A triiodobenzoic acid derivative, and a preparation method and application thereof

Abstract

The application relates to the technical field of medicines, and discloses a triiodobenzoic acid derivative, a preparation method and application thereof. The triiodobenzoic acid derivative provided by the application has a high iodine atom load in the molecular structure, can effectively guarantee the X-ray absorption effect, and further guarantees excellent imaging contrast. Meanwhile, the derivative has excellent water solubility, is more beneficial to the preparation and administration of clinical preparations, has a non-ionic structure, can significantly reduce the system osmotic pressure and solution viscosity, reduces physiological stimulation to the body, improves in-vivo tolerance and biological safety, and has less damage to the kidney. When the derivative is applied to the clinic as a contrast agent or a developing agent, the derivative has higher use safety and application reliability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a triiodobenzoic acid derivative, its preparation method, and its application. Background Technology

[0002] X-ray contrast imaging is an indispensable and important tool in clinical imaging diagnosis. Iodine-containing contrast agents are widely used in medical imaging examinations such as angiography and CT enhanced scanning because iodine has a high X-ray absorption coefficient.

[0003] Currently used iodine-containing contrast agents in clinical settings are mainly divided into two categories: ionic and non-ionic. Ionic contrast agents, due to their high osmotic pressure and significant toxic side effects, are gradually being replaced by non-ionic contrast agents. Existing non-ionic contrast agents typically use a triiodobenzene ring as the core structure, and introduce hydrophilic side chains to improve water solubility and reduce the incidence of adverse reactions.

[0004] However, existing iodine-containing developing agents still have the following shortcomings: 1) it is difficult to balance high iodine content with high water solubility; 2) high viscosity at high iodine concentrations leads to significant injection resistance; 3) poor in vivo tolerance; and 4) complex synthesis routes, numerous steps, and high costs. Therefore, it is still necessary to develop new developing agents to overcome these shortcomings. Summary of the Invention

[0005] This invention provides a triiodobenzoic acid derivative, its preparation method, and its application, to solve the problems of existing developers being unable to balance high iodine content and high water solubility, having high viscosity at high iodine concentrations, and poor in vivo tolerance.

[0006] In a first aspect, the present invention provides a triiodobenzoic acid derivative having a structure as shown in formula (I): Formula (I), R1 is selected from at least one of unsubstituted or hydroxyl-substituted C1-C20 straight-chain alkyl groups and unsubstituted or hydroxyl-substituted C3-C20 branched alkyl groups.

[0007] In one alternative embodiment, R1 is selected from at least one of C1-C10 straight-chain alkyl groups that are unsubstituted or substituted with 1-7 hydroxyl groups, and C3-C10 branched alkyl groups that are unsubstituted or substituted with 1-7 hydroxyl groups.

[0008] In one optional embodiment, R1 is selected from at least one of the following: unsubstituted or substituted n-propyl, unsubstituted or substituted isopropyl, unsubstituted or substituted n-butyl, unsubstituted isobutyl, unsubstituted or substituted n-pentyl, unsubstituted or substituted C5 branched alkyl, unsubstituted or substituted hexyl, and unsubstituted or substituted hexyl.

[0009] In one alternative embodiment, the triiodobenzoic acid derivative has any of the following structures:

[0010] In one optional embodiment, the triiodobenzoic acid derivative contains 20-80% iodine by mass, preferably 50-70%.

[0011] In a second aspect, the present invention provides a method for preparing the above-mentioned triiodobenzoic acid derivatives, comprising the following steps: activating 2,4,6-triiodobenzoic acid with a condensing agent and a catalyst in the presence of a solvent, and then subjecting it to an esterification reaction with a basic reagent and a polyol to obtain the triiodobenzoic acid derivatives shown in formula (I).

