KR101209633B1 - Pegylated triiodinated aryl compounds and X-ray constrast media including the same - Google Patents

Abstract

The present invention relates to pegylated triiodide aryl compounds and X-ray contrast agents comprising them. The pegylated triiodide aryl compounds of the present invention not only exhibit low viscosity and osmolality, but also do not cause problems of nephrotoxicity and can be effectively used in X-ray contrast agents.

PEGylation, triiodide aryl compounds, X-ray contrast agents

Description

PEGylated triiodinated aryl compounds and X-ray constrast media including the same}

The present invention relates to pegylated triiodide aryl compounds and X-ray contrast agents comprising them. More specifically, the present invention relates to pegylated triiodide aryl compounds and low-viscosity and osmolarity, as well as X-ray contrast agents comprising the same, which do not cause problems of renal toxicity.

Many iodide compounds have been developed and marketed as X-ray contrast agents to date. Successful X-ray contrast agents have some common characteristics. X-ray contrast agents, for example, should be stable and show no pharmacological action in vivo. In addition, factors such as the weight ratio, water solubility and toxicity of radiopaque species per molecule, such as iodine, also influence the effect of the X-ray contrast agent. Toxicity of compounds may be related to lipophilic (hydrophobic), ionic strength, osmolality and viscosity.

The elements are often known to be interrelated. For example, as the number of iodine atoms increases, the molecules gradually become lipophilic, leading to poor water solubility and increased toxicity. However, since the number of iodine atoms in a single molecule is directly related to the clarity of the X-ray image, high iodine content is also a necessary characteristic.

Initially iodine benzoic acid was used due to its low toxicity, but fully iodinated benzoic acid was not practical because other functional groups were needed to impart the solubility and pharmacological properties required for the molecule.

Triiodide benzene molecules with functional groups are well known X-ray contrast agents. In general, attaching functional groups to three of the carbons in the benzene ring was necessary for solubilization and reduced toxicity. In addition, dimers, trimers and polymers of the iodinebenzene moiety have been prepared to increase the number of iodine atoms than the three iodine atoms in the conventional single molecule described above.

The solubility of the iodide molecule can be significantly increased by introducing ionized functional groups (eg carboxylic acid groups, amino groups) into the molecule. However, the osmolality of body fluids is affected by the high dosage concentrations required. Since high osmolalities can cause toxicity, the development of X-ray contrast agents has been concentrated on nonionic, water-soluble iodide compounds.

However, commercial triiodide benzene-based X-ray contrast agents with high iodine concentrations of about 300 mg I / mL have relatively high viscosities. Such viscosities cause problems for the administrator because they require relatively large orifice needles or have to apply high pressure, especially in pediatric radiography and radiographs that require rapid injection, for example angiography. Indeed, viscosity above 30 mPas at body temperature (37 ° C.) is so high that it cannot be used for conventional X-ray examinations, especially pediatric irradiation.

In addition, commercial triiodide benzene-based X-ray contrast agents are known to cause renal toxicity.

Therefore, there is an urgent need for the development of triiodic benzene-based X-ray contrast agents that exhibit low viscosity and osmolality and do not cause kidney toxicity problems.

The present inventors have diligently studied to solve the problems of the triiodyl benzene-based X-ray contrast agent, and found that renal toxicity can be significantly reduced by pegylation of the tri-iodine benzene-based X-ray contrast agent. The present invention has been completed.

Accordingly, it is an object of the present invention to provide a pegylated triiodide aryl compound of formula 1 or 2, which can be used as an X-ray contrast agent.

Another object of the present invention is to provide an X-ray contrast agent which does not cause the problem of nephrotoxicity, which contains a pegylated triiodyl aryl compound of the general formula (1) or (2).

The present invention relates to a PEGylated triiodide aryl compound of formula 1 or 2 below, which can be used as an X-ray contrast agent.

