R 33 , R 34 , and R 35 is H. Compounds of formula V may be prepared by: (a) administering to a patient a compound selected from the group consisting of one, two, three, four, or five iodophenyl-containing -OR groups; 30 Note that the hydroxyl group (a) contains two C3 alkyl-aminocarbonyl groups and one C3 alkyl-carbonylamino group, which may collectively contain 0, 1, 2, 3, or 4 hydroxyl groups.

[0022] In some embodiments, the present disclosure provides a compound of formula VI:

[0023] [ka]

[0024] In the formula, R 41 , R 42 , R 43 , and R 44 Each of R 41 , R 42 , R 43 , and R 44 At least one of R is defined above. 30 H and R, provided that 30 are independently selected from, or In the formula, R 41 +R 42 and R 43 +R 44 taken together, at least one of the groups represented by formula IV:

[0025] [ka]

[0026] where n is 1, 2, 3, 4, or 5, and any non-cyclizing substituent R41 , R 42 , R 43 , and R 44 is H, in this case,

[0027] [ka]

[0028] The group is attached to at least one of the nitrogen atoms. In some embodiments, the present disclosure provides a compound of formula VII:

[0029] [ka]

[0030] In the formula, R 51 , R 52 , R 53 , R 54 , R 55 , and R 56 Each of R 41 , R 42 , R 43 , and R 44 At least one of R is defined above. 30 H and R, provided that 30 are independently selected from, or In the formula, R 51 +R 52 and R 53 +R 54 taken together, at least one of the groups represented by formula IV:

[0031] [ka]

[0032] where n is 1, 2, 3, 4, or 5, and any non-cyclizing substituent R 51 , R 52 , R 53 , R 54 , R 55 , and R 56is H, in which case

[0033] [ka]

[0034] The group is attached to at least one of the nitrogen atoms. In some embodiments, the present disclosure provides a compound of formula VIII:

[0035] [ka]

[0036] In the formula, R 61 , R 62 , R 63 , R 64 , R 65 , and R 66 Each of R 61 , R 62 , R 63 , R 64 , R 65 , and R 66 At least one of R is defined above. 30 H and R, provided that 30 are independently selected from, or In the formula, R 61 +R 62 , R 63 +R 64 , and R 65 +R 66 taken together, at least one of the groups represented by formula IV:

[0037] [ka]

[0038] where n is 1, 2, 3, 4, or 5, and any non-cyclizing substituent R 61 , R 62 , R 63 , R 64 , R 65 , and R66 is H, in which case

[0039] [ka]

[0040] The group is attached to at least one of the nitrogen atoms. In some embodiments, the present disclosure provides a compound of formula IX

[0041] [ka]

[0042] In the formula, R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , and R 79 Each of R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , and R 79 At least one of R is defined above. 30 H and R, provided that 30 are independently selected from, or In the formula, R 71 +R 72 , R 73 +R 74 , R 75 +R 76 , and R 77 +R 78 taken together, at least one of the groups represented by formula IV:

[0043] [ka]

[0044] where n is 1, 2, 3, 4, or 5, and any non-cyclizing substituent R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , and R 78 is H, in which case

[0045] [ka]

[0046] The group is attached to at least one of the nitrogen atoms. In any of the above structures, n can be 1, 2, 3, 4, or 5, but is typically 1, 2, 3, or 4, and more typically 3 or 4.

[0047] In any of the above structures, m can be 0, 1, 2, 3, 4, 5, 6 or more, and more typically 0, 1, or 2. In some embodiments, the molar ratio of hydroxyl groups to iodophenyl-containing groups in the iodine compounds of the present disclosure may range from 0:1 to 10:1 or more, for example, in some cases, from 0:1 to 0.1:1 to 0.2:1 to 0.5:1 to 1:1 to 2:1 to 5:1 to 10:1.

[0048] In a further aspect, the present disclosure relates to a composition comprising one or more iodine compounds, comprising one or more iodine compounds according to any of the above aspects and embodiments. In various embodiments, such compositions include (a) one or more iodine compounds according to any of the above aspects and embodiments, and (b) at least one polymer. Such compositions include liquid and solid compositions.

