Compound, contrast agent, and method for producing the compound

Abstract

The present invention pertains to a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, wherein in formula (1), R1 to R3 each independently are a predetermined amino group, a predetermined amide group, or a group represented by formula (2), and at least one among R1 to R3 is a group represented by formula (2).

Description

[Technical Field]

[0001] This invention relates to compounds, contrast agents, and methods for producing compounds. [Background technology]

[0002] Contrast-enhanced X-ray examinations using iodine contrast agents have greatly improved the diagnostic accuracy of X-ray images and have become an important diagnostic method in many medical departments. Most iodine contrast agents are excreted by the kidneys. Therefore, contrast-induced nephropathy is a problem as a side effect.

[0003] As one way to resolve the above problems, for example, Patent Document 1 proposes using a conjugate of a nonionic iodine contrast agent and a group recognized by a hepatocyte-specific transporter. This conjugate becomes a substrate for the transporter and is taken up by hepatocytes, or is excreted from hepatocytes, with a portion of the renal excretion being excreted in the bile, thereby reducing nephrotoxicity. Specifically, Patent Document 1 discloses a conjugate having iohexol as the nonionic iodine contrast agent and a group derived from an ethoxybenzyl group or ursodeoxycholic acid as the group recognized by the hepatocyte-specific transporter. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 2018-062475 [Overview of the project] [Problems that the invention aims to solve]

[0005] Iodine contrast agents are preferably administered by intravenous injection. When an injectable agent containing the conjugate described in Patent Document 1 is administered intravenously at a high concentration, the viscosity of the drug may increase. Therefore, iodine contrast agents are required to have the ability to reduce nephrotoxicity while also being easy to handle during administration.

[0006] The problem to be solved by the present invention is to provide a novel compound that can be used as an iodine contrast agent.

Means for Solving the Problem

[0007] As a result of intensive studies to solve the above problems, the present inventors have found a novel compound that can be an iodine contrast agent and completed the present invention.

[0008] That is, the present invention is as follows. [1] A compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[10] The linker has the following structure: [ka] [ka] (In the formula, L 0 is -O- or -NHC(=O)-, N is a non-negative integer, n is a non-negative integer, m2 is an integer greater than or equal to 1. N' is either 0 or 1. The compound described in [9] or a pharmaceutically acceptable salt thereof, represented by any of the following:

[11] The aforementioned amino group is represented by one of the following structures: [ka] The aforementioned amide group is represented by one of the following structures: [ka] A compound described in any one of [1] to

[10] or a pharmaceutically acceptable salt thereof.

[12] The amino group is an acetylamino group. A compound described in any one of [1] to

[11] or a pharmaceutically acceptable salt thereof.

[13] In equation (1), R 1 ~R 3 All of these are bases represented by equation (2), A compound described in any one of [1] to

[12] or a pharmaceutically acceptable salt thereof.

[14] A compound or a pharmaceutically acceptable salt thereof, represented by any of the following structures. [ka]

[15] A compound or a pharmaceutically acceptable salt thereof, represented by the following structure. [ka]

[16] A compound or a pharmaceutically acceptable salt thereof, represented by the following structure. [ka]

[17] A contrast agent comprising any one of the compounds described in [1] to

[16] or a pharmaceutically acceptable salt thereof.

[18] The process includes reacting a reaction substrate, which consists of an atomic group portion that binds to an asial glycoprotein receptor and a linker portion, with a reaction substrate of a nonionic iodine contrast agent portion. A method for producing a compound described in any one of [1] to

[16] or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0009] According to the present invention, it is possible to provide a novel compound that can be used as an iodine contrast agent. [Brief explanation of the drawing]

[0010] [Figure 1] This figure shows the results of the HepG2 uptake inhibition tests for the example compounds RYO-1, MEG-1, and MEG-2. [Figure 2] This figure shows the results of the uptake inhibition tests in Panc-1 for the compounds RYO-1, MEG-1, and MEG-2, which are examples of this study. [Figure 3] This figure shows the results of the HepG2 uptake inhibition tests for the example compounds MEG-2, MEG-4, RYO-1, and RYO-2. [Figure 4] This figure shows a CT image taken one hour after administering MEG-1, the compound used in the examples, to a mouse. [Modes for carrying out the invention]

[0011] The embodiments for carrying out the present invention will be described in detail below. However, the present invention is not limited to the following embodiments and can be implemented in various ways within the scope of its gist.

[0012] [Compound] The compound of the present invention is represented by formula (1). Furthermore, the present invention also includes pharmaceutically acceptable salts of the compound represented by formula (1). In this specification, the term "compound" may refer to a compound including pharmaceutically acceptable salts.

[0013] [ka]

[0014] In formula (1), R 1 ~R 3 Each of them operates independently. -NR x R y (R x and R y Each of these independently represents an amino group (a hydrogen atom, a C1-C6 hydrocarbon group which may have a substituent, or a C2-C7 acyl group which may have a substituent), Alternatively, -C(=O)NR z R w (R z and R w Each of these independently represents an amide group (which may have a hydrogen atom or a C1-C6 hydrocarbon group), Or, Formula (2): [ka] (In formula (2), Atomic groups are groups of atoms that bind to asial glycoprotein receptors. A Linker is any linker. ) is a base represented by R 1 ~R 3 At least one of them is a base represented by formula (2). In the compound of the present invention, R 1 ~R 3 If one of them is a base represented by formula (2), then R 1 ~R 3The remaining two are selected from the above amino groups or amide groups, R 1 ~R 3 If the two of these are groups represented by formula (2), then R 1 ~R 3 The remaining one is selected from the above amino group or the above amide group. The compound of the present invention is R 1 ~R 3 This also includes the case where the three elements are the base represented by equation (2). The compound R of the present invention 1 ~R 3 In each of the groups, if it contains multiple groups represented by formula (2), multiple amino groups, or multiple amide groups, these groups may be the same or different. As the compound of the present invention, R 1 ~R 3 Regarding R 1 ~R 3 Regarding the embodiments described in each explanation, any combination of them may be used, regardless of whether they are preferred or not.

[0015] The compounds of the present invention can be used as contrast agents. In the present invention, a contrast agent refers to a pharmaceutical or pharmaceutical composition administered to a patient in diagnostic imaging to enhance contrast in images or to highlight specific tissues. The Atomic Group in the compound of the present invention is recognized by the asialoglycoprotein receptor, which is specifically expressed in hepatocytes, thereby enabling the compound to be taken up by hepatocytes. While most existing iodine-based contrast agents are entirely excreted in urine by the kidneys, placing a burden on the kidneys, the compound of the present invention can be taken up by the liver and excreted in bile. In other words, the compound of the present invention allows for a dual drug metabolism pathway through urine and bile, thereby reducing nephrotoxicity. Furthermore, when administered in the form of an injectable preparation, the compounds of the present invention tend to maintain a constant viscosity even at high concentrations, resulting in excellent handling and easy administration to the target recipient.

[0016] The compound represented by formula (1) of the present invention can be represented, for example, by the following formulas (1-1), (1-2), (1-3), (1-4), (1-5), or (1-6). The compound represented by formula (1) of the present invention preferably has two or more groups represented by formula (2), and more preferably has three groups represented by formula (2). That is, the compound of the present invention is preferably represented by the following formulas (1-2), (1-3), or (1-5), and more preferably by the following formula (1-3). In such embodiments, the interaction between the compound of the present invention and the substrate recognition site of the asialoglycoprotein receptor (e.g., the galactose recognition site) tends to be further improved, and the compound tends to be introduced into hepatocytes more efficiently.

[0017] [ka] [ka]

[0018] In equations (1-1) to (1-6), R x , R y , R z , R w , Atomic Group and Linker are R in equation (1). x , R y , R z , R w This is synonymous with Atomic Group and Linker. -NR x R y -C(=O)NR z R w If there are multiple Atomic Groups or Linkers, they may be the same or different, but it is preferable that they be the same.

[0019] In equation (1), -NR x R y R in the amino group represented by x and R yEach of these independently represents a hydrogen atom, a C1-C6 hydrocarbon group which may have substituents, or a C2-C7 acyl group which may have substituents. x and R y They may be the same or different, but R x and R y Preferably, one of them represents a hydrogen atom, and the other represents a C1-C6 hydrocarbon group which may have substituents, or a C2-C7 acyl group which may have substituents. Alternatively, R x and R y A preferred embodiment is one in which one of the members represents a C1-C6 hydrocarbon group which may have substituents, and the other represents a C2-C7 acyl group which may have substituents. R x and R y In this, the carbon number of the hydrocarbon group, which may have substituents, is preferably 1 to 5, and more preferably 1 to 4. Furthermore, the carbon number of the acyl group, which may have substituents, is preferably 2 to 6, and more preferably 2 to 5.

[0020] -C(=O)NR z R w R in the amide group represented by z and R w Each of these independently represents a hydrogen atom or a C1-C6 hydrocarbon group which may have substituents. z and R w They may be the same or different, but R x and R y Preferably, one of the atoms represents a hydrogen atom, and the other represents a C1-C6 hydrocarbon group which may have substituents. R z and R w In this, the number of carbon atoms in the hydrocarbon group, which may have substituents, is preferably 1 to 5, and more preferably 1 to 4.

[0021] As the hydrocarbon groups of C1 to C6 above, they may be saturated or unsaturated, linear, branched or cyclic hydrocarbon groups. For example, alkyl groups having 1 to 6 carbon atoms, alkenyl groups having 2 to 6 carbon atoms, alkynyl groups having 2 to 6 carbon atoms, aryl groups having 6 carbon atoms, etc. may be mentioned. The hydrocarbon groups of C1 to C6 above are preferably saturated, linear or branched hydrocarbon groups.

[0022] In this specification, as the alkyl groups having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, pentyl group, hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc. may be mentioned. In this specification, as the alkenyl groups having 2 to 6 carbon atoms, specifically, allyl group, methallyl group, 1-buten-1-yl group, 2-buten-1-yl group, 3-buten-1-yl group, 1-buten-3-yl group, etc. may be mentioned. In this specification, as the alkynyl groups having 2 to 6 carbon atoms, specifically, 2-propyn-1-yl group, 2-butyn-1-yl group, 3-butyn-1-yl group, etc. may be mentioned. In this specification, as the aryl groups having 6 carbon atoms, specifically, phenyl group, etc. may be mentioned.

[0023] The acyl groups of C2 to C7 above are groups represented by R-CO-, and R is, for example, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 carbon atoms, etc. As the acyl groups of C2 to C7 above, specifically, acetyl group, acryloyl group, benzoyl group, etc. may be mentioned.

[0024] R x 、R y 、R z 及びR w The substituents in and R are not particularly limited. For example, hydroxy group, halogen atom, organic oxy group represented by -OR A 、-N(R B )(R C) include amino groups represented by etc. The above substituents are R x , R y , R z and R w and are not limited to these, and may be included in any part of the compounds of the present invention. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. R A includes, for example, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 carbon atoms, etc. R B and R C each independently include, for example, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 carbon atoms, etc.

[0025] -NR x R y The amino group represented by is an acetylamino group (-NHCOR, where R is a C1-C6 hydrocarbon group which may have a substituent. The definition of the C1-C6 hydrocarbon group which may have a substituent is the same as that of R x and R y ). Preferably, the amino group represented by -NR x R y is also preferably represented by any of the following structures. [Chemical formula]

[0026] -C(=O)NR z R w The amide group represented by is preferably represented by any of the following structures. [Chemical formula]

[0027] -NR xR y The amino group and -C(=O)NR represented by z R w The left-hand bond in the amide group represented by this, and in the specific structure shown, the bond from NH or N, or the bond from C=O, respectively, are the bonds that connect to the triiodobenzene skeleton in formula (1).

