JPH05208921A - Iodobenzene derivative and x-ray contrast medium composition containing the same - Google Patents

Abstract

PURPOSE:To provide a new highly safe nonionic iodobenzene derivative batisfying physicochemical properties such as contrast medium ability, water solubility, viscosity and stability required for X-ray contrast media, low in the immunostimulative adverse effect, and reduced in by-effects. CONSTITUTION:An iodobenzene derivative of formula I (R1-R4 are nonionic hydrophilic group; further R<2> is H, lower alkyl), e.g. 5-bis[(2,3-dihydroxypropyl) oxy]-2,4,6-triiodobenzoic acid-(2,3,-dihydroxypropylamide). The compound can be produced from easily available resorcylic acid through three processes comprising the introduction of the amide type side chain of the carboxyl group, the introduction of the ether side chains to the two phenolic hydroxyl groups and an iodization process. The three processes may be performed in any order, but preferably carried out in the above-mentioned order.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel nonionic iodobenzene derivative used as an X-ray contrast agent and a contrast agent composition containing the compound.

[0002]

2. Description of the Related Art An X-ray contrast examination is a useful means for clarifying morphological changes in diseases such as blood vessels and organs and making an accurate diagnosis, and is widely used. Among X-ray contrast examinations, a contrast agent is indispensable for imaging body cavities such as blood vessels, urinary tract, ventricles, bronchi, spinal cord, biliary tract, and digestive tract. Since these organs are negative for X-ray contrast, a compound having an X-ray blocking effect is administered as a contrast agent for the purpose of providing contrast to an image. Iodobenzene derivatives are suitable for achieving this purpose, and many compounds have been developed so far and are already frequently used.

Conditions required for an X-ray contrast medium include high contrast ability, low chemical toxicity, high water solubility, low osmotic pressure, low side effects, low viscosity, high stability, low cost and the like. Among these, in the case of an iodobenzene derivative type contrast agent, the number of iodine in one molecule is reflected in the contrast ability. It is clear that the higher the iodine number, the better the contrasting ability,
On the other hand, increasing the number of iodine causes unfavorable improvement in hydrophobicity and increase in chemical toxicity. Therefore, compounds having 3 iodine atoms per benzene ring are most often used at present.

Finally, there is provided a compound which has physical and chemical properties which can be used as a contrast agent and which can be formulated in an aqueous solution so as to contain 250 mg or more iodine atom in terms of weight composition per ml. desirable.

Regarding chemical toxicity, a higher degree of safety is required as compared with many compounds normally used in medicine. The reason is that the dose of the X-ray contrast agent is much larger than that of the therapeutic drug. For example,
In coronary angiography, 20 to 60 ml of a contrast agent having a concentration of 300 mg / ml in terms of iodine is administered at one time. LD ₅₀ in intravenous injection in animals for evaluation of chemotoxicity
The value serves as a guide. LD ₅₀ value for intravenous injection in rat is 2.0 g / Kg or more, preferably 10.0 g / K in terms of iodine.
g or more is desired.

With respect to the problems of water solubility and osmotic pressure, great progress has been made in recent years due to the development of nonionic contrast agents. Nonionic contrast agents have greatly contributed to the reduction of side effects, which have been problems with conventional ionic contrast agents. High water solubility is one of the physical properties required for contrast media used for blood vessels, urinary tract, and myelography. In the case of an iodobenzene derivative, it is necessary to introduce a highly polar group in order to ensure this water solubility.

In ionic contrast agents, ionic functional groups such as amino groups and carboxyl groups have been introduced as highly polar groups and have been used in the form of some kind of salt. However, since the ionic functional group dissociates into ions in a solution, it exhibits a very high osmotic pressure, which has been a major cause of various side effects. In order to solve this, a compound using a nonionic functional group that does not dissociate, such as a hydroxy group, has been developed in recent years, and the incidence of side effects has been greatly reduced. It is said that the introduction of the nonionic highly polar group contributes not only to lowering the osmotic pressure but also to reducing toxicity such as neurotoxicity.

The side effects of the X-ray contrast medium are mild ones such as nausea, prurigo and heat sensation which occur within a relatively short period after administration, and serious ones leading to death such as circulatory disturbance, pulmonary edema and cardiac arrest. Even things have been reported. Although the incidence of side effects has been reduced by the development of nonionic contrast agents, it has not been completely resolved.

There are many studies on the mechanism of side effects, but many have not been clarified yet. Lasser et al. Have classified the side effect factors into two types: those caused by the chemical toxicity of the contrast agent itself and those caused by the systemic reaction induced by the contrast agent (Lasser EC et al.). , Invest Radiol, 1
5 , S2-S5 (1980)).

