JP4833626B2 - Higher fatty acid esters and amide derivatives having diethylenetriamine type metal chelate structure - Google Patents

Description

  The present invention relates to higher fatty acid esters and amide derivatives having a diethylenetriamine type metal chelate structure. The present invention further relates to a liposome containing the compound, a chelate compound containing the compound, or any salt thereof as a membrane component, and a contrast agent containing the liposome.

  As a non-invasive diagnosis method for arteriosclerosis, there is mainly an X-ray angiography. However, since this method is a method of imaging a blood flow with a water-soluble iodine contrast medium, it is difficult to distinguish between a diseased tissue and a normal tissue. Therefore, only lesions with stenosis of 50% or more can be detected, and it is difficult to detect lesions before the onset of an ischemic disease.

  As a diagnostic method other than the above, in recent years, a method for detecting a disease by nuclear magnetic resonance tomography (MRI) using a contrast agent that is dynamically distributed in atherosclerotic plaque has been reported. However, any of the compounds reported as the contrast agent has a problem when used in diagnostic methods. For example, hematoporphyrin derivatives (see Patent Document 1) have been pointed out to have defects in deposition and coloration on the skin, and gadolinium complexes having a perfluoro side chain (non-contained) reported to accumulate in lipid-rich plaques. Patent Document 1) is concerned about accumulation in lipid-rich tissues and organs such as fatty liver, kidney epithelium, and muscle tissue tendons.

  From the viewpoint of a compound, a compound in which phosphatidylethanolamine (PE) having two fatty acid esters and diethylenetriaminepentaacetic acid (DTPA) are amide-bonded is known (for example, Non-Patent Document 2). There is also a report on gadolinium complex liposomes (Non-patent Document 3). However, since this complex is hardly soluble, the operability during the formation of liposomes is poor, and there are concerns about accumulation in vivo and toxicity.

The gadolinium complex (see Patent Document 2 and Non-Patent Document 4) in which one fatty acid ester, which has been reported separately, is introduced as a hydrophobic group, has improved solubility as compared with the above compound. However, since a methylene chain is used for the linker part for linking the complex fatty acid ester part and the gadolinium complex part and the hydrophobicity is high, there is a concern that the affinity with the liposome-constituting phospholipid at the time of liposome preparation is concerned.
US Patent No. 4577636 U.S. Pat. Circulation, 109, 2890 (2004) Polymeric Materials Science and Engineering, 89, 148 (2003) Inorganica Chimica Acta, 331, 151 (2002) Journal of the American Chemical Society, 126, 3097 (2004)

  An object of the present invention is to provide a compound suitable for a liposome contrast agent for lesion-selective imaging, and particularly excellent in solubility and compatibility with liposome membrane components. Another object of the present invention is to provide an MRI contrast agent and a scintigraphic contrast agent containing the compound.

  As a result of studies conducted by the present inventors to solve the above-mentioned problems, the higher fatty acid esters and amide compounds having a diethylenetriamine type metal chelate structure of the present invention are highly soluble, and the composition of liposomes as MRI contrast agents It has been found that it has excellent properties as a component. The present invention has been completed based on the above findings.

［式中、Ｒは８〜３０個の炭素原子からなるアルキル基またはアルケニル基を示し；Ｘ¹及びＸ²はそれぞれ独立に単結合、−Ｏ−、又は−ＮＺ¹−（Ｚ¹は水素原子、または炭素原子１〜３個の低級アルキル基を示す）を示すが、Ｘ¹及びＸ²が同時に単結合を示すことはなく；Ｘ³は−Ｏ−又は−ＮＺ²−（Ｚ²は水素原子、または炭素原子１〜３個の低級アルキル基を示す）を示し；ｎは１〜１０の整数を示し；Ｌは２価の連結基（Ｌは炭素原子、水素原子及びヘテロ原子（ヘテロ原子とは酸素原子、窒素原子および硫黄原子をいう）からなる群から選択される原子により構成され、かつＬを構成する酸素原子は０〜９個、窒素原子は０〜４個、硫黄原子は０〜２個であり、Ｌの炭素原子及びヘテロ原子の総原子数は１〜２０個である）を示す。］で表される化合物又はその塩を提供するものである。 That is, the present invention provides the following general formula (I):

[Wherein, R represents an alkyl group or an alkenyl group composed of 8 to 30 carbon atoms; X ¹ and X ² each independently represent a single bond, —O—, or —NZ ¹ — (Z ¹ represents a hydrogen atom; Or a lower alkyl group having 1 to 3 carbon atoms), but X ¹ and X ² do not simultaneously represent a single bond; X ³ represents —O— or —NZ ² — (Z ² represents hydrogen). Represents an atom or a lower alkyl group having 1 to 3 carbon atoms; n represents an integer of 1 to 10; L represents a divalent linking group (L represents a carbon atom, a hydrogen atom and a heteroatom (heteroatom). Is an atom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom), and 0 to 9 oxygen atoms, 0 to 4 nitrogen atoms and 0 sulfur atom constituting L ˜2 and the total number of carbon atoms and heteroatoms of L is 1-20) It is. Or a salt thereof.

According to a preferred embodiment of the present invention, the above compound or salt thereof in which at least one of X ¹ , X ² and X ³ is an oxygen atom; the above compound or salt thereof in which X ³ is an oxygen atom; L is a carbon atom, oxygen The above compound or a salt thereof, which is a divalent linking group composed of an atom selected from the group consisting of an atom, a nitrogen atom, and a hydrogen atom; Or a salt thereof, wherein L is a divalent linking group composed of a carbon atom and a hydrogen atom.

According to another preferred embodiment of the present invention, the main chain of L (the main chain refers to an atomic group connecting X ² and X ³ in the shortest number), X ² , and the sum of the number of heteroatoms contained in X ³ Where j is the number of carbon atoms contained in the main chain of L, and k is a quotient obtained by dividing k by j, or a salt thereof; the compound or a salt thereof, wherein the quotient is 2 or less; X ² is —O— or —NZ ¹ — (Z ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms), L is an alkylene group having 1 to 12 carbon atoms, or — ( CH ₂ CH ₂ Y) _m CH ₂ CH ₂ — (m represents an integer of 1 to 6, Y represents —O— or —NZ ³ — (Z ³ represents a hydrogen atom or a methyl group), and m represents multiple Y when two or more or a linking group represented by may also be different) with the same above compound or a salt thereof; X ² is -O- or -NZ ¹ - in Ri (Z ¹ represents a hydrogen atom, or a carbon atom one to three lower alkyl group), L is _{- (CH 2 CH 2 Y)} m CH 2 CH 2 - (m represents an integer of 1-6, Y represents —O— or —NZ ³ — (Z ³ represents a hydrogen atom or a methyl group), and when m is 2 or more, a plurality of Ys may be the same or different. One of the above compounds or a salt thereof; X ² is —O— or —NZ ¹ — (Z ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms), and L is — (CH ₂ CH ₂ O) ₁ CH ₂ CH ₂ — (wherein 1 represents an integer of 1 to 6), or a salt thereof; R is a linear alkyl group having 10 to 22 carbon atoms Provided is the above compound or a salt thereof, which is a group or alkenyl group, or a branched alkyl group or alkenyl group

  According to still another preferred embodiment of the present invention, a chelate compound comprising one of the above compounds and a metal ion or a salt thereof; the metal ion has an atomic number of 21-29, 31, 32, 37-39, 42-44, 49 The chelate compound which is a metal ion of an element corresponding to 57-83 or a salt thereof; the chelate compound wherein the metal ion is a metal ion of a paramagnetic element corresponding to atomic number 21-29, 42, 44, 57-71 Or a salt thereof is provided.