[0012] In one alternative embodiment, the solvent includes polar solvents and / or non-polar solvents; In one optional embodiment, the polar solvent includes at least one of N,N-dimethylformamide, dimethyl sulfoxide, acetone, and acetonitrile; In one optional embodiment, the nonpolar solvent includes at least one selected from n-hexane, cyclohexane, n-heptane, dichloromethane, diethyl ether, benzene, and toluene. In one optional embodiment, the condensing agent comprises at least one of 1-ethyl-(3-dimethylaminopropyl)carbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, O-benzotriazole-tetramethylurea hexafluorophosphate, and O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate. In one optional embodiment, the catalyst comprises at least one selected from 4-dimethylaminopyridine, 4-pyrrolylpyridine, 4-piperidinylpyridine, 2,6-dimethylpyridine, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 1-methylimidazolium, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride, and ethyl 2-cyano-2-(hydroxyimino)acetate; In one alternative embodiment, the basic reagent includes at least one of triethylamine, pyridine, piperidine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, imidazole, and 1,8-diazabicyclo[5.4.0]undec-7-ene; In one optional embodiment, the polyol includes at least one of glycerol, 1,2-propanediol, butylene glycol, erythritol, sorbitol, pentaerythritol, and mannitol. In one optional embodiment, the mass ratio of the 2,4,6-triiodobenzoic acid to the volume ratio of the solvent is 1:1-5, in g:mL; In one optional embodiment, the molar ratio of 2,4,6-triiodobenzoic acid to the condensing agent is 1:1.2-1.5; In one optional embodiment, the molar ratio of 2,4,6-triiodobenzoic acid to the catalyst is 1:0.001-0.5; In one optional embodiment, the molar ratio of 2,4,6-triiodobenzoic acid to the basic reagent is 1:1-2.5, in mL:g. In one optional embodiment, the molar ratio of 2,4,6-triiodobenzoic acid to polyol is 1:1.5-5; In one optional embodiment, the activation temperature is -20 to 10°C, the time is 20 to 40 minutes, and the rotation speed is 20 to 60 rpm. In one alternative embodiment, the esterification reaction is carried out under the protection of nitrogen and / or an inert gas; In one optional embodiment, the esterification reaction is carried out at a temperature of 40-60°C for 5-12 hours and at a rotation speed of 20-60 rpm. In one optional embodiment, the esterification reaction is further followed by steps of cooling, filtration, concentration, and purification. In one alternative embodiment, the concentration method is vacuum concentration and / or rotary evaporation; In one optional embodiment, the purification method is column chromatography; In one alternative embodiment, the eluent for the column chromatography comprises a mixed solvent of dichloromethane and methanol in a volume ratio of 6-9:1.

[0013] Thirdly, the present invention provides the use of the above-mentioned triiodobenzoic acid derivatives or the triiodobenzoic acid derivatives prepared by the above-mentioned preparation method in the preparation of contrast agents and / or imaging agents.

[0014] Fourthly, the present invention provides a contrast agent comprising the above-mentioned triiodobenzoic acid derivatives or triiodobenzoic acid derivatives prepared by the above-mentioned preparation method.

[0015] Fifthly, the present invention provides a developer comprising the above-described triiodobenzoic acid derivatives or triiodobenzoic acid derivatives prepared by the above-described preparation method.

[0016] The technical solution of this invention has the following advantages: 1. The present invention provides a triiodobenzoic acid derivative with a high iodine atom loading in its structure, which can effectively ensure X-ray absorption and thus guarantee excellent imaging contrast. At the same time, the derivative has excellent water solubility, which is more conducive to the preparation and administration of clinical formulations. Furthermore, its non-ionic structure can significantly reduce the osmotic pressure and solution viscosity of the system, reduce physiological stimulation to the body, improve in vivo tolerance and biosafety, and cause less damage to the kidneys. When used as a contrast agent or imaging agent in clinical practice, it has higher safety and reliability.

[0017] 2. The preparation method of the above-mentioned triiodobenzoic acid derivatives provided by the present invention includes the following steps: activating 2,4,6-triiodobenzoic acid with a condensing agent and a catalyst in the presence of a solvent, and then performing an esterification reaction with a basic reagent and a polyol to obtain the triiodobenzoic acid derivatives shown in formula (I). This method has mild reaction conditions and simple steps, making it suitable for industrial-scale production. The obtained triiodobenzoic acid derivatives have excellent water solubility and imaging performance, and can be widely used in the field of medical imaging diagnosis, showing good prospects for industrial production and clinical application. Detailed Implementation

[0018] The following embodiments are provided to better understand the present invention, but the following embodiments do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the scope of protection of the present invention.

[0019] Unless otherwise specified, all experimental steps or conditions in the examples were performed according to conventional experimental procedures and conditions in the art. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0020] Example 1 This embodiment provides a triiodobenzoic acid derivative, wherein the triiodobenzoic acid derivative is compound 1 having the following structure: .

[0021] This embodiment also provides a method for preparing compound 1, comprising the following steps: 2,4,6-Triiodobenzoic acid (5 g, 10 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). At 0 °C, condensing agent 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (2.3 g, 12 mmol) and catalyst 4-dimethylaminopyridine (DMAP) (0.001 g, 0.01 mmol) were added. The mixture was activated under nitrogen protection at 0 °C and 20 rpm for 20 min by stirring. Then, triethylamine (1.01 g, 10 mmol) was added, followed by dropwise addition of glycerol (1.38 g, 15 mmol). The reaction was carried out at 50 °C and 20 rpm for 6 h. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove inorganic salts, concentrated under reduced pressure, and the crude product was purified by column chromatography (using a mixture of dichloromethane and methanol in a volume ratio of 8:1 as the eluent) to obtain a white solid, which was compound 1, with a yield of 78%.