[Formula 1]

 [Formula 2]

Where

A, B and D are the same or different and are -CON (R) R ₁ or -N (R) COR ₂ ,

E is the same or different and is -CON (R)-, -N (R) CO- or -N (COR ₃ )-,

X is a covalent bond; Or a C ₁ -C ₈ straight or branched alkylene chain unsubstituted or substituted by 1 to 6 substituents selected from the group consisting of OH and -CONHR,

R is hydrogen; Or OH, straight or branched alkyl group of C ₁ -C ₆ alkoxy group and C ₁ -C ₆ alkyl group that is hydroxy is optionally substituted by 1 to 5 substituents selected from the consisting of C ₁ -C ₆ of the ego,

R ₁ is OH, a straight-chain or branched C ₁ -C ₆ alkoxy group and C ₁ -C ₆ alkyl group that is hydroxy is optionally substituted by 1 to 5 substituents selected from the consisting of C ₁ -C ₆ of the A topographic alkyl group,

R ₂ is OH, a straight-chain or branched C ₁ -C ₆ alkoxy group and C ₁ -C ₆ alkyl group that is hydroxy is optionally substituted by 1 to 5 substituents selected from the consisting of C ₁ -C ₆ of the It is a topographic alkyl group,

R ₃ is OH, C ₁ -C ₆ alkoxy group and C ₁ -C ₆ hydroxy alkyl group having 1 to 2 substituents in the optionally substituted straight-chain or branched, unsubstituted C ₁ -C ₃ by selected from the group consisting of A topographic alkyl group,

All or part of the hydroxyl groups present in A, B, D, E and X are substituted by -OCO (CH ₂ ) _m (OCH ₂ CH ₂ ) _n OR ₄ ,

R ₄ is hydrogen or a C ₁ -C ₆ straight or branched alkyl group, preferably hydrogen or methyl group, most preferably methyl group,

n is an integer from 2 to 400, preferably from 2 to 120,

m is 1-10, Preferably it is 1-6, More preferably, it is an integer of 1-3.

Pegylated triiodyl aryl compounds of the present invention include iodinated contrast-based compounds such as pegylated iohexol, iodixanol, iopamidol, iopromide, etc. One is not limited thereto.

Preferably, the compound of the present invention comprises a pegylated iohexol of formula (3).

(3)

Where

Y is the same or different and is hydrogen or -CO (CH ₂ ) _m (OCH ₂ CH ₂ ) _n OR ₄ ,

R ₄ is hydrogen or a C ₁ -C ₆ straight or branched alkyl group, preferably hydrogen or methyl group, most preferably methyl group,

n is an integer from 2 to 400, preferably from 2 to 120,

m is 1-10, Preferably it is 1-6, More preferably, it is an integer of 1-3.

In addition, the compounds of the present invention preferably include pegylated iodisanol of formula (4).

[Formula 4]

Where

Y is the same or different and is hydrogen or -CO (CH ₂ ) _m (OCH ₂ CH ₂ ) _n OR ₄ ,

R ₄ is hydrogen or a C ₁ -C ₆ straight or branched alkyl group, preferably hydrogen or methyl group, most preferably methyl group,

n is an integer from 2 to 400, preferably from 2 to 120,

m is 1-10, Preferably it is 1-6, More preferably, it is an integer of 1-3.

The compounds of the present invention can be prepared, for example, according to the methods shown in Schemes 1-2 below. The method described in the following reaction formulas exemplifies the method typically used in the present invention, and the order of the unit operation, the reaction reagent, the reaction conditions, and the like may be changed as required.

[Reaction Scheme 1]

The pegylated iohexol of Formula 3 may be prepared by combining the iohexol of Formula 5 with a polyethylene glycol (PEG) derivative of Formula 6.

 Scheme 2

The PEGylated iodisanol of Formula 4 may be prepared by combining the iodisanol of Formula 7 with the polyethylene glycol (PEG) derivative of Formula 6.

The iohexol and iodisanol may be obtained commercially or prepared according to methods known in the art.The PEG derivative of Chemical Formula 6 is a compound in which a carboxyl group is bonded through an alkylene linkage to a terminal hydroxy group of PEG, Commercially available or readily prepared according to methods known in the art. Polymer Bulletin, 1999, 43, 1436-2449 and the like.

In Reaction Schemes 1 and 2, 4-dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) -N'-ethylcarbodii Preference is given to performing in the presence of mid (N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC)).

As the reaction solvent, N, N'-dimethylformamide (DMF), dichloromethane (DCM), chloroform and the like are preferably used, and the reaction temperature is preferably room temperature.