[0028] The Atomic Group in the compound of the present invention is an atomic group that binds to an asialoglycoprotein receptor, and is not particularly limited as long as it has a structure that is recognized by the asialoglycoprotein receptor. Examples of structures of the Atomic Group that are recognized by the asialoglycoprotein receptor include sugar residues that bind to the asialoglycoprotein receptor and groups of peptide chains derived from immunoglobulin A (IgA), etc., and the Atomic Group itself may include groups derived from sugar residues that bind to the asialoglycoprotein receptor, or groups of peptide chains derived from immunoglobulin A (IgA), etc. The Atomic Group in the compounds of the present invention is preferably a sugar residue that binds to an asialoglycoprotein receptor, and more preferably a group derived from galactose, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, or galactose-N-acetylglucosamine (also known as "galactosyl-N-acetylglucosamine"). Galactose-N-acetylglucosamine refers to a disaccharide obtained by dehydration condensation of galactose and N-acetylglucosamine at the hydroxyl group at position 1 of galactose.

[0029] In this specification, "derived from galactose," "derived from N-acetylgalactosamine," "derived from N-trifluoroacetylgalactosamine," or "derived from galactose-N-acetylglucosamine" means that a part of galactose, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, or galactose-N-acetylglucosamine may have been structurally modified for linking with Linker. An example of structural modification is that one of the hydroxyl groups of galactose, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, or galactose-N-acetylglucosamine is substituted with a primary amino group (-NH2).

[0030] Galactose, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, or galactose-N-acetylglucosamine may interact with the Linker via any of the functional groups in the sugar. When the Linker is bound to a sugar residue that binds to an asialoglycoprotein receptor, the carbon position to which the Linker binds may be position 1, 2, 3, 4, or 6 of the sugar, but is preferably position 1. Galactose-N-acetylglucosamine is not particularly limited as long as it is a sugar chain recognized by the asialoglycoprotein receptor, but the bond between galactose and N-acetylglucosamine may be a β1,3 linkage or a β1,4 linkage, and preferably a β1,3 linkage.

[0031] The group represented by formula (2) in the compound of the present invention is preferably a group represented by formula (2-1) or formula (2-2), and more preferably a group represented by formula (2-1). The group represented by formula (2) may also be a group represented by formula (2-3) or (2-4).

[0032] [ka]

[0033] The Linker in formulas (2-1), (2-2), (2-3), and (2-4) is synonymous with the Linker in formula (1). The bond between the Linker and a group derived from galactose, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, or N-acetylglucosamine is shown with a wavy line, meaning that it may be an α-bond or a β-bond. The above wavy line bond is preferably a β-bond.

[0034] In the compounds of the present invention, a linker refers to a structure that connects an atomic group bound to an asialocryprotein acceptor with a triiodobenzene skeleton. When the compounds of the present invention have two or more linkers, these two or more linkers may be the same or different, but it is preferable that they be the same. The linker in the compound of the present invention is preferably a hydrocarbon chain which may have substituents, and where one or both of the ends of such hydrocarbon chain may have a heteroatom, an amide bond, an ester bond, a carbonyl bond, or an aromatic heterocycle. That is, the linker in the compound of the present invention may be a hydrocarbon chain which may have substituents, having one or both of the ends of a heteroatom, an amide bond, an ester bond, a carbonyl bond, and an aromatic heterocycle. The hydrocarbon chain may contain unsaturated bonds and may be a straight, branched, or cyclic hydrocarbon group. The hydrocarbon chain may also be a combination of a straight and / or branched hydrocarbon and a cyclic hydrocarbon. Examples of the hydrocarbon chain include alkylene chains, alkenylene chains, alkylylene chains, and arylene groups, as well as combinations thereof. The hydrocarbon chain may contain atoms other than carbon atoms and hydrogen atoms (e.g., oxygen atoms and nitrogen atoms) in the main chain. The hydrocarbon chain may also have a carbonyl structure in the main chain. The linker may have a heteroatom, amide bond, ester bond, carbonyl bond, or aromatic heterocycle at either of its ends, and it is preferable that it has a heteroatom, amide bond, ester bond, carbonyl bond, or aromatic heterocycle at either of its ends. That is, in the compound of the present invention, it is preferable that the bonding portion between the atomic group or triiodobenzene skeleton that binds to the asialocrytoprotein acceptor and the linker is independently a heteroatom, amide bond, ester bond, carbonyl bond, or aromatic heterocycle.

[0035] The hydrocarbon chain described above is more preferably an alkylene chain which may have substituents, or a hydrocarbon chain in which two or more alkylene chains which may have substituents are linked via at least one selected from the group consisting of heteroatoms, amide bonds, ester bonds, carbonyl bonds, and aromatic heterocycles. Here, the alkylene chain may be a straight chain or a branched chain. The elements constituting the main chain of the alkylene chain described above may include atoms other than carbon atoms, but it is preferable that the main chain of the alkylene chain described above is composed only of carbon atoms.

[0036] When the main chain is an alkylene chain that connects the group of atoms bound to the asialocrytoprotein acceptor and the triiodobenzene skeleton in the shortest possible distance, the number of carbon atoms constituting the main chain is preferably 1 to 10, more preferably 1 to 8, and even more preferably 1 to 6. Within the above range, the number of carbon atoms is more preferably 2 or more, and may be, for example, 2 to 6. As the number of carbon atoms falls within the above range, the compounds of the present invention tend to interact more readily with the substrate recognition site (e.g., galactose recognition site) of the asialoclycoprotein receptor, and are more efficiently introduced into hepatocytes. In particular, when the compounds of the present invention have two or more (or three) groups represented by formula (2) in formula (1), as the number of carbon atoms falls within the above range, the interaction between the compounds of the present invention and the substrate recognition site (e.g., galactose recognition site) of the asialoclycoprotein receptor tends to be further improved, and they tend to be introduced into hepatocytes more efficiently. The number of carbon atoms here does not include carbon atoms of functional groups that may be included in alkylene chains, such as aromatic heterocycles, amide bonds, ester bonds, and carbonyl bonds, which will be described later.

[0037] Examples of heteroatoms include oxygen atoms, sulfur atoms, nitrogen atoms, etc. These heteroatoms are preferably included as ether bonds (-O-), thioether bonds (-S-), or amine bonds (-NH-). The heteroatoms may be included in the alkylene chain, or they may be positioned at the terminal of the alkylene chain, i.e., at the atomic group that binds to the asialocrycoprotein acceptor, or at the bonding position with the triiodobenzene skeleton. The amide bond, ester bond, and carbonyl bond are represented by -NH-CO-, -CO-O-, and -CO-, respectively. The amide bond, ester bond, and carbonyl bond may be contained within the alkylene chain, or they may be located at the terminal of the alkylene chain, i.e., at the atomic group that binds to the asialocrytoprotein acceptor, or at the bond position to the triiodobenzene skeleton. Examples of aromatic heterocycles include triazole rings, with 1,2,3-triazole being particularly preferred. The aromatic heterocycle may be contained within an alkylene chain, or it may be positioned at the terminal of the alkylene chain, i.e., at the atomic group that binds to the asialocrytoprotein acceptor, or at the bonding site with the triiodobenzene skeleton. Aromatic heterocycles, heteroatoms, amide bonds, ester bonds, and carbonyl bonds may be present in one or more units in an alkylene chain. The total number of aromatic heterocycles, heteroatoms, amide bonds, ester bonds, and carbonyl bonds in a single hydrocarbon chain is preferably two or more, more preferably two to six, and even more preferably two to four. The orientation of the amide bond and ester bond is not particularly limited; the amide bond may be -NH-CO- or -CO-NH-, and the ester bond may be -CO-O- or -O-CO-. The position and orientation of the aromatic heterocycle bond are not particularly limited; for example, if the alkylene chain contains 1,2,3-triazole, it may be bonded at positions 1 and 4. Also, if 1,2,3-triazole is bonded at positions 1 and 4, position 1 may be on the side of the atomic group that binds to the asialocrycoprotein receptor, and position 4 may be on the side of the atomic group that binds to the asialocrycoprotein receptor.

[0038] In the compound of the present invention, when the linker has an alkylene chain as the main chain that connects the group of atoms that bind to the asialocrypoprotein receptor and the triiodobenzene skeleton in the shortest possible way, the number of atoms constituting the main chain is preferably 1 to 15, more preferably 1 to 13, and even more preferably 1 to 12. Within the above range, the number of atoms constituting the main chain is preferably 2 or more, 3 or more, or 4 or more, and may be 5 or more. Also, within the above range, the number of atoms may be 11 or less. When the number of atoms is within the above range, the compound of the present invention tends to interact more easily with the substrate recognition site (e.g., galactose recognition site) of the asialocrypoprotein receptor and is efficiently introduced into hepatocytes. The above number of atoms may be within a range obtained by arbitrarily combining the above upper and lower limits.

[0039] The substituents that the above hydrocarbon chain and alkylene chain may have are R x , R y , R z and R wExamples of substituents similar to those in the above are possible, but preferably selected from a hydroxyl group or an amino group (-NH2), and more preferably a hydroxyl group. The substituent may be an alkyl group substituted with a hydroxyl group, or a side chain substituted with a hydroxyl group and an alkyl group substituted with a hydroxyl group.

[0040] A preferred embodiment of the linker in the compound of the present invention is a linker represented by the following structure. [ka]

[0041] Here, in the formula, L 0 is -O- or -NHC(=O)-, and L x It is represented by the following structure: [ka] L y This represents a single bond, or is represented by the following structure (preferably a single bond), [ka] L z It is represented by the following structure. [ka]

[0042] In the above formula, R' is independently selected from a hydrogen atom, a C1-C3 alkyl group which may have substituents, or a hydroxyl group; L 1 Each of these is independently selected from an ether bond (-O-), a thioether bond (-S-), an amine bond (-NH-), an amide bond, an ester bond, or a carbonyl bond; L 2 L is a divalent group derived from an amide bond or an aromatic heterocycle; 3This is one of the following selected from -OCH2-, -NHCH2-, -C(=O)NH-, -C(=O)NHCH2-, or -NHC(=O)-. m1, m2, and m4 are each independent integers greater than or equal to 1; m3 is an integer greater than or equal to 0; and N and N2 are each independent integers greater than or equal to 0.

[0043] L 0 This represents the binding site between the linker and the atomic group that binds to the asialocrytoprotein acceptor. 0 The bond is preferably -O- (ether bond). 0 When is -NHC(=O)-, the atomic group that binds to the asialocrycoprotein receptor and the Linker are bound in the following order: (atomic group that binds to the asialocrycoprotein receptor)-NHC(=O)-Linker.

[0044] L x , L y , and L z In this, examples of C1-C3 alkyl groups that may have substituents in R' include methyl, ethyl, n-propyl, and isopropyl groups. Examples of substituents that the above C1-C3 alkyl groups may have include R x , R y , R z and R w Examples of substituents similar to those in the above are possible, but preferably selected from a hydroxyl group or an amino group (-NH2). L 1 In this, the orientation of the amide bond and ester bond is not particularly limited; the amide bond may be -NH-CO- or -CO-NH-, and the ester bond may be -CO-O- or -O-CO-. 2 The same applies to the amide bond in this case. L 2In this context, a divalent group derived from an aromatic heterocycle refers to a divalent group obtained by removing two hydrogen atoms from an aromatic heterocycle. Such a divalent group is not particularly limited, but examples include a divalent group obtained by removing the hydrogen atoms at positions 1 and 4 of 1,2,3-triazole. In this case, the orientation of the divalent group derived from 1,2,3-triazole is not limited, and position 1 is L x It may be combined with, or the 4th position is L x It may also be combined with this.

[0045] L 1 Preferred embodiments include, for example, ether bonds and amide bonds. 3 Preferred embodiments include, for example, -C(=O)NHCH2- and -NHC(=O)-. m1, m2, and m4 are each independent integers of 1 or more, preferably between 1 and 5, more preferably between 1 and 4, or between 1 and 3. m1, m2, and m4 may each be independent integers of 2 or more. m2 may be between 1 and 10, between 1 and 8, or between 1 and 6. m3 is an integer greater than or equal to 0, and may be an integer between 1 and 5, or between 1 and 4, or between 1 and 3. N and N2 are independent integers greater than or equal to 0, but may be 5 or less, preferably 4 or less, and more preferably 3 or less. The sum of N and N2 is preferably between 0 and 4, and more preferably between 1 and 3.