[0049] In certain embodiments, at least one polymer is a hydrophilic polymer. In certain embodiments, at least one polymer is a hydrophobic polymer. Hydrophilic polymers for use in the compositions of the present disclosure include homopolymers and copolymers having repeating hydrophilic backbone units comprising ethylene oxide, propylene oxide, imide, amide, and ester units, as well as homopolymers and copolymers having repeating units comprising one or more pendant groups selected from the following: hydroxyl groups, carboxylic acid groups and salts thereof, carboxylic acid ester groups, amino groups, amide groups, sulfonic acid groups and salts thereof, phosphate groups, and thiol groups.

[0050] Polymers for use in the compositions of the present disclosure include, among others, polyvinyl alcohol homopolymers and copolymers, polyvinylpyrrolidone homopolymers and copolymers, poly(ethylene oxide) polymers and copolymers (e.g., poly(ethylene oxide)-poly(propylene oxide) copolymers such as PEO-PPO-PEO block copolymers), polyoxazoline homopolymers and copolymers, polysulfonic acid homopolymers, copolymers and salts thereof, polyacrylic acid homopolymers, copolymers and salts thereof, poly(hydroxyalkyl acrylate) homopolymers and copolymers, polymethacrylic acid homopolymers, copolymers and salts thereof, poly(hydrogen methyl acrylate) homopolymers and copolymers, poly(ethylene oxide) copolymers and salts thereof, poly(ethylene oxide)-poly(propylene oxide) copolymers and salts thereof, poly(hydroxyalkyl acrylate) homopolymers and copolymers, poly(methacrylic acid) homopolymers, copolymers and salts thereof, poly(hydroxyalkyl acrylate) homopolymers and copolymers, poly(hydroxyalkyl acrylate) homopolymers and copolymers, poly(ethylene oxide) homopolymers, copolymers and salts thereof ... poly(hydroxyalkyl methacrylate) homopolymers and copolymers, polyamide homopolymers and copolymers, including polyamide block copolymers, polyacrylamide homopolymers and copolymers, including poly(hydroxyalkyl acrylamide) homopolymers and copolymers, polymethacrylamide homopolymers and copolymers, including poly(hydroxyalkyl methacrylamide) homopolymers and copolymers, cellulose, methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, starch, chitosan, alginates, gelatin, polysaccharide gums such as carrageenan, guar gum, xanthan gum, gellan gum, locus bean gum, and gum arabic.

[0051] Polymers for use in the compositions of the present disclosure also include, among others, polyolefin homopolymers and copolymers, including homopolymers and copolymers of ethylene, propylene, butylene, butadiene, and the like; polyvinyl chloride homopolymers and copolymers; polysiloxane homopolymers and copolymers; polysulfone homopolymers and copolymers; acrylic acid ester homopolymers and copolymers, including homopolymers and copolymers of ethyl acrylate, propyl acrylate, butyl acrylate, and the like; homopolymers and copolymers of methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, and the like; methacrylate homopolymers and copolymers, including methacrylate ester homopolymers and copolymers, polystyrene homopolymers and copolymers, fluorinated homopolymers and copolymers, polyacrylonitrile homopolymers and copolymers, including poly(acrylonitrile-co-butadiene-co-styrene) (ABS), polyimide homopolymers and copolymers, polycarbonate homopolymers and copolymers, polyurethane homopolymers and copolymers, polyester homopolymers and copolymers, including polyethylene terephthalate, polybutylene terephthalate, and homopolymers and copolymers of lactide, glycolide, and caprolactone.

[0052] Compositions according to the present disclosure may have radiopacity in the range of, for example, 10 to 10,000 Hounsfield Units (HU) or greater, such as in the range of 10 HU to 25 HU to 50 HU to 100 HU to 250 HU to 500 HU to 1,000 HU to 2,500 HU to 5,000 HU to 10,000 HU.

[0053] Compositions according to the present disclosure may have a range of iodine contents. In some embodiments, compositions according to the present disclosure may have iodine in an amount ranging from 1 to 80% by weight, typically 5 to 40% by weight, e.g., 10 to 30% by weight or 15 to 25% by weight. In some embodiments, compositions according to the present disclosure may have iodine in an amount ranging from 2 to 1200 mgI / cm. 3 , typically 50-900 mgI / cm 3, e.g., 100-800 mgI / cm 3 , 150-500 mg I / cm 3 , or 200–400 mgI / cm 3 The amount of iodine may range from 0.1 to 1.0.