[0022] 1H NMR spectrum: 400 MHz, CDCl3 δ6.82 (s, 2H), 4.47 (s, 2H), 4.53 (d, 2H), 4.07 (tt, 1H), 3.50 (d, 2H), the structure has been confirmed to be correct.

[0023] Example 2 This embodiment provides a triiodobenzoic acid derivative, wherein the triiodobenzoic acid derivative is compound 2 having the structure shown below: .

[0024] This embodiment also provides a method for preparing compound 2, including the following steps: 2,4,6-Triiodobenzoic acid (5 g, 10 mmol) was dissolved in anhydrous dichloromethane (10 mL). The condensing agent N,N'-dicyclohexylcarbodiimide (DCC) (2.68 g, 13 mmol) and the catalyst 4-pyrrolidinylpyridine (0.001 g, 0.01 mmol) were added at 5 °C with stirring for 40 min under nitrogen protection at 5 °C and 60 rpm. Then, N,N-diisopropylethylamine (1.94 g, 15 mmol) was added, followed by dropwise addition of glycerol (2.12 g, 20 mmol). The reaction was continued at 40 °C and 60 rpm for 7 h. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove inorganic salts, concentrated under reduced pressure, and the crude product was purified by column chromatography (using a 7:1 volume ratio of dichloromethane and methanol as eluent) to obtain a white solid, which was compound 2, with a yield of 50%.

[0025] 1H NMR spectrum: 400 MHz, CDCl3 δ6.89(s,2H), δ4.47(s,2H), δ4.32(t,2H), δ3.60(tt,1H), δ3.50(d,2H), δ2.20(s,2H), the structure has been confirmed to be correct.

[0026] Example 3 This embodiment provides a triiodobenzoic acid derivative, wherein the triiodobenzoic acid derivative is compound 3 having the structure shown below: .

[0027] This embodiment also provides a method for preparing compound 3, including the following steps: 2,4,6-Triiodobenzoic acid (5 g, 10 mmol) was dissolved in anhydrous dimethyl sulfoxide (15 mL). The condensing agent O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU) (5.69 g, 15 mmol) and the catalyst 1-hydroxybenzotriazole (HOBt) (0.405 g, 3 mmol) were added at 10 °C. The mixture was activated by stirring at 10 °C and 40 rpm for 30 min under nitrogen protection. Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.04 g, 20 mmol) was added, followed by dropwise addition of erythritol (3.05 g, 25 mmol). The reaction was carried out at 60 °C and 40 rpm for 5 h. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove inorganic salts, concentrated under reduced pressure, and the crude product was purified by column chromatography (using a 9:1 mixture of dichloromethane and methanol as eluent) to obtain a white solid, which was compound 3, with a yield of 48%.

[0028] 1H NMR spectrum: 400 MHz, CDCl3 δ8.20(s,2H), δ4.48(d,2H), δ4.40(s,3H), δ4.00(td,1H), δ3.90(td,1H), δ3.50(d,2H). The structure has been confirmed to be correct.

[0029] Example 4 This embodiment provides a triiodobenzoic acid derivative, wherein the triiodobenzoic acid derivative is compound 4 having the structure shown below: .

[0030] This embodiment also provides a method for preparing compound 4, including the following steps: 2,4,6-Triiodobenzoic acid (5 g, 10 mmol) was dissolved in anhydrous N,N-dimethylformamide (25 mL). Condensing agent HBTU (4.55 g, 12 mmol) and catalyst 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM) (1.474 g, 5 mmol) were added at -5 °C. The mixture was activated by stirring at -5 °C and 20 rpm for 20 min under nitrogen protection. Then, DBU (3.81 g, 25 mmol) was added, followed by dropwise addition of sorbitol (5.47 g, 30 mmol). The reaction was carried out at 50 °C and 20 rpm for 12 h. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove inorganic salts, and concentrated under reduced pressure. The crude product was purified by column chromatography (using a 6:1 mixture of dichloromethane and methanol as eluent) to obtain a white solid, which was compound 4, with a yield of 58%.

[0031] 1H NMR spectrum: 400 MHz, CDCl3 δ8.30(s,2H), δ4.70(s,3H), δ4.69(d,2H), δ4.00(td,2H), δ3.90(dd,2H), δ3.50(d,2H), δ2.90(s,1H), δ2.10(s,1H). The structure has been confirmed to be correct.