The molecular weight and degree of PEGylation of the PEG derivatives in Schemes 1 and 2 may be appropriately selected according to the use, form, etc. of the X-ray contrast agent. When a low viscosity X-ray contrast agent is required, the molecular weight of the PEG derivative is preferably 200 to 500.

On the other hand, the present invention relates to an X-ray contrast agent comprising the pegylated triiodide aryl compound according to the invention together with a pharmaceutically acceptable carrier.

X-ray contrast agents of the present invention can be used for angiography, urography, opacity of body cavities, etc., and can be formulated in oral or parenteral dosage forms. Parenteral formulations preferably comprise sterile aqueous solutions or suspensions comprising the compounds of the invention, and various techniques for preparing pharmaceutical aqueous solutions or suspensions are known in the art. The solution may also include pharmaceutically acceptable buffers, stabilizers, antioxidants and electrolytes such as sodium chloride. Parenteral formulations may be injected directly or mixed with large amounts of parenteral formulations.

Formulations for oral administration can vary widely and are known in the art. Such formulations generally comprise an aqueous solution or suspension comprising a diagnostically effective amount of a compound according to the invention. The oral formulation may optionally include buffers, surfactants, adjuvants, thixotropic agents, and the like. Formulations for oral administration may also include ingredients for increasing flavor and other functionalities.

X-ray contrast agents according to the invention are administered in an amount effective to achieve the desired augmentation of the X-ray image. Such dosages can vary widely depending on the degree of iodide, the organ or tissue being subjected to the imaging procedure, the X-ray imaging apparatus used, and the like. Typical total doses of X-ray contrast agents range from about 320 to 600 mg I / kg body weight. It is common to administer the total dose in several portions at lower doses. The concentration of the X-ray contrast agent is preferably in the range from 160 to 350 mg I / mL.

X-ray contrast agents of the present invention are used in a conventional manner in X-ray examination. For example, an X-ray contrast agent may be administered systemically to a mammal or locally to an organ or tissue being imaged, in an amount sufficient to provide adequate visualization, and then the mammal may be x-rayed.

The pegylated triiodide aryl compounds of the present invention not only exhibit low viscosity and osmolality, but also do not cause problems of nephrotoxicity and can be effectively used in X-ray contrast agents.

In addition, because the conventional contrast agent has a low molecular weight, it can not be circulated for a long time in the body and discharged through the kidneys in a short time to obtain an image for a long time, the compound according to the present invention is a non-toxic biopolymer of polyethylene glycol Although the concentration of iodine, which plays an important role in contrast enhancement according to the dose, is lowered, it is expected that there is no significant difference in contrast enhancement due to the increase of residence time.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it is obvious to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1: mPEG ₆ Preparation of Iohexol Esters

Example 1-1: (mPEG5K) ₆ Preparation of Iohexol Esters

Iohexol (27.4 mg, 0.033 mmol) was dissolved in anhydrous N, N'-dimethylformamide (DMF), 4-dimethylaminopyridine (DMAP) (24.4 mg, 0.2 mmol) and mPEG5K-PA ( PEG derivative of formula (6), wherein R ₄ is a methyl group and has a molecular weight of 5000 (1.0 g, 0.2 mmol), is added dicyclohexylcarbodiimide (DCC) (41.3 mg, 0.2 mmol) and Stir at room temperature for 12 hours. The DMF was removed under reduced pressure, and the residue was dissolved in dichloromethane (DCM) and the insoluble suspended solids were filtered off. The filtrate was washed with 1N HCl aqueous solution and water, and again with saturated NaHCO ₃ aqueous solution and water. The organic layer was dried with MgSO ₄ anhydride and concentrated under reduced pressure. The mixture was separated using silica gel column chromatography under MeOH: DCM (1:10) to give a white solid mPEG ₆ -iohexel ester (6 Y). (980 mg) were obtained, all of which were PEGylated.