[0054] Other aspects of the present disclosure include medical articles comprising a composition according to any of the above-described aspects and embodiments, such as medical devices and implants selected from catheters, including catheter tubing, catheter balloons, and catheter tips, guidewires, needles, endoscopes, filters, stents, stent grafts, vascular grafts, vascular access ports, embolizing compositions, embolizing particles, embolizing devices, tissue bulking compositions, tissue bulking particles, tissue bulking devices, myocardial plugs, wound drains, gastrointestinal tubes, urethral inserts, pacemaker leads, drug delivery depots, defibrillator leads, shunts, cardiac prostheses, heart valves, vascular valves, sutures, suture anchors, anastomotic clips and rings, tissue staples and ligation clips, cannulas, orthopedic prostheses, and joint prostheses.

[0055] In some embodiments, the composition comprises an entire medical article (e.g., an embolic or bulking particle or liquid, a drug delivery depot, a plug, a tube, a graft, a filter membrane, a valve, a suture, etc.), a portion of a medical article (e.g., a catheter balloon, a catheter tube, a catheter tip, a marker band, etc.), a laminate layer or coating on a medical article (e.g., a laminate layer or coating disposed over all or a portion of the medical article in the preceding paragraph).

[0056] In some embodiments, the composition comprises a PVA or a copolymer of PVA. In some embodiments, the PVA or copolymer thereof may comprise an iodinated aromatic group covalently bonded to the polyvinyl alcohol backbone, and in some embodiments, the aromatic group is an iodinated phenyl group.

[0057] In some embodiments, the composition comprises or is a liquid embolic composition comprising PVA or a PVA copolymer and one or more of the compositions described herein. The PVA or PVA copolymer may contain covalently bound iodine, such as a covalently bound iodinated phenyl group. Typically, such compositions are provided as a solution in a solvent suitable for injection, such as DMSO. In such cases, the PVA or PVA copolymer precipitates from the solution in the blood to form an embolus. Examples of such PVA polymers and copolymers are provided in WO2020 / 003147, WO2020 / 003153, and WO2011 / 110589.

[0058] In the case of a coating or laminate layer, the thickness of the composition can be varied to provide the desired radiopacity. As a coating or laminate layer, the composition according to the present disclosure can be applied to a substrate that is polymeric, metallic, ceramic, or a combination thereof. The coating can be applied in any known manner, for example, from a solution, dispersion, or melt containing one or more polymers and one or more iodine compounds, by spraying, brushing, pad printing, dipping, etc., and as a powder coating.

[0059] Another aspect of the present disclosure relates to a process for making iodine compounds, including those described above. In some embodiments, such a process comprises: (a) treating at least one compound comprising at least one 2,4,6-triiodobenzene moiety, wherein at least one of the hydrogens at the 1-, 3-, and 5-positions of the 2,4,6-triiodobenzene moiety is replaced by a polyhydroxylated substituent; (b) treating at least one compound represented by Formula XI, XII, or XIX with a hydroxyl group selected from the group consisting of 1, 3, and 5;

[0060] [ka]

