WO2010133180A1

WO2010133180A1 - Poly-iodo benzene compound, preparation method and use thereof

Info

Publication number: WO2010133180A1
Application number: PCT/CN2010/073039
Authority: WO
Inventors: 史命锋
Original assignee: 北京华禧联合科技发展有限公司
Priority date: 2009-05-22
Filing date: 2010-05-21
Publication date: 2010-11-25
Also published as: CN101891696A

Abstract

Disclosed is a kind of poly-iodo benzene compound shown by general formula (I). The poly-iodo benzene compounds have low toxicity, high chemical stability, and are easy to be chemically synthesized. The concentrated aqueous solutions of the compounds have low viscosity and low osmolality. The compounds are very suitable to use as nonionic contrast agents in clinic.

Description

Polyiodobenzene ring compound and preparation method and application thereof

The present invention is in the field of chemical synthesis and, in particular, relates to a novel polyiodophenone compound and a preparation method and application thereof. Background technique

Among the X-ray contrast agents, the water-soluble iodine contrast agent excreted by the kidney is the most widely used contrast agent. The development of X-ray contrast agents can be roughly divided into initial iodine contrast agents, ionic contrast agents, and non-ionic contrast agents.

By non-ionic contrast agent, it is meant that such contrast agents are not ionized in solution. It is formed by reacting a carboxyl group on the phenyl ring of the ionic contrast agent with a polyhydroxy-containing amine to form an amide. On the one hand, the contrast agent is not ionized in the aqueous solution, and on the other hand, the introduction of the polyhydroxy group greatly increases the contrast agent. Water soluble, Ami Parker

(Amipaque) is the introduction of a glucosyl group on a ubiquitinamide. Its osmotic pressure is close to human plasma osmotic pressure, low viscosity, low toxicity, but because it can not tolerate high temperature sterilization, it can not be used as an injection, can only be made into freeze-dried powder for clinical use. It brings a lot of inconvenience.

Iopamidol, Bracco, Italy, 1977, Nycoming, Norway, 1979

(Iohexol) of the company (Nycomed imaging AS), Iopromide of the German Schering AG in 1982, Itopol of the 1982 US All Science and Technology Corporation (Ioversol) and ₁₉₉₅ In the United States, Cookig Contrast Company and Japan's Chuwai Pharmaceutical Co., Ltd. jointly launched Ioxilan (Ioxilan).

Because these non-ionic contrast agents are chemically stable and can withstand high temperature sterilization, they can be made into solutions for clinical direct use. However, clinical applications have one or the other disadvantages, or toxicity or hypertonicity or excessive viscosity.

After that, many scholars have carried out a large number of chemical structural transformations on the compound of the triiodobenzene ring as a mother nucleus, and synthesized many derivatives, mainly introducing various substituents on the (acyl) amino group at the 5-position ( Including heterocyclic substituents), but their application properties have no significant breakthrough. On the contrary, due to the increase of side chains, the water solubility is affected to some extent, the side effects are also increased, and the production cost is also increased. Therefore, it has not been extended to clinical applications.

In recent years, Petta et al. have explored tetraiodophenone nonionic X-ray contrast agents, and Priebe et al. have developed another new type of polyene polyiodide type non-ionic X-ray contrast agent. Since the molecule contains four iodine atoms, the number of molecules (particles) in the solution is only three-quarters of that of the triiodobenzene ring when the same iodine content (ie, the iodine content per unit volume is the same), so the osmotic pressure is lowered. And to increase the contrast density, played a positive role. At the same time, the production cost of such contrast agents is comparable to or even lower than that of monocyclic triiodobenzene-based contrast agents. Therefore, such compounds may become novel non-ionic X-ray contrast agents. However, due to the difference in chemical structure, it is difficult for the intramolecular hydrophilic hydroxyl group to completely shield the hydrophobic iodobenzene (or iodobenzene) group, and its clinical application performance is not satisfactory, and it is only at the research stage.

In 1995, the US FDA approved the formulation and clinical development of iodolan by Cooking Contrast Agents of the United States and Sino-foreign Pharmaceuticals of Japan (Ioxilan is notable for the chemical structure of iodirapin and other clinically used non-ionic contrast agents. The difference is that the side chain at the 3rd and 5th positions on the benzene ring of the contrast agent is asymmetric, and the viscosity is lower, and the side reaction after injection is lower than that of iohexol in the side chain. One of the ventricular fibrillation and vascular pain is the lowest among the currently used non-ionic contrast agents.

The ideal (ie, biologically inert) urinary tract contrast agent should accommodate the rapid development and clinical use of CT technology. As an ideal iodine-containing nonionic contrast agent, it should have the following characteristics: (1) high content of contrast components (ie, high iodine content); (2) high purity of synthesis; (3) good stability in vitro and in vivo; (4) It has infinite water solubility; (5) low viscosity; (6) no biological activity.

The known technique shows that while introducing a side chain hydroxyl group and enhancing the water solubility of the contrast compound, the osmotic pressure and viscosity of the contrast compound are further increased, and the stability and water solubility of the contrast compound are not affected, and the Further modification and modification of the structure of the compound further enhance the contrast effect and reduce the adverse reactions and side effects of the compound in clinical use.