[0046] In the linker described above, L x Preferably, it has one of the following structures: [ka] L y Preferably, it is a single bond or one of the following structures: [ka] Lz Preferably, it has one of the following structures: [ka]

[0047] In the above formula, k1 is an independent integer between 1 and 3; k2 is 0 or 1; m3 is an integer greater than or equal to 0; and N and N2 are independent integers greater than or equal to 0.

[0048] Each k1 is an independent integer between 1 and 3, and when N is 2 or greater, multiple k2s may be the same or different. The preferred numerical ranges for m3, N, and N2 are the same as described above.

[0049] Another preferred embodiment of the linker in the compound of the present invention is a linker represented by the following structure. [ka]

[0050] In the formula, R' is independently selected from a hydrogen atom, an optionally substituted C1-C3 alkyl group, or a hydroxyl group. L 0 is -O- or -NHC(=O)-, L 1 Each of these independently represents either a single bond or one of the following: an ether bond (-O-), a thioether bond (-S-), an amine bond (-NH-), an amide bond, an ester bond, or a carbonyl bond. m1 and m2 are each independent integers greater than or equal to 1. N is a non-negative integer, N' is either 0 or 1.

[0051] Examples of C1-C3 alkyl groups that may have substituents include methyl, ethyl, n-propyl, and isopropyl groups. Examples of substituents on C1-C3 alkyl groups that may have substituents include R x , R y , R z and R w Similar substituents to those in can be listed.

[0052] L 0 This has the same definition as above, and is preferably -O- (ether bond). m1 and m2 are each preferably independent integers between 1 and 5, more preferably between 1 and 4, and even more preferably between 1 and 3. m2 may be between 1 and 10, between 1 and 8, or between 1 and 6.

[0053] N is not particularly limited as long as it is a non-negative integer, but is preferably 0 to 5, more preferably 0 to 4, and even more preferably 1 to 3. When N is 0, the above linker structure can be expressed by the following equation. [ka]

[0054] N' is either 0 or 1. When N' is 0, the linker in the above formula is expressed as follows. N' is preferably 1. [ka]

[0055] The linker in the compound of the present invention is more preferably represented by any of the following structures. [ka] [ka] In the formula, L 0 n is -O- or -NHC(=O)-; n is a non-negative integer; n is a non-negative integer; m² is a non-negative integer; and N' is 0 or 1.

[0056] L 0 This has the same definition as above, and is preferably -O- (ether bond). N is preferably 0 to 5, more preferably 0 to 4, and even more preferably 1 to 3. n is preferably 0 or an integer between 1 and 5, more preferably 0 or an integer between 1 and 4, and even more preferably 0 or an integer between 1 and 3. m2 may be an integer between 1 and 10, between 1 and 8, or between 1 and 6, preferably between 1 and 5, more preferably between 1 and 4, and even more preferably between 1 and 3. When N or n is 0, it is preferable that m2 is an integer between 1 and 10, inclusive. When N or n is an integer of 1 or greater, it is preferable that m2 is an integer between 1 and 6, inclusive. N' is preferably 1.

[0057] The compound of the present invention is, in formula (1), -NR x R y The amino group represented by -C(=O)NR z R w The amide group represented by and the group represented by formula (2) may be any combination of the preferred embodiments described for each. Similarly, the preferred embodiments described for each group may also be any combination. That is, although not particularly limited, as an example, -NR x R y The amino group represented by -C(=O)NR z R w Regarding the amide group represented by and the group represented by formula (2), only the group represented by formula (2) may be in a particularly preferred form, -NR xR y The amino group represented by -C(=O)NR z R w For the amide group represented by formula (2) and the group represented by formula (2), -NR x R y The amino group and -C(=O)NR represented by z R w The amide group represented by may be a specific preferred embodiment described in each of the following terms.

[0058] The compound represented by any of the following formulas is preferred as the compound of the present invention. [ka] [ka]

[0059] As the compound of the present invention, a compound represented by any of the following formulas is more preferable. [ka]

[0060] Compounds represented by any of the following formulas are even more preferred as the compounds of the present invention. [ka] [ka]

[0061] In the compounds shown above as preferred embodiments of the present invention, the structure of each linker portion (i.e., the structure corresponding to the Linker understood from the compound represented by any of the above formulas and formulas (2-1) to (2-4)) is a preferred Linker structure in the compound represented by formula (1). In other words, any linker as Linker in formula (1) may be a linker in a compound represented by any of the above formulas, and any linker as Linker in formulas (2-1) to (2-4) may also be a linker in a compound represented by any of the above formulas. Furthermore, the linker described as "a preferred embodiment of the linker in the compound of the present invention is a linker represented by the following structure" may be a linker in a compound represented by any of the above formulas.

[0062] Examples of pharmaceutically acceptable salts of the compounds of the present invention include inorganic salts such as hydrochloride, sulfate, and phosphate, and organic salts such as acetate, propionate, tartrate, fumarate, maleate, malate, citrate, methanesulfonate, p-toluenesulfonate, and trifluoroacetate. Examples of pharmaceutically acceptable salts of the compounds of the present invention include alkali metals such as sodium salts, potassium salts, and calcium salts, or alkaline earth metals.

[0063] [Method for producing compounds] The compounds of the present invention can be produced by organic synthesis methods. The compounds of the present invention consist of an atomic group portion that binds to the asialocrycoprotein receptor, a linker portion, and a nonionic iodine contrast agent portion. The compounds of the present invention can be produced by reacting and linking the reaction substrates corresponding to the atomic group portion that binds to the asialocrycoprotein receptor, the linker portion, and the nonionic iodine contrast agent portion, respectively. The compounds of the present invention can be produced, for example, by reacting a reaction substrate consisting of an atomic group portion that binds to the asialocrycoprotein receptor and a linker portion with a reaction substrate of a nonionic iodine contrast agent portion, or by introducing a linker portion into the reaction substrate of the nonionic iodine contrast agent portion and then reacting it with a reaction substrate corresponding to the atomic group portion that binds to the asialocrycoprotein receptor. A preferred method for producing the compound of the present invention involves reacting a reaction substrate, composed of an atomic group portion that binds to an asialocrytoprotein receptor and a linker portion, with a reaction substrate of a nonionic iodine contrast agent portion. The method for producing the compound represented by formula (1) can be represented, for example, by the following scheme. One aspect of the present invention is a method for producing the compound represented by formula (1), comprising the step of reacting a reaction substrate, composed of an atomic group portion that binds to an asialocrytoprotein receptor and a linker portion, with a reaction substrate of a nonionic iodine contrast agent portion. The reaction substrate of the nonionic iodine contrast agent portion is preferably a compound having a triiodobenzene skeleton.

[0064] [ka]

[0065] In the scheme, X 1 And, X 2 At least one of these includes a reactive group, X 1 The reactive group and X 2 It reacts with the reactive group to form a chemical bond. X other than the reactive group 2 -NR x R y Or -C(=O)NR z R w It is preferable that (R x , R y , R z and R w The definition is the same as above. The chemical bonds formed here are not particularly limited, but examples include carbon-carbon bonds (which may be saturated or unsaturated), ether bonds (-O-), thioether bonds (-S-), amine bonds (-NH-), amide bonds, ester bonds, carbonyl bonds, and aromatic heterocycles. Known organic synthesis reactions can be used to form these bonds.

[0066] When forming a carbon-carbon bond, the reaction is not particularly limited, but examples include the Wittig reaction, the Grignard reaction, the Suzuki-Miyaura coupling reaction, and the Negishi coupling reaction. 1 and X 2 The organic group that reacts in these reactions can be any organic group. In the case of the Wittig reaction, for example, X 1 and X 2 Preferably, one of the groups is an aldehyde group or a ketone group, and the other is a phosphorus ylide group. In the case of a Grignard reaction, for example, X 1 and X 2 Preferably, one of the groups is an aldehyde group or a ketone group, and the other is a group that forms a Grignard reagent (-MgX). In the case of the Suzuki-Miyaura coupling reaction, for example, X 1 and X 2 Preferably, one of the groups is a boronic acid or boronic acid ester group, and the other is a halogen group or a triflate group. In the case of the Negishi coupling reaction, for example, X 1 and X 2 Preferably, one of the groups is an organozinc group (-ZnX) and the other is a halogen group.

[0067] When an ether bond is formed, for example, X 1 and X 2 Preferably, one of the groups is a hydroxyl group and the other is a halogen group. When forming a thioether bond, for example, X 1 and X 2 Preferably, one of the groups is a thiol group and the other is a halogen group. When forming an amine bond, for example, X 1 and X 2 Preferably, one of the groups is an amino group and the other is a halogen group.

[0068] When forming an amide bond, for example, X 1 and X 2Preferably, one of the groups is an amino group, and the other is a carboxylic acid group, an acid halide group (-CO-X), or an acid anhydride group. When forming an ester bond, for example, X 1 and X 2 Preferably, one of the groups is a hydroxyl group and the other is a carboxylic acid group or an acid halide group (-CO-X). When forming a carbonyl bond, for example, X 1 and X 2 Preferably, one of the groups is a Weinreb amide group (-CO-N(OMe)2) and the other is a group that forms a Grignard reagent (-MgX) or an organolithium group (-Li). When forming aromatic heterocycles, click reactions, such as the Huisgen cyclization reaction, can be used. For example, X 1 and X 2 If one of the groups is an azide group (-N3) and the other is a terminal alkyne, a 1,2,3-triazole ring can be formed.

[0069] Among the bonds formed, amide bonds are preferred. In this case, X 1 is an amino group, X 2 It is preferable that X is a carboxylic acid group, an acid halide group (-CO-X), or an acid anhydride group. 1 is an amino group, X 2 It is more preferable that the group is an acid halide group (-CO-X).

[0070] The reaction substrate S1 (hereinafter also referred to as intermediate S1), which consists of an atomic group portion that binds to the asialoglycoprotein receptor and a linker portion, and the reaction substrate S2 (hereinafter also referred to as intermediate S2), which is a nonionic iodine contrast agent portion, can be synthesized by appropriate organic synthesis methods. For example, intermediate S1 has a linker moiety introduced to the group that will become the atomic group, followed by the reactive group X 1It can be prepared by introducing. When the atomic group is a sugar residue structure, it is as shown in the following scheme. Specifically, starting with a sugar or its derivative such as penta-O-acetyl-D-galactopyranose or hepta-O-acetyl-D-galactopyranosyl-N-acetylglucosamine, introducing a linker moiety, and subsequently introducing a reactive group X 1 It can be prepared by introducing. In the synthesis of intermediate S1, it may appropriately include conversion steps necessary for the synthesis of intermediate S1, such as protection and / or deprotection steps of functional groups with protecting groups of functional groups.

[0071]

Chemical formula

[0072] Before bonding the atomic group portion that binds to the asialoglycoprotein receptor and the linker portion, the functional group of the atomic group portion that binds to the asialoglycoprotein receptor may be previously converted to another substituent. When the atomic group is a sugar residue structure, for example, the hydroxyl group of the sugar portion may be previously converted to another substituent. Such substituents include a primary amino group, an acylamino group, and the like. As described above, by previously converting the functional group of the atomic group portion that binds to the asialoglycoprotein receptor to another substituent, the atomic group portion that binds to the asialoglycoprotein receptor and the linker can be bonded by an arbitrary bond. For example, when the atomic group is a sugar residue structure, the hydroxyl group of the sugar portion can be substituted with an amino group as follows, and thereby the sugar portion and the linker can be bonded by an amide bond.

[0073]

Chemical formula

[0074] The introduction of the linker may be carried out stepwise. That is, the linker structure may be extended by a reaction in two or more steps to obtain the final linker structure.