From another aspect of the present invention, a liposome containing the above-mentioned compound or a salt thereof as a membrane component is provided. According to a preferred embodiment, the liposome containing phosphatidylcholine and phosphatidylserine as membrane components is provided.
In addition, according to the present invention, an MRI contrast agent containing the above-described liposome is provided. According to a preferred embodiment of the present invention, the MRI contrast agent used for imaging of vascular disease; the MRI contrast agent used for imaging of vascular smooth muscle cells abnormally proliferated under the influence of foamed macrophages; a tissue in which macrophages are localized or The above-mentioned MRI contrast medium used for imaging of a diseased site; the above-mentioned MRI contrast medium selected from the group consisting of liver, spleen, alveoli, lymph nodes, lymphatic vessels, and kidney epithelium; The MRI contrast agent is provided, wherein the localized disease site is selected from the group consisting of a tumor, an inflammation site, and an infection site.

  Similarly, the present invention provides a scintigraphic contrast agent comprising the above-described liposome. According to a preferred aspect of the present invention, the scintigraphic contrast agent used for imaging of vascular disease; the scintigraphic contrast agent used for imaging of vascular smooth muscle cells abnormally proliferated under the influence of foamed macrophages; The above scintigraphic imaging agent used for imaging a tissue or a diseased site; the above scintigraphic imaging wherein the tissue in which macrophages are localized is selected from the group consisting of liver, spleen, alveoli, lymph nodes, lymphatic vessels, and kidney epithelium Agent: The scintigraphic contrast agent described above, wherein the disease site where macrophages are localized is selected from the group consisting of a tumor, an inflammation site and an infection site.

  According to still another aspect of the present invention, there is provided the use of the above compound, chelate compound, or any salt thereof for the manufacture of the above MRI contrast agent / scintigraphy contrast agent; A method comprising MRI imaging / scintigraphy imaging after administering a liposome containing the above-mentioned compound, chelate compound, or any salt thereof as a membrane component to a mammal including a human; Imaging of a lesion of a vascular disease A method comprising the steps of MRI imaging / scintigraphy imaging after administering a liposome containing the above-mentioned compound, chelate compound, or any salt thereof as a membrane component to a mammal including a human, the present invention. Provided by.

  The compound of the present invention, the chelate compound, and any one of these salts have excellent properties as a constituent lipid of liposomes for MRI contrast agents, and MRI contrast / scintigraphic imaging is performed using liposomes containing this compound. This makes it possible to selectively image the lesion of the blood vessel.

  R represents an alkyl group or an alkenyl group composed of 8 to 30 carbon atoms. The alkyl group or alkenyl group may be linear, branched or cyclic, but is preferably linear or branched. The number of carbon atoms constituting R is more preferably 8-25, and most preferably 10-22. When R represents an alkenyl group, the double bond may be either E or Z configuration, and when there are a plurality of them, it may be a mixture of both, but the double bond is vicinal disubstituted. In some cases, the Z configuration is preferred. Further, the position and number of double bonds are not particularly defined.

X ¹ and X ² each independently represents a single bond, —O— or —NZ ¹ —. However, both X ¹ and X ² do not show a single bond at the same time. Z ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and Z ¹ is preferably a hydrogen atom or a methyl group. X ³ represents —O— or —NZ ² —. Z ² represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and Z ² is preferably a hydrogen atom or a methyl group. Preferred embodiments represented by X ^1, X ^2, X ^3, at least one of X ^1, X ^2, X ³ is a case where an oxygen atom, may X ³ represents an oxygen atom and most preferred.

  n represents an integer of 1 to 10. Preferably n is 1-4, most preferably n is 1.

L is a divalent linking group in which the main chain (the main chain is an atomic group connecting X ² and X ³ with the shortest number) is composed of carbon atoms or an atomic group in which carbon atoms and heteroatoms are arbitrarily combined. To express. Here, the hetero atom means a nitrogen atom, an oxygen atom and a sulfur atom. A hetero atom is preferably a nitrogen atom or an oxygen atom, and most preferably an oxygen atom. L may be composed of only carbon atoms and hydrogen atoms. The total number of carbon atoms and heteroatoms constituting L is 1 to 20, preferably 5 to 20, and more preferably 8 to 18. When L is composed of carbon atoms and heteroatoms, 0 to 9 oxygen atoms, 0 to 4 nitrogen atoms, and 0 to 2 sulfur atoms constitute L. Of the heteroatoms constituting L, the preferred number of oxygen atoms is 1 to 7, more preferably 1 to 5. The number of nitrogen atoms is preferably 0 to 3, more preferably 0 to 2. A preferable number of sulfur atoms is 0 to 1. More preferably, the main chain of L is a case where oxygen atoms or nitrogen atoms are contained in a certain ratio or more with respect to carbon atoms. A preferred ratio is that the sum of the number of heteroatoms contained in the main chain of L, X ² and X ³ is j, and the quotient obtained by dividing k by j is 3 or less, where k is the number of carbon atoms contained in the main chain of L More preferably, the quotient is 2 or less.

  In the divalent linking group represented by L, the atoms constituting L may be contained as a substituent for the main chain. The number and position of the substituents are not particularly limited, and when two or more substituents are present, they may be the same or different. However, the total number of carbon atoms and heteroatoms constituting L including a partial structure having a substituent shall not exceed 20. Examples of substituents include alkyl, cyano, hydroxyl, nitro, carboxyl, ether, acyloxy, carbamoyloxy, alkoxycarbonyloxy, amino, acylamino, aminocarbonylamino, alkoxycarbonylamino, sulfamoylamino, alkylsulfonylamino, mercapto , Alkylthio, sulfamoyl, sulfo, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, carbamoyl, azo, imide and the like, but are not limited thereto. The substituent is preferably an alkyl, oxo, carboxyl, hydroxyl, ether, acyloxy, carbamoyloxy, alkoxycarbonyloxy, amino, acylamino, alkoxycarbonylamino, alkoxycarbonyl, carbamoyl group, more preferably an alkyl, oxo, hydroxyl group. It is.