Therefore, the design, synthesis and development of new/improved derivatives of 2,4,6-triiodo-1,3-benzenediamide as X-my contrast diagnostic reagents further increase the iodine content and decrease in drug molecules. Osmotic pressure and viscosity, which are of great practical significance for achieving enhanced contrast, reducing adverse reactions and side effects, enhancing safety, effectiveness, and improving the structure of clinical medications. Summary of the invention

When the inventors further modified the polyiodophenylene compound, it was found that not only the 1, 3 carboxy group The side chain solubilizing group introduced by the group can make the necessary improvement, and the introduction of the polymethylene nitrogen-containing heterocyclic compound at the 5-position can significantly reduce the number of hydroxyl groups without lowering the water solubility of the compound.

Accordingly, it is a primary object of the present invention to provide a novel polyiodobenzene compound.

A second object of the present invention is to provide a process for producing the polyiodobenzene ring compound.

Still another object of the present invention is to provide an application of the polyiodobenzene compound.

The polyiodobenzene ring compound of the present invention has a structure represented by the general formula (I) -

among them:

n is any integer from 1 to 4;

R1 and R3 are selected from:

R2 and R4 are selected from the group consisting of: —H, —CH ₃ .

According to the invention, the groups R1 and R3 may be the same or different.

According to the invention, the groups R2 and R4 may also be the same or different.

The compound of the formula (I) of the present invention has a molecular weight of 700 to 1000;

According to the present invention, each of the monomer units of the compound of the formula (I) has 2 to 6 hydroxyl groups and each has 1 to 3 tertiary nitrogen atoms, preferably 1 or 3 tertiary nitrogen atoms.

The compound of the formula (I) of the present invention can be produced by the following method -

1) 5-amino-2,4,6-triiodo-1,3-isophthalic acid II is used as a raw material to obtain 5-amino-2, 4 in the presence of an acid chloride reagent such as thionyl chloride. 6-triiodo- 1, 3-isophthaloyl chloride III;

2) 5-Amino-2,4,6-triiodo-1,3-isophthaloyl chloride III reacts with the corresponding side chain acid chloride at low temperature to form an amide, or with a corresponding side chain carboxylic acid in the chloride Reaction in the presence of a sulfone to form an amide; 3) 5-amino-2,4,6-triiodo-1,3-isophthaloyl chloride III undergoes amidolytic reaction with the corresponding amino alcohol at a basic low temperature to obtain the corresponding compound V, which is generally No need to separate, directly participate in the next reaction;

4) Compound V undergoes further amination reaction with the corresponding amino alcohol under alkaline low temperature conditions to obtain compound VI;

5) Compound VI undergoes its own condensed ring reaction under basic conditions to obtain compound I.

According to the present invention, the alkaline environment in the step 5) is formed using sodium hydroxide, potassium hydroxide, an alkaline earth metal or a mixture thereof, and the alkaline earth metal is preferably calcium hydroxide.

The compound of the formula (I) of the present invention can be used as a nonionic contrast agent.

The polyiodobenzene ring compound of the present invention has low toxicity, high chemical stability, and easy chemical synthesis. The concentrated aqueous solution of the compound has low viscosity and low osmotic pressure, and is very suitable for clinical use as a nonionic contrast agent. DRAWINGS

Fig. 1 is a HPLC analysis chart of the polyiodophenylene compound of the present invention before and after alkali treatment and heat treatment, wherein A is before treatment and B is after treatment.

2 is a photograph of a small intestine CT scan of a Beagle dog of the present invention, wherein A is a pure horizontal scan photograph, B is a pure water enhanced scan photograph, and C is a plain scan photograph of the polyiodobenzene compound obtained in Example 1, D is Example 1 An enhanced scanning photograph of the obtained polyiodophenylene compound. detailed description

The present invention will be further described below in conjunction with specific embodiments. It is to be understood that the following examples are merely illustrative of the invention and are not intended to limit the scope of the invention.

First, the preparation example

Example 1, 5-(3-oxomorpholine)-^ N,-bis(2,3-hydroxypropyl)-2,4,6-triiodo-1,3-m-xylylene Preparation of amide

1.1. Preparation of 5-amino-2,4,6-triiodo-1,3-isophthaloyl chloride

Into a 1000 ml three-neck reactor, 134.4 g (0.24 mol) of 5-amino-2, 4,6-triiodo-1,3-di-benzenedicarboxylic acid, 600 ml of toluene, and 1 ml of DMF were added, and stirred to form a suspension solution. The temperature was raised to 60 ° C, 108 ml of thionyl chloride was slowly added, the temperature was slowly raised to 75 to 80 ° C, and the reaction was kept for 8 hours (TLC controlled reaction end point PE: EA = 2: 1 ), and distilled under reduced pressure. The obtained solid was dissolved in 1500 ml of ethyl acetate, and the obtained organic solution was washed three times with saturated sodium carbonate 300 ml three times, and three times with saturated brine 300 ml, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure and dried at 60 ° C. Light yellow solid 140.6 g, yield 98.5%, moisture content 1.1%, HPLC purity 98.4%, column YMC AA12S05-1546WT, 150*4.6 mml. D, S-5 m, area normalization method.