The former can be predicted to some extent by the above-mentioned measurement of chemical toxicity. However, it is difficult to predict the latter because the mechanism of occurrence is complicated. At present, it is considered that a method for capturing the behavior of biological substances involved in allergic reaction is useful as an index.

Regarding the viscosity, since the injection is usually carried out by using a syringe, the high viscosity causes a heavy burden on the administrator. That is, it is preferable that the viscosity is as low as possible at the use concentration, and 6.5 cp or less at 37 ° C. at the concentration of 300 mgI / ml.

Regarding the stability, it is required that it should not undergo a chemical change when stored at room temperature and that it should be stable enough to withstand autoclave sterilization. The conditions necessary for sufficient sterilization as an injection are usually 120 ° C. for 20 minutes, and at least stability under these conditions is required.

As the nonionic X-ray contrast agents of iodobenzene derivatives, many compounds are already known as shown below. Patent publication No. 23404, 1981, 3,5-
Disubstituted-2,4,6-triiodoaniline derivatives are disclosed. Japanese Patent Publication No. 27264, 1983, discloses 2,4,6-triiodoisophthalic acid derivatives. Further, Patent Publication No. 91161 of 1986 discloses a triiodotriaminobenzene derivative.
Further, Japanese Patent Publication No. 23108, 1985 discloses a dimer type nonionic contrast agent. By using a dimer, the iodine content per molecule can be increased.

Although these compounds almost satisfy the conditions required for the above-mentioned contrast agent, there are still some problems that cannot be solved. One of them is the problem of the above-mentioned side effects. Although the incidence of side effects is lower than that of ionic contrast agents, cases of side effects have been reported for nonionic contrast agents, and further safer contrast agents are desired.

[0015]

DISCLOSURE OF THE INVENTION An object of the present invention is a nonionic X which has high physicochemical properties such as contrast ability, water solubility, viscosity and stability, and has few side effects and high safety. It is to provide a line contrast agent.

[0016]

The above object is achieved by the iodobenzene derivative represented by Chemical formula 2 according to the present invention.

[Chemical 2] (In the formula, R ₁ represents a nonionic hydrophilic group, R ₂ represents a hydrogen atom, a lower alkyl group or a nonionic hydrophilic group, and R
₃ and R ₄ may be the same or different and represent a nonionic hydrophilic group. ).

In the iodobenzene derivative represented by Chemical Formula 2 according to the present invention, the nonionic hydrophilic group is a hydroxyalkyl group having 2 to 5 hydroxy groups and having 2 to 6 carbon atoms. Preferably.

Further, the above object is achieved by an X-ray contrast agent composition containing the iodobenzene derivative shown in Chemical formula 2 above.

The lower alkyl group in the iodobenzene derivative of the present invention may have either a straight-chain structure or a branched structure, but is preferably one having 1 to 6 carbon atoms. Examples include methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl,
It is possible to use tertiary butyl or the like.

The nonionic hydrophilic group is a substituent having a high polarity and does not ionize in an aqueous solution, and a hydroxyalkyl group, a cyanoalkyl group, a polyether group, or a sugar residue is used. Is also possible.
Further, the group may contain an ether bond, an ester bond, an amide bond or the like. An example of this is a case where two or more nonionic hydrophilic groups are in a state of being polymerized through these bonds.

The hydroxyalkyl group refers to an alkyl group having a linear or branched structure substituted with several hydroxy groups, preferably having 2 to 5 carbon atoms and having 2 to 6 hydroxy groups. Is good. Examples of hydroxyalkyl groups that can be used are 2-hydroxyethyl, 2,3-dihydroxypropyl, 1,3-dihydroxyisopropyl, 1,3-dihydroxy-2-methylisopropyl, 2,3,4-trihydroxy-n. -Butyl, tris (hydroxymethyl) methyl and the like, but other than those mentioned here may be used.

In producing the iodobenzene derivative of the present invention, resorcinic acid, which is easily available, is used as a raw material, and an amide type side chain is introduced into the carboxyl group.
This can be achieved through three steps of introducing an ether side chain into one phenolic hydroxyl group and iodination. The target compound can be obtained by performing the three steps in any order, but it is most preferable to perform the steps in the order described.

The amide type side chain can be introduced into the carboxyl group of resorcinic acid according to a number of known methods.
For example, it can be achieved by an acid halide method, an amidation method after esterification, a mixed acid anhydride method, a method using a condensing agent, or the like. In the case of the acid halogenation method, it can be carried out, for example, by reacting resorcinic acid with thionyl chloride to form an acid chloride, and then reacting with an amine having a corresponding hydrophilic side chain.