L may be linear, branched, cyclic, or a combination thereof, but is preferably linear or branched. The linking group may be a saturated group or a group containing an unsaturated bond. When L is a group containing an unsaturated bond, its type, position and number are not particularly defined. Preferred examples of L include an alkylene structure, a polyethylene glycol structure, a polypropylene glycol structure, a polyglycerin structure, a polyglycolic acid structure, a polylactic acid structure, a polyethyleneamine structure, a polypeptide structure, or a combination thereof. An alkylene structure, a polyethylene glycol structure, a polypropylene glycol structure, a polyethylene amine structure or a combination thereof is more preferable, and an alkylene structure, a polyethylene glycol structure, a polyethylene amine structure or a combination thereof is more preferable. Specifically, L is an alkylene group consisting of 1 to 12 carbon atoms, or — (CH ₂ CH ₂ Y) _m CH ₂ CH ₂ — (m represents an integer of 1 to 6, Y represents —O—. Or —NZ ³ — (Z ³ represents a hydrogen atom or a methyl group), and when m is 2 or more, a plurality of Ys may be the same or different. - more preferably a linking group represented _{by, - - (CH 2 CH 2} Y) m CH 2 CH 2 and (l is an integer from 1 to 6 _{- (CH 2 CH 2 O)} l CH 2 CH 2 Most preferably, it is a linking group represented by: m and l are preferably 2 to 6, and more preferably 2 to 4.

Although the preferable example of the compound of this invention is shown below, the compound of this invention is not limited to these examples.

  Hereinafter, general methods for synthesizing the compound of the present invention will be described, but the methods for synthesizing the compound of the present invention are not limited thereto. As the long-chain fatty acid which is a partial structure of the compound of the present invention, a commercially available product may be used, or may be appropriately synthesized according to the use. When obtained by synthesis, the corresponding alcohol, alkyl halide, or the like can be used as a raw material by the method described in, for example, Richard C. Larock, Comprehensive organic transformations (VCH).

  The long-chain fatty acid is condensed with α, ω-diol or diamine, α-amino-ω-alcohol such as diethylene glycol, diethanolamine, diethylenetriamine and the like to lead to a monoacyl compound. In this case, if necessary, a protecting group can be used. In this case, the protecting group is described in, for example, Protecting groups in organic synthesis (John Wiley & Sons, Inc.) by TW Green & PGM Wuts. Can be appropriately selected and used.

  The above-mentioned monoacyl compound can be synthesized by linking the ω-position hydroxy group or amino group to a polyamine derivative having metal coordination ability. The method can be synthesized, for example, according to the method described in Bioconjugate Chem. 10, 137 (1999). However, these methods are examples, and the present invention is not limited to these.

  The chelate compound of the present invention is a chelate compound comprising the above-mentioned compound and a metal ion. The metal ion is not particularly limited, but as a metal ion suitable for the purpose of imaging and radiotherapy such as MRI, X-ray, ultrasonic contrast, scintigraphy, paramagnetic metal, heavy metal, radioactive metal isotope It is preferable to use metal ions. More specifically, a metal ion of an element selected from atomic numbers 21-29, 31, 32, 37-39, 42-44, 49, 57-83 is preferable. In addition, when using the chelate compound of the present invention as an MRI contrast agent, a metal ion of an element selected from atomic numbers 21-29, 42, 44, and 57-71 can be cited as an appropriate metal ion. More preferred metals for use in preparing positive MRI agents are atomic numbers 24 (Cr), 25 (Mn), 26 (Fe), 63 (Eu), 64 (Gd), 66 (Dy), 67 (Ho) More preferred metals for use in the preparation of negative MRI agents are atomic numbers 62 (Sm), 65 (Tb), 66 (Dy). Most preferred are atomic numbers 25 (Mn), 26 (Fe), and 64 (Gd), with Mn (II), Fe (III), and Gd (III) being particularly preferred.

  The compound or chelate compound of the present invention has one or more asymmetric centers. In this case, stereoisomers such as optically active substances or diastereoisomers based on the asymmetric centers exist. Any stereoisomers in pure form, mixtures of any stereoisomers, racemates, and the like are all encompassed within the scope of the present invention. In addition, the compound of the present invention may have one or more olefinic double bonds, but the arrangement may be either E or Z, and may exist as a mixture of both. . The compounds of the invention may exist as tautomers, but any tautomer, or mixture thereof, is included within the scope of the invention. Furthermore, the compound of the present invention may form a salt, and the free form compound or the salt form compound may form a hydrate or a solvate. Is included. The kind of salt is not particularly limited, and may be either an acid addition salt or a base addition salt.

The compound of the present invention or a salt thereof can be used as a membrane constituent of a liposome. When a liposome is prepared using the compound of the present invention or a salt thereof, the amount of the compound of the present invention or the salt thereof used is about 10 to 90% by mass, preferably 10 to 80% by mass with respect to the total mass of the membrane constituent components. %, More preferably 20 to 80% by weight. Although the compound of this invention may use 1 type as a film | membrane structural component, you may use it in combination of 2 or more types.
As other membrane constituent components of the liposome, any lipid compound usually used in the production of liposomes may be used. For example, Biochim. Biophys. Acta 150 (4), 44 (1982), Adv. In Lipid. Res. 16 (1), 1 (1978), RESEARCH IN LIPOSOMES_ (P. Machy, L. Leserman, John Libbey EUROTEXT Co., Ltd.), “Liposome” (Nojima, Sunamoto, Inoue Hen, Nankodo) and the like. As the lipid compound, phospholipid is preferable, and phosphatidylcholine (PC) is particularly preferable. Preferred examples of phosphatidylcholines include eggPC, dimyristoyl PC (DMPC), dipalmitoyl PC (DPPC), distearoyl PC (DSPC), dioleyl PC (DOPC), etc., but are not limited thereto. .

Preferable examples of the membrane component of the liposome include a combination of phosphatidylcholine and phosphatidylserine (PS). Examples of phosphatidylserine include compounds having the same lipid moiety as the phospholipids listed as preferred examples of phosphatidylcholine. When phosphatidylcholine and phosphatidylserine are used in combination, the preferred use molar ratio of PC and PS is between PC: PS = 90: 10 to 10:90, more preferably between 30:70 to 70:30. is there.
Another preferable example of the liposome of the present invention includes a liposome containing phosphatidylcholine and phosphatidylserine as membrane constituents, and further containing a dialkyl phosphate. The two alkyl groups constituting the dialkyl ester of the phosphoric acid dialkyl ester are preferably the same, and each alkyl group preferably has 6 or more carbon atoms, more preferably 10 or more, and even more preferably 12 or more. . Examples of preferred dialkyl phosphates include, but are not limited to, dilauryl phosphate, dimyristyl phosphate, dicetyl phosphate, and the like. In this embodiment, the preferred amount of dialkyl phosphate used relative to the total weight of phosphatidylcholine and phosphatidylserine is 1 to 50% by weight, preferably 1 to 30% by weight, more preferably 1 to 20% by weight. .