Preparation of 5-(2-chloroethoxyacetyl)amino- 2,4,6-triiodo-1,3-isophthaloyl chloride

In a 250 ml three-neck reaction flask, 14.1 g (0.0236 mol) of 5_amino-2, 4,6-triiodo_1, 3_isophthaloyl chloride, 60 ml of 2-chloroethoxyacetic acid, 1 ml of DMF were added, and the temperature was raised to 6 ° (0.0730 mol) of thionyl chloride was added dropwise at 60 ° C under the conditions of holding, and the reaction was stirred at 65 to 80 ° C for 3 hours (TLC monitoring reaction, condition PE: EA = 2: 1 ), to the reaction. End. After cooling to room temperature, 1120 ml of ice water was added to precipitate a solid, which was filtered, and the filter cake was washed with 200 ml of water, and dried at 5 CTC to obtain 14.6 g of a white solid, yield 86.7%, HPLC purity 95%, column YMC AA12S05-1546WT, 150 *4.6mml. D, S-5 m, area normalization method.

Preparation of 5-(2-chloroethoxyacetyl)amino Ν'-bis(2,3-hydroxypropyl)-2,4,6-triiodo-1,3-isophthalamide

In a three-neck reaction flask, 5-(2-chloroethoxyacetyl)amino-2,4,6-triiodo-1,3-isophthaloyl chloride (0.0230 mol), 30 ml of DMF was added and stirred to form a transparent The clarified solution was further added with 4.6 g (0.0434 mol) of anhydrous sodium carbonate.

After cooling to below 0 °C, add 15.1 g (0.165 mol) of 3-amino-1,2-propanediol dissolved in DMF (m/m=l:2), and add dropwise to maintain 0 °C. After stirring for 1 hour, the bath was removed, and the reaction was controlled at room temperature for 24 hours, and the reaction was monitored by TLC (developing solvent condition EA: MeOH = 2: l) until the end of the reaction. Post processing is divided into three methods.

Post-treatment method 1: Filtration, the filter cake was washed with 10 ml of DMF, the filtrate was combined, 30 ml of water was added, and 150 ml of ethyl acetate was further added thereto, the solution became cloudy, and the solid was precipitated by stirring.

Filtration, the filter cake was washed with anhydrous ethanol (20 ml), and dried in vacuo to give a white solid, 16.7 g, yield 88%. The TLC layer was analyzed as one point (TLC condition EA: MeOH = 1:2), HPLC purity 98.5%, column YMC AA12S05-2546WT, 250*4.6 mml. D, S-5 m, area normalization.

Post-treatment method 2: Filtration, the filter cake is washed with 10 ml DMF, the filtrate is combined, and the DMF is distilled off under reduced pressure at a temperature not exceeding 90 ° C. The residue is dissolved in a mixed solvent of 45 ml of methanol and 25 ml of water, and 10% hydrogen is added at 50 ° C. After the pH of the sodium oxide was adjusted to be stable at 10.5 to 11, the hydrochloric acid was adjusted to pH Ο, and the solid was stirred and precipitated.

Filtration, the filter cake was washed with anhydrous ethanol (20 ml), and dried in vacuo to give a white solid, 16.2 g, yield 96%. The TLC ply was analyzed as a point (TLC condition EA: MeOH = 1 : 2). HPLC purity 98.6%, column YMC AA12S05-2546WT, 250*4.6mml. D, S-5 m, area normalization method.

Post-treatment method 3: Filtration, the filter cake is washed with 10 ml of DMF, and the filtrate is combined. The temperature is not more than 90 ° C. The DMF is distilled off under reduced pressure. The residue is crystallized from methylene chloride and dried in vacuo to give a white solid 15.5 g. . The TLC layer was analyzed as one point (TLC condition EA: MeOH = 1 : 2 ) o HPLC purity 98.1%, column YMC AA12S05-2546WT, 250*4.6 mml. D, S- m, area normalization method.

1.4, 5-(3-oxomorpholine)-N, Ν'-bis(2,3-hydroxypropyl)-2,4,6-triiodo-1,1-isophthalamide

7.4 g ( 0.009 mol) 5-(2-chloroethoxyacetyl)amino-N,N,-bis(2,3-hydroxypropyl)-2,4,6 triiodo-1, 3-benzene The dimethylformamide was suspended in 20 ml of water, heated to 8 (TC, 2N sodium hydroxide (0.009 mol) and 0.5 g of calcium hydroxide (0.006 mol) were added under heat preservation, and after the reaction was kept for 30 minutes, the reaction was terminated by TLC (TLC condition acetic acid). Ethyl ester: methanol = 2: 1, plus formic acid), cooled to room temperature, the reaction was terminated with glacial acetic acid, filtered, and the filtrate was passed through 732 type cation exchange resin and type 717 anion exchange resin, and washed with deionized water. The filtrate was evaporated to dryness under reduced pressure, and then evaporated to dryness, and then evaporated to dryness. The solvent was evaporated to remove the solvent. The obtained solid was recrystallized from methanol-isopropanol, and 6.2 g of a white solid obtained in vacuo at 50 ° C, yield 88 %. HPLC purity 99.2 %, column YMC AA12S05-2546WT, 250*4.6mml. D, S-5, area normalization method.

Example 2 5-(4-oxooxazoline-3-yl)-N,N,-bis(2,3-hydroxypropyl)-2,4,6-triiodo-1, 3- Preparation of phthalic acid amide

2.1. Preparation of 5-amino-2,4,6-triiodo-1,3-isophthaloyl chloride

Prepared by the method described in Step 1.1 of Example 1.