In this case, a suitable solvent such as dimethylformamide, dimethylacetamide, tetrahydrofuran or dimethylsulfoxide may be used. Further, in the method of undergoing esterification, a carboxylic acid ester is first formed by a dehydration reaction with an alcohol in the presence of an acid, and then reacted with a corresponding amine to obtain an amide compound.

In any case, when a functional group other than the amino group present in the amine having a hydrophilic side chain to be introduced may participate in the reaction, it is necessary to protect it in advance before use.

The reaction for introducing an ether type side chain into a phenolic hydroxyl group can be obtained by reacting a hydrophilic compound having a leaving group with a base in the presence of a suitable solvent. The leaving group is preferably an alkylsulfonyl group, a halogen group or the like. Specific examples of the hydrophilic compound having a leaving group include 1-tosyloxy-2,3-dihydroxypropane, 2-tosyloxy-1,3-dihydroxypropane, 1-tosyloxy-2,3,4-trihydroxy-.
n-butane, 1-bromo-2,3-dihydroxypropane, 2-bromo-1,3-dihydroxypropane, 1-
Bromo-2,3,4-trihydroxy-n-butane and the like are mentioned, and an appropriate protected form thereof may be used.

Examples of the base that can be used in this reaction include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium-t-butoxide and the like. As the solvent, alcohol, dioxane, dimethylformamide, dimethylacetamide,
Tetrahydrofuran, ether, dimethyl sulfoxide and the like can be mentioned.

The iodination reaction can also be performed by a known method. For example, reacting with iodine chloride in the presence of dilute acid, or NaIC
l ₂ or with iodine in the presence of hydrogen peroxide,
Alternatively, it can be obtained under the condition of reacting with iodine in the presence of a base such as morpholine or triethylamine. As the reaction solvent, water, alcohol, dioxane, acetone or the like is used.

Purification of the final product obtained is treated with activated carbon,
It is carried out by a conventional method in synthetic chemistry such as desalting by ion exchange, column chromatography, or recrystallization.

Further, in the present invention, in order to use the iodobenzene derivative represented by Chemical formula 2 as an X-ray contrast agent composition, an aqueous solution containing additives such as buffers and stabilizers which are used in usual injectable preparations is added. And As the buffer, trishydroxyaminomethane, phosphate, borate, etc. are used, and as the stabilizer, ethylenediamine tetraacetate, etc. are used. The obtained aqueous solution is filtered, sealed in an ampoule, a vial, or the like, sterilized by autoclaving, and used for imaging.

The amount of free histamine and the value of complement activity were used as indexes for predicting the occurrence of side effects of the contrast agent composition according to the present invention.

Regarding the relationship between the occurrence of side effects and the release of histamine by the administration of a contrast medium, the following examples have been reported.
Peter and the like are methylglucamine iodipamate (methyl glu) as an iodine contrast agent.
It was reported that the administration of canine iodipamate doubled the free histamine level compared to the case where no side effect was observed (Peter G. A. et al., Journal of. Allergies (The Journal o
f Allergy) 38, 74-83 (196)
6)).

Siegel et al. Reported that the histamine level in leukocytes of a patient whose side effect was caused by an iodine contrast agent was measured and found to be 1.5 to 2 times that of a normal person (Siegel et al. Siegel RL
et al. ), Investigative Radiology
y) 11, 98-101 (1975)).

Furthermore, Rockat et al. Directly demonstrated histamine release by administration of a contrast agent using cultured mast cells (Rockatt S. et al.
D. et al. ), Investigative Radiologi
gy) 7,177 (1972)). In addition to this, many experimental examples demonstrating that histamine release is involved in the occurrence of side effects have been reported.

Further, there are the following reports on side effects and involvement of the complement system. Arroyave et al. Reported data that administration of a contrast agent reduced the 50% hemolysis value (CH50) which is an index value of complement activity (Arroyave et al. (Arroyave CM et al.
l. ), Journal of Allergy Clinic Immunology (J. Allegy. Clin. Immun
ol. 63, 276-280 (1979)).

Also, Till et al. Reported that a significant decrease in CH50 was observed in the side effect-occurring cases (Till GR et al.
l. ), International Archives of Allergy and Applied Immunology (Int.
Arch. Allergy Appl. Immuno
l. ), 56, 543-550 (1978)).

