Water-soluble X-ray contrast agents

Abstract

To provide an X-ray contrast medium which is unlikely to cause an allergic reaction in humans. [Solution] Contrast agent 1 is an ester bond compound of a carboxylated linear iodoalkane having 2 or 3 carbon atoms and a disaccharide. As the carboxylated linear iodoalkane having 2 or 3 carbon atoms, published hydrocarbons such as ethylenetriol and glycerin can be used, or ethanol, ethylenediol, propanol (including 1-propyl alcohol and n-propyl alcohol), propylene glycol, etc. to which a hydroxyl group has been further added can be used. As the disaccharide, for example, sucrose or trehalose can be used.

Description

[Technical field]

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

[0002] Conventionally, computed tomography (CT) has been used in the medical field. When performing CT, X-ray contrast agents are sometimes used to visualize blood vessels.

[0003] However, some of the X-ray contrast agents currently available cause allergic reactions in humans, and some patients cannot use them.

[0004] Regarding this point, 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 which is unlikely to cause an allergic reaction in humans.

[0007] The contents of the above "Background Art" and "Problems 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 Heisei 17 (Gyo-Ke) No. 10042 and the Japan Patent Office Examination Guidelines as of the filing date, Part II, Chapter 2, Section 2, 3.2.1). [Means for solving the problem]

[0008] The present invention relates to a carboxylated linear iodoalkane having 2 or 3 carbon atoms. Not iodized It is an ester bonded compound with disaccharides. water soluble Provide an X-ray contrast agent. Effect of the Invention

[0009] According to the present invention, it is possible to provide an X-ray contrast medium which is unlikely to cause an allergic reaction in humans. [Brief description 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. [Diagram 2] 1 is the structural formula of the prior art Iopamidol. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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 that is currently in common use. Iopamidol has three iodines bonded to a benzene ring. Therefore, the distance between the iodine atoms is short, so X-rays can be effectively blocked and clear images can be obtained. In addition, iopamidol has five hydroxyl groups in the molecule, making it highly water-soluble.

[0013] However, since neither iopamidol itself nor the benzene ring that constitutes iopamidol are substances that humans normally ingest, it is believed 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 has been 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 media) FIG. 1 shows the structural formula of contrast agent 1. As shown in FIG. 1, contrast agent 1 is a compound consisting of a saccharide and an iodized linear hydrocarbon having 2 or 3 carbon atoms (R 1 .) is an ester bond compound. Figure 1 shows R 1 Although only two types are shown, the bonding position or number of bonds of I (iodine) is different from that of R 1 may be different from.

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

[0018] The straight-chain hydrocarbon is selected from hydrocarbons that can be metabolized by humans, and straight-chain alkanes with 2 or 3 carbon atoms can be used. When iodinating, it is convenient in terms of ease of reaction if the moiety to be iodized is a hydroxyl group. Such hydrocarbons include published hydrocarbons such as ethylenetriol and glycerin, and also ethanol, ethylenediol, propanol (including 1-propyl alcohol and n-propyl alcohol), propylene glycol, etc., to which a hydroxyl group has been further added. A compound in which iodine has been added to a straight-chain alkane is called a straight-chain iodoalkane.

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

[0020] (Summary of manufacturing method) The imaging agent 1 can be prepared by the following three procedures. (Step 1) Three iodines are added to a triol to produce an iodoalkane. (Step 2) Carboxylate the iodoalkane. (Step 3) The carboxylated iodoalkane is linked to a sugar via an ester bond. Each step is explained below.

[0021] (Step 1) Three iodines are added to a triol to produce an iodoalkane. (1)P 4 O 10 Dissolve 2.5 mmol of alcohol and 5 mmol of NaI in 8 ml of acetonitrile that has been dried with 200° C. and cool on ice. (2) Add 2 ml of the solution (1) above to BF 3 / O(C 2 H 5 ) 25 ml is dripped over 15 minutes. (3) The reaction mixture of (2) above is poured into 20 ml of cold water and 15% Na 2 S 2 O 3 The unreacted iodine and NaI are removed by aqueous solution. (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 dissolved in NaSO 4 Dry in. (7) The solvent is removed from (6) above, and the remainder is subjected to silica gel chromatography (eluent: petroleum ether with a bp (boiling point) of 60 to 80°C) to separate each component contained in (6) and obtain the target iodoalkane.

[0022] According to the above (Step 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, written by Manac Corporation, Maruzen Publishing Co., Ltd., published 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 appropriately selected 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) The carboxylated iodoalkane is linked to a sugar via an ester bond. There are many known methods for producing ester-bonded compounds between 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 iodines in a straight-chain hydrocarbon, and the number of iodines can be increased. The distance between each iodine atom is also short. Therefore, it has an X-ray shielding effect that is almost the same as or even greater than that of conventional X-ray contrast agents.

[0027] In addition, 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 decomposed in the human body and is unlikely to cause an allergic reaction.

[0029] (effect) As described above, contrast agent 1 of the present invention is an ester bond 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 cause allergies in humans, or if any, they rarely cause allergies. Similarly, Imaging agent 1 does not cause allergies in humans, or if any, they rarely cause allergies.

[0031] In addition, 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 unlikely to cause an allergic reaction in humans. In addition, since contrast agent 1 has excellent water solubility, it has the effect of allowing an injection containing contrast agent 1 to be prepared in the same manner as conventional X-ray contrast agents.

Claims

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

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