Preparation of 5-(2-chloromethoxyacetyl)amino- 2,4,6-triiodo-1,3-isophthaloyl chloride

In a 250 ml three-neck reaction flask, 14.1 g (0.0236 mol) of 5_amino-2, 4,6-triiodo_1, 3_isophthaloyl chloride, 2-chloromethoxyacetic acid 40 ml, and quinoline 0.2 ml were added. The temperature was raised to 60 ° C, and 6 ml (0.073 mol) of thionyl chloride was added dropwise under the heat preservation condition. After the dropwise addition, the reaction was stirred at 65 to 80 ° C for 3 hours (TLC monitoring reaction, condition PE: EA=2: 1 ) The reaction is over. After cooling to room temperature, 120 ml of ice water was added to crystallize and filtered, and the filter cake was washed with 30 ml of water, and dried under vacuum at 50 ° C to obtain 15.2 g of a white solid, yield 92%. HPLC purity 96.7%, column YMC AA12S05-1546WT, 150*4.6 mml. D, S-5,, area normalization method.

2.3, 5-(2-chloromethoxyacetyl)amino-N, Ν'-bis(2,3-hydroxypropyl)_2, 4,6-triiodo-1,3-isophthalamide preparation

In the reaction flask, add 5-(2-chloromethoxyacetyl)amino-2,4,6-triiodo-1,3-isophthaloyl chloride (0.0230 mol), 30 ml of DMF, and then add 4.6 g. (0.0434 mol) anhydrous sodium carbonate.

Cool to below 0 °C, add 15g (0.165mol) of 3-amino-1,2-propanediol dissolved in DMF (m/m=l:2), add dropwise, keep warm at 0 °C After 1 hour, the bath was removed, reacted at room temperature for 24 hours, and the reaction was monitored by TLC (developing solvent condition EA: MeOH = 2:1) to the end.

After filtration, the filter cake was washed with 30 ml of DMF, and the filtrate was combined, and 30 ml of water was added thereto, and then 150 ml of ethyl acetate was added thereto, the solution became cloudy, and the solid was precipitated by stirring.

After filtration, the filter cake was washed with anhydrous ethanol (20 m.sub.2), and dried in vacuo to yield white solids, 16.7 g, yield 89%. The TLC layer was analyzed as one point (TLC condition EA: MeOH = 1:2), HPLC purity 98.7%, column YMC AA12S05-2546WT, 250*4.6 mml. D, S-5nm, area normalization, method.

2.4, 5-(4-oxooxazolin-3-yl)-N,N,-bis(2,3-hydroxypropyl)-2,4,6-triiodo-1,3-m-phenylene Preparation of formamide

5-(2-Chloromethoxyacetyl)amino-N, N,-bis(2,3-hydroxypropyl)-2,4,6-triiodo-1,3-isophthalic acid amide The mol was suspended in 20 ml of water, heated to 80 ° C, and 2N sodium hydroxide (0.009 mol) and 0.5 g of calcium hydroxide (0.0065 mol) were added under heat preservation. After the reaction was kept for 30 minutes, the reaction was terminated by TLC (ethyl acetate in TLC). : methanol = 2: 1, plus formic acid), cooled to room temperature, the reaction was terminated with glacial acetic acid, filtered, and the filtrate was passed through 732 type cation exchange resin and type 717 anion exchange resin, and washed with deionized water to reduce the filtrate. The mixture was distilled to dryness, and anhydrous ethanol was added, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from methanol-isopropanol, and dried under vacuum at 50 ° C to yield 5.0 g of white solid. HPLC purity 99.0%, column YMC AA12S05-2546WT, 250*4.6 mml. D, S-5fom, area normalization method. Example 3, 5-(3-oxo-[1,4]oxodiazane-4-yl)-N, Ν'-bis(2,3-hydroxypropyl)_2, 4, 6- Preparation of iodine-1,3-isophthalamide

3.1. Preparation of 5-amino-2,4,6-triiodo-1,3-isophthaloyl chloride

Prepared as described in step 1.1 of the examples.

Preparation of 5-(2-chloropropoxyacetyl)amino- 2,4,6-triiodo-1,3-isophthaloyl chloride

Preparation of 3-(2-chloropropoxyacetyl)amino-indole, -bis(2,3-hydroxypropyl)-2,4,6-dimethylformamide

Into the reaction flask, add 5-(2-chloropropoxyacetyl)amino-2,4,6-triiodo-1,3-isophthaloyl chloride 0.030 molK DMF 30 ml, stir to form a solution, add 4.6 g (0.0434 mol) anhydrous sodium carbonate.

After cooling to below 0 ° C, 15 g (0.165 mol) of 3-amino-1,2-propanediol dissolved in DMF (m/m = 1:2) was added dropwise, and the mixture was stirred at 0 ° C for 1 hour, then removed. The external bath was controlled at room temperature for 24 hours, and the reaction was monitored by TLC (developing solvent condition EA: MeOH = 2: l) until the end of the reaction.