[0032] Example 5 This embodiment provides a triiodobenzoic acid derivative, wherein the triiodobenzoic acid derivative is compound 5 having the structure shown below: .

[0033] This embodiment also provides a method for preparing compound 5, comprising the following steps: 2,4,6-Triiodobenzoic acid (5 g, 10 mmol) was dissolved in anhydrous acetone (25 mL). The condensing agent DCC (2.48 g, 12 mmol) and the catalyst DMAP (0.001 g, 0.01 mmol) were added at -10 °C. The mixture was activated by stirring at -10 °C and 20 rpm for 20 min under nitrogen protection. Then, pyridine (0.79 g, 10 mmol) was added, followed by the dropwise addition of pentaerythritol (5.45 g, 40 mol). The reaction was carried out at 50 °C and 20 rpm for 6 h. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove inorganic salts, concentrated under reduced pressure, and the crude product was purified by column chromatography (using a mixture of dichloromethane and methanol in a volume ratio of 8:1 as the eluent) to obtain a white solid, which was compound 5, with a yield of 46%.

[0034] 1H NMR spectrum: 400 MHz, CDCl3 δ8.20(s,2H), δ4.40(s,3H), δ4.15(s,2H), δ3.28(s,6H), the structure has been confirmed to be correct.

[0035] Example 6 This embodiment provides a triiodobenzoic acid derivative, wherein the triiodobenzoic acid derivative is compound 6 having the structure shown below:

[0036] This embodiment also provides a method for preparing compound 6, including the following steps: 2,4,6-Triiodobenzoic acid (5 g, 10 mol) was dissolved in anhydrous N,N-dimethylformamide (25 mL). Condensing agent DCC (2.48 g, 12 mmol) and catalyst DMAP (0.001 g, 0.1 mmol) were added at 0 °C. The mixture was activated under nitrogen protection at 0 °C and 20 rpm for 20 min by stirring. Then, triethylamine (2.53 g, 25 mmol) was added, followed by dropwise addition of xylitol (4.56 g, 30 mmol). The reaction was carried out at 50 °C and 20 rpm for 12 h. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove inorganic salts, and concentrated under reduced pressure. The crude product was purified by column chromatography (using a mixture of dichloromethane and methanol in a volume ratio of 8:1 as the eluent) to obtain a white solid, which was compound 6, with a yield of 37%.

[0037] 1H NMR spectrum: 400 MHz, CDCl3 δ6.9 (s, 2H), δ5.5 (s, 4H), δ4.43 (d, 2H), δ4.00 (dt, 2H), δ3.91 (dd, 1H), δ3.42 (d, 2H), the structure has been confirmed to be correct.

[0038] Example 7 This embodiment provides a triiodobenzoic acid derivative, wherein the triiodobenzoic acid derivative is compound 7 having the structure shown below: .

[0039] This embodiment also provides a method for preparing compound 7, including the following steps: 2,4,6-Triiodobenzoic acid (5 g, 10 mmol) was dissolved in anhydrous diethyl ether (25 mL). The condensing agent DCC (2.48 g, 12 mmol) and the catalyst DMAP (0.001 g, 0.01 mmol) were added at -20 °C. The mixture was activated by stirring at -20 °C and 20 rpm for 30 min under nitrogen protection. Then, triethylamine (1.11 g, 11 mmol) was added, followed by dropwise addition of 1,2-propanediol (1.14 g, 15 mmol). The reaction was carried out at 50 °C and 20 rpm for 6 h. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove inorganic salts, and concentrated under reduced pressure. The crude product was purified by column chromatography (using a mixture of dichloromethane and methanol in a volume ratio of 8:1 as the eluent) to obtain a white solid, which was compound 7, with a yield of 72%.

[0040] 1H NMR spectrum: 400 MHz, CDCl3 δ8.20(s,2H), δ4.45(d,1H), δ4.40(s,1H), δ4.40(d,1H), δ4.1(tq,1H), δ1.31(d,3H), the structure has been confirmed to be correct.

[0041] Example 8 This embodiment provides a triiodobenzoic acid derivative, wherein the triiodobenzoic acid derivative is compound 8 having the structure shown below: .