[0061] with a compound of formula (I) under conditions to form a bond containing a moiety selected from an ether, an ester, a cyclic acetal, or a hemiacetal, wherein n is 1, 2, 3, 4, or 5; and R 81 is selected from -H, -CH3, -CH2CH3, -F, -Cl, -Br, -I, anhydride, -OH, imidazolide, or O-acylisourea; R 70 is H or C1-C6 alkyl, m is 0, 1, 2, 3, 4, 5, 6, or more, and when m is 0, X is -O - Na + and when m is 1, 2, 3, 4, 5, 6, or more, X is -F, -Cl, -Br, or -I. 81 When forming an ester bond from compound XI where R is -OH, -CH, or -CHCH, an acid catalyst can be used to promote esterification or transesterification, and 81 When R is -F, -Cl, -Br, -I, or an anhydride, the esterification can be catalyzed by a tertiary amine or other base. For the formation of O-acylisourea, the catalyst N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) is used to catalyze the esterification of XI (where R 81 is -OH). - Na +When forming an ether bond from XII, which is (sodium phenolate), one or more hydroxyl groups on at least one compound from (a) (i.e., on at least one compound comprising at least one 2,4,6-triiodobenzene moiety, where at least one of the hydrogens at the 1-, 3-, and 5-positions of the 2,4,6-triiodobenzene moiety is replaced by a polyhydroxylated substituent) can be converted to one or more halide groups, such as with a hydrogen halide, a phosphorus halide, thionyl chloride, or the like, and reacted with the sodium phenolate moiety to form the ether bond via a Williamson reaction. When m is 1, 2, 3, 4, 5, 6, or more, and X is a halide, one or more hydroxyl groups on at least one compound from (a) can be reacted with a compound of formula XII under basic conditions catalyzed by NaOH, KOH, NaCO, KCO, NaH, or the like to form the ether bond via a Williamson reaction. In the case of intermediate XIX, an activated form of aniline or N-substituted aniline is formed by reaction with CDI followed by reaction with at least one compound from (a). Alternatively, at least one compound from (a) may be activated by reaction with CDI followed by reaction with aniline or N-substituted aniline. Suitable solvents for these reactions described above may be selected from aprotic solvents such as dimethyl sulfoxide, N-methylpyrrolidinone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyloxazolidinone, and the like.

[0062] In some embodiments, the at least one compound comprising at least one 2,4,6-triiodobenzene moiety, wherein at least one of the hydrogens at the 1, 3, and 5 positions of the 2,4,6-triiodobenzene moiety is replaced by a polyhydroxylated substituent, is the following compound:

[0063] [ka]

[0064] [ka]

[0065] [ka]

[0066] may be selected from: [Brief explanation of the drawings]

[0067] [Figure 1A] 1A and 1B show the FTIR spectra of two iodine compounds according to the present disclosure. [Figure 1B] Same as above. [Figure 2A] 2A and 2B show the proton NMR spectra of two iodine compounds according to the present disclosure. [Figure 2B] Same as above. [Figure 3] 3 shows a micro-CT image of a strand of liquid embolic material according to the present disclosure within an agar phantom, with the inset being a micro-CT image of the dissection of the liquid embolic material. [Figure 4] FIG. 4 is an optical image of an embolism created by delivery of a liquid embolic material according to the present disclosure into a 5 mm silicone tubing perfused with a constant flow of phosphate buffered saline (PBS) at a rate of 400 ml / min (at 37° C.). [Figure 5] FIG. 5 is an optical image of a balloon coated with a coating of PVA and an iodine compound according to the present disclosure. [Figure 6] FIG. 6 shows μCT analysis of the coated balloon of FIG. 5 and its cross-sectional analysis (inset). DETAILED DESCRIPTION OF THE INVENTION

[0068] Iodine compounds have been synthesized from hydrophilic contrast agents, specifically 5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide (iohexol) (Formula XII) and 5-[acetyl-[3-[acetyl-[3,5-bis(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodo-phenyl]amino]-2-hydroxy-propyl]amino]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-benzene-1,3-dicarboxamide (iodixanol) (Formula XVII), by reacting available hydroxyl groups with additional iodinating groups. The resulting compounds contain high levels of iodine, which can be further adjusted by controlling the level of reactive hydroxyl groups. By varying the ratio of hydrophobic iodinated moieties to hydrophilic OH groups, the interaction between the additive and the medium can be adjusted to achieve desired viscosity fluid and solidification properties.

[0069] In addition to the synthesis of iodine compounds, a liquid embolic formulation prepared from iodinated PVA with hydrophilic functional groups and the iodine compounds disclosed herein is also described. Injectability and radiopacity were demonstrated. Embolic capability was also demonstrated by delivering the liquid embolic material through a 5 mm silicone tube perfused with a constant flow of phosphate-buffered saline (PBS) at a flow rate of 400 ml / min (37°C).