¹ H-NMR (CDCl ₃ ) 300 MHz δ 4.58 (t, 3H), 4.11 (m, 6H), 3.7-3.3 (m, PEG and 6H), 3.24 (s, 18H), 1.76 (bs, 3H)

Example 1-2: (mPEG0.75K) ₆ Preparation of Iohexol Esters

Iohexol (18.2 mg, 0.022 mmol), 4-dimethylaminopyridine (16.3 mg, 0.13 mmol), mPEG0.75K-PA (PEG derivative of formula 6 wherein R ₄ is methyl and molecular weight 750) (100.0 mg, 0.13 mmol ) And dicyclohexylcarbodiimide (27.5 mg, 0.13 mmol) were used in the same manner as in Example 1-1, to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 300 MHz δ 4.58 (t, 3H), 4.11 (m, 6H), 3.7-3.3 (m, PEG and 6H), 3.24 (s, 18H), 1.76 (bs, 3H)

Example 1-3: (mPEG 0.35K) ₆ Preparation of Iohexol Esters

Iohexol (39.1 mg, 0.048 mmol), 4-dimethylaminopyridine (34.9 mg, 0.29 mmol), mPEG0.35K-PA (PEG derivative of formula 6 wherein R ₄ is a methyl group and has a molecular weight of 350) (100.0 mg, 0.29 mmol ) And dicyclohexylcarbodiimide (59.0 mg, 0.29 mmol), except that the title compound was obtained in the same manner as in Example 1-1.

¹ H-NMR (CDCl ₃ ) 300 MHz δ 4.58 (t, 3H), 4.11 (m, 6H), 3.7-3.3 (m, PEG and 6H), 3.24 (s, 18H), 1.76 (bs, 3H)

Example 2: mPEG ₃ Preparation of Iohexol Esters

Example 2-1: (mPEG5K) ₃ Preparation of Iohexol Esters

Iohexol (11.0 mg, 0.013 mmol) was dissolved in anhydrous N, N'-dimethylformamide (DMF), 4-dimethylaminopyridine (DMAP) (6.4 mg, 0.052 mmol) and mPEG5K-PA ( 200 mg, 0.040 mmol), and then N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) (23.0 mg, 0.120 mmol) ) Was added and stirred at room temperature under nitrogen gas for 12 hours. The DMF was removed under reduced pressure, and the residue was dissolved in dichloromethane (DCM) and the insoluble suspended solids were filtered off. The filtrate was washed with 1N HCl aqueous solution and water, and again with saturated NaHCO ₃ aqueous solution and water. The organic layer was dried with MgSO ₄ anhydride and concentrated under reduced pressure. The mixture was separated using silica gel column chromatography under MeOH: DCM (1:10) to give a white solid mPEG ₃ -iohexel ester (3 Y). (185 mg) was obtained.

¹ H-NMR (CDCl ₃ ) 300 MHz δ 4.58 (t, 3H), 3.7-3.3 (m, PEG and 12H), 3.24 (s, 18H), 1.77 (bs, 3H)

Example 2-2: (mPEG0.75K) ₃ Preparation of Iohexol Esters

Iohexol (10.9 mg, 0.013 mmol), 4-dimethylaminopyridine (63.5 mg, 0.52 mmol), mPEG0.75K-PA (300 mg, 0.40 mmol) and N- (3-dimethylaminopropyl) -N'-ethyl The title compound was obtained in the same manner as in Example 2-1, except that carbodiimide (230 mg, 1.20 mmol) was used.

¹ H-NMR (CDCl ₃ ) 300 MHz δ 4.58 (t, 3H), 3.7-3.3 (m, PEG and 12H), 3.24 (s, 18H), 1.77 (bs, 3H)

Example 2-3: (mPEG0.35K) ₃ Preparation of Iohexol Esters

Iohexol (78.2 mg, 0.095 mmol), 4-dimethylaminopyridine (45.4 mg, 0.37 mmol), mPEG0.35K-PA (100 mg, 0.29 mmol) and N- (3-dimethylaminopropyl) -N'-ethyl The title compound was obtained in the same manner as in Example 2-1, except that carbodiimide (164 mg, 0.86 mmol) was used.