[0075] Intermediate S2 is, for example, as shown in the following scheme, R S1 ~R S3 Starting with an aromatic compound having any substituent represented by , an iodine group is introduced, followed by a reactive group X 2 It can be prepared by introducing and inducing S2. In the synthesis of intermediate S2, transformation steps necessary for the synthesis of intermediate S2 may be included as appropriate, such as a step of protecting and / or deprotecting the functional group with a protecting group.

[0076] [ka]

[0077] R S1 ~R S3 It is preferable that the substituents differ depending on the number of atomic groups introduced that bind to the asialocrytoprotein acceptor.

[0078] The synthesis of the compounds of the present invention may be carried out in the presence of a reaction solvent, catalyst, additives, etc., as appropriate. Reaction conditions such as reaction temperature, reaction pressure, and reaction time may also be adjusted as appropriate. Furthermore, the obtained product may be acquired as the compound of the present invention after appropriate post-treatment. Specific post-treatment methods include known purification methods such as extraction and / or crystallization, recrystallization, and chromatography.

[0079] [Contrast agent] The compounds of the present invention can be used as contrast agents. Therefore, one embodiment of the present invention is a contrast agent containing the compounds of the present invention.

[0080] The imaging techniques to which the contrast agent of the present invention is applied are envisioned to include almost all contrast-enhanced X-ray examinations performed using existing iodine-based contrast agents. This includes contrast-enhanced CT scans from the head and neck to the chest, upper and lower abdomen, and limbs, as well as examinations and treatments using vascular catheters in the brain, heart, aorta, and abdomen. Furthermore, since this contrast agent is excreted in bile and urine, it is expected to be applicable to excretory urography, excretory cholangiopancreatography, and the like.

[0081] The compounds of the present invention can be used in the form of pharmaceutical compositions known as contrast agents. The above pharmaceutical compositions can be manufactured by conventionally known methods. The compounds of the present invention may be used individually or as a mixture of two or more compounds. The contrast agent of the present invention may contain pharmaceutically acceptable additives. These additives are not limited to, but include stabilizers, excipients, binders, disintegrants, lubricants, antioxidants, flavoring agents, colorants, and fragrances.

[0082] The contrast agent of the present invention is formulated to be suitable for therapeutically appropriate routes of administration, including intravenous, intradermal, subcutaneous, oral (including, for example, inhalation), transdermal, and transmucosal administration, but is preferably administered by intravenous injection due to its excellent handling properties.

[0083] The dosage of the contrast agent of the present invention is determined appropriately depending on the patient's condition, the method of administration, and other factors.

[0084] The present invention further provides a pharmaceutical composition comprising a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. Such a pharmaceutical composition may further contain pharmaceutically acceptable additives. The pharmaceutical composition may be used as a contrast agent. The present invention also provides a contrast-enhanced X-ray examination method using a pharmaceutical composition comprising a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. The present invention also provides a compound represented by formula (1) or a pharmaceutically acceptable salt thereof for use in contrast-enhanced X-ray examinations. [Examples]

[0085] Hereinafter, the present embodiment will be described in detail by way of examples, but the present invention is not limited to the following examples.

[0086] [Example 1] Synthesis of MEG-1 For the synthesis of MEG-1, first, the synthesis of Intermediate I and Intermediate II was carried out.

[0087] <Synthesis of Intermediate I> Intermediate I was synthesized according to the following scheme.

[0088] [Chemical formula]

[0089] Commercially available diatrizoic acid (manufactured by Tokyo Chemical Industry Co., Ltd., 2.01 g, 3.27 mmol) was dissolved in thionyl chloride (20.0 mL), and refluxed at 120 °C for 3 hours using an oil bath. After distilling off thionyl chloride, it was washed with n-hexane to obtain Intermediate I (1.39 g, 67%) as a yellowish-white powder. For Intermediate I 1 The 1H-NMR was as follows. 1 1H-NMR (500 MHz, DMSO-D6) δ: 10.13 (s, 1H), 10.04 (s, 1H), 2.03 (s, 6H)

[0090] <Synthesis of Intermediate II> Intermediate II was synthesized according to the following scheme.

[0091] [Chemical formula]

[0092] (Step 1) The reaction conditions for Step 1 and subsequent Step 2 were referred to Patent No. 4293735. Specifically, first, commercially available penta-O-acetyl-β-D-galactopyranose (manufactured by Tokyo Chemical Industry Co., Ltd., 3.89 g, 9.97 mmol) and 2-bromoethanol (0.71 mL, 9.45 mmol) were dissolved in anhydrous methylene chloride (41.0 mL) under argon. Next, boronic acid (4.11 mL, 32.1 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 1 hour, followed by stirring overnight in the dark. After stirring, the reaction solution turned orange. Water was added to the reaction solution to stop the reaction, and the solution was concentrated. After the reaction, an appropriate amount of ethyl acetate was added, and the solution was separated using water, saturated sodium carbonate aqueous solution, and saturated brine. After drying with sodium sulfide, the solution was filtered and concentrated. Subsequently, the solution was purified using silica gel column chromatography (n-hexane:ethyl acetate = 3:2) to obtain the bromo compound (3.03 g, 67%) as a colorless, transparent, candy-like substance. Bromo form 1 The H-NMR results were as follows: 1 H-NMR (500 MHz,CDCl3) δ: 5.40 (dd, J = 3.5, 1.0 Hz, 1H), 5.24 (dd, J = 10.9, 8.0 Hz, 1H), 5.03 (dd, J = 10.3, 3.4 Hz, 1H), 4.54 (d, J = 8.0 Hz, 1H), 4.17-4.21 (m, 2H), 4.12 (dd, J = 11.2, 6.6 Hz, 1H), 3.92 (td, J = 6.6, 1.1 Hz, 1H), 3.80-3.85 (m, 1H), 3.46-3.51 (m, 2H), 2.16 (s, 3H), 2.09 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H)

[0093] (Step 2) The bromo compound (3.02 g, 6.66 mmol) obtained in Step 1 and sodium azide (1.00 g, 15.4 mmol) were dissolved in anhydrous dimethylformamide (35.0 mL) under argon and stirred overnight at 80°C. After the reaction, an appropriate amount of ethyl acetate was added, and the mixture was separated using water, saturated sodium carbonate aqueous solution, and saturated brine. After drying with sodium sulfide, the mixture was filtered and concentrated. Subsequently, the mixture was purified using silica gel column chromatography (n-hexane:ethyl acetate = 3:2) to obtain the azide compound (2.37 g, 86%) as a colorless, transparent oily substance. Azidoid body 1 The H-NMR results were as follows: 1 H-NMR (500 MHz, CDCl3) δ: 5.41 (dd, J = 3.5, 1.5 Hz 1H), 5.27 (dd, J = 10.5, 8.0 Hz 1H), 5.04 (dd, J = 10.0, 3.5 Hz 1H), 4.56 (d, J = 8.0 Hz 1H), 4.11-4.21 (m, 2H), 4.03-4.07 (m, 1H), 3.91 (td, J = 7.0, 1.0 Hz 1H), 3.68-3.72 (m, 1H), 3.49-3.54 (m, 1H), 3.29-3.33 (m, 1H), 2.16 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H)

[0094] (Step 3) The reaction conditions for Step 3 and the subsequent Step 4 were referenced from Journal of Medicinal Chemistry, 2005, 48, 645-652. Specifically, the azide compound (1.75 g, 4.21 mmol) obtained in Step 2 was dissolved in dehydrated methanol (40.0 mL) under argon. A sodium methoxide methanol solution (1 M in MeOH) was added until the pH reached 9. Then, the mixture was stirred at room temperature until the reaction was completed (TLC: iso-PrOH-water = 7:3, Rf = 0.810), and neutralized using an ion exchange resin (12.0 g, Amberlite H+). After filtering the solution, it was concentrated using an evaporator to obtain the deacetylated compound (1.02 g, 97%) as a yellow or brown oily substance. The deacetylated compound 1 1H-NMR was as follows. 1 1H-NMR (500 MHz, D2O) δ: 4.29 (d, J = 8.0 Hz, 1H), 3.77 - 3.78 (m, 1H), 3.64 - 3.71 (m, 1H), 3.53 - 3.62 (m, 4H), 3.50 (dd, J = 10.0, 3.7 Hz, 1H), 3.36 - 3.41 (m, 3H)

[0095] (Step 4) The deacetylated compound (52.9 mg, 0.212 mmol) obtained in Step 3 and palladium carbon catalyst (10% Pd-C, 6.70 mg) were added to dehydrated methanol (4.50 mL), and hydrogen substitution was carried out. After stirring at room temperature for 20 hours, it was filtered and concentrated using an evaporator to obtain Intermediate II (43.3 mg, 92%) as a yellow or brown solid. 1 1H-NMR (500 MHz, D2O) δ: 4.26 (d, J = 7.4 Hz, 1H), 3.76 - 3.81 (m, 1H), 3.63 (d, J = 4.0 Hz, 1H), 3.53 - 3.61 (m, 4H), 3.50 (dd, J = 10.0, 3.7 Hz, 1H), 3.38 (dd, J = 9.7, 8.0 Hz, 1H), 2.70 - 2.73 (m, 2H)

[0096] <Synthesis of MEG-1> MEG-1 was synthesized according to the following scheme.

[0097] [ka]

[0098] Specifically, intermediate II (29.1 mg, 0.130 mmol) and intermediate I (82.2 mg, 0.130 mmol) were first dissolved in anhydrous DMF (4.00 mL). Then, triethylamine (19.9 μmL) was slowly added dropwise, and the mixture was stirred overnight at room temperature. The solvent was concentrated using an evaporator and purified by silica gel column chromatography (chloroform:methanol = 4:1) to obtain crude MEG-1 (38.6 mg, 36%) as a yellow or brown solid. Subsequently, further purification was performed using size exclusion chromatography (SEC) to obtain MEG-1 as colorless, transparent crystals. MEG-1 1 The 1H-NMR results were as follows: 1 H-NMR (500 MHz, D2O) δ: 4.31-4.35 (m, 1H), 3.80-3.99 (m, 1H), 3.78-3.88 (m, 1H), 3.74 (s, 1H), 3.46-3.66 (m, 6H), 3.36-3.40 (m, 1H), 2.11 (s, 6H)

[0099] [Example 2] Synthesis of MEG-2 Following the synthesis method for MEG-1 in Example 1, MEG-2 was synthesized according to the following scheme. First, intermediate II' was synthesized.

[0100] <Synthesis of intermediate II'> Intermediate II' was synthesized according to the following scheme.