In the liposome containing phosphatidylcholine, phosphatidylserine, dialkyl ester phosphate and the compound of the present invention as membrane constituents, the preferred mass ratio of the above components is PC: PS: dialkyl phosphate ester: 5-40% by mass of the compound of the present invention It can be selected between 5-40% by weight: 1-10% by weight: 15-80% by weight.
The constituent components of the liposome of the present invention are not limited to the above four, and other components can be added. Examples thereof include cholesterol, cholesterol ester, sphingoemilin, FEBS Lett. 223, 42 (1987); Proc. Natl. Acad. Sci., USA 85, 6949 (1988) and the like, Chem. Lett. 2145 (1989); Biochim. Biophys. Acta 1148, 77 (1992) and other glucuronic acid derivatives, Biochim. Biophys. Acta 1029, 91 (1990); FEBS Lett. 268, 235 (1990), etc. However, the present invention is not limited to this.

  The liposome of the present invention may be produced by any method available to those skilled in the art. Examples of production methods include, in addition to the above-listed liposome documentation, Ann. Rev. Biophys. Bioeng. 9, 467 (1980), "Liposomes" (MJ Ostro, MARCELL DEKKER, INC.), Etc. Are listed. Specific examples include sonication, ethanol injection, French press method, ether injection method, cholic acid method, calcium fusion method, freeze-thaw method, reverse phase evaporation method, etc. Absent. The size of the liposome of the present invention may be any of the sizes that can be produced by the above method, but the average is usually 400 nm or less, and preferably 200 nm or less. The structure of the liposome is not particularly limited, and may be any form such as unilamellar or multilamellar. Moreover, it is also possible to mix | blend the 1 type (s) or 2 or more types of a suitable drug and another contrast agent in the inside of a liposome.

  When the liposome of the present invention is used as a contrast agent, it can be preferably administered parenterally, more preferably intravenously administered. For example, a preparation in the form of an injection or infusion is provided as a powdered composition in a lyophilized form, and is dissolved in water or other appropriate medium (for example, physiological saline, infusion of grapes, buffer, etc.) Or it can be resuspended. When the liposome of the present invention is used as a contrast agent, the dose can be appropriately determined so that the compound content in the liposome is comparable to the compound content of a conventional contrast agent.

  Without being bound by any particular theory, in vascular diseases such as arteriosclerosis or restenosis after PTCA, the vascular smooth muscle cells that form the vascular media grow abnormally and migrate to the intima at the same time However, it is known to narrow the blood flow path. Although the triggers for normal vascular smooth muscle cells to begin to grow abnormally have not yet been fully clarified, macrophage migration and foaming are known to be important factors, followed by vascular smoothness. It has been reported that myocytes undergo phenotype conversion (from contraction to synthesis).

  When the liposome of the present invention is used, a compound that serves as a defined contrast agent can be selectively taken into vascular smooth muscles that have abnormally grown under the influence of foamed macrophages. As a result, it is possible to contrast the lesion and the non-disease site with contrast. Therefore, the contrast agent of the present invention can be suitably used particularly for MRI imaging of vascular diseases. For example, imaging such as arteriosclerotic lesion or restenosis after PTCA can be performed.

  Further, as described in, for example, J. Biol. Chem., 265, 5226 (1990), liposomes composed of phospholipids, particularly liposomes formed from PC and PS, accumulate in macrophages via scavenger receptors. It is known to be easy. Therefore, by using the liposome of the present invention, the compound of the present invention can be accumulated in a tissue or a disease site where macrophages are localized. When the liposome of the present invention is used, more defined compounds can be accumulated in macrophages than when a suspension or oil emulsion, which is a known technique, is used.

  Examples of tissues in which macrophage localization is recognized and can be suitably imaged with the liposome of the present invention include blood vessels, liver, alveoli, lymph nodes, lymphatic vessels, and kidney epithelium. Further, in certain diseases, it is known that macrophages are accumulated at the disease site. Examples of such diseases include tumors, arteriosclerosis, inflammation, infection and the like. Therefore, these disease sites can be identified by using the liposome of the present invention. In particular, it is known that foamed macrophages that have incorporated a large amount of denatured LDL via a scavenger receptor accumulate in the early stage of atherosclerotic lesions [Am. J. Pathol., 103, 181 ( 1981), Annu. Rev. Biochem., 52, 223 (1983)], and by integrating the liposomes of the present invention in these macrophages and performing MRI imaging, the position of the early stage of arteriosclerosis difficult by other means can be determined. It is possible to specify.

  The imaging method using the liposome of the present invention is not particularly limited. For example, the contrast can be performed by measuring the change in the T1 / T2 relaxation time of water in the same manner as a conventional contrast method using an MRI contrast agent. Moreover, it can also be used as a scintigraphic contrast agent, an X-ray contrast agent, a photoimage forming agent, or an ultrasonic contrast agent by appropriately using an appropriate metal ion.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example. In addition, the compound number in the following Example respond | corresponds to the number of the compound example shown above. Moreover, the structure of the compound in an Example was confirmed by the NMR spectrum and the mass spectrum.

The compound of the present invention and its gadolinium complex were synthesized according to the synthetic route shown below.

Compound A ₂₄
1.5 g of phytanic acid and 3.5 mL of tetraethylene glycol were dissolved in 20 mL of toluene, and several drops of concentrated sulfuric acid were added. A Dean-Stark extractor was attached and refluxed for 4 hours, and the resulting water was distilled off. After cooling, a saturated aqueous sodium bicarbonate solution was added to neutralize. The aqueous layer was extracted with ethyl acetate, and the resulting organic layer was dried over magnesium sulfate. After the solvent was distilled off, silica gel column chromatography (solvent system: hexane / ethyl acetate = 1: 1) to give Compound A ₂₄ 1.8 g (61%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.21 to 4.27 (2H, m), 3.58 to 3.76 (14H, m), 2.33 (1H, dd), 2.15 (1H, dd), 1.88 to 2.00 (1H, m), 0.98 to 1.60 (21H, m), 0.92 (3H, d), 0.81 to 0.89 (12H , M).

Compound A ₁₀₁
5.1 g of palmitic acid and 9.5 mL of diethylene glycol were dissolved in 30 mL of toluene, and several drops of concentrated sulfuric acid were added. A Dean-Stark extractor was attached and refluxed for 3 hours, and the resulting water was distilled off. After cooling, a saturated aqueous sodium bicarbonate solution was added to neutralize. The aqueous layer was extracted with ethyl acetate, and the resulting organic layer was dried over magnesium sulfate. After distilling off the solvent, 6.8 g (99%) of compound A ₁₀₁ was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.22 to 4.26 (2H, m), 3.58 to 3.63 (2H, m), 3.68 to 3.78 (4H, m) 2.33 (2H, t), 1.58 to 1.67 (2H, m), 1.21 to 1.36 (24H, m), 0.88 (3H, t).

