Water soluble x-ray contrast agents

Abstract

To provide an X-ray contrast medium hardly causing allergic reaction in human.SOLUTION: Imaging agent 1 is an ester-linked compound of a carboxylated linear iodoalkane having 2 or 3 carbon atoms and a disaccharide. Examples of the carboxylated linear iodoalkane having a carbon number of 2 or 3 include aliphatic hydrocarbons such as ethylene triol and glycerin, or aliphatic hydrocarbons such as ethanol, ethylene diol, propanol (including 1-propyl alcohol and n-propyl alcohol), and the like. ) Propylene glycol or the like to which a hydroxy group is further added can be used. As the disaccharide, for example, sucrose or trehalose can be used.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to an X-ray contrast agent. [Background technology]

[0002] Computed tomography (CT) has traditionally been used in medical settings, and X-ray contrast agents are sometimes used to visualize blood vessels during CT scans.

[0003] However, some of the X-ray contrast agents available today can cause allergic reactions in humans, and some patients may not be able to use them.

[0004] In this regard, a technique has been proposed in which an antiallergic agent is added to an injection solution of an X-ray contrast medium (for example, Patent Document 1), but this technique does not cure the cause of the problem. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 6261550 Summary of the Invention [Problem to be solved by the invention]

[0006] The problem to be solved by the present invention is to provide an X-ray contrast medium that is unlikely to cause an allergic reaction in humans.

[0007] The contents of the above "Background Art" and "Problem to be Solved by the Invention" indicate the opportunity (trigger) that led to the invention, and do not limit the technical scope of the invention, nor do they permit a limited interpretation of the technical scope of the invention (see 2005 (Gyo-Ke) No. 10042 and the Patent Office Examination Guidelines, Part II, Chapter 2, Section 2, 3.2.1 as of the filing date). [Means for solving the problem]

[0008] The present invention provides an X-ray contrast agent which is an ester-linked compound of a carboxylated linear iodoalkane having 2 or 3 carbon atoms and a disaccharide. [Effects of the Invention]

[0009] According to the present invention, it is possible to provide an X-ray contrast medium that is unlikely to cause an allergic reaction in humans. [Brief explanation of the drawings]

[0010] [Figure 1] 1 is a structural formula of an X-ray contrast agent according to one embodiment of the present invention. [Figure 2] 1 is the structural formula of prior art iopamidol. DETAILED DESCRIPTION OF THE INVENTION

[0011] An X-ray contrast agent according to one embodiment of the present invention (hereinafter also referred to as contrast agent 1) will be described in detail below with reference to the drawings.

[0012] (Basic Concept) Figure 2 shows the structural formula of iopamidol, an example of an X-ray contrast agent currently in common use. Iopamidol has three iodine atoms attached to a benzene ring. This means that the distance between the iodine atoms is short, effectively blocking X-rays and allowing for clear images to be obtained. Furthermore, iopamidol has five hydroxyl groups in its molecule, making it highly water-soluble.

[0013] However, since neither iopamidol itself nor the benzene ring that constitutes it are substances that humans normally ingest, it is thought that the human body recognizes iopamidol as a foreign substance and causes an allergic reaction.

[0014] The present invention provides a novel contrast agent 1 that was developed based on the structure of sucrose fatty acid ester, a substance with which humans are already exposed.

[0015] Sucrose fatty acid esters are decomposed in the body into sucrose and fatty acids, which are also ultimately metabolized (see, for example, Yamada Toshinobu, Kawase Nobuyuki, and Hagimoto Kenji, "On Sucrose Fatty Acid Esters," Oil Chemistry, Vol. 29, No. 8 (1980), Japan Oil Chemists' Society, pp. 543-553, especially "4. Physiological Properties"). Since contrast agent 1 provided by the present invention has a similar structure to sucrose fatty acid esters, it is similarly metabolized in the body.

[0016] (Composition of X-ray contrast agent) Figure 1 shows the structural formula of contrast agent 1. As shown in Figure 1, contrast agent 1 is an ester-bonded compound of a saccharide and an iodinated linear hydrocarbon having two or three carbon atoms (R1 in Figure 1). Although only two types of R1 are shown in Figure 1, the bonding position or number of I (iodine) bonds may be different from those of R1 shown in Figure 1.

[0017] The sugars include disaccharides, and sucrose and trehalose are preferred from the viewpoint of safety.

[0018] The straight-chain hydrocarbon can be selected from hydrocarbons that can be metabolized by humans, and straight-chain alkanes with two or three carbon atoms can be used. For iodination, it is convenient to use a hydroxyl group as the moiety to be iodized, as this facilitates the reaction. Examples of such hydrocarbons include published hydrocarbons such as ethylenetriol and glycerin, as well as ethanol, ethylenediol, propanol (including 1-propyl alcohol and n-propyl alcohol), and propylene glycol, to which a hydroxyl group has been added. Compounds in which iodine has been added to straight-chain alkanes are called straight-chain iodoalkanes.