Further, Kolb et al. Have reported that a contrast agent causes structural change of complement protein to cause activation (Kolb WP, Journal of Immunology (J. Immunol. )
121, 1232-1238 (1978)).

As described above, chemical mediators such as histamine, factors involved in the complement system and kinin system, and c-A.
Many cases have been reported that demonstrate the relationship between the behavior of intracellular transfer factors such as MP and the occurrence of side effects, and a study comparing these measured values for ionic contrast agents and nonionic contrast agents. Therefore, it has been reported that the ionic contrast agent, which is more likely to cause side effects, has a higher immunological stimulating ability, and the probability of occurrence of side effects and these index values have a certain degree of correlation. At present, as an index for predicting side effects induced by a contrast agent, it is considered that a method of capturing the behavior of a biological substance involved in an allergic reaction is useful, and thus the amount of free histamine and the complement activity value were used.

The present invention will be described in more detail with reference to the following examples.

[0040]

【Example】

(Example 1) 3,5-bis [(2,3-dihydroxypropyl) oxy
Si] -2,4,6-triiodobenzoic acid- (2,3-di
Hydroxypropylamide) <Compound-1> synthesis .

[0041]

[Table 1]

[0042]

[Chemical 3]

3,5-bis [(2,3-dihydroxypropyl) oxy] -2 shown in Chemical formula 3 by the route shown in Table 1
4,6-Triiodobenzoic acid- (2,3-dihydroxypropylamide) synthesis was performed. The details are as follows.

The synthetic methods and spectral data of the individual compounds of the following Examples are shown below. The equipment and measurement conditions used to confirm the structure are as follows.

Nuclear Magnetic Resonance Analysis (NMR) Device: EX-90 (90 MHz) manufactured by JEOL Measurement solvent: CDCl ₃ (when not mentioned) Infrared spectroscopic analysis (IR) Device: IR-8 manufactured by JASCO
Type 10 Measurement method: Chloroform solution or KBr tablet method Mass spectrometry (MS) Device: J-30 made by JEOL
Type 0 ionization method: FAB (glycerin matrix)

Synthesis of methyl resorcinate α-resorcinic acid (manufactured by Nacalai Tesque) 5.0 kg
(32.4 mol) was dissolved in 8.0 L of methanol, 0.5 L of methanol hydrochloric acid was added, and the mixture was heated under reflux for 15 hours.
After confirming by TLC that the raw material was not observed, the reaction was stopped. The reaction was reduced to dryness on a rotary evaporator. The obtained solid was ground with a mill and dried in a vacuum desiccator.

Yield 5.3 kg (Yield 97.3%) ¹ H-NMR (δppm): 3.8 (d, CH ₃ ), 7.
1-7.9 (q, Arom.) IR (νcm ^-1 ): 3300 (OH), 1750
(C = O).

Resorcinic acid- (2,3-dihydroxy
Cypropylamide) synthesis 500 g (2.97 mol) of methyl resorcinate and 3-
Amino-1,2-propanediol (manufactured by Tokyo Chemical Industry Co., Ltd.) 6
23 g (6.84 mol) was mixed well in a mortar, placed in a flask equipped with an air cooler, and stirred and reacted on an oil bath at 80 ° C. The suspended particles dissolved as the reaction proceeded.

After 24 hours, 300 mL of water was added to dissolve the contents, and excess amine was removed through a column filled with a cation exchange resin. The eluate was evaporated to dryness with a rotary evaporator and further dried in a vacuum desiccator for 5 days or longer to obtain resorcinic acid- (2,3-dihydroxypropylamide).

Yield 642 g (yield 95.1%) ¹ H-NMR (δ ppm, DMSO-d ₆ ): 3.5-
3.8 (m, CH ₂ X2, CH), 6.5 (s, H, A
rom. ), 6.7 (s, 2H, Arom.) IR (νcm ⁻¹ ): 3300 (OH), 1670
(C = O).

3,5-bis (2,2-dimethyl-
1,3-dioxolane-4-methoxy) benzoic acid-
Synthesis of (2,3-dihydroxypropylamide) A 4-necked flask was equipped with a stir bar, a dropping funnel, an air cooler equipped with a nitrogen bubbler, and a silicone rubber septum, and resorcinic acid- (2,3-dihydroxypropylamide) 500 g (2 .20 mol) and potassium carbonate 69
1 g (5.0 mol) was taken. After substituting the inside with dry nitrogen, dry dimethylformamide 1.0 from the septum.
L was added. After stirring and reacting on an oil bath at 80 ° C for 30 minutes, while stirring at 80 ° C, 1,2-
A solution of 1.6 kg (5.1 mol) of dihydroxy-3-tosyloxypropane acetonide in 2.0 L of anhydrous dimethylformamide was added dropwise over 10 hours.