Compound A ₁₀₂
5.1 g of palmitic acid and 13.3 mL of triethylene glycol were dissolved in 30 mL of toluene, and several drops of concentrated sulfuric acid were added. A Dean-Stark extractor was attached and refluxed for 3 hours, and the resulting water was distilled off. After cooling, a saturated aqueous sodium bicarbonate solution was added to neutralize. The aqueous layer was extracted with ethyl acetate, and the resulting organic layer was dried over magnesium sulfate. After the solvent was distilled off, the residue was dissolved in hexane and cooled to -20 ° C. The precipitated crystals were collected by filtration to obtain 7.5 g (97%) of Compound A ₁₀₂ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.22 to 4.25 (2H, m), 3.60 to 3.78 (10H, m), 2.33 (2H, t), 1.57 ˜1.68 (2H, m), 1.20-1.36 (24H, m), 0.88 (3H, t).

Compound A ₁₀₃
5.1 g of palmitic acid and 13.8 mL of tetraethylene glycol were dissolved in 20 mL of toluene, and several drops of concentrated sulfuric acid were added. A Dean-Stark extractor was attached and refluxed for 3 hours, and the resulting water was distilled off. After cooling, a saturated aqueous sodium bicarbonate solution was added to neutralize. The aqueous layer was extracted with ethyl acetate, and the resulting organic layer was dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 1: 1) to obtain 4.9 g (57%) of Compound A ₁₀₃ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.22 to 4.25 (2H, m), 3.58 to 3.75 (14H, m), 2.33 (2H, t), 1.58 ˜1.68 (2H, m), 1.21-1.35 (24H, m), 0.88 (3H, t).

Compound A ₁₀₄
2.6 g of palmitic acid and 4.2 mL of pentaethylene glycol were dissolved in 100 mL of toluene, and several drops of concentrated sulfuric acid were added. A Dean-Stark extractor was attached and refluxed for 5 hours, and the resulting water was distilled off. After cooling, a saturated aqueous sodium bicarbonate solution was added to neutralize. The aqueous layer was extracted with ethyl acetate, and the resulting organic layer was dried over magnesium sulfate. After the solvent was distilled off, silica gel column chromatography (solvent system: hexane / ethyl acetate = 1: 1 to 1: 2) to give Compound A ₁₀₄ 1.6 g (34%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.20 to 4.26 (2H, m), 3.58 to 3.76 (18 H, m), 2.32 (2H, t), 1.55 ˜1.68 (2H, m), 1.20-1.38 (24H, m), 0.87 (3H, t).

Compound A ₁₀₅
2.6 g of palmitic acid and 5.0 mL of hexaethylene glycol were dissolved in 20 mL of toluene, and several drops of concentrated sulfuric acid were added. A Dean-Stark extractor was attached and refluxed for 5 hours, and the resulting water was distilled off. After cooling, a saturated aqueous sodium bicarbonate solution was added to neutralize. The aqueous layer was extracted with ethyl acetate, and the resulting organic layer was dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 2: 3-ethyl acetate only) to obtain 3.0 g (58%) of Compound A ₁₀₅ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.20 to 4.27 (2H, m), 3.58 to 3.75 (22H, m), 2.33 (2H, t), 1.58 ˜1.68 (2H, m), 1.20-1.36 (24H, m), 0.88 (3H, t).

Compound A ₁₀₉
5.1 g of palmitic acid and 4.6 mL of 2- (methylamino) ethanol were dissolved in 50 mL of dichloromethane, and 100 mg of N, N-dimethylaminopyridine and 7.7 g of EDC were added at 0 ° C. After 1 hour, the mixture was warmed to room temperature and further stirred overnight. Water was added to stop the reaction, excess amine and reaction byproducts were removed by an extraction operation, and the aqueous layer was back-extracted with ethyl acetate. The obtained organic layers were combined, washed with saturated brine, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (solvent system: hexane / acetone = 1: 4) to obtain 4.5 g (63%) of Compound A ₁₀₉ .
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.19 (2H, t), 3.57 (2H, t), 2.71 (2H, t), 2.60 (2H, t), 2. 33 (3H, s), 2.31 (2H, t), 1.55 to 1.69 (2H, m), 1.20 to 1.37 (24H, m), 0.88 (3H, t) .

Compound A ₁₁₈
To a mixed solution of 1.6 g of 2- (2-bromoethoxy) ethyl palmitate, 30 mL of THF and 10 mL of DMF, 1.8 mL of 2- (2-aminoethoxy) ethanol was added and heated to 50 ° C. for 1 day at room temperature. Stir the day. Saturated aqueous sodium hydrogen carbonate solution was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate. The composition product obtained after distilling off the solvent was dissolved in 10 mL of dioxane, cooled at 0 ° C., and 0.82 mL of di-t-butyl dicarbonate and 3.6 mL of 1M aqueous sodium hydroxide solution were added dropwise simultaneously. After stirring for 1 hour, the mixture was warmed to room temperature and further stirred for 4 hours. The reaction solution was diluted with water and ethyl acetate for extraction, and the resulting organic layer was washed with saturated brine and dried over sodium sulfate. The reaction solution was concentrated, the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 2: 1 to 1: 1), to give the desired compound D ₁₁₈ 0.80 g (20% / 2 steps) It was.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.19 to 4.24 (2H, m), 3.39 to 3.73 (14H, br.m), 2.33 (2H, t), 1 .55 to 1.67 (2H, m), 1.46 (9H, s), 1.20 to 1.35 (24H, m), 0.88 (3H, t).

Compound A ₁₂₈
2.6 g of palmitic acid and 3.5 mL of 1,7-heptanediol were dissolved in 30 mL of toluene, and several drops of concentrated sulfuric acid were added. A Dean-Stark extractor was attached and refluxed for 3 hours, and the resulting water was distilled off. After cooling, a saturated aqueous sodium bicarbonate solution was added to neutralize. The aqueous layer was extracted with ethyl acetate, and the resulting organic layer was dried over magnesium sulfate. After the solvent was distilled off, silica gel column chromatography (solvent system: hexane / ethyl acetate = 4: 1 to 3: 1) to give Compound A ₁₂₈ 2.3 g (62%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.07 (2H, t), 3.64 (2H, q), 2.28 (2H, t), 1.52-1.68 (6H, m ), 1.18-1.45 (30H, m), 0.88 (3H, t).

Compound A ₁₂₉
Palmitic acid (2.2 g) and 1,12-dodecanediol (3.3 g) were dissolved in toluene (90 mL), and several drops of concentrated sulfuric acid were added. A Dean-Stark extractor was attached and refluxed for 3 hours, and the resulting water was distilled off. After cooling, a saturated aqueous sodium bicarbonate solution was added to neutralize. The aqueous layer was extracted with ethyl acetate, and the resulting organic layer was dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 5: 1) to obtain 2.3 g (61%) of Compound A ₁₂₉ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.05 (2H, t), 3.64 (2H, q), 2.29 (2H, t), 1.52-1.68 (6H, m ), 1.18-1.45 (40H, m), 0.89 (3H, t).