¹ H-NMR (CDCl ₃ ) 300 MHz δ 4.58 (t, 3H), 3.7-3.3 (m, PEG and 12H), 3.24 (s, 18H), 1.77 (bs, 3H)

Example 3: mPEG ₉ Preparation of Iodisanol Esters

Example 3-1: (mPEG5K) ₉ Preparation of Iodisanol Esters

Iodixanol (20.0 mg, 0.013 mmol) was dissolved in 7.0 ml of anhydrous N, N'-dimethylformamide (DMF) and 4-dimethylaminopyridine (DMAP) (18.4 mg, 0.151 mmol ) And mPEG5K-PA (696.8 mg, 0.139 mmol) were added, then dicyclohexylcarbodiimide (DCC) (46.0 mg, 0.223 mmol) was added and stirred at room temperature under nitrogen gas for 12 hours. The DMF was removed under reduced pressure, and the residue was dissolved in dichloromethane (DCM) and the insoluble suspended solids were filtered off. The filtrate was washed with 1N HCl aqueous solution and water, and again with saturated NaHCO ₃ aqueous solution and water. The organic layer was separated with water using MgSO ₄ anhydride and concentrated under reduced pressure. The mixture was separated using silica gel column chromatography under MeOH: DCM (1:10) to give a white solid of mPEG ₉ -iodicanol ester (9 Compound (4) (660 mg) in which all Y are PEGylated.

¹ H-NMR (CDCl ₃ ) 300 MHz δ 4.60 (t, 5H), 4.12 (m, 8H), 3.7-3.3 (m, PEG and 8H), 3.24 (s, 27H), 1.78 (bs, 6H)

Example 3-2: (mPEG0.75K) ₉ Preparation of Iodisanol Esters

Iodisanol (30.0 mg, 0.019 mmol), 4-dimethylaminopyridine (21.3 mg, 0.174 mmol), mPEG0.75K-PA (130.6 mg, 0.174 mmol) and dicyclohexylcarbodiimide (39.5 mg, 0.192 mmol) Except for using, the title compound was obtained in the same manner as in Example 3-1.

¹ H-NMR (CDCl ₃ ) 300 MHz δ 4.60 (t, 5H), 4.12 (m, 8H), 3.7-3.3 (m, PEG and 8H), 3.24 (s, 27H), 1.78 (bs, 6H)

Example 3-3: (mPEG0.35K) ₉ Preparation of Iodisanol Esters

Iodisanol (50.0 mg, 0.032 mmol), 4-dimethylaminopyridine (35.5 mg, 0.290 mmol), mPEG0.35K-PA (101.6 mg, 0.290 mmol) and dicyclohexylcarbodiimide (65.9 mg, 0.319 mmol) Except for using, the title compound was obtained in the same manner as in Example 3-1.

¹ H-NMR (CDCl ₃ ) 300 MHz δ 4.60 (t, 5H), 4.12 (m, 8H), 3.7-3.3 (m, PEG and 8H), 3.24 (s, 27H), 1.78 (bs, 6H)

Example 4: mPEG ₅ Preparation of Iodisanol Esters

Example 4-1: (mPEG5K) ₅ Preparation of Iodisanol Esters

Iodixanol (10.4 mg, 0.007 mmol) was dissolved in 3 ml of anhydrous N, N'-dimethylformamide (DMF) and 4-dimethylaminopyridine (DMAP) (4.10 mg, 0.034 mmol ) And mPEG5K-PA (167.7 mg, 0.034 mmol), followed by N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) (19.3 mg, 0.101 mmol) was added and stirred at room temperature under nitrogen gas for 12 hours. The DMF was removed under reduced pressure, and the residue was dissolved in dichloromethane (DCM) and the insoluble suspended solids were filtered off. The filtrate was washed with 1N HCl aqueous solution and water, and again with saturated NaHCO ₃ aqueous solution and water. The organic layer was separated with water by MgSO ₄ anhydride and concentrated under reduced pressure. The mixture was separated using silica gel column chromatography under conditions of MeOH: DCM (1:10), to give a white solid mPEG ₅ -io disanol ester (5 Y) is PEGylated compound of formula 4) (160 mg).

¹ H-NMR (CDCl ₃ ) 300 MHz δ 4.58 (t, 5H), 3.7-3.3 (m, PEG and 14H), 3.24 (s, 18H), 1.77 (bs, 6H)

Example 4-2: (mPEG0.75K) ₅ Preparation of Iodisanol Esters

Iodisanol (20.0 mg, 0.013 mmol), 4-dimethylaminopyridine (7.9 mg, 0.065 mmol), mPEG0.75K-PA (48.4 mg, 0.065 mmol) and N- (3-dimethylaminopropyl) -N'- The title compound was obtained in the same manner as in Example 4-1, except for using ethyl carbodiimide (37.1 mg, 0.194 mmol).