[0042] This embodiment also provides a method for preparing compound 8, including the following steps: 2,4,6-Triiodobenzoic acid (5 g, 10 mmol) was dissolved in anhydrous N,N-dimethylformamide (25 mL). The condensing agent DCC (2.48 g, 12 mmol) and the catalyst DMAP (0.001 g, 0.01 mmol) were added at 0 °C. The mixture was activated under nitrogen protection at 0 °C and 20 rpm for 30 min with stirring. Then, triethylamine (1.52 g, 15 mmol) was added, followed by dropwise addition of isobutanol (1.11 g, 15 mmol). The reaction was carried out at 50 °C and 20 rpm for 6 h. After the reaction was complete, the mixture was cooled to room temperature, filtered to remove inorganic salts, concentrated under reduced pressure, and the crude product was purified by column chromatography (using a mixture of dichloromethane and methanol in a volume ratio of 8:1 as the eluent) to obtain a white solid, which was compound 8, with a yield of 72%.

[0043] 1H NMR spectrum: 400 MHz, CDCl3 δ8.20 (s, 2H), δ4.29 (d, 2H), δ1.74 (m, 1H), δ0.95 (d, 6H), the structure has been confirmed to be correct.

[0044] Comparative Example 1 This comparative example provides a triiodobenzoic acid derivative, named sodium diatrizoate, purchased from McLean Company, catalog number: S818454-250g, specification: 250g.

[0045] Comparative Example 2 This comparative example provides a triiodobenzoic acid derivative, named iohexol, purchased from McLean Company, catalog number: I799290-1g, specification: 1g.

[0046] Experimental Example 1 The mass percentage of iodine in the compounds of each example and Comparative Example 2 was determined by oxygen flask combustion-titration method.

[0047] Test method: Accurately weigh 20 mg of each compound from the examples and Comparative Example 2, and place them in a combustion flask containing 10 mL of absorption liquid (i.e., 5% sodium hydroxide solution by mass) as the test sample. Use a blank absorption liquid as a blank control. Then, perform combustion decomposition of the test sample according to the oxygen flask combustion method described in Chinese Pharmacopoeia 2020 Edition, Part IV, 0703. The blank control is exactly the same as the test sample except that no test sample is added. After complete combustion, shake the combustion flask thoroughly to ensure that the generated iodide is completely absorbed by the absorption liquid. Then, add 3 mL of 4% potassium permanganate solution to the absorption liquid for oxidation reaction until the solution turns a persistent deep purple color. After ensuring complete oxidation, add 80% formic acid solution and shake thoroughly until the purple color in the solution disappears. Then, add 1-2 drops more to ensure that the excess potassium permanganate is completely removed and its interference is eliminated. The reaction solution was then transferred to an Erlenmeyer flask, and 10 mL of 10% potassium iodide solution and 5 mL of dilute sulfuric acid were added. The flask was immediately stoppered tightly, and water was added to seal it. The flask was then placed in the dark for 5 minutes. Next, it was titrated with sodium thiosulfate titrant (0.1 mol / L) until the solution turned pale yellow. Then, 2 mL of starch indicator solution was added, and titration continued until the blue color just disappeared and did not fade within 30 seconds. This indicated the titration endpoint. The volume of sodium thiosulfate titrant consumed by the sample was recorded as V, and the volume of sodium thiosulfate titrant consumed by the blank control was recorded as V0. Three parallel determinations were performed, and the average value was taken.

[0048] Calculation formula: (1) Theoretical mass percentage of iodine W 理论 (%) = n×126.90 / Mw×100%; where n is the number of iodine atoms in the molecular formula; Mw is the relative molecular mass of the compound.

[0049] (2) Measured mass percentage of iodine W 实测(%) = (V-V0)×C×21.15 / m×100%; where V is the volume of titrant consumed by the sample (mL); V0 is the volume of titrant consumed by the blank control (mL), and the average consumption of the blank control in this experiment was V0=0.05mL; C is the concentration of sodium thiosulfate titrant (mol / L); and m is the sample weight (mg).

[0050] Test results: As shown in Table 1, the iodine content of Examples 1-8 of the present invention is significantly higher than that of the commercially available reference standard iohexol (Comparative Example 2), and they have a higher unit iodine density.

[0051] Table 1 Results of Iodine Content Determination

[0052] Experiment Example 2 The water solubility of the triiodobenzoic acid derivatives in each embodiment was tested.

[0053] Test method: Under a constant temperature environment of 25℃, weigh out 1.0g (W) of each sample. 样 The compounds of each embodiment and comparative example were placed in small beakers, and then deionized water was added dropwise using a precision pipette. After each addition, the mixture was magnetically stirred for 30 minutes. When the solution changed from turbid to clear and transparent without suspended particles, the corresponding volume of water consumed (V) was recorded. 水 The solubility S is calculated using the following formula: S = W 样 / V 水 Each sample was measured in parallel three times, and the average value and standard deviation of the solubility of each compound in water were calculated.