Compound B
Aspartic acid β-benzyl-α-t-butyl ester hydrochloride (5.3 g) and 2-bromoethyldi (t-butyloxycarbonylmethyl) amine (13.4 g) were suspended in 40 mL of acetonitrile, and a phosphate buffer solution (pH 7). 40 mL of pure water was added to 32.6 g of K ₂ HPO ₄ and 4.7 g of NaH ₂ PO ₄ ) and vigorously stirred at room temperature for 2 hours. After liquid separation, the aqueous layer was extracted with acetonitrile (10 mL × 3) and added to the organic layer. 40 mL of a phosphate buffer solution was newly added to the organic layer, and the mixture was vigorously stirred for 20 hours. After the reaction, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 4: 1) to obtain 9.2 g (66%) of the desired compound B.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-7.29 (5H, m), 5.13 (1H, d) 5.07 (1H, d), 3.82 (1H, t) 3.41 (8H, s), 2.81 (1H, dd), 2.72 (8H, br. S), 2.56 (1H, dd), 1.47 (9H, s), 44 (36H, s).

Compound C
Compound B (1.3 g) was dissolved in a mixed solvent of ethanol (9 mL) and cyclohexene (4.5 mL). 10% Pd / C 0.18 g was added, and the mixture was heated to reflux for 1.5 hours. After cooling the reaction solution, the catalyst was removed by celite filtration. After the solvent was distilled off, the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 1: 1) to obtain 1.1 g (93%) of the desired compound C.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.35 (1H, t), 3.45 (4H, d), 3, 41 (4H, d), 2.92 (8H, br. S), 2.68-2.72 (1H, br.m), 1.49 (9H, s), 1.45 (36H, s).

Compound D ₂₄
Dissolve 0.27 g of alcohol A ₂₄ and 0.30 g of carboxylic acid C in 1.0 mL of CH ₂ Cl _2, add N, N-dimethylaminopyridine (10 mg) and EDC (0.10 g) at 0 ° C., and stir for 2 hours. The mixture was heated to room temperature, stirred for 22 hours, and further heated to reflux for 6 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 2: 1) to obtain 0.28 g (57%) of the desired compound D ₂₄ .
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.17 to 4.24 (4H, m), 3.76 (1H, t), 3.62 to 3.71 (12H, m), 3.42 (8H, s), 2.79 (1H, dd), 2.66 to 2.77 (8H, br. S), 2.54 (1H, dd), 2.31 (1H, dd), 2. 14 (1H, dd), 1.88 to 2.00 (1H, m), 1.45 (45H, s), 0.98 to 1.62 (21 H, m), 0.92 (3H, d) 0.81-0.89 (12H, m).

Compound D ₁₀₁
0.13 g of alcohol A ₁₀₁ and 0.25 g of carboxylic acid C were dissolved in 0.8 mL of CH ₂ Cl ₂ , N, N-dimethylaminopyridine (10 mg) and EDC (0.08 g) were added at 0 ° C. and stirred for 2 hours. The mixture was warmed to room temperature and further stirred for 20 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 3.5: 1) to obtain 0.21 g (52%) of the desired compound D ₁₀₁ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.20 to 4.24 (4H, m), 3.83 (1H, t), 3.67 to 3.71 (4H, m), 3.44 (8H, s), 2.81 (1H, dd), 2.72 to 2.81 (8H, br. S), 2.57 (1H, dd), 2.32 (2H, t), 1. 59-1.65 (2H, m), 1.45 (45H, s), 1.22-1.34 (24H, m), 0.88 (3H, t).

Compound D ₁₀₂
0.15 g of alcohol A ₁₀₂ and 0.25 g of carboxylic acid C were dissolved in 0.8 mL of CH ₂ Cl ₂ , N, N-dimethylaminopyridine (10 mg) and EDC (0.08 g) were added at 0 ° C. and stirred for 2 hours. The mixture was warmed to room temperature and further stirred for 20 hours. The reaction solution was concentrated, the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 3: 1) to obtain an objective compound D ₁₀₂ 0.25g (67%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.18 to 4.24 (4H, m), 3.78 (1H, t), 3.66 to 3.72 (4H, m), 3.63 (4H, s), 3.41 (8H, s), 2.79 (1H, dd), 2.68-2.76 (8H, br. S), 2.53 (1H, dd), 2. 33 (2H, t), 1.58 to 1.64 (2H, m), 1.45 (45H, s), 1.22 to 1.30 (24H, m), 0.88 (3H, t) .

Compound D ₁₀₃
Dissolve 0.21 g of alcohol A ₁₀₃ and 0.33 g of carboxylic acid C in 1.5 mL of CH ₂ Cl _2, add N, N-dimethylaminopyridine (10 mg) and EDC (0.10 g) at 0 ° C., and stir for 2 hours. The mixture was warmed to room temperature and further stirred for 20 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 2: 1) to obtain 0.52 g (99%) of the desired compound D ₁₀₃ .
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.22 (4H, m), 3.78 (1 H, t), 3.66 (12 H, m), 3.40 (8 H, s), 2. 81 (1H, dd), 2.72 (8H, br.s), 2.53 (1H, dd), 2.31 (2H, t), 1.62 (2H, m), 1.58 (9H) , S), 1.45 (36H, s), 1.25 (24H, m), 0.88 (3H, t).

Compound D ₁₀₄
Dissolve 0.29 g of alcohol A ₁₀₄ and 0.40 g of carboxylic acid C in 1.1 mL of CH ₂ Cl _2, add N, N-dimethylaminopyridine (10 mg) and EDC (0.13 g) at 0 ° C., and stir for 2 hours. The mixture was warmed to room temperature and further stirred for 22 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 1: 1 to 2: 1) to obtain 0.51 g (78%) of the desired compound D ₁₀₄ .
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.18 to 4.23 (4H, m), 3.76 (1H, t), 3.62 to 3.72 (16H, m), 3.42 (8H, s), 2.80 (1H, dd), 2.68 to 2.76 (8H, br. S), 2.53 (1H, dd), 2.32 (2H, t), 1. 58-1.66 (2H, m), 1.45 (45H, s), 1.21-1.35 (24H, m), 0.88 (3H, t).

Compound D ₁₀₅
Dissolve 0.31 g of alcohol A ₁₀₅ and 0.40 g of carboxylic acid C in 1.1 mL of CH ₂ Cl _2, add N, N-dimethylaminopyridine (10 mg) and EDC (0.13 g) at 0 ° C., and stir for 2 hours. The mixture was further warmed to room temperature and further stirred for 22 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 1: 1) to obtain 0.42 g (62%) of the desired compound D ₁₀₅ .
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.18 to 4.25 (4H, m), 3.76 (1H, t), 3.62 to 3.72 (20H, m), 3.42 (8H, s), 2.79 (1H, dd), 2.68 to 2.76 (8H, br. S), 2.53 (1H, dd), 2.31 (2H, t), 1. 58-1.65 (2H, m), 1.45 (45H, s), 1.22-1.35 (24H, m), 0.88 (3H, t).