Further, stirring was continued at 80 ° C. for 24 hours. Attach the distillation head to the flask and concentrate the contents to 1/5.
1.5 L of water was added and the mixture was extracted 4 times with 2.0 L of ethyl acetate.
The combined extracts were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. This was concentrated and purified on a silica gel column using ethanol 1 / ethyl acetate 9 as an elution solvent.

Yield 723 g (72.2%) ¹ H-NMR (δ ppm): 1.4 (d, acetni)
de), 3.4-4.5 (m, CH ₂ X6, CHX
3), 6.5 (s, H, Arom.), 6.9 (s, 2)
H, Arom. ) IR (νcm ⁻¹ ): 3350 (OH), 1650
(C = O), 1230 (-O-).

3,5-bis [(2,3-dihydroxy
Cypropyl) oxy] -2,4,6-triiodobenzoic acid
Synthesis of acid- (2,3-dihydroxypropylamide) In a flask equipped with an air cooler, 3,5-bis (2,2-dimethyl-1,3-dioxolane-4-methoxy) benzoic acid- (2,3 -Dihydroxypropylamide) (100 g, 0.22 mol) was taken, and 300 mL of 0.3N hydrochloric acid was added to suspend. When stirring reaction is performed on an oil bath at 70 ° C. for 1 hour, the solution becomes uniform due to hydrolysis of acetonide. Iodine chloride 123 on the air cooler
A dropping funnel with a side tube containing g (0.73 mol) was attached, and the mixture was added dropwise to it several times over about 5 hours while continuing heating and stirring at 70 ° C. The reaction was continued for 10 hours as it was.

After allowing the flask to cool, the content was filtered to remove free elemental iodine. The filtrate was evaporated to dryness on a rotary evaporator to remove hydrochloric acid and residual iodine. 100 mL of water was added to the evaporation residue, desalted through a column of cation exchange resin and then a column of anion exchange resin, and the eluate was evaporated to dryness.

The obtained oily substance was taken in a small amount of ethanol, dispersed in an ethanol / methylene chloride solution, and the precipitated powder was separated by filtration and dried in a vacuum desiccator to obtain 3,5-bis [(2 , 3-Dihydroxypropyl) oxy] -2,4,6-triiodobenzoic acid- (2,3-dihydroxypropylamide) was obtained.

Yield 117 g (Yield 71.2%) Molecular formula: C ₁₆ H ₂₂ N ₁ O ₉ I ₃ ¹ H-NMR (δ ppm, D ₂ O): 3.5-4.2
(M, CH ₂ X6, CHX3) IR (νcm ⁻¹ ): 3350 (OH), 1640
(C = O) FAB-MS (M / Z): 754 (MH ^<+> ).

The physicochemical properties of this compound such as water solubility, solution viscosity and stability were suitable as an X-ray contrast agent.

(Example 2) 3,5-bis [(2,3-dihydroxypropyl) oxy
Si] -2,4,6-triiodobenzoic acid- (1,3-di
Used instead of Example 3-amino-1,2-propanediol in 1 hydroxy isopropylamide) 2-amino-1,3-dihydroxypropane 623g (6.84mol), in the same manner as in Example 1 3,5-bis [(2,3-dihydroxypropyl) oxy] -2, whose structure is shown in Chemical formula 4,
4,6-Triiodobenzoic acid- (1,3-dihydroxyisopropylamide) was obtained.

[0060]

[Chemical 4]

Yield 12.00 g (yield 49.2%) when 5.0 kg of resorcinic acid was used as a starting material Molecular formula: C ₁₆ H ₂₂ N ₁ O ₉ I ₃ ¹ H-NMR (δ ppm, D ₂ O ): 3.4-4.1
(M, CH ₂ X6, CHX3) IR (νcm ⁻¹ ): 3350 (OH), 1645
(C = O) FAB-MS (M / Z): 754 (MH ^<+> ).

(Example 3) 3,5-bis [(2,3-dihydroxypropyl) oxy
Si] -2,4,6-triiodobenzoic acid- [Tris
Synthesis of (hydroxymethyl) methylamide] In Example 1, tris (hydroxymethyl) aminemethane (manufactured by Sigma) 829 g (6.84 mol) was used in place of 3-amino-1,2-propanediol,
By the same method as in Example 1, 3,5-bis [(2,3-dihydroxypropyl) oxy] -2,4,6-triiodobenzoic acid- [tris (hydroxymethyl) methylamide whose structure is shown in Chemical formula 5 was used. ] Was obtained.