[0101] [ka]

[0102] (Step 5) The reaction conditions for Step 5 and the subsequent Step 6 were referenced from Chinese Journal of Chemistry, 2006, 24, 1058-1061. Specifically, first, commercially available penta-O-acetyl-β-D-galactopyranose (manufactured by Tokyo Chemical Industry Co., Ltd., 3.91 g, 10.0 mmol) and 2-(2-chloroethoxy)ethanol (1.70 mL, 16.0 mmol) were dissolved in anhydrous methylene chloride (41.0 mL) under argon. Next, boronic acid (3.90 mL, 30.4 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 1 hour, followed by stirring overnight in the dark. After stirring, the reaction solution turned orange. Water was added to the reaction solution to stop the reaction, and the solution was concentrated. After the reaction, an appropriate amount of ethyl acetate was added, and the solution was separated using water, saturated sodium carbonate aqueous solution, and saturated brine. After drying with sodium sulfide, the solution was filtered and concentrated. Subsequently, the solution was purified using silica gel column chromatography (n-hexane:ethyl acetate = 3:2) to obtain the chloro compound as a colorless, transparent oily substance. Chloride 1 The H-NMR results were as follows: 1 H-NMR (500 MHz, CDCl3) δ: 5.39 (s, 1H), 5.19-5.23 (m, 1H), 5.02 (td, J = 6.7, 3.4 Hz, 1H), 4.59 (dd, J = 7.7, 2.0 Hz, 1H), 4.09-4.20 (m, 2H), 3.91-3.99 (m, 2H), 3.72-3.78 (m, 3H), 3.61-3.69 (m, 4H), 2.15 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H)

[0103] (Step 6) The chloro compound (1.84 g, 4.06 mmol) obtained in Step 5 and sodium azide (0.612 g, 9.41 mmol) were dissolved in anhydrous dimethylformamide (35.0 mL) under argon and stirred overnight at 80°C. After the reaction, an appropriate amount of ethyl acetate was added, and the mixture was separated using water, saturated sodium carbonate aqueous solution, and saturated brine. After drying with sodium sulfide, the mixture was filtered and concentrated. Subsequently, the mixture was purified using silica gel column chromatography (n-hexane:ethyl acetate = 3:2) to obtain the azide compound (1.75 g, 94%) as a clear yellow oily substance. Azidoid body 1 The H-NMR results were as follows: 1 H-NMR (500 MHz, CDCl3) δ: 5.39 (d, J = 3.4 Hz, 1H), 5.22 (dd, J = 10.9, 8.0 Hz, 1H), 5.01 (dd, J = 11.0, 3.5 Hz 1H), 4.59 (d, J = 8.0 Hz, 1H), 4.11-4.20 (m, 2H), 3.91-3.99 (m, 2H), 3.75-3.79 (m, 1H), 3.62-3.71 (m, 4H), 3.38 (m, 2H), 2.15 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H)

[0104] (Step 7) The reaction conditions for Step 7 were based on Org. Biomol. Chem., 2018, 16, 8413-8419. Specifically, the azide compound (383 mg, 0.830 mmol) obtained in step 6 was dissolved in anhydrous methanol (18.0 mL) under argon. Sodium methoxide methanol solution (1 M in MeOH) was added until the pH reached 9. The mixture was then stirred at room temperature until the reaction was complete (TLC: iso-PrOH-water = 7:3, Rf=0.818), and neutralized using ion exchange resin (3.00 g, Amberlite H+). After filtering the solution, it was concentrated using an evaporator to obtain the deacetylated compound (1.02 g, 97%) as a brown oily substance. Deacetylated 1 The H-NMR results were as follows: 1 H-NMR (500 MHz, CD3OD) δ: 4.26-4.28 (d, J = 7.4 Hz, 1H), 3.99-4.03 (m, 1H), 3.82 (s, 1H), 3.65-3.77 (m, 9H), 3.45-3.54 (m, 3H)

[0105] (Step 8) The reaction conditions for Step 8 were based on J. Med. Chem., 2005, 48, 645-652. Specifically, the deacetylated product obtained in step 7 (1.0 g, 3.64 mmol) and a palladium-carbon catalyst (10% Pd-C, 0.135 g) were added to anhydrous methanol (35.0 mL), and hydrogenation was performed. After stirring at room temperature for 18 hours, the mixture was filtered and concentrated using an evaporator to obtain intermediate II' (833 mg, 86%) as a brown, oily substance. Intermediate II' 1 The H-NMR results were as follows: 1 H-NMR (500 MHz, CD3OD) δ: 4.26-4.27 (d, J = 7.4 Hz, 1H), 3.97-4.04 (m, 1H), 381-3.82 (m, 1H), 3.66-3.77 (m, 9H), 3.52-3.56 (m, 3H)

[0106] <Synthesis of MEG-2> MEG-2 was synthesized according to the following scheme.

[0107] [Chemical formula]

[0108] Specifically, intermediate II' (67.0 mg, 0.251 mmol) and intermediate I (159 mg, 0.252 mmol) were dissolved in dehydrated DMF (3.00 mL). Subsequently, triethylamine (34.8 μL) was slowly added dropwise, and the mixture was stirred overnight at room temperature. The solvent was concentrated using an evaporator and purified by silica gel column chromatography (chloroform: methanol = 4: 1) to obtain crude MEG-2 (31.0 mg, 16%) as a yellow or brown solid. Thereafter, further purification was performed using size exclusion chromatography (SEC) to obtain MEG-2 as colorless transparent crystals. For MEG-2 1 The 1H-NMR was as follows. 1 1H-NMR (500 MHz, D2O) δ: 4.24 - 4.26 (m, 1H), 3.89 - 3.93 (m, 1H), 3.74 (s, 1H), 3.42 - 3.69 (m, 11H), 3.32 - 3.37 (m, 1H), 2.10 (s, 6H)

[0109] [Example 3] Synthesis of RYO-1 For the synthesis of RYO-1, first, the synthesis of intermediate III was carried out.

[0110] <Synthesis of intermediate III> Intermediate III was synthesized according to the following scheme. The synthesis of intermediate III was carried out referring to Jinyong Fan et al, Journal of Materials Science: Materials in Medicine, 2010, 21, 319 - 327.

[0111] [Chemical formula]

[0112] Specifically, first, an anhydrous dimethyl sulfoxide (DMSO) solution of lactone as the starting material and excess ethylenediamine was refluxed for 2 hours. The product, intermediate III, was precipitated by adding acetone, and the resulting yellow precipitate was dried under reduced pressure. The results of the mass spectrometry of the obtained intermediate III were as follows. LCMS (ESI) m / z [M+H] + calcd for C 14 H 29 N2O 11 : 401; found: 401.

[0113] The above lactone was synthesized according to the following scheme by referring to Alexandra. M. B et al, European polymer journal, 2012, 48, 963-973.

[0114] [Chemical formula]

[0115] Specifically, first, an aqueous solution of deionized water (375 mL) containing 18.0 g (50 mmol) of 4-O-β-galactopyranosyl-D-gluconic acid (manufactured by Fujifilm Wako Pure Chemical Corporation) was heated at 40°C for 1 hour. Then, water was removed under reduced pressure, and the residue was washed with methanol (375 mL). Subsequently, methanol was evaporated, and this operation was repeated 4 times, and this operation was further performed 2 times using 2-propanol. The target lactone was obtained as a white solid (14.19 g, 83%).

[0116] [Synthesis of RYO-1] According to the synthesis method of MEG-1 in Example 1, RYO-1 was synthesized according to the following scheme.

[0117] [ka]

[0118] Intermediate I was dissolved in DMF (3 ml), and intermediate III (100 mg, 0.25 mmol) was added at room temperature. The reaction mixture was then stirred overnight at 50°C. Subsequently, the reaction mixture was separated using direct silica gel column chromatography (chloroform:methanol:water = 30:20:4; v / v) to obtain a white solid (Rf = 0.24; chloroform:methanol:water = 30:20:4; v / v). The product was then separated using size exclusion recycling HPLC (eluent: water, flow rate: 3 ml / mins), and the fraction containing the product was dried at 60°C to obtain RYO-1 as a white solid. RYO-1 1 The 1H-NMR results were as follows: 1 H-NMR (500 MHz, D2O) δ: 8.04 (s, 1H), 4.38 (d, J = 7.4 Hz, 1H), 4.25 (d, J = 1.7 Hz, 1H), 4.05 (s, 1H), 3.33-3.83 (m, 14H), 2.08 (d, J = 2.3Hz, 6H)

[0119] [Example 4] Synthesis of MEG-3 To synthesize MEG-3, we first synthesized intermediate IV.

[0120] <Synthesis of Intermediate IV> Intermediate IV was synthesized according to the following scheme. [ka]

[0121] (Step 9) The reaction conditions for Step 9 were based on Chinese Patent No. 102503814. Specifically, a solution of triiodomesitylene (1.0 g, 2.0 mmol) in pyridine (30 ml) and water (10 ml) was stirred at 60°C for 10 minutes. Triiodomesitylene was synthesized by referring to US Patent 6310243. Next, potassium permanganate (12 g, 75.9 mmol) was added little by little over 5 hours at 90°C. After stirring for 24 hours, the reaction mixture was filtered while hot and washed with a 5% aqueous potassium hydroxide solution. The filtrate was concentrated at 60°C under reduced pressure. Water was added to the residue, and the mixture was filtered to remove the insoluble white solid. A 5 N aqueous hydrochloric acid solution was added to adjust the pH to 1, and the filtrate was extracted 3 times with ethyl acetate. The organic phase was distilled off to obtain the carboxylic acid as a white solid (0.82 g, 70%).

[0122] (Step 10) The reaction conditions of Step 10 were referred to US Patent No. 6310243. Specifically, the carboxylic acid (200 mg, 0.339 mmol) obtained in Step 9 was placed in a eggplant flask, thionyl chloride (1 mL) and DMF (1 drop) were added, and the mixture was refluxed at 120°C for 2.5 hours. After distilling off under reduced pressure at 50°C, it was dissolved in toluene (10 mL) and stirred at 50°C for 2 hours. Then, after removing the solid by filtration, it was concentrated, washed with a small amount of hexane, and Intermediate IV (92.6 mg, 43%) was obtained as a white powder.

[0123] <Synthesis of MEG-3> MEG-3 was synthesized according to the following scheme.

[0124] [Chemical formula]

[0125] Specifically, intermediate II (56.3 mg, 0.252 mmol) and intermediate IV (50.1 mg, 0.0781 mmol) were first dissolved in anhydrous DMF (5.00 mL). Then, triethylamine (30.0 μmL) was slowly added dropwise, and the mixture was stirred overnight at room temperature. After concentrating the solvent using an evaporator, the mixture was purified three times using size exclusion chromatography (SEC) to obtain MEG-3 as a brown, transparent crystal. MEG-3 1 The 1H-NMR results were as follows: 1 H-NMR (500 MHz, D2O) δ: 4.36-4.36 (m, 1H), 3.96-4.01 (m, 1H), 3.81-3.86 (m, 1H), 3.76-3.79 (m, 1H), 3.50-3.60 (m, 6H), 3.39-3.42 (m, 1H)

[0126] [Example 5] Synthesis of MEG-4 MEG-4 was synthesized according to the following scheme, following the synthesis method for MEG-3 in Example 4.

[0127] [ka]

[0128] Specifically, intermediate II' (25.1 mg, 0.0935 mmol) and intermediate IV (20.0 mg, 0.0312 mmol) were dissolved in anhydrous DMF (3.30 mL). Subsequently, triethylamine (13.0 μmL) was slowly added dropwise, and the mixture was stirred overnight at room temperature. After concentrating the solvent using an evaporator, the mixture was purified by size exclusion chromatography (SEC) to obtain MEG-4 as a mixture. MEG-4 1 The results of the 1H-NMR and mass spectrometry were as follows. 1H-NMR (500 MHz, D2O) δ: 4.24-4.33 (dd, J = 7.4, 5.2 Hz, 1H), 3.87-3.94 (m, 3H), 3.79-3.80 (m, 3H), 3.51-3.71 (m, 33H), 3.34-3.46 (m, 3H); HRMS (ESI) m / z [M+Na] + calcd for C 63 H 84 I3N3O 36 : 1358.0592; found 1358.0599.

[0129] [Example 6] Synthesis of KBT To synthesize KBT, we first synthesized the intermediate III'.

[0130] <Synthesis of intermediate III'> Intermediate III' was synthesized according to the following scheme.