Compound D ₁₀₉
Dissolve 0.24 g of alcohol A ₁₀₉ and 0.50 g of carboxylic acid C in 3.4 mL of CH ₂ Cl _2, add N, N-dimethylaminopyridine (10 mg) and EDC (0.26 g) at 0 ° C., and stir for 2 hours. The mixture was warmed to room temperature and further stirred for 20 hours. The reaction solution was concentrated, the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 3.5: 1 to 2: 1) to obtain an objective compound D ₁₀₉ 0.26 g (36%) .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.12 to 4.20 (4H, m), 3.78 (1H, t), 3.42 (8H, s), 2.78 (1H, dd) ) 2.65-2.78 (12H, br.m), 2.50 (1H, dd), 2.35 (3H, s), 2.32 (2H, t), 1.53-1. 65 (2H, m), 1.45 (45H, s), 1.22-1.34 (24H, m), 0.87 (3H, t).

Compound D ₁₁₈
0.22 g of alcohol A ₁₁₈ , 0.30 g of carboxylic acid C, 0.13 g of Ph ₃ P were dissolved in 1.0 mL of THF, and diethyl azodicarboxylate toluene solution (2.2 M, 0.23 mL) was added at 0 ° C. for 15 minutes. Stir. The mixture was stirred at room temperature for 20 hours, and further stirred at 50 degrees for 8 hours. The reaction solution was concentrated, the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 3: 1 to 2: 1) to obtain an objective compound D ₁₁₈ 0.22g (45%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.16 to 4.22 (4H, m), 3.76 (1H, t), 3.40 to 3.65 (12H, br.m), 3 .42 (8H, s), 2.79 (1H, dd), 2.68-2.80 (8H, br.s), 2.54 (1H, dd), 2.32 (2H, t), 1.54-1.64 (2H, m), 1.44 (54H, s), 1.22-1.37 (24H, m), 0.88 (3H, t).

Compound D ₁₂₈
0.29 g of alcohol A _128, 0.29 g of carboxylic acid C and 0.12 g of Ph ₃ P were dissolved in 1.0 mL of THF, diethyl azodicarboxylate toluene solution (2.2 M, 0.20 mL) was added at room temperature, and the mixture was stirred for 24 hours. . The reaction solution was concentrated, the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 10: 1) to obtain an objective compound D ₁₂₈ 0.26g (59%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.00 to 4.08 (4H, m), 3.77 (1H, t), 3.42 (8H, s), 2.76 (1H, dd ), 2.67-2.78 (8H, br.s), 2.48 (1H, dd), 2.27 (2H, t), 1.55-1.68 (6H, m), 1. 45 (45H, s), 1.20 to 1.40 (30H, m), 0.87 (3H, t).

Compound D ₁₂₉
Dissolve 0.29 g of alcohol A ₁₂₉ and 0.50 g of carboxylic acid C in 1.0 mL of CH ₂ Cl _2, add N, N-dimethylaminopyridine (10 mg) and EDC (0.16 g) at 0 ° C., and stir for 2 hours. The mixture was warmed to room temperature and stirred for 22 hours. Further EDC (0.08 g) added 24 hours after stirring the reaction solution was concentrated, the residue was purified by silica gel column chromatography (solvent system: hexane / ethyl acetate = 5: 1), the desired compound D ₁₂₉ 0 .35 g (46%) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.00 to 4.10 (4H, m), 3.77 (1H, t), 3.41 (8H, s), 2.67 to 2.82 (9H, m), 2.49 (1H, dd), 2.28 (2H, t), 1.55 to 1.66 (6H, m), 1.45 (45H, s), 1.21 1.37 (40H, m), 0.88 (3H, t).

Compound 24 _acid , 24 _Gd
0.28 g of Compound D ₂₄ was dissolved in 4.0 mL of 4M hydrogen chloride dioxane solution at room temperature and stirred for 19 hours. Dioxane was distilled off, and the resulting white crystals were washed with a hexane / ethyl acetate mixed solvent and collected by filtration to obtain 0.18 g (74%) of Compound 24 _acid . Compound 24 _acid was dissolved in 9 mL of methanol, 0.068 g of gadolinium chloride was added and stirred for 2 hours, and then a 1M aqueous sodium hydroxide solution was added dropwise to adjust the solution pH to 6. The resulting crystals were filtered off, washed with water and methanol, and dried to give 0.14 g (71%) of compound 24 _Gd .

Compound 101 _acid , 101 _Gd
0.21 g of compound D ₁₀₁ is dissolved in 2.5 mL of 4M hydrogen chloride dioxane solution at room temperature and stirred for 26 hours. After confirming the completion of the reaction by NMR, dioxane was distilled off to obtain white crystals (compound 101 _acid ). Mass (MALDI-TOF): m / z (A-cyano-4-hydroxycinnamic acid) 778 (M-3HCl) ⁺ . This was dissolved in 10 mL of methanol without isolation, 0.055 g of gadolinium hydrochloride was added and stirred for 2 hours, and then 1M aqueous sodium hydroxide solution was added dropwise to adjust to pH 6. The resulting crystals were filtered off and dried to give 0.074 g (38% / 2 steps) of compound 101 _Gd .

Compound 102 _acid , 102 _Gd
0.25 g of Compound D ₁₀₂ was dissolved in 2.8 mL of 4M hydrogen chloride dioxane solution at room temperature and stirred for 14 hours. Dioxane was distilled off to obtain white crystals (compound 102 _acid ). Mass (MALDI-TOF): m / z (A-cyano-4-hydroxycinnamic acid) 822 (M-3HCl) ⁺ . This was dissolved in 12 mL of methanol without isolation, 0.064 g of gadolinium hydrochloride was added and stirred for 2 hours, and then 1M aqueous sodium hydroxide solution was added dropwise to adjust the pH to 6. The resulting crystals were filtered off and dried, yielding 0.08 g of compound 102 _Gd (36% / 2 steps).

Compound 103 _acid , 103 _Gd
Compound D _{103 (} 0.52 g) was dissolved in a 4M hydrogen chloride dioxane solution at room temperature and stirred for 14 hours. Dioxane was distilled off to give white crystals (compound 103 _acid ). This was dissolved in 20 mL of methanol without isolation, and 0.19 g of gadolinium acetate tetrahydrate was added and stirred for 2 hours, and then 1M aqueous sodium hydroxide solution was added dropwise to adjust the pH to 6. The resulting crystals were filtered off and dried, yielding 0.24 g (51%) of compound 103 _Gd . Mass (MALDI-TOF): m / z (A-cyano-4-hydroxycinnamic acid) 1041 (M-Na) ⁻ .