[0054] Test results: Table 2 Water solubility test results

[0055] As shown in Table 2, the solubility of the compounds obtained in each example is not less than 600 mg / mL. Examples 4, 6, and 8 are extremely soluble in water, while the other examples are readily soluble in water. The aqueous solutions of all the compounds in the examples are clear and transparent, with no visible precipitate.

[0056] Experimental Example 3 Viscosity and osmotic pressure tests were performed on the compounds of each embodiment and comparative example.

[0057] Test method: 1. Viscosity: The compounds of each example and comparative example were prepared into aqueous solutions with an iodine content of 300 mg per milliliter. Their dynamic viscosity was measured using a rotational viscometer at 25°C and 60 rpm.

[0058] 2. Osmotic pressure: Using a freezing point osmotic pressure meter, 100 μL of the solution prepared in the above viscosity test is injected into the measuring chamber. The instrument automatically cools down and calculates the osmotic pressure based on the freezing point drop.

[0059] Test results: Table 3. Viscosity and osmotic pressure test results

[0060] As shown in Table 3, the triiodobenzoic acid derivatives prepared in this invention maintain a high iodine concentration while exhibiting low dynamic viscosity and excellent osmotic pressure balance. In clinical applications, this effectively reduces resistance during high-pressure injection, alleviates vascular endothelial pressure, and significantly reduces patient pain and heat sensation during injection, demonstrating high clinical application potential. However, Comparative Example 1 suffers from excessively high osmotic pressure, which not only exacerbates discomfort at the injection site but may also lead to cell dehydration and increased vascular irritation due to the large osmotic pressure difference, hindering safe clinical use. Comparative Example 2 has a relatively higher viscosity than all other examples. This relatively high viscosity significantly increases high-pressure injection resistance, burdens the vascular endothelium, and increases the difficulty of injection. Furthermore, the relatively high osmotic pressure further exacerbates vascular irritation and patient discomfort. Therefore, the sodium diatrizoate in Comparative Example 1 and the iohexol in Comparative Example 2 are inferior to those of this invention in terms of viscosity and permeability.

[0061] Experiment Example 4 The compounds of each embodiment and comparative example were subjected to X-ray imaging performance tests.

[0062] Test Method: The compounds from each example and comparative example were prepared into aqueous solutions with iodine contents of 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg per milliliter. 1.0 mL of each concentration was transferred to a 1.5 mL centrifuge tube, which was then placed in a PMMA (polymethyl methacrylate) multi-functional CT phantom (model: Gammex 1472). Scanning was performed using a clinical CT scanner with the following parameters set: tube voltage 120 kV, tube current 200 mA. The selected area of ​​the image workstation ROI was 10 mm². 2 Record the CT value (HU) for each group, and take the average value for each centrifuge tube after 5 repeated measurements.

[0063] Test results: Table 4. CT value results for each group at different iodine concentrations.

[0064] Higher iodine concentrations result in higher CT values ​​(HU). At the same iodine concentration, a higher CT value indicates stronger X-ray attenuation and better imaging contrast. As shown in Table 4, at the same iodine concentration, between 50-100 mg I / mL, the compounds of the embodiments of the present invention exhibited imaging contrast comparable to or higher than the comparative examples. After a concentration of 200 mg I / mL, the CT values ​​of the embodiments of the present invention were significantly higher than those of the comparative examples, demonstrating better imaging contrast.

[0065] Experimental Example 5 In vivo tolerability tests were performed on the compounds of each example and comparative example.

[0066] Test method: 1. Median lethal dose 1) Experimental animals: 100 Kunming rats (half male and half female) were randomly divided into 10 groups, with 10 rats in each group.

[0067] 2) Preparation of test solutions: Accurately weigh the compounds of each example and comparative example, calculate the required mass based on the theoretical iodine ion content, and add water for injection for cell culture (WFI) as a dilution solution. When the initial pH value of the solution is lower than 6.8 after the compound is dissolved, the pH value needs to be adjusted to 6.8-7.4 by adding 0.1 mol / L alkaline buffer tromethamine, and add 0.01% (w / v) disodium ethylenediaminetetraacetate as a stabilizer. After stirring and mixing until dissolved, dilute to volume with WFI until the iodine ion concentration of the solution is 300 mg I / mL, and then filter the bacteria through a 0.22 μm filter membrane.

[0068] 3) Experimental procedure: The constant ratio method was used to set the dose gradient to ensure accurate capture of the reagent conversion range of each test compound. Based on the preliminary experimental results, five dose levels were set: 13.0, 15.6, 18.7, 22.5 and 27.0 gI / kg, with the proportion factor (group interval) between adjacent dose groups kept constant at 1.2.

