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WO2024093387A1 - Composé de contraste et son procédé de préparation, et matériau d'embolisation imageable et son procédé de préparation - Google Patents

Composé de contraste et son procédé de préparation, et matériau d'embolisation imageable et son procédé de préparation Download PDF

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Publication number
WO2024093387A1
WO2024093387A1 PCT/CN2023/109272 CN2023109272W WO2024093387A1 WO 2024093387 A1 WO2024093387 A1 WO 2024093387A1 CN 2023109272 W CN2023109272 W CN 2023109272W WO 2024093387 A1 WO2024093387 A1 WO 2024093387A1
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Prior art keywords
group
developing
microspheres
compound
formula
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PCT/CN2023/109272
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English (en)
Chinese (zh)
Inventor
孙宏涛
肖劲鹏
李鑫
孙蓬
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Cardiolink Science Shenzhen Medical Technology Development Co Ltd
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Cardiolink Science Shenzhen Medical Technology Development Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring

Definitions

  • the present application relates to the technical field of embolic microspheres, and in particular to a developing compound and a preparation method thereof, a developing embolic material and a preparation method thereof.
  • These molecules require very complex synthesis steps to be synthesized, and the synthesis efficiency is not high.
  • the purpose of the present application is to provide a developing compound and a preparation method thereof, a developing embolic material and a preparation method thereof, which can improve the elasticity of microspheres and correspondingly improve the embolic effect, drug loading capacity and drug loading speed of the microspheres.
  • Ionic water-soluble contrast agents such as diatrizoic acid or iodapoxetine are usually directly used to prepare imaging injections.
  • the compound structure shows that the agent has a carboxyl group that can react with the hydroxyl group on the embolic microspheres.
  • the inventors speculated that the carboxyl group of diatrizoic acid or iodine is directly connected to the benzene ring and there is a steric hindrance effect between the two iodine groups, which leads to low reactivity of the carboxyl group and difficulty in reacting with the hydroxyl or amino group on the microspheres.
  • an embodiment of the present application provides a developing compound, wherein the developing compound has a structural formula shown in the following formula I or formula II:
  • R1 group, the R2 group and the R3 group are C1 to C5 alkyl groups respectively;
  • the X group is -O-, -NH- or -NR-, wherein R is a C1-C5 alkyl group;
  • the Y group consists of two parts, including a connecting part and a reactive group.
  • the connecting part is a connecting group having 1 to 8 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S, and can be an alkylene group of 1 to 4 carbon atoms.
  • the reactive group is a group that can react with a hydroxyl group, such as a carboxyl group, an acyl halide, a carbonyl imidazole and other carboxyl groups and their variants, an aldehyde group, a hemiacetal and an acetal medium aldehyde group and their variants. These reactive groups allow the developer to be connected to the embolic material with a hydroxyl group through chemical bonds such as ester bonds and cyclic ether bonds, thereby forming a developed embolic material.
  • the amide group on the benzene ring can improve the hydrophilicity of the developing compound;
  • the extended connecting group increases the flexibility of the side chain, and connecting to the polyhydroxy microspheres can reduce the rigidity and strength of the microspheres, and improve the elasticity of the microspheres, thereby correspondingly improving the embolization effect, drug loading capacity and drug loading speed of the microspheres.
  • the Y group has suitable reactivity, which facilitates the coupling of the developing compound to the polyhydroxy microspheres.
  • the X group is -O-, -NH-, or
  • the X group selects a specific group to facilitate the implementation of the synthetic route; at the same time, the X group is -NH- or
  • the amide group on the benzene ring is formed by the adjacent carbonyl group, the hydrophilicity of the developing compound can also be improved.
  • the Y group is a carboxyl group attached to a methylene group, an acyl chloride group attached to a methylene group, a carbonylimidazole group attached to a methylene group, an aldehyde group or a hemiacetal group attached to an ethylene group.
  • the Y group selects a specific group to facilitate the implementation of the synthesis route and also facilitate the reaction between the developing compound and the polyhydroxy compound.
  • the R1 group is methyl or propyl.
  • the R2 group and the R3 group are each methyl or ethyl.