¹ H-NMR (CDCl ₃ ) 300 MHz δ 4.58 (t, 5H), 3.7-3.3 (m, PEG and 14H), 3.24 (s, 18H), 1.77 (bs, 6H)

Example 4-3: (mPEG0.35K) ₅ Preparation of Iodisanol Esters

Iodisanol (50.0 mg, 0.032 mmol), 4-dimethylaminopyridine (19.7 mg, 0.161 mmol), mPEG0.35K-PA (56.4 mg, 0.161 mmol) and N- (3-dimethylaminopropyl) -N'- The title compound was obtained in the same manner as in Example 4-1, except that ethyl carbodiimide (92.7 mg, 0.484 mmol) was used.

¹ H-NMR (CDCl ₃ ) 300 MHz δ 4.58 (t, 5H), 3.7-3.3 (m, PEG and 14H), 3.24 (s, 18H), 1.77 (bs, 6H)

Test Example 1: Measurement of viscosity and osmolality

The compounds of the present invention obtained in Examples 1 and 3 and the viscosity and osmolality of the commercially available iohexole and iodisanol as a control was measured and shown in Table 1 below.

[Table 1]

compound Iodine concentration
(mg / ml) Viscosity ^†
(mPas at 37 ℃) Osmolality ^‡
(mOsmol / kg H ₂ O) Example 1-1 10 15.0 930 Examples 1-2 55 10.2 840 Example 1-3 102 5.1 760 Example 3-1 11 16.4 450 Example 3-2 61 11.2 300 Example 3-3 110 5.6 270 Iohexol 350 10.4 830 Iodisanol 320 11.4 290 ^† DV-II + Viscometer (Brookfield)
^‡ OsmOmat 30 (Gonotec)

As shown in Table 1, the pegylated triiodide aryl compound of the present invention prepared using a PEG derivative having a molecular weight of 350 is significantly reduced in viscosity compared to the conventional non-pegylated compound, the osmolality is similar results Got.

Test Example 2: Determination of Kidney Toxicity

The kidney toxicity of the compounds of the present invention obtained in Examples 1-3 and 3-3 and commercially available iohexel, iodinanol and iomidol as a control was measured as follows.

Preparation and Measurement

Sprague-Dawley, 180 ± 10 g in weight, adapted to solid feed for 1 week under constant conditions (temperature: 22 ± 0.5 ° C, humidity: 46-60%, contrast: 12 hours light / dark cycle). Male rats were used. Each compound was suspended in 2% Tween 80 and 20 mg / kg was administered by vascular injection. The animals were fed with water for 12 hours before treatment. The control group was also subjected to the same conditions.

Preparation of sample

0.04M picric acid solution: 12.5 g of the refined picric acid was dissolved in water to make 1 L, and after standing for 24 hours, the supernatant 900 ml and 300 ml of water were mixed.

Creatinine Standard Solution (100 mg / dl; creatine is measured by transformation with creatinine): 100 mg of creatinine was dissolved in 0.1 N hydrochloric acid to make 100 ml.

Standard solution: The standard solution was diluted 500, 200, and 100 times with water to make 0.2 mg / dl, 0.5 mg / dl, 1 mg / dl. 0.5 mg / dl standard solution was used in this test.

Sampling

A week later, urine was collected to measure creatine in the urine. Urinary creatine was used as a kit using a variation of the Jaffe response.

Toluene was used as a preservative when collecting urine, and diluted 250 times with distilled water based on 1 ml of urine. In each of the four tubes, 5 ml of distilled water and a standard solution used as a standard solution were placed in a blank, and 5 ml of diluted urine samples were taken in two other tubes. Each test tube was immersed in water at 25 ° C. for 10 minutes, 2.0 ml of picric acid solution and 2.0 ml of 0.75N sodium hydroxide solution were mixed well, and then left at 25 ° C. for 15 minutes. The absorbance of the sample and the standard solution was measured by comparing the blank at 515 nm with a spectrophotometer and calculated as follows.

Creatine concentration (mg / dl) = standard solution X (sample absorbance / standard solution absorbance)

The result is shown in FIG.

As shown in Figure 1, the pegylated triiodide aryl compound of the present invention was found to significantly reduce the creatine increase after administration compared to the conventional compound to reduce the renal toxicity.