[0131] [ka]

[0132] (Step 11) Triiodomesitylene (19.5 g, 39 mmol) was added to a mixture of glacial acetic acid (200 ml), acetic anhydride (400 ml), and concentrated sulfuric acid (40 ml). Potassium permanganate (24.6 g, 156 mmol) was added in small amounts over 3 hours. After stirring for 16 hours, the solvent was removed by distillation, and water (200 ml) was added. The suspension was extracted with dichloromethane (250 ml), the organic phase was washed with water, dried over magnesium sulfate, and then removed by distillation. The solid residue was purified by silica gel chromatography (eluent: chloroform). 8.2 g of the acetylated compound (1,3,5-triiodo-2,4,6-triacetoxymethylbenzene) was obtained (yield 31%). Acetyl compounds 1 The 1H-NMR results were as follows: 1H-NMR (CDCl3) δ: 5.70 (s, 1H), 2.11 (s, 2H)

[0133] (Step 12) The acetylated compound (7.56 g, 11.25 mmol) obtained in Step 11 was suspended in methanol (120 ml), and K2CO3 (0.26 g, 1.9 mmol) was added. The mixture was stirred at ambient temperature for 16 hours. After neutralization with 2 M aqueous hydrochloric acid, the organic solvent was removed by distillation. The residue was suspended in water, and the white solid was collected by filtration. The mixture was then washed sequentially with water, methanol, and ether to obtain 6.0 g of alcohol (1,3,5-triiodo-2,4,6-trihydroxymethylbenzene) (yield 94%). Alcohol 1 The 1H-NMR results were as follows: 1 H-NMR (DMSO-d6) δ: 5.11-5.07 (s, 6H), 3.32 (s, 3H)

[0134] (Step 13) The alcohol (1.0 g, 1.83 mmol) obtained in Step 12 was suspended in thionyl chloride (50 mL). Three drops of DMF were added, and the mixture was heated under reflux for 3 hours. Thionyl chloride was removed under reduced pressure. The solid residue was suspended in toluene (20 mL), and the solution was poured onto ice. The product was extracted with toluene, and the organic phase was washed three times with water and once with saturated brine. After drying with sodium sulfate, the mixture was filtered and concentrated to obtain 5.9 g of the chloro compound (1,3,5-tri(chloromethyl)-2,4,6-triiodobenzene) (yield 97%). Chloride 1 The 1H-NMR results were as follows: 1 H-NMR (CDCl3) δ: 5.29 (s, 6H)

[0135] (Step 14) Sodium azide (65 mg, 1 mmol) was added to a DMSO solution of the chloro compound (0.1 g, 0.17 mmol) obtained in Step 13 under an argon atmosphere. After the solution was stirred at 60 °C for 1 hour, the reaction was quenched with water. The product was extracted three times with ethyl acetate, and the organic phase was washed with saturated brine. After drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure, azide (1,3,5-tri(azidomethyl)-2,4,6-triiodobenzene) (0.1017 g, yield 98%) was obtained as a white solid. Of azide 1 1H-NMR was as follows. 1 1H-NMR (CDCl3) δ: 5.20 (s, 6H).

[0136] (Step 15) Triphenylphosphine (0.79 g, 3 mmol) was added to a THF (5 ml) solution of the azide (0.53 g, 0.85 mmol) obtained in Step 14 at 0 °C under an argon atmosphere. The reaction mixture was stirred for 10 minutes. After adding water (0.8 ml) to this solution at 0 °C, the mixture was stirred overnight at ambient temperature. The product was extracted with 2 N aqueous hydrochloric acid solution, and the aqueous solution was washed once with ether to remove triphenylphosphine and four times with ethyl acetate to remove triphenylphosphine oxide. To the aqueous layer, 5 N aqueous potassium hydroxide solution was added until the pH reached about 14, and then the product was extracted three times with chloroform. The organic layer was concentrated under reduced pressure to obtain Intermediate III' as a white solid. Of Intermediate III' 1 1H-NMR was as follows. 1 1H-NMR (CDCl3) δ: 4.47 (s, 6H)

[0137] <Synthesis of KBT> KBT was synthesized according to the following scheme.

[0138]

Chemical formula

[0139] Intermediate III' (10 mg, 0.018 mmol) and the lactone (27 mg, 0.079 mmol) used as a starting material in the synthesis of intermediate III were mixed in acetonitrile (3 mL) and refluxed for 120 hours. After cooling, chloroform and water were added to the mixture and extracted with chloroform. The organic layer was concentrated under reduced pressure to obtain white crystals. The crystals were purified by size exclusion chromatography using water as the eluent to obtain KBT. KBT 1 The 1H-NMR results were as follows: 1 H-NMR (500 MHz, D2O) δ: 4.85 (s, 6H), 4.40 (d, J = 7.4 Hz, 3H), 4.23-4.28 (m, 3H), 4.03 (br s, 3H), 3.86-3.39 (m, 33H)

[0140] [Example 7] Synthesis of RYO-2 RYO-2 was synthesized according to the following scheme.

[0141] [ka]

[0142] Specifically, to a solution of intermediate IV (50 mg, 0.78 mmol) dissolved in DMF (3 ml), intermediate III (109 mg, 0.27 mmol), synthesized in the same manner as in Example 3, and DIPEA (diisopropylethylamine) (48 μL, 0.27 mmol) were added at room temperature. Next, the reaction mixture was stirred overnight at 50°C. Subsequently, the reaction mixture was separated using direct silica gel column chromatography (methanol:water = 1:1; v / v) to obtain a white solid. Subsequently, the product was separated using size exclusion recycling HPLC (eluent: water, flow rate: 5 ml / mins), and the fraction containing the product was dried at 60°C to obtain RYO-2 as a white solid. RYO-2 1The 1H-NMR results were as follows: 1 H-NMR (500 MHz, D2O) δ: 8.04 (s, 3H), 4.38 (d, J = 7.4 Hz, 3H), 4.25 (s, 3H), 4.05 (s, 3H), 3.81 (dd, J = 6.6, 4.3 Hz, 3H), 3.67-3.75 (m, 9H), 3.32-3.62 (m, 33H)

[0143] [Example 8] Synthesis of PK-1 and PK-2 To synthesize PK-1, we first synthesized intermediate V'. Furthermore, intermediate V for the synthesis of PK-2 can be synthesized as follows.

[0144] <Synthesis of intermediates V' and V> Intermediate V' was synthesized according to the following scheme. Intermediate V can be synthesized according to the following scheme.

[0145] [ka]

[0146] (Step 16) A mixture of sodium bicarbonate (742 mg, 8.83 mmol) and 37% formaldehyde aqueous solution (27 mL) was slowly mixed with diethyl malonate (15 mL, 99.4 mmol) at room temperature, and the mixture was stirred for 4 hours. The reaction was stopped by adding saturated saline solution, and the product was extracted four times with diethyl ether. The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. Diethyl 2,2-bis(hydroxymethyl)malonate (21.3 g, 98%) was obtained as a colorless oil (Rf = 0.31, ethyl acetate:n-hexane = 1:1; v / v). Diethyl 2,2-bis(hydroxymethyl)malonate 1 The 1H-NMR results were as follows: 1H-NMR (500 MHz, CDCl3) δ: 4.15-4.26 (m, 4H), 4.06 (m, J = 12.0 Hz, 4H), 3.13-3.41 (m, 2H), 1.18-1.24 (m, 6H)

[0147] (Step 17) Under an argon atmosphere, diethyl 2,2-bis(hydroxymethyl)malonate (5.00 g, 22.9 mmol) and super-anhydrous acetone (15 mL) were mixed, followed by the addition of acetone dimethyl acetal (3.62 mL, 29.5 mmol), and then concentrated sulfuric acid (0.1 mL). The reaction mixture was stirred at room temperature for 24 hours, then saturated sodium bicarbonate aqueous solution was added and stirred for 15 minutes. The mixture was filtered, and the filtrate was extracted twice with acetone, and the solvent was removed under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the residue, and the product was extracted with diethyl ether and washed with saturated saline solution. The extract was dried over sodium sulfate, filtered, concentrated, and the residue purified by neutral silica gel column chromatography to obtain diethyl 2,2-dimethyl-1,3-dioxane-5,5-dicarboxylate (4.25 g, 71%) as a colorless oil (Rf = 0.9, ethyl acetate:n-hexane = 1:1; v / v). Diethyl 2,2-dimethyl-1,3-dioxane-5,5-dicarboxylate 1 The 1H-NMR results were as follows: 1 H-NMR (500 MHz, CDCl3) δ: 4.25 (s, 4H), 4.20 (q, J = 7.1 Hz, 4H), 1.38 (s, 6H), 1.23 (t, J = 7.2 Hz, 6H)

[0148] (Step 18) A mixed solution of diethyl 2,2-dimethyl-1,3-dioxane-5,5-dicarboxylate (391 mg, 1.5 mmol), sodium chloride (106 mg, 1.81 mmol), water (2-3 drops), and DMSO (3 mL) was refluxed at 180°C for 20 hours. After cooling to room temperature, saturated saline solution was added, and the product was extracted four times with diethyl ether and washed twice with saturated saline solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was distilled (6 Torr, 153°C) to obtain 2,2-dimethyl-5-carboethoxy-1,3-dioxane (181 mg, 64%) as a pale yellow oil. 2,2-dimethyl-5-carboethoxy-1,3-dioxane 1 The 1H-NMR results were as follows: 1 H-NMR (500 MHz, CDCl3) δ: 4.17 (q, J = 21.8 Hz, 2H), 4.04 (d, J = 20.0 Hz, 4H), 2.80 (m, J = 28.1 Hz, 1H), 1.45 (s, 3H), 1.42 (s, 3H), 1.27 (d, J = 14.3 Hz, 3H)

[0149] (Steps 19-20) Step 19 can be carried out by hydrolyzing 2,2-dimethyl-5-carboethoxy-1,3-dioxane with lithium hydroxide in THF solvent. Step 20 can be carried out by reacting the product obtained in Step 19 with oxalyl chloride in methylene chloride solvent at room temperature.

[0150] (Step 21) Under an argon atmosphere, a solution of lithium aluminum hydride (88.3 mg, 2.33 mmol) in THF (2 mL) was added dropwise to a solution of 2,2-dimethyl-5-carboethoxy-1,3-dioxane (207 mg, 1.10 mmol) in THF (2 mL), and the mixed solution was heated under reflux for 20 hours. After cooling, 10 mL of 6 M aqueous sodium hydroxide solution was added, and the product was extracted four times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2,2-dimethyl-1,3-dioxane-5-methanol (80 mg, 50%) as a pale yellow oil. 2,2-dimethyl-1,3-dioxane-5-methanol 1 The 1H-NMR results were as follows: 1 H NMR (500MHz, CDCl3) δ: 4.03 (dd, J = 12.0, 4.0 Hz, 2H), 3.77-3.80 (m, 4H), 1.83 (m, 1H), 1.66 (t, J = 5.1 Hz, 1H), 1.45 (s, 3H), 1.41 (s, 3H)

[0151] (Step 22) 2,2-dimethyl-1,3-dioxane-5-methanol (59 mg, 0.40 mmol), dichloromethane (2 mL), and triethylamine (0.1 mL) were mixed and cooled to 0°C. Tosyl loride (102 mg, 0.7 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was then washed twice with saturated ammonium chloride and once with saturated brine, and the product was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated to obtain intermediate V' (L = p-toluenesulfonyl) (82 mg, 90%) as a light brown oil. Intermediate V' (L = p-toluenesulfonyl) 1 The 1H-NMR results were as follows: 1H-NMR (500 MHz, CDCl3) δ: 7.79 - 7.81 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.17 (d, J = 6.9 Hz, 2H), 3.97 (dd, J = 12.3, 3.7 Hz, 2H), 3.68 (dd, J = 12.0, 4.6 Hz, 2H), 2.45 (s, 3H), 1.95 (m, J = 22.3 Hz, 1H), 1.40 (s, 3H), 1.30 (s, 3H)

[0152] <Synthesis of Intermediate VI' and VI> Next, Intermediate VI' is synthesized from Intermediate V' according to the following scheme. Also, Intermediate VI is synthesized from Intermediate V according to the following scheme.

[0153]

Chem.

Chem.

[0154] Specifically, the synthesis of Intermediate VI' can be carried out by hydrolyzing commercially available diatrizoic acid with hydrochloric acid and then reacting it with Intermediate V'. The synthesis of Intermediate VI can be carried out by treating commercially available diatrizoic acid with a base and then reacting it with Intermediate V.

[0155] <Synthesis of PK-1 and PK-2> Using the azide compound obtained in Step 2 of the synthesis method of Intermediate II in Example 1 and Intermediate VI' or VI, the following PK-1 and PK-2 can be synthesized.

Chem.