After filtration, the filter cake was washed with 30 ml of DMF, and the filtrate was combined, and 30 ml of water was added to form a clear clear solution, and then 150 ml of ethyl acetate was further added and stirred overnight. After filtration, the filter cake was washed with anhydrous ethanol (20 ml*2) and dried in vacuo to give a white solid (13.7 g). The TLC ply was analyzed as one point (TLC condition EA: MeOH = 1:2), HPLC purity 94.8%, column YMC AA12S05-2546 WT, 250*4.6 mml. D, S-5 m, area normalization.

3.4, 5-(3_Oxo-[1,4]oxoazacyclo-4-yl)-N,N,-bis(2,3-hydroxypropyl)_2,4,6-triiodo- Preparation of 1, 3-isophthalamide

5-(2-Chloropropoxyacetyl)amino-N,N,-bis(2,3-hydroxypropyl)-2,4,6-triiodo-1,3-isophthalic acid amide The mol was suspended in 20 ml of water, heated to 80 ° C, and 2N sodium hydroxide (0.009 mol) and 0.5 g of hydrogen peroxide (0.0065 mol) were added under heat preservation. After the reaction was kept for 45 minutes, the reaction was terminated by TLC (ethyl acetate in TLC). : methanol = 2: 1, plus formic acid), cooled to room temperature, the reaction was terminated with glacial acetic acid, filtered, and the filtrate was passed through 732 type cation exchange resin and type 717 anion exchange resin, and washed with deionized water to reduce the filtrate. The mixture was distilled to dryness, and anhydrous ethanol was added, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from methanol-isopropyl alcohol, and dried (yield: HPLC purity 95.2%, column YMC AA12S05-2546WT, 250*4.6 mml. D, S-5 m, area normalization method. Example 4, 5-(3-oxo-[1,4]oxaoxacan-4-yl)-N,N,-bis(2,3-hydroxypropyl)-2,4,6-triiodo-1 , 3-isophthalamide preparation

Preparation of 5-(2-chlorobutoxyacetyl)amino- 2,4,6-triiodo-1,3_isophthaloyl chloride

In a three-neck reaction flask, 14.1 g (0.0236 mol) of 5_amino-2,4,6-triiodo-1,3_isophthaloyl chloride, 30 ml of DMF, 5 ml of triethylamine, and cooled to 0 ° C, were added. 0.19 mol of 2-chlorobutoxyacetyl chloride was added, and the reaction was stirred at 5 to 10 ° C for 3 hours, and then slowly warmed to room temperature for 20 hours (TLC monitoring reaction, condition PE: EA = 2: 1 ) Until the end of the reaction. Add 120 ml of ice water to precipitate a solid, filter, and filter cake with 30 ml*2 Water washing, vacuum drying at 50 ° C gave 13.2 g of a white solid, yield 75.2%. HPLC purity 95.3 %, column YMC AA12S05-1546WT, 150*4.6 mml. D, S-5, area normalization method.

4.2, 5-(2-chlorobutoxyacetyl)amino-N, N,-bis(2,3-hydroxypropyl)-2,4,6-triiodo-1,3-isophthalamide Preparation

In the reaction flask, add 5-(2-chlorobutoxyacetyl)amino-2,4,6-triiodo-1,3-isophthaloyl chloride 0.0230 mol, DMF 30 ml, stir to form a solution, add 4.6 g (0.0434 mol) anhydrous sodium carbonate.

After cooling to 0 ° C, 15 g (0.165 mol) of a solution of 3-amino-1,2-propanediol dissolved in DMF (m/m-l:2) was added dropwise, and the mixture was stirred at 0 ° C for 1 hour. Bath, control room temperature reaction for 24 hours, TLC monitor reaction (developing agent condition EA: MeOH = 2: l) until the end of the reaction.

After filtration, 30 ml of water was added to the filtrate, and 150 ml of ethyl acetate was further added, and stirred overnight.

After filtration, the filter cake was washed with anhydrous ethyl alcohol (30 ml), and dried in vacuo to yield 11.4 g of white solid.

The TLC layer was analyzed as one point (TLC condition EA: MeOH = 2:3), HPLC purity 93.4%, column YMC AA12S05-2546WT, 250*4.6 mml. D, S-5 m, area normalization method.

4.3, 5-(3-oxo-[1,4] oxazocan-4-yl)-N, Ν'-bis(2,3-hydroxypropyl)_2, 4, 6_triiodo-1, 3- Preparation of isophthalamide

5-(2-Chlorobutoxyacetyl)amino-indole, indole,-bis(2,3-hydroxypropyl)-2,4,6-triiodo-1,3-isophthalic acid amide 0.009 The mol was suspended in 20 ml of water, heated to 80 ° C, and 5 ml of 2N sodium hydroxide (0.009 mol) and 0.5 g of calcium hydroxide (0.0065 mol) were added under heat preservation. After the reaction was kept for 30 minutes, the reaction was terminated by TLC (ethyl acetate in TLC). : methanol = 3 : 2, plus formic acid), cooled to room temperature, the reaction was terminated with glacial acetic acid, filtered, and the filtrate was passed through 732 type cation exchange resin and type 717 anion exchange resin, and washed with deionized water to reduce the filtrate. The mixture was distilled to dryness, and anhydrous ethanol was added, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from methanol-isopropanol, and dried in vacuo to yield 2.8 g of white or off-white solid. HPLC Purity 93.6%, column YMC AA12S05-2546WT, 250*4.6mml. D, S-5 m, area normalization method.