[0070] A coating composition prepared from PVA and an iodine compound according to the present disclosure is also described. The composition is used to coat catheter balloons. The coating is adhesive, flexible, and stable to repeated balloon inflation / deflation cycles, and exhibits radiopacity, as described more fully below. Radiopaque coatings are desirable for balloon catheter coatings because the position of the balloon's edges and surface can be tracked in real time within the body under fluoroscopy. In current clinical practice, balloons are filled with a contrast agent to enable radiopacity, but a radiopaque polymer coating on the balloon's exterior replaces the need for contrast agents and allows the use of saline to inflate the balloon. Therefore, balloon catheters can be improved by providing a radiopaque polymer coating on the balloon's exterior. Because the radiopaque polymer coating can be dipped, sprayed, or pad-printed onto the balloon, different patterns of radiopaque coatings can be formed on the balloon. These patterns can also be designed to provide useful information to medical professionals during interventional procedures.

[0071] Example 1: Preparation of iohexol and iodixanol derivatives. Iohexol (see Formula XII) powder (2.5 grams) was placed in a 250 mL flask and dissolved in 10 mL of anhydrous DMSO by heating to 50 °C under magnetic stirring. 2,3,5-Triiodobenzoic acid (TIBA) (9.9 grams) was dissolved in 15 mL of anhydrous DMSO in a 100 mL round-bottom flask, followed by the very slow addition of carbonyldiimidazole (CDI) powder (3.21 grams) at room temperature with constant stirring to release the evolved carbon dioxide. The addition / stirring took approximately 30 minutes, resulting in the formation of CDI-activated TIBA. This reaction mixture was then added to the flask containing the iohexol solution, and the reaction was carried out under magnetic stirring at 60 °C for 20 hours. After the reaction, the mixture was poured into 500 mL of aqueous sodium carbonate (2.5 w / w%) with vigorous magnetic stirring. The white precipitate was collected and filtered through a Buchner funnel. The white powder was further washed with deionized water to remove residual Na2CO3 salt and solvent until the washing solution reached a neutral pH. The white powder was then extracted three times with 500 mL of acetonitrile at 60 °C under magnetic stirring. The final product was collected and dried under vacuum at 40 °C overnight, yielding 5.5 grams of powder.

[0072] Iodixanol (see Formula XVII) powder (3.0 grams) was placed in a 250 mL flask and dissolved in 10 mL of anhydrous DMSO by heating to 50 °C under magnetic stirring. 2,3,5-Triiodobenzoic acid (TIBA) (9.2 grams) was dissolved in 15 mL of anhydrous DMSO in a 100 mL round-bottom flask, followed by the very slow addition of carbonyldiimidazole (CDI) powder (2.98 grams) at room temperature with constant stirring to release the evolved carbon dioxide. The addition / stirring took approximately 30 minutes, resulting in the formation of CDI-activated TIBA. This reaction mixture was then added to the flask containing the iodixanol solution, and the reaction was carried out under magnetic stirring at 60 °C for 20 hours. After the reaction, the mixture was poured into 500 mL of aqueous sodium carbonate (2.5 w / w%) with vigorous magnetic stirring. The white precipitate was collected and filtered through a Buchner funnel. The white powder was further washed with deionized water to remove residual Na2CO3 salt and solvent until the washing solution reached a neutral pH. The white powder was then extracted three times with 500 mL of acetonitrile at 60 °C under magnetic stirring. The final product was collected and dried under vacuum at 40 °C overnight, yielding 6.2 grams of powder.

[0073] Table 1 lists the theoretical iodine content and elemental analysis results of the iohexol and iodixanol derivatives obtained using the reaction process described above. The goal was to achieve either 100% reacted -OH groups (referred to as iohexol derivative (I) and iodixanol derivative (III)) or 50% reacted -OH groups (referred to as iohexol derivative (II) and iodixanol derivative (IV)) for these two compounds. Only approximately 65%–68% iodine content was obtained, which could be explained as the effect of steric hindrance from the activated intermediate 2,3,5-triiodobenzoic acid imidazolide.

[0074] [Table 1]

[0075] Figures 1A and 1B show the FTIR spectra of two of the iohexol and iodixanol derivatives, specifically iohexol derivative (I) and iodixanol derivative (III). Figures 2A and 2B show the proton NMR spectra of the two iohexol and iodixanol derivatives (in DMSO-d6 as solvent). The NMR spectra show some unreacted starting material residue, which should disappear with further purification.