[0069] The test solutions of different doses were injected into the tail vein of rats at extremely rapid speed, with the injection volume adjusted in real time according to the model's body weight. The mortality of rats in each group was observed over 72 hours, and the median lethal dose (LD50) was calculated as: LD50 = log[Xm - i(sumP - 0.5)]. Parameter explanations: Xm: Logarithm of the dose in the highest dose group. i: Logarithm of the ratio of doses between adjacent groups. sumP: Sum of amplifications in each group (expressed as a decimal, e.g., 1.0 for all deaths). 0.5: Empirical bias.

[0070] 2. Renal tolerance (nephrotoxicity evaluation) 1) Experimental animals: 60 SD rats were selected and randomly divided into groups of 6 rats each, according to the examples and comparative examples.

[0071] 2) Preparation of test solutions: Accurately weigh the compounds from each example and comparative example, calculate the required mass based on the theoretical ion content, add WFI, and control the volume to approximately 80% of the final volume. Precisely adjust the pH to 7.2 ± 0.2 using 0.1 mol / L tromethamine solution. Add 0.01% (w / v) disodium ethylenediaminetetraacetate as a metal ion hinge stabilizer. Make up to the required volume with WFI until the iodine ion concentration is 370 mg I / mL. Then filter sterilize using a 0.22 μm polyethersulfone (PES) membrane before use.

[0072] 3) Experimental Procedure: The test solution was injected via tail vein injection at a dose of 10g iodine per kg of rat body weight. Blood samples were collected before administration, 24 hours after administration, and 48 hours after administration. Serum creatinine (Scr) was measured using a blood biochemistry analyzer. The renal function of the rats was evaluated based on the rate of Scr increase: Scr increase rate (%) = (Maximum Scr after administration - Pre-administration Scr / Pre-administration Scr) × 100%.

[0073] Test results: Table 5 Results of in vivo tolerance tests

[0074] As shown in Table 5, the LD50 of Examples 1-8 were all higher than that of 16 g I / kg rats, and the Scr elevation rate was less than 10%, indicating good clinical tolerability. Among them, Example 4 showed the best LD50 and renal tolerability. Compared with Comparative Example 1, sodium diatrizoate, which had an LD50 of only 7.5 g I / kg rats, the present invention improved the LD50 by more than 2 times, and the Scr elevation rate was greater than 25%, which posed a significant risk of pain and kidney damage in clinical use. Compared with Comparative Example 2, iohexol, the present invention showed a lower Scr elevation rate at the same iodine concentration.

[0075] Sodium diatrizoate (Comparative Example 1) is an ionic contrast agent. Its high osmotic pressure can lead to erythrocyte aggregation and microcirculatory disturbances, resulting in an extremely low LD50. However, the embodiments of the present invention are non-ionic and have even lower osmotic pressure, thus significantly improving the LD50 and demonstrating a qualitative leap in safety.

[0076] Meanwhile, although iohexol (Comparative Example 2) is a non-ionic contrast agent, when it is highly concentrated within the renal tubule lumen, it leads to an increase in the local osmotic pressure and viscosity of the intratubular fluid. This extremely high luminal pressure physically compresses the renal tubular epithelial cells, resulting in increased reabsorption pressure in the renal tubules. In contrast, the embodiments of this invention, through in-depth optimization of the hydrophilic side chain structure of the benzoic acid backbone, reduce stimulation of the renal tubular epithelial cells, maintaining a low Scr elevation rate. These data strongly demonstrate the breakthrough in biosafety of the triiodobenzoic acid derivatives of this invention as contrast agents or contrast agents. Combining the results of Experimental Examples 1 and 4, compared with the commercially available contrast agents of Comparative Examples 1-2, the compounds of this invention, under the same contrast effect, can achieve further reductions in osmotic pressure and viscosity and lessen the burden on the kidneys by reducing the dosage.

[0077] In summary, the triiodobenzoic acid derivatives with nonionic structures provided by this invention can effectively balance high iodine content and in vivo tolerance, and have better water solubility, lower osmotic pressure and viscosity. When used as contrast agents or developer, they provide good imaging contrast and high safety.

[0078] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A triiodobenzoic acid derivative, characterized in that, The triiodobenzoic acid derivatives have the structure shown in formula (I): Equation (I), R1 is selected from at least one of unsubstituted or hydroxyl-substituted C1-C20 straight-chain alkyl groups and unsubstituted or hydroxyl-substituted C3-C20 branched alkyl groups.