Example 5 5-(3-oxomorpholine)-N-(2,3-light propyl)-N,-(2-light ethyl)-2,4,6-triiodo- 1 3- Preparation of isophthalamide

5.1. Preparation of 5-(2-chloroethoxyacetyl)amino-2,4,6-triiodo-1,3-isophthaloyl chloride Prepared according to the procedures of steps 1.1 and 1.2 in the examples.

5.2, 5-(2-Chloroethoxyacetyl)amino-N-(2,3-hydroxypropyl)-Ν'- (2-hydroxyethyl)-2, 4, 6- 1, 3- Preparation of phthalic acid amide

In a three-neck reaction flask, add 5-(2-chloroethoxyacetyl)amino-2,4,6-triiodo-1,3-phthaloyl chloride 0.0230 mol, DMF 30 ml, stir to form a solution, and then add 5 ml of triethylamine.

Cool to below 0 ° C, add 2.0 g (O.Ollmol) of aminoethanol dissolved in DMF (m / m = l : 2 ), maintain 0 ° C and stir for 1 hour, then warm to 5 ~ The reaction was carried out at 10 ° C for 6 to 8 hours, and the reaction was monitored by TLC (developing solvent condition EA: MeOH = 2: l), cooled to below 5 ° C, 3 -amino-1, 2-propanediol was added dropwise in DMF (m/m 3.8 g (0.014 mol) of the solution formed in =l:2). After filtration, 30 ml of water was added to the filtrate, and 150 ml of ethyl acetate was further added and stirred overnight.

After filtration, the filter cake was washed with absolute ethyl alcohol (150 ml), and dried in vacuo to give 8.6 g of white solid.

The TLC layer was analyzed as one point (TLC condition EA: MeOH = 1:2), HPLC purity 94.6%, column YMC

AA12 S05-2546WT, 250*4.6mml. D, S-5 m, area normalization method.

5.3, 5-(3-oxomorpholine)-^^-(2,3-hydroxypropyl)-Ν'-(2-hydroxyethyl)-2,4,6-triiodo-1, 3- Preparation of isophthalamide

7.9 g (O.Olmol) 5-(2-chloroethoxyacetyl)amino-_N_(2,3-hydroxypropyl)-Ν'-(2-hydroxyethyl)-2, 4, 6- Triiodo-1,3-isophthalamide was suspended in 30 ml of water, heated to 80 ° C, 2N sodium hydroxide (O.Omol) and 0.5 g of calcium hydroxide (0.0065 mol) were added under heat preservation, and the reaction was kept for 30 minutes. After that, TLC monitored the reaction (ethyl acetate: methanol = 2:1, plus formic acid), cooled to room temperature, the reaction was terminated with glacial acetic acid, filtered, and the filtrate was passed through 732 cation exchange resin and 717 anion exchange. The resin was washed with deionized water, and the filtrate was evaporated to dryness under reduced pressure. The obtained solid was recrystallized from methanol-isopropanol, and dried (yield: <RTIgt; HPLC purity 97.3%, column YMC AA12S05-2546WT, 250*4.6 mml. D, S- 5μηι, area normalization method. Example 6, 5-(3-oxomorpholine)-indole-(2,3,4-hydroxybutyl)-indole, _(2-hydroxyethyl) _2, 4,6-triiodo-1, Preparation of 3-isophthalamide

6.1. Preparation of 5-(2-chloroethoxyacetyl)amino-2,4,6-triiodo-1,3-isophthaloyl chloride Prepared according to the procedures of Steps 1.1 and 1.2 in Example 1.

6.2, 5-(2-Chloroethoxyacetyl)amino-indole-(2,3,4-hydroxybutyl)-indole, _(2-hydroxyethyl)-2,4,6-triiodo- Preparation of 1, 3-isophthalamide

Prepared according to the procedure of Example 5.2 in Example 5, yield 36%. The TLC layer was analyzed as one point (TLC condition EA: MeOH = 1:2), HPLC purity 94%, column YMC AA12S05-2546WT, 250*4.6 mml. D, 8-5μηι, area normalization.

6.3, 5-(3-oxomorpholine)_1^-(2,3,4-hydroxybutyl)-Ν'-(2-hydroxyethyl)-2, 4,6-triiodo-1, 3 - Preparation of isophthalamide

Prepared according to the procedure of Example 5.3 in Example 5, yield 78%. HPLC purity 97.6%, column YMC AA12S05-2546WT, 250*4.6 mml. D, S-5 m, area normalization method. Example 7, 5-(2-chloroethoxyacetyl)amino-N-(2,3-hydroxypropyl)-N-methyl-N,-(2-hydroxyethyl)-2, 4, Preparation of 6-triiodo-1,3-isophthalamide

7.1. Preparation of 5-(2-chloroethoxyacetyl)amino-2,4,6-triiodo-1,3-isophthaloyl chloride Prepared according to the procedures of Steps 1.1 and 1.2 in Example 1.

7.2, 5-(2-Chloroethoxyacetyl)amino-N-(2,3,4-hydroxybutyl)-N-methyl-N,-(2-hydroxyethyl)-2, 4, Preparation of 6-triiodo-1,3-isophthalamide

Prepared according to the procedure of Step 5.2 in Example 5, yield 32%. The TLC ply was analyzed as one point (TLC condition EA: MeOH = 1:2), HPLC purity 93.6%, column YMC AA12S05-2546 WT, 250*4.6 mml. D, S-5 m, area normalization.