  • the R1 group, the R2 group, and the R3 group are selected to be specific groups, which can appropriately extend the connecting group to effectively increase the flexibility of the side chain.
  • the developing compound has the formula:
  • an embodiment of the present application provides a method for preparing the developing compound as described in the above embodiment, comprising:
  • the host material comprising at least one of diatrizoic acid, a homologue of diatrizoic acid, iodapoxetine and a homologue of iodapoxetine;
  • the carboxyl group of the main material is reacted with thionyl chloride to form an acyl chloride, and then the X group and the Y group are connected through a substitution reaction; or, the main material is quenched with water to connect the X group and the Y group.
  • diatrizoic acid and its homologues are used as the main materials to connect the X group and the Y group, and the synthesis route is simple.
  • an embodiment of the present application provides a developing embolic material, comprising a coupling compound covalently coupled to a developing compound as in the above embodiment and polyhydroxy microspheres, wherein the coupling compound has the following structural formula:
  • the X group is -O-, -NH- or -NR-, the R group is a C1-C5 alkyl group;
  • Y is a reactive group with a linking group;
  • the group has the following structural formula shown in Formula III or Formula IV:
  • the polyhydroxy microspheres are polyvinyl alcohol microspheres.
  • the developing embolic material provided in the embodiment of the present application is conveniently obtained by coupling reaction of the developing compound with the polyhydroxy microspheres.
  • the polyhydroxy microspheres are connected with the developing compound provided in the above embodiment, and have good hydrophilicity; at the same time, the elasticity of the microspheres is improved, and the embolic effect, drug loading capacity and drug loading speed of the microspheres are correspondingly improved.
  • the X group is -O-, -NH-, or
  • an embodiment of the present application provides a method for preparing a developing embolic material as in the above embodiment, comprising: covalently coupling polyhydroxy microspheres and a developing compound as in the above embodiment.
  • the developer reacts with the polyhydroxy microspheres through the reactive group Y, has good reaction activity and is simple to synthesize.
  • an embodiment of the present application provides a developing compound, wherein the developing compound has a structural formula shown in the following formula I or formula II:
  • R1 group, the R2 group and the R3 group are C1 to C5 alkyl groups respectively;
  • the X group is -O-, -NH- or -NR-, wherein the R group is a C1-C5 alkyl group;
  • the Y group consists of two parts, including a connecting part and a reactive group.
  • the connecting part is a connecting group having 1 to 8 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S.
  • the reactive group is a group that can react with a hydroxyl group, such as a carboxyl group, an acyl halide, a carbonyl imidazole, an aldehyde group, a hemiacetal and an acetal.
  • two R1 groups represent that two substitution sites are connected with the same group, which can be selected as methyl, ethyl, propyl, butyl or pentyl.
  • the R2 group and the R3 group represent that the two groups can be independently selected as methyl, ethyl, propyl, butyl or pentyl, that is, the R2 group and the R3 group can be the same or different.
  • the R group may be selected to be methyl, ethyl, propyl, butyl or pentyl.
  • the amide group on the benzene ring can improve the hydrophilicity of the developing compound;
  • the extended connecting group increases the flexibility of the side chain, and connecting to the polyhydroxy microspheres can reduce the rigidity and strength of the microspheres, and improve the elasticity of the microspheres, thereby correspondingly improving the embolization effect, drug loading capacity and drug loading speed of the microspheres.
  • ionic water-soluble developers such as diatrizoate and iodine iodide have carboxyl groups that can react with hydroxyl groups, they are difficult to react with the microspheres because the carboxyl groups directly connected to the benzene ring have low reactivity and are located between two iodine groups, which has too much steric hindrance.
  • the X group and the Y group have suitable reactivity, which facilitates the coupling of the developer compound to the polyhydroxy microspheres.
  • ionic water-soluble developers such as diatrizoate and iodapoxetine
  • the synthesis process of connecting the developer to the microspheres is simpler.
  • the X group is -O-, -NH-, or
  • the X group selects a specific group to facilitate the implementation of the synthetic route; at the same time, the X group is -NH- or
  • the amide group on the benzene ring is formed by the adjacent carbonyl group, the hydrophilicity of the developing compound can also be improved.