[0156] Specifically, PK-1 can be synthesized according to the following scheme. The azide obtained in step 2 of the synthesis method for intermediate II is aminated by the method in step 4 of the synthesis method for intermediate II in Example 1. The resulting amino compound is coupled with intermediate VI' using a peptide bond-forming reagent such as DCC or EDC, and then deprotected by base treatment and acid treatment to obtain PK-1. [ka]

[0157] Similarly, PK-2 can be synthesized from intermediate VI according to the following scheme.

[0158] [ka] [Example 9] Synthesis of KOG-1 To synthesize KOG-1, we first synthesized the intermediate II''.

[0159] <Synthesis of Intermediate II''> Intermediate II'' was synthesized according to the following scheme. [ka]

[0160] (Step 23) Under an argon atmosphere, commercially available penta-O-acetyl-β-D-galactopyranose (Tokyo Chemical Industries, Ltd., 5.04 g, 12.9 mmol) and benzylamine (2.8 mL, 25.6 mmol) were dissolved in anhydrous THF (50 mL). After stirring at room temperature for 23 hours, the solvent was removed under reduced pressure, and ethyl acetate was added. This organic layer was washed with 2.0 M hydrochloric acid, dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 1:1) to obtain 2,3,4,6-tetra-O-acetyl-β-D-galactopyranose (4.5 g, quantitatively) as a colorless oil (Rf = 0.36, n-hexane:ethyl acetate = 1:1). 2,3,4,6-tetra-O-acetyl-β-D-galactopyranose 1 The 1H-NMR results were as follows: 1 H-NMR (500 MHz, CDCl3) δ: 5.52 (t, J = 3.4 Hz, 1H), 5.48 (t, J = 1.7 Hz, 1H), 5.42 (dd, J = 10.9, 3.4 Hz, 1H), 5.16 (dd, J = 10.9, 3.4 Hz, 1H), 4.48 (t, J = 6.6 Hz, 1H), 4.07-4.16 (m, 2H), 3.48 (br, 1H), 2.16 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H)

[0161] (Step 24) Under an argon atmosphere, 2,3,4,6-tetra-O-acetyl-β-D-galactopyranose (3.87 g, 11.1 mmol) and trichloroacetonitrile (5.50 mL, 55.4 mmol) were dissolved in anhydrous dichloromethane (35 mL). Under ice cooling, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU, 0.34 mL, 2.23 mmol) was added dropwise, and the mixture was stirred for 2 hours. The solvent was then removed under reduced pressure, and ethyl acetate was added. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 1-(2,2,2-trichloroethanimidate)-2,3,4,6-tetraacetate-β-D-galactopyranoside (Rf = 0.40, n-hexane:ethyl acetate = 2:1). 1-(2,2,2-trichloroethaneimidate)-2,3,4,6-tetraacetate-β-D-galactopyranoside 1 The 1H-NMR results were as follows: 1 H-NMR (400 MHz, CDCl3) δ: 8.67 (s, 1H), 6.60 (d, J = 3.5 Hz, 1H), 5.56 (d, J = 2.0 Hz, 1H), 5.35-5.45 (m, 2H), 4.44 (t, J = 6.5 Hz, 1H), 4.06-4.19 (m, 2H), 2.17 (s, 3H), 2.02-2.05 (m, 9H)

[0162] (Step 25) Under an argon atmosphere, crude 1-(2,2,2-trichloroethaneimidate)-2,3,4,6-tetraacetate-β-D-galactopyranoside and 2-[2-(2-chloroethoxy)ethoxy]ethanol (2-[2-(2-chloroethoxy)ethoxy]ethanol) (4.6 mL, 32.2 mmol) were dissolved in anhydrous dichloromethane (90 mL). Diethyl boron trifluoride etherate (10.6 mL, 86.2 mmol) was added dropwise under ice cooling, and the mixture was stirred for 1 hour under ice cooling conditions. After that, the mixture was kept out of light and stirred overnight at room temperature. After the reaction, water was added and the solvent was removed under reduced pressure. Ethyl acetate was added, and the mixture was washed sequentially with water, saturated sodium bicarbonate solution, and saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered. The filtrate was concentrated under reduced pressure and purified using silica gel column chromatography (n-hexane:ethyl acetate = 4:1) to obtain crude (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(2-(2-chloroethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate as a yellow oily substance. The resulting chloro compound 1 The results of the 1H-NMR and mass spectrometry were as follows. 1 H-NMR (500 MHz, CDCl3) δ: 5.38 (q, J = 1.4 Hz, 1H), 5.20 (dd, J = 10.9, 8.0 Hz, 1H), 5.01 (dd, J = 10.3, 3.4 Hz, 1H), 4.56 (d, J = 8.0 Hz, LRMS (ESI) m / z [M+Na] + calcd for C 20 H31 C l3 NaO 12 : 521; found 521.

[0163] (Step 26) Under an argon atmosphere, the obtained chloro compound and sodium azide (709 mg, 10.9 mmol) were dissolved in anhydrous DMSO (32 mL) and stirred overnight at 80°C. After the reaction, ethyl acetate was added, and the organic layer was sequentially washed with water, saturated sodium bicarbonate aqueous solution, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (n-hexane:ethyl acetate = 2:3) to obtain (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate ((2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate) (94 mg, 44% in 3 steps) as a yellow oily substance. The obtained azide compound 1 The results of the 1H-NMR and mass spectrometry were as follows. 1 H-NMR (500 MHz, CDCl3) δ: 5.46 (d, J = 2.9 Hz, 1H), 5.37 (dd, J = 10.9, 3.4 Hz, 1H), 5.17 (d, J = 3.4 Hz, 1H), 5.13 (dd, J = 10.9, 3.4 Hz, 1H), 4.33-4.17 (m, 2H), 4.16-4.04 (m, 2H), 3.72-3.61 (m, 9H), 3.40 (t, J = 4.9 Hz, 2H), 2.14 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H); LRMS (ESI) m / z [M+Na] + calcd for C 20 H31 N3NaO 12 : 528; found 528.

[0164] (Step 27) The obtained azide (330 mg, 0.65 mmol), 10% palladium on carbon (30 mg) and dehydrated methanol (8 mL) were mixed and stirred at room temperature for 24 hours under a hydrogen atmosphere. After the reaction, it was filtered and the solvent was distilled off under reduced pressure to obtain intermediate II'' as a brown oil (170 mg, 54%) of (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate). For intermediate II'' 1 1H-NMR was as follows. 1 1H-NMR (500 MHz, CDCl3) δ: 5.39 (d, J = 3.4 Hz, 1H), 5.21 (dd, J = 10.3, 8.0 Hz, 1H), 5.02 (dd, J = 10.3, 3.4 Hz, 1H), 4.58 (d, J = 8.0 Hz, 1H), 4.20-4.10 (m, 2H), 3.99-3.90 (m, 2H), 3.79-3.73 (m, 1H), 3.69-3.59 (m, 8H), 3.52 (t, J = 5.2 Hz, 2H), 2.88 (t, J = 5.2 Hz, 2H), 2.15 (s, 3H), 2.06 (d, J = 6.3 Hz, 6H), 1.99 (s, 3H)

[0165] <Synthesis of KOG-1> KOG-1 can be synthesized from intermediate VII according to the following scheme. Intermediate VII was synthesized from intermediate II'' and intermediate IV.

[0166] [ka]

[0167] (Step 28) Under an argon atmosphere, intermediate II'' (800 mg, 1.68 mmol) and intermediate IV (308 mg, 0.48 mmol) were dissolved in anhydrous DMF (10 mL), and triethylamine (810 μL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 23 hours, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1), and then further purified by size exclusion chromatography (chloroform) to obtain intermediate VII, a precursor of KOG-1. The results of the mass spectrometry analysis of intermediate VII were as follows: LRMS (ESI) m / z [M+Na] + calcd for C 69 H 96 N3NaO 39 : 1994; found 1994.

[0168] (Step 29) Intermediate VII is dissolved in dehydrated methanol, and a 1 M methanol methoxide / methanol solution is added until the pH reaches 9. The mixture is stirred at room temperature for 3 hours. Neutralization is achieved by adding ion exchange resin (Amberlite H+), and the filtrate is filtered and concentrated to obtain KOG-1.

[0169] [Example 10] Synthesis of MEG-4 MEG-4 was synthesized according to the following scheme, which differs from Example 5. [ka]

[0170] (Step 30) 2-(2-azidoethoxy)ethyl-2,3,4,6-tetraacetate-β-D-galactopyranoside (33.7 mg, 0.731 mmol), the azide obtained in step 2 of the synthesis method for intermediate II in Example 1, was mixed with 10% palladium carbon (3.7 mg) and anhydrous methanol / isopropanol (1.0 mL / 1.5 mL), and stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction, the mixture was filtered, and the solvent was removed under reduced pressure to obtain crude (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(2-aminoethoxy)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (31.6 mg, 99%) as a brown oily substance (Rf = 0.13, chloroform:methanol = 9:1). The obtained amine 1 The 1H-NMR results were as follows: 1 H-NMR (500 MHz, CDCl3) δ: 5.40 (d, J = 2.9 Hz, 1H), 5.18 (dd, J = 10.3, 8.0 Hz, 1H), 5.08 (dd, J = 10.9, 3.4 Hz, 1H), 4.60 (d, J = 8.0 Hz, 1H), 4.21 (q, J = 5.9 Hz, 1H), 4.13 (dd, J = 11.5, 6.9 Hz, 1H), 3.97-4.02 (m, 2H), 3.68-3.76 (m, 5H), 3.17 (s, 2H), 2.18 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H)

[0171] (Step 31) Under an argon atmosphere, the obtained amine (product synthesized from 1.90 mmol of the azide) and intermediate IV (302 mg, 0.471 mmol) were dissolved in anhydrous DMF (10 mL), and triethylamine (660 μL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 45 hours, and the solvent was removed under reduced pressure. The residue was purified using silica gel column chromatography (chloroform:methanol = 100:1~1:9), and then further purified using size exclusion chromatography (chloroform) to obtain intermediate VIII (42.2 mg, 5%), a precursor of MEG-4, as a yellow oily substance. Intermediate VIII 1 The results of the 1H-NMR and mass spectrometry were as follows. 1 H-NMR (500 MHz, CDCl3) δ: 5.38 (d, J = 3.2 Hz, 3H), 5.14-5.18 (m, 3H), 4.98-5.01 (m, 3H), 4.50-4.53 (m, 3H), 4.11-4.15 (m, 6H), 3.97 (s, 6H), 3.63-3.75 (m, 21H), 2.15 (s, 9H), 2.02-2.05 (m, 18H), 1.98 (s, 9H); HRMS (ESI) m / z [M+Na] + calcd for C 63 H 84 I3N3O 36 : 1862.1694; found 1862.1686.

[0172] (Step 32) Under an argon atmosphere, intermediate VIII (5.2 mg, 2.83 μmol) was dissolved in anhydrous methanol (1.0 mL), and 1 M methanol methoxide / methanol solution was added until the pH reached 9. The mixture was then stirred at room temperature for 3 hours. Subsequently, the reaction solution was neutralized with ion exchange resin (Amberlite H+), filtered, and the filtrate was concentrated to obtain MEG-4.