[0063]

[Chemical 5]

Yield 10.67 kg (5.0% yield) when 5.0 kg of resorcinic acid was used as starting material Molecular formula: C ₁₇ H ₂₄ N ₁ O ₁₀ I ₃ ¹ H-NMR (δ ppm, D ₂ O ): 3.5-4.6
(M, CH ₂ X7, CHX2) IR (νcm ⁻¹ ): 3370 (OH), 1660
(C = O) FAB-MS (M / Z): 784 (MH ^<+> ).

(Example 4) 3,5-bis [(2,3-dihydroxypropyl) oxy
Si] -2,4,6-triiodobenzoic acid- (2,3,4
- using 2,3,4-trihydroxy -n- butylamine 829g (6.84mol) in place of 3-amino-1,2-propanediol in Synthesis Example 1 of trihydroxy -n- butylamido) Example 1
In the same manner as described above, 3,5-bis [(2,3-dihydroxypropyl) oxy] -2, whose structure is shown in Chemical formula 6,
4,6-Triiodobenzoic acid- (2,3,4-trihydroxy-n-butyramide) was obtained.

[0066]

[Chemical 6]

Yield 10.99 g (yield 43.3%) when 5.0 kg of resorcinic acid was used as starting material Molecular formula: C ₁₇ H ₂₄ N ₁ O ₁₀ I ₃ ¹ H-NMR (δ ppm, D ₂ O ): 3.4-4.4
(M, CH ₂ X6, CHX4) IR (νcm ⁻¹ ): 3350 (OH), 1660
(C = O) FAB-MS (M / Z): 784 (MH ^<+> ).

Example 5 3,5-bis [(1,3-dihydroxyisopropyl)
Oxy] -2,4,6-triiodobenzoic acid- [2-
Synthesis of (2,3-dihydroxypropyl) amide] In Example 1, 1,3-dihydroxy-2-tosyloxypropane acetonide was replaced with 1,3-dihydroxy-2-tosyloxypropane acetonide 1.46k.
Using g (5.1 mol), 3,5-bis [(1,3-dihydroxyisopropyl) oxy] -2,4,6-triiodobenzoic acid whose structure is shown in Chemical formula 7 is prepared in the same manner as in Example 1. Acid- [2- (2,3-dihydroxypropyl) amide] was obtained.

[0069]

[Chemical 7]

Yield 9.97 g (yield 40.8%) when 5.0 kg of resorcinic acid was used as a starting material Molecular formula: C ₁₆ H ₂₂ N ₁ O ₉ I ₃ ¹ H-NMR (δ ppm, D ₂ O ): 3.5-4.2
(M, CH ₂ X6, CHX3) IR (νcm ⁻¹ ): 3350 (OH), 1650
(C = O) FAB-MS (M / Z): 754 (MH ^<+> ).

(Example 6) 3,5-bis [tris (hydroxymethyl) methoxy]
-2,4,6-triiodobenzoic acid- (2,3-dihydride
B carboxymethyl Instead tris (hydroxymethyl Synthesis Example 1 1,2-dihydroxy-3-tosyloxy-propane acetonide propyl amide)) tosyloxy propane acetonide 1.61g
(5.1 mol) and in the same manner as in Example 1, 3,5-bis [tris (hydroxymethyl) methoxy] -2,4,6-triiodobenzoic acid- (2 , 3-dihydroxypropylamide) was obtained.

[0072]

[Chemical 8]

Yield when 5.0 kg of resorcinic acid was used as a starting material 9.11 kg (yield 34.6%) Molecular formula: C ₁₈ H ₂₆ N ₁ O ₁₁ I ₃ ¹ H-NMR (δ ppm, D ₂ O ): 3.3-4.6
(M, CH ₂ X8, CHX1) IR (νcm ⁻¹ ): 3350 (OH), 1655
(C = O) FAB-MS (M / Z): 814 (MH ^<+> ).

Example 7 3,5-bis [(2,3,4-trihydroxy-n-bu]
Cyl) oxy] -2,4,6-triiodobenzoic acid-
Synthesis of (2,3-dihydroxypropylamide) 1.41 kg of 1,2,3-trihydroxy-4-tosyloxy-n-butaneacetonide instead of 1,2-dihydroxy-3-tosyloxypropane acetonide in Example 1. Using (5.1 mol) and in the same manner as in Example 1, 3,5-bis [(2,3,4-trihydroxy-n-butyl) oxy] -2,4 whose structure is shown in Chemical formula 9 , 6-Triiodobenzoic acid- (2,3-dihydroxypropylamide) was obtained.