  • the Y group is a carboxyl group attached to a methylene group, an acyl chloride group attached to a methylene group, a carbonylimidazole group attached to a methylene group, an aldehyde group or an acetal group attached to a methylene, ethylene or propylene group.
  • the Y group is a carboxyl group attached to a methylene group, an acyl chloride group attached to a methylene group, a carbonylimidazole group attached to a methylene group, an aldehyde group or a hemiacetal group attached to an ethylene group.
  • the Y group selects a specific group, which is convenient for the implementation of the synthesis route and also convenient for the Y group and the X group to break when the developing compound reacts with the polyhydroxy microspheres.
  • the R1 group is methyl or propyl.
  • the R2 group and the R3 group are methyl or ethyl, respectively. That is, in Formula II, there are the following group selection situations: the R2 group is methyl and the R3 group is methyl; the R2 group is methyl and the R3 group is ethyl; the R2 group is ethyl and the R3 group is ethyl; and the R2 group is ethyl and the R3 group is methyl.
  • the R1 group, the R2 group, and the R3 group are selected to be specific groups, which can appropriately extend the connecting group to effectively increase the flexibility of the side chain.
  • the developing compound has the formula:
  • an embodiment of the present application provides a method for preparing the developing compound as described in the above embodiment, comprising:
  • the host material comprising at least one of diatrizoic acid, a homologue of diatrizoic acid, iodapoxetine and a homologue of iodapoxetine;
  • the carboxyl group of the main material is reacted with thionyl chloride to form an acyl chloride, and then the X group and the Y group are connected through a substitution reaction; or, the main material is quenched with water to connect the X group and the Y group.
  • providing the main material refers to preparing the main material, which can be purchased directly or synthesized by oneself.
  • Diatrizoic acid and its homologues are synthesized to form a developing compound as shown in Formula I.
  • the R1 group in Formula I is a methyl group; when the main material is a homologue of diatrizoic acid, R1 is a C2-C5 alkyl group.
  • Iotalamic acid and its homologues are used to synthesize the developing compound shown in Formula I.
  • the R2 group and the R3 group in Formula II are both methyl groups; when the main material is a homologue of iotalamic acid, at least one of the R2 group and the R3 group is selected to be a C2-C5 alkyl group.
  • the main material and thionyl chloride are subjected to a reflux reaction so that the carboxyl group of the main material forms an acyl chloride; then the acyl chloride product, triethylamine, and a raw material containing the X group and the Y group are reacted.
  • N,N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) is used as a solvent
  • triethylamine and a raw material containing an X group and a Y group are added under nitrogen protection to react, and then purified water is added to carry out a water quenching reaction.
  • diatrizoic acid and its homologues are used as the main materials to connect the X group and the Y group, and the synthesis route is simple.
  • an embodiment of the present application provides a developing embolic material, comprising a coupling compound covalently coupled to a developing compound as in the above embodiment with polyhydroxy microspheres, wherein the coupling compound has the following structural formula:
  • the X group is -O-, -NH- or -NR-, the R group is a C1-C5 alkyl group; and Y is a reactive group with a connecting group;
  • the group has the following structural formula shown in Formula III or Formula IV:
  • the polyhydroxy microspheres can be polyenol microspheres, chitosan microspheres, etc.
  • the polyhydroxy microspheres are polyvinyl alcohol microspheres.
  • the X group and The group is provided by removing the Y group from the developer compound of the above embodiment, wherein the selection of the X group, the R1 group, the R2 group and the R3 group can refer to the above description of the developer compound embodiment, which will not be repeated here.
  • the X group and The structure outside the group is provided by removing part of the hydroxyl hydrogen from the polyhydroxy microspheres, and the spherical structure surrounding the middle is the microsphere.
  • the developing compound is covalently coupled to the hydroxyl oxygen group of the polyhydroxy microspheres by removing the hydroxyl hydrogen through the X group of the Y group.
  • the developing embolic material provided in the embodiment of the present application is conveniently obtained by coupling reaction of the developing compound with the polyhydroxy microspheres.
  • the polyhydroxy microspheres are connected with the developing compound provided in the above embodiment, and have good hydrophilicity; at the same time, the elasticity of the microspheres is improved, and the embolic effect, drug loading capacity and drug loading speed of the microspheres are correspondingly improved.