[0076] Example 2: Preparation of iodinated PVA polymer Degassed, purged with nitrogen, and provided with a nitrogen blanket. 50ml HEL Ltd Dry DMSO (20 ml) was added to a PolyBLOCK™ vessel (Borehamwood WD6 1GW, UK) with stirring at 500 rpm. 5.0 g of PVA (31-50 kDa, 99% hydrolyzed) was then added and heated to 65°C (internal probe) with stirring at 500 rpm until all solids were completely dissolved. After this time, 0.4 equivalents of 2,3,5-triiodobenzaldehyde per PVA-1,3-diol unit (TIBA - prepared according to Example 1 of WO 2015 / 033092) were added, followed by 0.075 equivalents of 2-sulfobenzaldehyde sodium salt (FSAS, Sigma-Aldrich UK).

[0077] After complete dissolution, methanesulfonic acid (2.2 mL) was added dropwise, and the reaction was stirred overnight at 65 °C. The orange solution was cooled to room temperature and added dropwise to a 500 mL glass breaker containing 200 mL of acetone. The white solid was collected, redissolved in 50 mL of DMSO, and precipitated again in 500 mL of acetone. The solid was collected on a Buchner funnel, and excess acid was neutralized with 0.1 N NaOH solution (approximately 100 mL) and washed with deionized water until a neutral pH was achieved. The solid was then dried overnight in a high vacuum oven at 28–32 °C to yield the desired product as an off-white solid (3.0 g, approximately 70% w / w yield). A 20% (w / w) solution in DMSO was prepared.

[0078] Example 3: Preparation of liquid embolic formulation A liquid embolic formulation was prepared from an iodinated PVA polymer (I-PVA) with hydrophilic functional groups and an iodine compound according to the present disclosure dissolved in DMSO solvent. Specifically, a solution containing I-PVA (18 wt%), the iodixanol derivative (III) from Example 1 (9.5 wt%), and DMSO (72.5 wt%) was prepared by adding 3.6 g of I-PVA and 1.9 g of iodixanol derivative (III) to a vial and gently mixing the powders together. Then, 14.5 g of DMSO was added to make a total of 20 g of solution. The vial was sealed and roller-mixed for at least 4 hours until both powders were completely solubilized in the solvent (DMSO). The vial was sterilized using dry heat (121°C for 0.5 hours).

[0079] Injectability was characterized by dynamic viscosity (μ) measurements using an Anton-Paar MCR 302 rheometer with a temperature sweep from 15 to 40 °C at 2.5 °C / min, yielding a viscosity value of μ = 400 mPas at 20 °C. Radiopacity (R) was characterized by micro-CT analysis, calculating the radiopacity in Hounsfield units (HU) of the liquid formulation, yielding a radiopacity value of R = 7052 HU. A micro-CT image is shown in Figure 3, showing strands of liquid embolic material within an agar phantom. The inset in Figure 3 is a CT image of a dissection of the liquid embolic material. Embolization efficiency was demonstrated by delivering the liquid embolic material into a 5 mm silicone tube perfused with a constant flow of phosphate-buffered saline (PBS) at a flow rate of 400 ml / min (37 °C). A flow reduction of over 99% was observed. Figure 4 shows an optical image of the resulting embolization.

[0080] Example 4: Radiopaque coating on a balloon catheter PVA coating solutions were prepared in DMSO solvent at various concentrations with radiopaque additives. In a specific case, 7% (w / w) PVA polymer (MW 31–50 kDa, 98% hydrolyzed, available from Sigma-Aldrich) was mixed with 8%–23% (w / w) iodixanol derivative in DMSO. A balloon catheter (Abbott Vascular Fox sv PTA Catheter (2–6 mm x 120 mm), Abbott Laboratories, Chicago, IL, USA) was inflated, and the balloon was dip-coated in the aforementioned DMSO solution for 5–10 seconds. The balloon was then placed in deionized water to exchange the water for DMSO. The resulting coating was adhesive, flexible, and stable to repeated balloon inflation / deflation cycles, as shown in Figure 5. The coated balloon was analyzed by μCT (the bottom image corresponds to a cross-sectional analysis of the balloon), as shown in Figure 6. A radiopacity of 4700 Hounsfield Units (HU) was measured.