[0075]

[Chemical 9]

Yield 9.83 g (yield 37.3%) when 5.0 kg of resorcinic acid was used as a starting material Molecular formula: C ₁₈ H ₂₆ N ₁ O ₁₁ I ₃ ¹ H-NMR (δ ppm, D ₂ O ): 3.3-4.3
(M, CH ₂ X6, CHX5) IR (νcm ^-1 ): 3350 (OH), 1655
(C = O) FAB-MS (M / Z): 814 (MH ^<+> ).

(Example 8) 3,5-bis [(2,3-dihydroxypropyl) oxy
Ci] -2,4,6-triiodobenzoic acid- [bis (2,2
3-dihydroxyisopropyl) amide] In Example 1, bis (2,3-dihydroxypropyl) was used instead of 3-amino-1,2-propanediol.
3,5-bis [(2,3-dihydroxypropyl) oxy] -2, the structure of which is shown in Chemical formula 10, was carried out in the same manner as in Example 1 using 991 g (6.0 mol) of amine.
4,6-Triiodobenzoic acid- [bis (2,3-dihydroxyisopropyl) amide] was obtained.

[0078]

[Chemical 10]

Yield 8.50 kg (starting amount 31.7%) when 5.0 kg of resorcinic acid was used as starting material Molecular formula: C ₁₉ H ₂₈ N ₁ O ₁₁ I ₃ ¹ H-NMR (δ ppm, D ₂ O ): 3.4-4.8
(M, CH ₂ X8, CHX4) IR (νcm ⁻¹ ): 3350 (OH), 1655
(C = O) FAB-MS (M / Z): 828 (MH ^<+> ).

Example 9 3,5-bis [(2,3-dihydroxypropyl) oxy
Si] -2,4,6-triiodobenzoic acid-[(2,3-
Synthesis of dihydroxyisopropyl) methylamide] In Example 1, 631 g (6.0 mol) of N-methyl-2,3-dihydroxypropylamine was used instead of 3-amino-1,2-propanediol.
By the method similar to,
Bis [(2,3-dihydroxypropyl) oxy]-
2,4,6-triiodobenzoic acid-[(2,3-dihydroxyisopropyl) methylamide] was obtained.

[0081]

[Chemical 11]

Yield 8.85 g (yield 35.5%) when 5.0 kg of resorcinic acid was used as a starting material Molecular formula: C ₁₇ H ₂₄ N ₁ O ₉ I ₃ ¹ H-NMR (δ ppm, D ₂ O ): 2.2 (s, C
_{H 3), 3.5-4.3 (m,} CH 2 X6, CHX3) IR (νcm - 1): 3350 (OH), 1690
(C = O) FAB-MS (M / Z): 768 (MH ^<+> ).

(Example 10) 3- (2,3-dihydroxypropyl) oxy-5-
(2,3,4-trihydroxy-n-butyl) oxy-
2,4,6-triiodobenzoic acid- (2,3-dihydro
Synthesis of xyisopropylamide ) In Example 1, 716 g of 1,2-dihydroxy-3-tosyloxypropane acetonide was replaced by 1,2-dihydroxy-3-tosyl oxypropane acetonide.
(2.5 mol) and 1,2,3-trihydroxy-4-
691 g (2.5 m) of tosyloxy-n-butane asenide
2) and the same procedure as in Example 1 is carried out except that the 3- (2,3-dihydroxypropyl) oxy- 5- (2,3,4-trihydroxy-n-butyl) oxy-2,4,6-triiodobenzoic acid- (2
3-dihydroxyisopropylamide) was obtained.

[0084]

[Chemical 12]

Yield 6.09 g (yield 24.0%) when 5.0 kg of resorcinic acid was used as a starting material Molecular formula: C ₁₇ H ₂₄ N ₁ O ₁₀ I ₃ ¹ H-NMR (δ ppm, D ₂ O ): 3.5-4.5
(M, CH ₂ X6, CHX4) IR (νcm ⁻¹ ): 3350 (OH), 1660
(C = O) FAB-MS (M / Z): 784 (MH ^<+> ).

Chemical formula 3 synthesized by these Examples 1 to 10
The physicochemical properties such as water solubility, solution state viscosity, and stability of the compounds shown in to 12 were suitable as an X-ray contrast agent. Other compounds according to the present invention, which are not shown in the examples, also showed similar physicochemical properties.