7.3, 5-(3-oxomorpholine)-N-(2,3,4-hydroxybutyl)-N-methyl_N'_(2-hydroxyethyl)-2, 4, 6_ 1, Preparation of 3-isophthalamide

Prepared according to the procedure of Step 5.3 in Example 5, yield 74%. HPLC purity 96.2%, column YMC AA12S05-2546WT, 250*4.6 mml. D, S-5 m, area normalization method. Example 8, 5-(3-oxomorpholine)-N-(2,3-hydroxypropyl)-N-methyl-N,-(2-hydroxyethyl)-2,4,6- Preparation of iodine-1,3-isophthalamide

8.1, 5-(2-Chloroethoxyacetamido)amino-2,4,6-triiodo-1,3_isophthaloyl chloride Preparation According to the procedures of Steps 1.1 and 1.2 in Example 1.

8.2, 5-(2-Chloroethoxyacetyl)amino-N-(2,3-hydroxypropyl)-N-methyl-N,-(2-hydroxyethyl)-2,4 6-three Preparation of iodine-1,3-isophthalamide

Prepared according to the procedure of Step 5.2 in Example 5, yield 53%. The TLC layer was analyzed as one point (TLC condition EA: MeOH = 1:2), HPLC purity 95.5%, column YMC AA12S05-2546WT, 250*4.6 mml. D, 8-5μηι, area normalization.

8.3, 5-(3-oxomorpholine)-N-(2,3-hydroxypropyl)-indole-methyl-oxime,-(2-hydroxyethyl)-2,4,6-triiodo- 1 _: Preparation of 3-isophthalamide

Prepared according to the procedure of Step 5.3 in Example 5, yield 89%. HPLC purity 97.6%, column YMC AA12S05-2546WT, 250*4.6 D, S-5 m, area normalization method. Example 9. Preparation of 5-(3-oxomorpholine) N,-bis(1,3-hydroxypropyl)-2,4,6-triiodo-1,3-isophthalamide

9.1. Preparation of 5-(2-chloroethoxyacetyl)amino-2,4,6-triiodo-1,3-isophthaloyl chloride Prepared according to the procedures of Steps 1.1 and 1.2 in Example 1.

9.2, 5-(2-Chloroethoxyacetyl)amino-N,N,-bis(1,3-hydroxypropyl)-2,4,6-triiodo_1, 3-m-phenylenecarboxamide Preparation

Prepared according to the procedure of Step 3.3 in Example 3, yield 64%. The TLC layer was analyzed as one point (TLC condition EA: MeOH = 1:2), HPLC purity 96.7%, column YMC AA12S05-2546WT, 250*4.6 mml. D, S-5 m, area normalization.

9.3, 5-(3-oxomorpholine)-N-(2,3-hydroxypropyl)-N-methyl-N,-(2-light ethyl)-2,4,6-triiodo- 1 _:

Preparation of 3-isophthalamide

Prepared according to the procedure of Step 3.4 in Example 5, yield 83%. HPLC purity 98.4%, column YMC AA12S05-2546WT, 250*4.6mml. D, S-5um, area normalization method. Example 10, 5-(3-oxomorpholine)-N, Ν'-bis(1,3,4-hydroxybutyl)_2,4,6-triiodo-1,3-isophthalamide Preparation

10.1. Preparation of 5-(2-chloroethoxyacetyl)amino-2,4,6-triiodo-1,3-isophthaloyl chloride The procedure was followed according to the procedures of Steps 1.1 and 1.2 in Example 1.

10.2, 5-(2-chloroethoxyacetyl)amino-1, ^-bis(1,3,4-hydroxybutyl)-2,4,6-triiodo-1,3-isophthalene Preparation of amide

Prepared according to the procedure of Step 3.3 in Example 3, yield 36%. The TLC layer was analyzed as one point (TLC condition EA: MeOH = 1:2), HPLC purity 95.6%, column YMC AA12S05-2546WT, 250*4.6 mml. D, S-5 m, area normalization method.

10.3, 5-(3-oxomorpholine)-indole, indole,-bis(1,3,4-hydroxybutyl)-2,4,6-triiodo-1,3-isophthalamide Preparation

Prepared according to the procedure of Example 3.4 in Example 5, yield 43%. HPLC purity 97.2%, column YMC AA12S05-2546WT, 250*4.6mml. D, S-5 m, area normalization method. Example 11, 5-(3-oxomorpholine)-N,N,-bis(2,3-hydroxypropyl)-N,N'-bismethyl-2,4,6-triiodo-1, Preparation of 3-isophthalamide

11.1 Preparation of 5-(2-chloroethoxyacetyl)amino-2,4,6-triiodo-1,3_isophthaloyl chloride The procedure was followed according to the procedures of Steps 1.1 and 1.2 in Example 1.

11.2, 5-(2-chloroethoxyacetyl)amino-indole, Ν'-bis(2,3-hydroxypropyl) Ν, Ν'-bismethyl-2, 4, 6_ triiodo-1, Preparation of 3-isophthalamide

Prepared according to the procedure of Step 3.3 in Example 3, yield 86%. The TLC layer was analyzed as one point (TLC condition EA: MeOH = 1:2), HPLC purity 97.8%, column YMC AA12S05-2546WT, 250*4.6 mml. D, S-5 m, area normalization.