1 is a graph showing the degree of nephrotoxicity induction of the compounds of the present invention obtained in Examples 1-3 and 3-3 and commercially available iohexol, iodisanol and iopamidol as controls.

Claims (14)

PEGylated triiodyl aryl compounds of formula 1 or 2 below: [Formula 1]

 [Formula 2]

Where A, B and D are the same or different and are -CON (R) R ₁ or -N (R) COR ₂ , E is the same or different and is -CON (R)-, -N (R) CO- or -N (COR ₃ )-, X is a covalent bond; Or a C ₁ -C ₈ straight or branched alkylene chain unsubstituted or substituted by 1 to 6 substituents selected from the group consisting of OH and -CONHR, R is hydrogen; Or OH, straight or branched alkyl group of C ₁ -C ₆ alkoxy group and C ₁ -C ₆ alkyl group that is hydroxy is optionally substituted by 1 to 5 substituents selected from the consisting of C ₁ -C ₆ of the ego, R ₁ is OH, a straight-chain or branched C ₁ -C ₆ alkoxy group and C ₁ -C ₆ alkyl group that is hydroxy is optionally substituted by 1 to 5 substituents selected from the consisting of C ₁ -C ₆ of the A topographic alkyl group, R ₂ is OH, a straight-chain or branched C ₁ -C ₆ alkoxy group and C ₁ -C ₆ alkyl group that is hydroxy is optionally substituted by 1 to 5 substituents selected from the consisting of C ₁ -C ₆ of the It is a topographic alkyl group, R ₃ is OH, C ₁ -C ₆ alkoxy group and C ₁ -C ₆ hydroxy alkyl group having 1 to 2 substituents in the optionally substituted straight-chain or branched, unsubstituted C ₁ -C ₃ by selected from the group consisting of A topographic alkyl group, All or part of the hydroxyl groups present in A, B, D, E and X are substituted by -OCO (CH ₂ ) _m (OCH ₂ CH ₂ ) _n OR ₄ , R ₄ is hydrogen or a C ₁ -C ₆ straight or branched alkyl group, n is an integer from 2 to 120, m is an integer of 1 to 10; The triiodinated aryl compound according to claim 1, which is a pegylated iohexol of formula (3): (3)

Where Y is the same or different and is hydrogen or -CO (CH ₂ ) _m (OCH ₂ CH ₂ ) _n OR ₄ , R ₄ is hydrogen or a C ₁ -C ₆ straight or branched alkyl group, n is an integer from 2 to 120, m is an integer of 1 to 10; The triiodinated aryl compound according to claim 1, which is a pegylated iodisanol of formula (4): [Formula 4]

Where Y is the same or different and is hydrogen or -CO (CH ₂ ) _m (OCH ₂ CH ₂ ) _n OR ₄ , R ₄ is hydrogen or a C ₁ -C ₆ straight or branched alkyl group, n is an integer from 2 to 120, m is an integer of 1 to 10; The triiodinated aryl compound according to any one of claims 1 to 3, wherein R ₄ is a methyl group. delete The triiodide aryl compound according to any one of claims 1 to 3, wherein m is an integer of 1 to 3. The method according to any one of claims 1 to 3, R ₄ is a methyl group, n is an integer from 2 to 120, m is an integer of 1 to 3, iodide aryl compound, characterized in that. The triiodide aryl compound according to claim 2 or 3, wherein Y is all —CO (CH ₂ ) _m (OCH ₂ CH ₂ ) _n OR ₄ . 9. The method of claim 8, R ₄ is a methyl group, n is an integer from 2 to 120, m is an integer of 1 to 3, iodide aryl compound, characterized in that. An x-ray contrast agent comprising the aryl iodide compound according to any one of claims 1 to 3 together with a pharmaceutically acceptable carrier. An x-ray contrast agent comprising the triiodinated aryl compound according to claim 7 together with a pharmaceutically acceptable carrier. An x-ray contrast agent comprising the iotrilated aryl compound according to claim 8 together with a pharmaceutically acceptable carrier. An x-ray contrast agent comprising the triiodated aryl compound according to claim 9 together with a pharmaceutically acceptable carrier. The X-ray contrast agent according to claim 10, which has a formulation in aqueous solution or suspension.

Images