(Example 11) Compounds shown in Chemical formulas 3 to 12 synthesized according to Examples 1 to 10
Evaluation of effect of histamine release on histamine release The evaluation of the effect of the compounds shown in Chemical formulas 3 to 12 synthesized according to Examples 1 to 10 on histamine release was carried out.
The measurement was performed using the method reported by Royave et al. (Arroyave et al.
M. ), Investigative Radiology (In
vest. Radiol. ), 15, S21-S25
(1980)).

Peripheral blood was supplemented with 2% glucose and 0.1 M ED.
The mixture was mixed with a solution of 6% dextran 70 (manufactured by Sigma) containing TA and left for 1 hour. The supernatant containing white blood cells was suspended in a phosphate isotonic buffer solution, and 0.5 mL of this suspension solution was added to
0.2 mL of the compound shown in Chemical formulas 3 to 12 according to the present invention adjusted to 0 mgI / mL was added, and the mixture was incubated at 37 ° C. for 45 minutes. The culture solution was centrifuged, and histamine in the supernatant was quantified by the Shore method (Shore P. A. et al., Journal.
Of Pharmacology and Experimental Therapeutics (J. Pharmacol. Ex
p. Ther. ), 127, 182 (1959)).

Table 2 shows the results obtained from the blood of 20 people. The numerical values are shown as a ratio with 100 when the contrast agent is not administered. As a comparative reference example, the results of administration of physiological saline and iohexol are also shown.

From Table 2, it is clear that the compounds according to the present invention have a significantly smaller amount of histamine release than the comparative compound iohexol.

[0091]

[Table 2]

Example 12 Compounds shown in Chemical formulas 3 to 12 synthesized according to Examples 1 to 10
Evaluation of the effect of the compounds shown in Chemical formulas 3 to 12 synthesized according to Examples 1 to 10 on the complement activity of Siegel (Siegl
e) and the like (see Siegel et al.
e R. L. et al. ), Investigative Radiology (Invest. Radiol.),
18, 387-389 (1982)).

That is, 200 μL of serum and 300 mgI / m
Compound 1 shown in Chemical formulas 3 to 12 according to the present invention adjusted to L
After incubating 00 μL at 37 ° C. for 60 minutes, the 50% hemolytic complement amount (CH50) was determined by a method such as Mayer (Mayer MM), Experimental Immunochemistry (Experimental I).
mmuno Chemistry) p133, C.I. C.
Thomas, (1961)) to determine the amount of total complement activated and consumed.

The results obtained with the sera of 20 persons are shown in Table 3. As a comparative reference example, the results of administration of physiological saline and iohexol are also shown.

[0095]

[Table 3]

From Table 3, it is clear that the compounds according to the present invention have a significantly higher CH50 value than the comparative compound iohexol, that is, they have little effect on the complement system.

(Example 13) Composition of contrast agent used for urinary tract or angiography by the following method
I got a thing.

3,5-bis [(2,3-dihydroxypropyl) oxy] -2,4,6-triiodobenzoic acid-
(1,3-dihydroxypropylamide) 59.34
g, ethylenediamine tetraacetic acid disodium salt 20 mg,
100 mg of tris (hydroxymethyl) aminomethane was dissolved in 90 mL of water for injection, and the pH was adjusted to 7.0 using a 0.1N aqueous sodium hydroxide solution.

Furthermore, an injection solution was added to this solution so that the whole amount became 100 mL, and the solution was filtered through a membrane filter. This was enclosed in an ampoule and sterilized using an autoclave at 120 ° C. for 20 minutes.

The contrast agent composition thus obtained was 1
It contains 300 mg of iodine per mL. The viscosity and storage stability of this composition were good.

When the obtained contrast medium composition was injected into the basilar artery of a pig using a catheter, the position of the blood vessel was clearly confirmed and the X-ray contrast was good.

[0102]

INDUSTRIAL APPLICABILITY According to the present invention, a novel iodobenzene derivative is obtained. As shown in the examples, the iodobenzene derivative has extremely low immunological stimulating ability, low incidence of side effects by administration, and high safety Sex can be suggested.

Further, the contrast medium composition containing the iodobenzene derivative of the present invention can be effectively used as an X-ray contrast medium because it has few side effects, high safety and good contrast ability.

Claims (2)

[Claims] 1. An iodobenzene derivative represented by Chemical formula 1. [Chemical 1] (In the formula, R ₁ represents a nonionic hydrophilic group, R ₂ represents a hydrogen atom, a lower alkyl group or a nonionic hydrophilic group, and R
₃ and R ₄ may be the same or different and represent a nonionic hydrophilic group. ) 2. An X-ray contrast agent composition containing the iodobenzene derivative according to claim 1.