11.3, 5-(3-oxomorpholine) - anthracene, Ν'-bis[2,3-hydroxypropyl)-indole, hydrazine,-bismethyl-2,4,6-triiodo-1

Preparation of 3-isophthalamide

Prepared according to the procedure of Example 3.4 in Example 5, yield 87%. HPLC purity 97.9%, column YMC AA12S05-2546WT, 250*4.6mml. D, S-5 m, area normalization method. Second, the application example Embodiment 12, stability test

The compounds obtained in the above Examples 1 to 11 were each dissolved in a 10 mM sodium hydroxide solution to obtain an aqueous solution having a pH of 12, and the resulting solution was sealed with a sealed tube, heated at 85 ° C or 100 ° C for a while, and cooled to sample HPLC. analysis. Figure 1 shows an HPLC analysis of one of the samples, where: A is the HPLC spectrum of the sample before treatment, B is the spectrum after treatment, and the spectrum of the ruthenium sample is substantially the same as that of Figure 1.

As is apparent from the results of Fig. 1, the polyiodobenzene ring compound of the present invention has little decomposition of the product under alkaline and heating conditions, and shows good stability. Example 13 for CT contrast detection

13.1 Preparation of injection

The compounds obtained in the above Examples 1 to 11 were respectively added to 500 ml of pyrogen-free water for injection containing 10 mmol of tris(trimethylol)carbamidine and 100 mg of Na ₂ Ca EDTA in a molar ratio of about 1:1. Dissolve in hot temperature, cool, adjust pH to 6.8 with 1N hydrochloric acid, and dilute with pyrogen-free water until 1000 ml, the solution was placed in a glass bottle of a 250 ml container in an aliquot of 200 ml, sealed with a rubber stopper, and heat-sterilized at 121 ° C for 20 minutes to prepare an injection.

13.2 CT imaging detection

Test animals: Beagle dogs, purchased from the Experimental Animal Center of Shanghai Second Military Medical University.

Take the injection prepared in the above step 13.1, and use pure water as a control, inject into the small intestine of the Beagle dog, and then perform CT imaging as follows - Beagle takes the supine position, applying Siemens SOMATOM Sensation 16 spiral CT examination, scanning, application of CARE DOSE 4D intelligent dose software, scanning range from dome to pelvic cavity, CT scan after plain scan.

The parameters are: 120kV, 150 mAs, layer thickness, layer spacing is 2 mm, bulb rotation time is 0.5 s, pitch is 1.0, weekly bed is 12 mm, Kernel coefficient B3 If smooth, FOV 220-300 mm.

Figure 2 shows CT images of the control and injection of the polyiodobenzene compound obtained in Example 1, wherein A and B are photographs of pure horizontal sweep and enhanced scan, respectively, and C and D are plain scans of the sample of Example 1, respectively. And the enhanced scanned photograph, the photographs of the remaining samples were substantially the same as those of the sample of Example 1.

As can be seen from the results of FIG. 2, when the injection solution of the polyiodophenylene compound of the present invention is used for gastrointestinal angiography, the image obtained is significantly clearer and easier to distinguish than the case without the contrast agent, so that it can be used as Contrast agent is used.

Claims

Claim

A polyiodobenzene ring compound, characterized in that the compound has a structure represented by the formula (I):

(I)

^ towel:

n is any integer from 1 to 4;

R2 and R4 are selected from the group consisting of: —H and — R1 and R3 are selected from:

.

2. A compound according to claim 1 wherein the groups R1 and R3 are the same.

3. A compound according to claim 1, characterized in that the groups R1 and R3 are different.

4. A compound according to claim 1 wherein the groups R2 and R4 are the same.

5. A compound according to claim 1 wherein the groups R2 and R4 are different.

A method of producing a polyiodophenylene compound according to claim 1, which comprises the steps of _:

1) 5-amino-2,4,6-triiodo-1,3-isophthalic acid II is used as a raw material to obtain 5-amino-2, 4 in the presence of an acid chloride reagent such as thionyl chloride. 6-triiodo-1,3-isophthaloyl chloride III;

2) 5-Amino-2,4,6-triiodo-1,3-isophthaloyl chloride III reacts with the corresponding side chain acid chloride at low temperature to form an amide, or with the corresponding side chain carboxylic acid in the chloride Reaction in the presence of a sulfone to form an amide;

3) 5-amino-2,4,6-triiodo-1,3-isophthaloyl chloride III is aminated at a low temperature and reacted with the corresponding amino alcohol to obtain the corresponding compound V;

4) Compound V undergoes further amination reaction with the corresponding amino alcohol under alkaline low temperature conditions to obtain compound VI; 5) Compound VI undergoes its own condensed ring reaction under basic conditions to obtain compound I.

7. The method according to claim 6, wherein the alkaline environment in the step 5) is formed using sodium hydroxide, potassium hydroxide, an alkaline earth metal or a mixture thereof.

8. The method of claim 7, wherein the alkaline earth metal is calcium hydroxide.

9. Use of a compound according to claim 1 as a nonionic contrast agent.