[0173] [Test Example 1] Compound Uptake Inhibition Test For RYO-1, MEG-1, and MEG-2 prepared in the examples, an uptake inhibition test mediated by the hepatocyte-specific asialoglycoprotein receptor was performed using the liver cancer cell line HepG2, in accordance with J Gastroenterol 1998, 33, 855-859. Specifically, the following method was used. First, osomucoid (Sigma) was asiatically converted by reacting it with immobilized neuraminidase (Sigma) at 37°C for 12 hours. This asiatically converted osomucoid (ASOR) was then labeled with radioactive iodine (125I) using the chloramine-T method to produce I-ASOR. The obtained I-ASOR was prepared as a 6 μg / mL PBS solution and reacted with HepG2 cells washed with ice-cold MEM (GIBCO) in a 6-well solution at 4°C for 30 minutes. After thoroughly washing the cells, they were lysed with 0.1 N NaOH, and the radiation dose A taken up by the cells was measured (control sample). The same measurement was performed by adding 100 μg / mL of MEG-1, MEG-2, or RYO-1 to I-ASOR, and the radiation dose A for each compound was measured. Next, to eliminate the effect of nonspecific binding of I-ASOR to cells, the background of nonspecific binding of I-ASOR was measured as follows. Specifically, I-ASOR (6 μg / mL) and unlabeled ASOR at 100 times the concentration (600 μg / mL) were mixed and reacted in the same manner as with HepG2. The resulting cells were then washed and lysed, and the radiation dose B was measured. The radiation dose B as background was used for all samples, including the control sample and the samples to which each compound was added. Next, for each sample, the I-ASOR specifically incorporated into HepG2 was calculated by calculating AB. The experiment was performed in a tripletic manner, and the standard deviation was calculated. In HepG2, it was revealed that RYO-1, MEG-1, and MEG-2 all competitively inhibit ligand uptake. The results of the uptake inhibition test in HepG2 are shown in Figure 1. In Figure 1, the sample labeled "6 μg / mL SP" is the control sample.

[0174] Similar experiments were conducted using Panc-1, a pancreatic cancer cell line lacking the asialoglycoprotein receptor. Specifically, the following method was used. In the same manner as described above, I-ASOR labeled with radioactive iodine (125I) was prepared as a 6 μg / mL PBS solution and reacted with Panc1 cells washed with ice-cold MEM (GIBCO) in 6 wells at 4°C for 30 minutes. After thoroughly washing the cells, they were lysed with 0.1 N NaOH and the radiation dose A taken up into the cells was measured (control sample). The same measurement was performed by adding MEG-1, MEG-2, or RYO-1 at 100 μg / mL in addition to I-ASOR to measure the radiation dose A when each compound was added. Next, to eliminate the effect of nonspecific binding of I-ASOR to cells, the background of nonspecific binding of I-ASOR was measured as follows. Specifically, I-ASOR (6 μg / mL) and unlabeled ASOR at 100 times the concentration (600 μg / mL) were mixed and reacted in the same manner as in Panc-1. The resulting cells were then washed and lysed, and the radiation dose B was measured. The radiation dose B as background was used for all samples, including the control sample and the samples to which each compound was added. Next, for each sample, the I-ASOR specifically incorporated into Panc-1 was calculated by calculating AB. The experiment was performed in a triplet manner, and the standard deviation was calculated. In Panc-1, neither RYO-1, MEG-1, nor MEG-2 inhibited ligand uptake. The results of the uptake inhibition test in Panc-1 are shown in Figure 2. From the above, it has become clear that the compound of the present invention is specifically taken up by hepatocytes.

[0175] [Test Example 2] Comparison of uptake activity via asialoglycoprotein receptors among compounds Using the same method as in Test Example 1 above, the uptake activity of MEG-2, MEG-4, RYO-1, and RYO-2 via the asialoglycoprotein receptor was compared. A PBS solution containing 0.4 μg / mL I-ASOR obtained in the same manner as in Test Example 1 and 1.0 mM / mL MEG-2, MEG-4, RYO-1, or RYO-2 was prepared and reacted with HepG2 washed with ice-cold MEM (GIBCO) on 6 wells at 37°C for 30 minutes. After thoroughly washing the cells, the cells were lysed with 0.1 N NaOH and the radiation dose A incorporated into HepG2 was measured. As a positive control, a PBS solution containing 0.4 μg / mL I-ASOR and 1000 μg / mL unlabeled ASOR was prepared, and the solution was incubated with HepG2 washed with ice-cold MEM (GIBCO) in a 6-well PBS solution at 4°C for 30 minutes. To eliminate the effect of nonspecific binding of I-ASOR to cells, the background of nonspecific binding of I-ASOR was measured as follows: I-ASOR (0.4 μg / mL) and unlabeled ASOR at 100 times the concentration (40 μg / mL) were mixed and reacted in the same manner as with HepG2. The resulting cells were then washed, lysed, and the radiation dose B was measured. The radiation dose B as background was used for all samples, including the control sample, the positive control sample, and the samples to which each compound was added. Next, for each sample, the I-ASOR specifically incorporated into HepG2 was calculated by calculating AB. The experiment was performed in a tripletic manner, and the standard deviation was calculated. MEG-2, MEG-4, RYO-1, and RYO-2 all competitively inhibited ligand uptake in HepG2. This inhibitory activity was higher with MEG-4 than with MEG-2, and higher with RYO-2 than with RYO-1. The results are shown in Figure 3. This suggests that compounds containing a greater number of atomic groups that bind to the asialocrytoprotein receptor exhibit higher uptake activity via the asialocrytoprotein receptor.

[0176] [Test Example 3] Contrast-enhanced experiment Nine-week-old male ICR mice, purchased from CREA Japan Co., Ltd., were anesthetized by isoflurane inhalation. MEG-1 was slowly administered by tail vein injection while monitoring respiratory status using DELPet μCT100 application software (DELBio). The MEG-1 dose was 52 mg / animal. CT images were taken before, during, 15 minutes after, and 1 hour after administration. Image data from the chest to the lower abdomen were reconstructed with a pixel size of 45 μm and converted to DICOM data. Further analysis of the images using VivoQuant software (inviCRO) confirmed the appearance of highly absorbent fluid in the intestinal tract and bladder over time, which was not observed before administration. Figure 4 shows the image taken one hour after administration.

[0177] Similar tests were conducted using MEG-2, MEG-4, or RYO-2 instead of MEG-1, and in all cases, it was confirmed that a highly absorbable fluid, which was not observed before administration, appeared in the intestinal tract and bladder over time. As shown in Figure 4 and the other results above, it has become clear that compounds having a site recognized by the asialoglycoprotein receptor have bile excretion function and are excreted through two excretory pathways. In other words, these compounds enable the reduction of side effects and the diagnosis of the liver by visualizing hepatocyte function. [Industrial applicability]

[0178] According to the present invention, there is industrial applicability in medical imaging and the like.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, represented by formula (1). 【Chemistry 1】 [In formula (1), R 1 ~R 3 Each of them operates independently. -NR x R y (R x and R y Each of these independently represents a hydrogen atom, a C1-C6 hydrocarbon group which may have substituents, or a C2-C7 acyl group which may have substituents.) Amino group represented by or -C(=O)NR z R w (R z and R w each independently represents a hydrogen atom or a C1-C6 hydrocarbon group which may have a substituent).), an amide group represented by Or, Formula (2): 【Chemistry 2】 (In formula (2), The Atomic Group is a group that binds to the asialocrycoprotein receptor, and is a group obtained by removing the hydrogen atom at the position to which the Linker is attached from any of the functional groups of the group consisting of galactose, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, and galactose-N-acetylglucosamine, as well as galactose, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, and galactose-N-acetylglucosamine in which one of the hydroxyl groups is substituted with -NH2. The Linker is a hydrocarbon chain which may have substituents. The group is represented by ( ), which may have one or both of the ends of the hydrocarbon chain, a heteroatom, an amide bond, an ester bond, a carbonyl bond, or an aromatic heterocycle. R 1 ~R 3 At least one of them is a base represented by formula (2). However, this excludes cases where the structure is one of the following: 【Transformation 3】 【Chemistry 4】

2. The group represented by formula (2) is one of the following formulas (2-1), (2-2), (2-3), or (2-4): 【Transformation 5】 (In equations (2-1), (2-2), (2-3), and (2-4), Linker has the same meaning as above.) A base represented by any of the following: The compound described in claim 1 or a pharmaceutically acceptable salt thereof.

3. In the aforementioned Linker, when the main chain is an alkylene chain that connects the group bound to the asialoclyoglycoprotein receptor and the triiodobenzene skeleton in the shortest possible way, the number of carbon atoms constituting the main chain is 1 or more and 10 or less. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. The hydrocarbon chain is either an alkylene chain which may have substituents, or a hydrocarbon chain in which two or more alkylene chains which may have substituents are linked via at least one selected from the group consisting of heteroatoms, amide bonds, ester bonds, carbonyl bonds, and aromatic heterocycles. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. The linker has the following structure: 【Transformation 6】 It is represented as, During the ceremony, L 0 is -O- or -NHC(=O)-, L x It is represented by the following structure: 【Transformation 7】 L y This represents a single bond, or is represented by the following structure: 【Transformation 8】 L z It is represented by the following structure: 【Chemistry 9】 In the above formula, Each R' is independently selected from a hydrogen atom, a C1-C3 alkyl group which may have substituents, or a hydroxyl group. L 1 Each of these is independently selected from an ether bond (-O-), a thioether bond (-S-), an amine bond (-NH-), an amide bond, an ester bond, or a carbonyl bond. L 2 It is a divalent group derived from an amide bond or an aromatic heterocycle. L 3 is, -OCH 2 -, -NHCH 2 -, -C(=O)NH-, -C(=O)NHCH 2 - or -NHC(=O)- is selected, m1, m2, and m4 are each independent integers greater than or equal to 1. m3 is a non-negative integer, N and N2 are independent integers of 0 or greater. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. L x However, it is one of the following structures: 【Chemistry 10】 L y However, it is either a single bond or one of the following structures: 【Chemistry 11】 L z However, it is one of the following structures: 【Chemistry 12】 In the above formula, k1 are independent integers between 1 and 3, k2 is either 0 or 1. m3 is a non-negative integer, N and N2 are independent integers of 0 or greater. The compound according to claim 5 or a pharmaceutically acceptable salt thereof.

7. The linker has the following structure: 【Chemistry 13】 (In the formula, Each R' is independently selected from a hydrogen atom, a C1-C3 alkyl group which may have substituents, or a hydroxyl group. L 0 is -O- or -NHC(=O)-, L 1 Each of these is independently selected from an ether bond (-O-), a thioether bond (-S-), an amine bond (-NH-), an amide bond, an ester bond, or a carbonyl bond. m1 and m2 are each independent integers greater than or equal to 1. N is a non-negative integer, N' is either 0 or 1. Represented by, The compound according to claim 5 or a pharmaceutically acceptable salt thereof.

8. The linker has the following structure: 【Chemistry 14】 【Chemistry 15】 (In the formula, L 0 is -O- or -NHC(=O)-, N is a non-negative integer, n is a non-negative integer, m2 is an integer greater than or equal to 1. N' is either 0 or 1. Represented by one of the following: The compound according to claim 7 or a pharmaceutically acceptable salt thereof.

9. The aforementioned amino group is represented by one of the following structures: 【Chemistry 16】 The aforementioned amide group is represented by one of the following structures: 【Chemistry 17】 A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. The amino group is an acetylamino group. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. A compound according to any one of claims 1 to 8, represented by formula (1-1), or a pharmaceutically acceptable salt thereof. [Chemistry 18] [In formula (1-1), -NR x R y Each of these is independent, as follows: 【Chemistry 19】 It is one of the following: Atomic Group and Linker are synonymous with the above.

12. In equation (1), R 1 ~R 3 These two are the bases represented by equation (2). A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

13. In equation (1), R 1 ~R 3 All of these are bases represented by equation (2), A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

14. A compound or a pharmaceutically acceptable salt thereof, represented by any of the following structures. 【Chemistry 20】

15. A compound or a pharmaceutically acceptable salt thereof, represented by the following structure. 【Chemistry 21】

16. A compound or a pharmaceutically acceptable salt thereof, represented by the following structure. 【Chemistry 22】

17. A contrast agent comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

18. The process involves reacting a reaction substrate, which is a linker moiety comprising a hydrocarbon chain having substituents, wherein one or both ends of the hydrocarbon chain may have a heteroatom, amide bond, ester bond, carbonyl bond, or aromatic heterocycle, with a reaction substrate of a nonionic iodine contrast agent moiety; with a reaction substrate of a nonionic iodine contrast agent moiety; A method for producing a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

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