[0019] (Method of manufacturing X-ray contrast agent) Below is an example of a method for producing contrast agent 1 using a straight-chain hydrocarbon having three carbon atoms and sucrose. In addition to this example, it is also possible to produce the agent using known methods. In the following examples, ethylene triol or glycerin, which are published as triols, is used. Unless otherwise specified, all temperatures are room temperature, and % represents % by mass.

[0020] (Summary of manufacturing method) Contrast agent 1 can be prepared by the following three steps. (Step 1) Three iodines are added to a triol to produce an iodoalkane. (Step 2) Carboxylate the iodoalkane. (Step 3) Carboxylated iodoalkane and sugar are esterified. Each step is explained below.

[0021] (Step 1) Three iodines are added to a triol to produce an iodoalkane. (1) P4O 10 Dissolve 2.5 mmol of alcohol and 5 mmol of NaI in 8 ml of acetonitrile that has been dried with HCl and cool on ice. (2) Add 25 ml of BF3 / O(C2H5) dropwise to 2 ml of the solution (1) above over 15 minutes. (3) The reaction mixture from (2) above is poured into 20 ml of cold water, and unreacted iodine and NaI are removed with a 15% aqueous solution of Na2S2O3. (4) The product of (3) above is extracted three times with 15 ml of ether. (5) Wash the extract from (4) above twice with 5 ml of water and once with 10 ml of saturated saline. (6) The product of (5) above is dried over NaSO4. (7) The solvent is removed from (6) above, and the remainder is subjected to silica gel chromatography (eluent: petroleum ether with a boiling point of 60 to 80°C) to separate the components contained in (6) and obtain the target iodoalkane.

[0022] According to the above (Procedure 1), iodoalkanes in which OH is replaced with I can be obtained in a yield of 90% or more.

[0023] (Step 1) is explained in detail in "Organic Synthesis of Bromine and Iodine Compounds," edited by Suzuki Hitomi and written by Manac Corporation, published by Maruzen Publishing Co., Ltd. on April 20, 2017, p. 475. The same book also describes a method for producing iodoalkanes from alcohols (pp. 425-426). These methods can be selected as appropriate.

[0024] (Step 2) Carboxylate the iodoalkane. The carboxylation of an alkane can be carried out by appropriately selecting from known methods. For example, a known synthesis method using a nucleophilic agent can be used. Examples of the nucleophilic agent can be appropriately selected from amines, alkoxides, enols, alkyllithiums, thiols, enolates, etc.

[0025] (Step 3) Carboxylated iodoalkane and sugar are esterified. There are many known methods for producing ester-bonded compounds of fatty acids and sucrose. For example, the methods described in Japanese Patent Nos. 2648936, 6276806, and 5945756 can be used as is or with slight modifications when forming an ester bond between a carboxylated iodoalkane and a saccharide.

[0026] (Characteristics of the produced X-ray contrast agent) Contrast Agent 1 has three iodine atoms in a linear hydrocarbon chain, and the number of iodine atoms can be increased. The distance between each iodine atom is also short. Therefore, it has an X-ray shielding effect that is comparable to or even superior to that of conventional X-ray contrast agents.

[0027] Furthermore, Contrast Agent 1 has five hydroxy groups in one molecule, and therefore has water solubility almost equivalent to that of conventional X-ray contrast agents.

[0028] In addition, contrast agent 1 is metabolically degraded in the human body and is unlikely to cause allergic reactions.

[0029] (effect) As described above, contrast agent 1 of the present invention is an ester-linked compound of a carboxylated linear iodoalkane having 2 or 3 carbon atoms and a disaccharide.

[0030] Imaging agent 1 has a structure similar to that of sucrose fatty acid esters. Sucrose fatty acid esters are highly safe and do not, or if at all, cause allergic reactions in humans, and even if they do, they are extremely rare. Similarly, Imaging agent 1 also does not, or if at all, causes allergic reactions in humans, and they are extremely rare.

[0031] Furthermore, sucrose fatty acid esters are decomposed and metabolized in the human body, and Imaging Agent-1 is also decomposed and metabolized in the human body.

[0032] Therefore, the present invention has the effect of providing an X-ray contrast agent that is less likely to cause allergic reactions in humans. Furthermore, since contrast agent 1 has excellent water solubility, an injectable solution containing contrast agent 1 can be prepared using the same formulation as conventional X-ray contrast agents.

Claims

[Claim 1] An X-ray contrast agent which is an ester bond compound of a carboxylated linear iodoalkane having 2 or 3 carbon atoms and a disaccharide.

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