  • the X group is -O-, -NH-, or
  • an embodiment of the present application provides a method for preparing a developing embolic material as in the above embodiment, comprising: covalently coupling polyhydroxy microspheres and a developing compound as in the above embodiment.
  • polyvinyl alcohol microspheres can be prepared according to methods known in the art.
  • polyvinyl alcohol (PVA) is dissolved in water by heating, N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA) is added, and then concentrated hydrochloric acid is added at room temperature to react to obtain a macromolecular polyvinyl alcohol monomer solution.
  • the aqueous phase containing the macromolecular polyvinyl alcohol monomer solution is added dropwise to the oil phase for reaction.
  • the developing compound reacts with the polyvinyl alcohol microspheres through the Y group, has good reaction activity and is simple to synthesize.
  • AMPS sodium acrylamido-2-methylpropanesulfonic acid sodium salt
  • the rotation speed was set to 400 rpm, and the aqueous phase was added dropwise to the oil phase; after the addition was completed, the temperature was raised to 55°C, 2.2 mL of tetramethylethylenediamine was added, and the reaction was continued for 8 hours. After a series of purification and drying, the raw material dry ball (i.e., polyvinyl alcohol microsphere) was obtained.
  • the raw material dry ball i.e., polyvinyl alcohol microsphere
  • chitosan dissolve it in 200mL 1% acetic acid solution, stir to dissolve, slowly add it to 500mL mixed solution (10% sodium hydroxide: 95% ethanol volume ratio 4:1), filter and wash to obtain chitosan microspheres.
  • the obtained microspheres are dispersed in 500mL purified water, add 2mL 25% glutaraldehyde solution, stir at 30 degrees for 3h, filter and wash to obtain cross-linked chitosan microspheres.
  • the obtained microspheres are shrunk with ethanol and dried to obtain 4.0g chitosan dry balls.
  • the developing compound of formula 1 is used to prepare a developing embolic material.
  • the developing compound of formula 2 is used to prepare a developing embolic material.
  • the developing compound of formula 3 is used to prepare a developing embolic material.
  • the developing compound of the molecular formula 4 is used to prepare a developing embolic material.
  • the developing compound of the molecular formula 5 is used to prepare a developing embolic material.
  • the developing compound of formula 6 is used to prepare a developing embolic material.
  • the developing compound of the molecular formula 7 is used to prepare a developing embolic material.
  • the developing compound of the molecular formula 8 is used to prepare a developing embolic material.
  • the developing compound of the molecular formula 9 is used to prepare a developing embolic material.
  • the developing compound of the molecular formula 10 is used to prepare a developing embolic material.
  • the developing compound of the molecular formula 11 is used to prepare a developing embolic material.
  • the developing compound of the molecular formula 12 is used to prepare a developing embolic material.
  • the developing compound of the molecular formula 3 is used to prepare the developing embolic material.
  • Triiodobenzaldehyde was used as the developer.
  • Diatrizoate was used as the developer.
  • Iodine content The iodine content is determined by the oxygen bottle combustion method. Take 5 mg of the dried sample and place it in an oxygen bottle with sodium hydroxide-vitamin C as the absorption liquid and silver nitrate as the titration liquid. Calculate the iodine content of the sample.
  • Strength and elasticity are important indicators for characterizing the embolic performance of embolic microspheres. Generally speaking, the strength of embolic microspheres cannot exceed 500g force, and they can recover to a spherical shape after compression. The microspheres are spread on a glass slide to form a single layer, and their strength and elasticity are measured using a texture analyzer (TA-XTplusC). Strength is defined as the maximum force during 50% compression, and elasticity is defined as whether the microspheres can recover to a spherical shape after 50% compression.
  • Drug loading amount 1 mL of the developing microspheres of the embodiment and the comparative example was measured respectively, the upper preservation solution was aspirated, 2 mL of a solution containing 40 mg of doxorubicin hydrochloride was added, and the mixture was gently shaken. Samples were taken at 30 min and 24 h respectively, and the doxorubicin content in the solution was measured by HPLC.