Claims

1. 1. A composition comprising one or more iodine compounds comprising at least one 2,4,6-triiodobenzene moiety, wherein at least one of the hydrogens at the 1-, 3-, and 5-positions of the 2,4,6-triiodobenzene moiety is replaced by an iodinated substituent comprising one or more iodophenyl-containing groups.

2. 2. The composition of claim 1, wherein the iodine compound comprises one or two 2,4,6-triiodobenzene moieties, and at least one of the hydrogens at the 1-, 3-, and 5-positions of each of the 2,4,6-triiodobenzene moieties is replaced by an iodinated substituent comprising one or more iodophenyl-containing groups.

3. 3. The composition of claim 1, wherein the one or more iodophenyl-containing groups are selected from one or more of a monoiodophenyl-containing group, a diiodophenyl-containing group, a triiodophenyl-containing group, a tetraiodophenyl-containing group, or a pentaiodophenyl-containing group.

4. 4. The composition of claim 1, wherein the one or more iodophenyl-containing groups are selected from an iodophenyloxy group, an iodophenylcarbonyloxy group, or an iodophenyl group attached through a cyclic acetal or carbamate group.

5. The iodinated substituent is C ２ ~C ６ C in which the alkyl hydrogens are replaced by (a) one or more iodophenyl-containing groups and (b) zero, one, or more hydroxyl groups. ２ ~C ６ The composition of any one of claims 1 to 4, comprising an alkyl-amino group.

6. The iodinated substituent is C ２ ~C ６ C in which the alkyl hydrogens are replaced by (a) one or more iodophenyl-containing groups and (b) zero, one, or more hydroxyl groups. ２ ~C ６ Alkyl-aminocarbonyl group or C ２ ~C ６ The composition according to any one of claims 1 to 4, wherein the alkyl group is an alkylcarbonylamino group.

7. 7. The composition of claim 5, wherein the molar ratio of hydroxyl groups to iodophenyl-containing groups ranges from 0:1 to 10:

1.

8. The composition of any one of claims 1 to 7, further comprising a polymer.

9. 9. The composition of claim 8, having a radiopacity in the range of 10 to 1000 Hounsfield Units (HU).

10. Iodine in an amount ranging from 5 to 40% by weight, or 50 to 900 mg I / cm ３ 9. The composition of claim 8 having an amount of iodine in the range of:

11. A medical product comprising the composition of any one of claims 9 to 11.

12. (a) at least one compound comprising at least one 2,4,6-triiodobenzene moiety, wherein at least one of the hydrogens at the 1-, 3-, and 5-positions of said 2,4,6-triiodobenzene moiety is replaced by a polyhydroxylated substituent; (b) a compound represented by Formula XI, Formula XII, or Formula XIX 【Chemistry 1】 wherein n is 1, 2, 3, 4, or 5; ８１ is selected from —H, —F, —Cl, —Br, —I, anhydride, —OH, imidazolide, or O-acylisourea; R ７０ is -H or C １ ~C ６ alkyl, m is 0, 1, 2, 3, 4, or 5, and when m is 0, X is —O － Na ＋ and when m is 1, 2, 3, 4, or 5, X is —F, —Cl, —Br, or —I. with a compound of formula (I) under conditions to form a bond comprising a moiety selected from an ether, an ester, a cyclic acetal, or a hemiacetal.

13. 13. The method of claim 12, wherein the ester-containing linkage is formed by carbodiimide coupling, the ether-containing linkage is formed by Williamson synthesis, or the cyclic acetal-containing linkage or hemiacetal is formed by acetalization of an aldehyde or ketone.

14. The polyhydroxylated substituent is polyhydroxylated C ２ ~C ６ The method of claim 12 , comprising an alkyl group.

15. The at least one compound is selected from the group consisting of: 【Chemistry 2】 【Transformation 3】 The method of claim 12, wherein the compound is selected from the group consisting of:

Images