2. The triiodobenzoic acid derivative according to claim 1, characterized in that, R1 is selected from at least one of C1-C10 straight-chain alkyl groups that are unsubstituted or substituted with 1-7 hydroxyl groups, and C3-C10 branched alkyl groups that are unsubstituted or substituted with 1-7 hydroxyl groups.

3. The triiodobenzoic acid derivative according to claim 1, characterized in that, R1 is selected from at least one of the following: unsubstituted or substituted n-propyl, unsubstituted or substituted isopropyl, unsubstituted or substituted n-butyl, unsubstituted isobutyl, unsubstituted or substituted n-pentyl, unsubstituted or substituted C5 branched alkyl, unsubstituted or substituted hexyl, and unsubstituted or substituted hexyl.

4. The triiodobenzoic acid derivative according to claim 1, characterized in that, The triiodobenzoic acid derivatives have any of the following structures: 。 5. The triiodobenzoic acid derivative according to claim 1, characterized in that, The triiodobenzoic acid derivative contains 20-80% iodine by mass, preferably 50-70%.

6. The method for preparing the triiodobenzoic acid derivative according to any one of claims 1-5, characterized in that, The process includes the following steps: activating 2,4,6-triiodobenzoic acid with a condensing agent and a catalyst in the presence of a solvent, and then esterifying it with a basic reagent and a polyol to obtain triiodobenzoic acid derivatives as shown in formula (I).

7. The method for preparing triiodobenzoic acid derivatives according to claim 6, characterized in that, The solvent includes polar solvents and / or non-polar solvents; Optionally, the polar solvent includes at least one of N,N-dimethylformamide, dimethyl sulfoxide, acetone, and acetonitrile; Optionally, the nonpolar solvent includes at least one selected from n-hexane, cyclohexane, n-heptane, dichloromethane, diethyl ether, benzene, and toluene; And / or, the condensing agent comprises at least one of 1-ethyl-(3-dimethylaminopropyl)carbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, O-benzotriazole-tetramethylurea hexafluorophosphate, and O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; And / or, the catalyst comprises at least one of 4-dimethylaminopyridine, 4-pyrrolylpyridine, 4-piperidinylpyridine, 2,6-dimethylpyridine, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 1-methylimidazolium, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride, and 2-cyano-2-(hydroxyimino)ethyl acetate; And / or, the basic reagent includes at least one of triethylamine, pyridine, piperidine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, imidazole, and 1,8-diazabicyclo[5.4.0]undec-7-ene; And / or, the polyol includes at least one of glycerol, 1,2-propanediol, butylene glycol, erythritol, sorbitol, pentaerythritol, and mannitol; And / or, the mass ratio of the 2,4,6-triiodobenzoic acid to the volume ratio of the solvent is 1:1-5, in g:mL; And / or, the molar ratio of the 2,4,6-triiodobenzoic acid to the condensing agent is 1:1.2-1.5; And / or, the molar ratio of the 2,4,6-triiodobenzoic acid to the catalyst is 1:0.001-0.5; And / or, the molar ratio of the 2,4,6-triiodobenzoic acid to the basic reagent is 1:1-2.5, in mL:g; And / or, the molar ratio of the 2,4,6-triiodobenzoic acid to the polyol is 1:1.5-5; And / or, the activation temperature is -20 to 10°C, the time is 20 to 40 min, and the rotation speed is 20 to 60 rpm; And / or, the esterification reaction is carried out under the protection of nitrogen and / or an inert gas; And / or, the esterification reaction is carried out at a temperature of 40-60°C for 5-12 hours and at a rotation speed of 20-60 rpm; And / or, the esterification reaction further includes steps of cooling, filtering, concentration, and purification; Optionally, the concentration method is vacuum concentration and / or rotary evaporation; Optionally, the purification method is column chromatography; Alternatively, the eluent for the column chromatography may comprise a mixed solvent of dichloromethane and methanol in a volume ratio of 6-9:

1.

8. The use of the triiodobenzoic acid derivatives according to any one of claims 1-5 or the triiodobenzoic acid derivatives prepared by the preparation method according to claim 6 or 7 in the preparation of contrast agents and / or imaging agents.

9. A contrast agent, characterized in that, The contrast agent includes triiodobenzoic acid derivatives as described in any one of claims 1-5 or triiodobenzoic acid derivatives prepared by the preparation method described in claim 6 or 7.

10. A developer, characterized in that, The developer includes triiodobenzoic acid derivatives as described in any one of claims 1-5 or triiodobenzoic acid derivatives prepared by the preparation method described in claim 6 or 7.

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