  • test results of iodine content, mechanical properties, drug loading amount and drug loading speed of the developing microspheres of each embodiment and comparative example 1 are shown in Table 1.
  • the developing microspheres prepared by using the developing compound provided in the examples of the present application have significantly reduced strength, improved elasticity, and significantly improved drug loading capacity and drug loading speed.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
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Abstract

L'invention concerne un composé de contraste de formule I ou de formule II et son procédé de préparation, et un matériau d'embolisation imageable comprenant le composé de contraste et son procédé de préparation. Le matériau d'embolisation imageable comprend une microsphère de polyhydroxy (telle qu'une microsphère d'alcool polyvinylique) et un composé conjugué couplé de manière covalente au composé de contraste. Le composé de contraste peut réduire l'élasticité de la microsphère et améliorer de manière correspondante l'effet d'embolisation, la capacité de chargement de médicament et la vitesse de chargement de médicament de la microsphère.
PCT/CN2023/109272 2022-11-01 2023-07-26 Composé de contraste et son procédé de préparation, et matériau d'embolisation imageable et son procédé de préparation Ceased WO2024093387A1 (fr)

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CN202211358523.4A CN117986193A (zh) 2022-11-01 2022-11-01 显影化合物及其制备方法、显影栓塞材料及其制备方法
CN202211358523.4 2022-11-01

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB867880A (en) * 1957-03-06 1961-05-10 Schering Ag N-acyl derivatives of (3:5-diamino-2:4:6-triiodobenzoyl)-amino acids and x-ray contrast media containing the same
US3097228A (en) * 1958-06-03 1963-07-09 Sterling Drug Inc Derivatives of 2, 4, 6-trhodobenzoyloxyalkanoic acids and preparation thereof
US3953501A (en) * 1972-02-16 1976-04-27 Schering Aktiengesellschaft Triiodoisophthalic acid monoamino acid amides
US4607123A (en) * 1984-02-29 1986-08-19 Dr. Franz Kohler Chemie Gmbh Water soluble 3,5-diacetamido-2,4,6-triiodobenzoic acid derivatives
US5346688A (en) * 1992-12-16 1994-09-13 Sterling Winthrop Inc. Iodinated wetting agents
CN114146190A (zh) * 2021-12-30 2022-03-08 科睿驰（深圳）医疗科技发展有限公司 一种高悬浮性显影微球及其制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB867880A (en) * 1957-03-06 1961-05-10 Schering Ag N-acyl derivatives of (3:5-diamino-2:4:6-triiodobenzoyl)-amino acids and x-ray contrast media containing the same
US3097228A (en) * 1958-06-03 1963-07-09 Sterling Drug Inc Derivatives of 2, 4, 6-trhodobenzoyloxyalkanoic acids and preparation thereof
US3953501A (en) * 1972-02-16 1976-04-27 Schering Aktiengesellschaft Triiodoisophthalic acid monoamino acid amides
US4607123A (en) * 1984-02-29 1986-08-19 Dr. Franz Kohler Chemie Gmbh Water soluble 3,5-diacetamido-2,4,6-triiodobenzoic acid derivatives
US5346688A (en) * 1992-12-16 1994-09-13 Sterling Winthrop Inc. Iodinated wetting agents
CN114146190A (zh) * 2021-12-30 2022-03-08 科睿驰（深圳）医疗科技发展有限公司 一种高悬浮性显影微球及其制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry 26 July 1986 (1986-07-26), ANONYMOUS: "Glycine, N-[3,5-bis(acetylamino) -2,4,6-triiodobenzoyl]-N-met hyl-", XP093167363, Database accession no. 103376-75-6 *
KLIEGER, ERICH; SCHRÖDER, EBERHARD: "Darstellung von N-(3-Acylamino-5-alkylcarbamoyl-2.4.6-trijod-benzoyl)-aminosäuren und ihre Verwendung als Röntgenkontrastmittel = Synthesis of N-(3-Acylamino-5-Alkylcarbamoyl-2,4,6-Triiodobenzoyl)amino Acids as x-ray Contrast Agents", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 10, no. 1, 31 December 1975 (1975-12-31), pages 84 - 88, XP009554950 *

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