Compound 104 _acid , 104 _Gd
0.51 g of Compound D ₁₀₄ is dissolved in 5.4 mL of 4M hydrogen chloride dioxane solution at room temperature and stirred for 8 hours. Dioxane was distilled off, and the resulting white crystals were washed with a hexane / ethyl acetate mixed solvent and collected by filtration to obtain Compound 104 _acid (0.27 g, 84%). Mass (MALDI-TOF): m / z (A-cyano-4-hydroxycinnamic acid) 910 (M-3HCl) ⁺ . 0.28 g of compound 104 _acid was dissolved in 14 mL of methanol, 0.11 g of gadolinium chloride was added and stirred for 1 hour, and then 1M aqueous sodium hydroxide solution was added dropwise to adjust to pH 6. The resulting crystals were filtered off and dried, yielding 0.17 g (56%) of compound 104 _Gd . Mass (MALDI-TOF): m / z (A-cyan-4-hydroxycinnamic acid) 1085 (M-Na) ⁻ .

Compound 105 _acid , 105 _Gd
0.42 g of Compound D ₁₀₅ is dissolved in 4.3 mL of 4M hydrogen chloride dioxane solution at room temperature and stirred for 8 hours. Dioxane was distilled off, and the resulting white crystals were washed with a hexane / ethyl acetate mixed solvent and collected by filtration to obtain 0.30 g (83%) of compound 105 _acid . Mass (MALDI-TOF): m / z (A-cyano-4-hydroxycinnamic acid) 954 (M-3HCl) ⁺ . 0.20 g of compound 105 _acid was dissolved in 9 mL of methanol, 0.075 g of gadolinium chloride was added and stirred for 1 hour, and then 1M aqueous sodium hydroxide solution was added dropwise to adjust the pH to 6. The resulting crystals were filtered off and dried to give 0.10 g (46%) of compound 105 _Gd .

Compound 109 _acid , 109 _Gd
0.26 g of Compound D ₁₀₁ was dissolved in 4 mL of 4M hydrogen chloride dioxane solution at room temperature and stirred for 6 hours. After confirming the completion of the reaction by MS, dioxane was distilled off to obtain 0.20 g (87%) of white crystal compound 109 _acid . Mass (MALDI-TOF): m / z (A-cyano-4-hydroxycinnamic acid) 791 (M-3HCl) ⁺ . 0.14 g of 109 _acid was dissolved in 8 mL of methanol, 0.06 g of gadolinium hydrochloride was added and stirred for 2 hours, and then a 1M aqueous sodium hydroxide solution was added dropwise to adjust the pH to 6. The resulting crystals were precipitated by centrifugation, dried after removing the solvent to give 0.05 g (33%) of compound 109 _Gd . Mass (MALDI-TOF): m / z (A-cyano-4-hydroxycinnamic acid) 966 (M-Na) ⁻ .

Compound 118 _acid , 118 _Gd
0.22 g of Compound D ₁₁₈ was dissolved in 4 mL of 4M hydrogen chloride dioxane solution at room temperature, stirred for 20 hours, and then dioxane was distilled off to obtain white crystals (Compound 118 _acid ). Mass (MALDI-TOF): m / z (A-cyano-4-hydroxycinnamic acid) 865 (M-3HCl) ⁺ . This was dissolved in 13 mL of methanol without isolation, 0.098 g of gadolinium hydrochloride was added and stirred for 2 hours, and then a 1M aqueous sodium hydroxide solution was added dropwise to adjust the pH to 6. The resulting crystals were filtered off and dried to give 0.15 g of compound 118 _Gd (76% / 2 steps).

Compound 128 _acid , 128 _Gd
0.25 g of Compound D ₁₂₈ is dissolved in 3.5 mL of 4M hydrogen chloride dioxane solution at room temperature and stirred for 21 hours. Dioxane was distilled off, and the resulting white crystals were washed with a hexane / ethyl acetate mixed solvent and collected by filtration to obtain 0.19 g (89%) of a compound 128 _acid . 0.19 g of compound 105 _acid was dissolved in 11 mL of methanol, 0.082 g of gadolinium chloride was added and stirred for 2 hours, and then 1M aqueous sodium hydroxide solution was added dropwise to adjust the pH to 6. The resulting crystals were filtered off and dried to give 0.11 g (57%) of compound 128 _Gd .

Compound 129 _acid 129 _Gd
0.35 g of Compound D ₁₂₈ is dissolved in 6 mL of 4M hydrogen chloride dioxane solution at room temperature and stirred for 9 hours. Dioxane was distilled off, and the resulting white crystals were washed with a hexane / ethyl acetate mixed solvent and collected by filtration to obtain a compound 129 _acid . Compound 129 _acid was dissolved in 16 mL of methanol, 0.12 g of gadolinium chloride was added and stirred for 2 hours, and then 1M aqueous sodium hydroxide solution was added dropwise to adjust the pH to 6. The resulting crystals were filtered off and dried, yielding 0.12 g (36% / 2 steps) of compound 129 _Gd . Mass (MALDI-TOF): m / z (A-cyano-4-hydroxycinnamic acid) 1027 (M-2Na + H)-.

Test Example 1: Solubility test Each gadolinium complex shown below was weighed to 1 mM, 1 mL of a mixed solvent of chloroform / methanol (1/1) was added, and the solubility (room temperature at 25 ° C) at that time was examined. As a result, it is clear that the compound of the present invention becomes a uniform solution as compared with Comparative Compound 1, and has excellent characteristics for preparing a liposome.

Test Example 2: Method for preparing liposome
According to the method described in J. Med. Chem., 25 (12), 1500 (1982), di palmitoyl PC (Funakoshi, No. 1201-41-0225), di palmitoyl PS (Funakoshi, No. .1201-42-0237), Compound 103 _Gd was dissolved in chloroform in an eggplant-shaped flask at the following concentration ratio to obtain a homogeneous solution, and then the solvent was distilled off under reduced pressure to form a thin film on the bottom of the flask. This thin film is dried in vacuum, 0.9% physiological saline (manufactured by Hikari Pharmaceutical Co., Ltd., No512) is added in an appropriate amount, and ultrasonic irradiation (Branson Co., No.3542 probe type oscillator, 0.1 mW) is applied for 5 minutes under ice cooling. After the implementation, a liposome dispersion having a particle size of 85 to 120 nm was prepared using a liposome preparation device (manufactured by Central Science Co., Ltd.).

Concentration ratio: PS 50 nmol + PC 50 nmol + Compound 103 _Gd 1 nmol

Test example 3: Mice 3 day continuous administration toxicity test ICR mouse male 6 weeks old (Charles River Japan) was purchased, and after a quarantine period of 1 week, in clean animal house (air conditioning: Hepafilter class 1000, room temperature: 20 C. to 24.degree. C. Humidity: 35% to 60%) for one week. Thereafter, in order to determine the MTD value, a mouse serum suspension was administered from the tail vein. The mouse serum suspension was administered using either physiological saline (manufactured by Hikari Pharmaceutical Co., Ltd.) or glucose solution (manufactured by Otsuka Pharmaceutical Co., Ltd.) as a solvent. Next, based on the determined MTD value, the compound 103 _Gd in 1/2 amount thereof was administered for 3 days from the tail vein for 3 consecutive days (n = 3 mice). Symptoms were observed up to 6 hours after each administration. After observing neurotoxicity, autopsy was performed and findings were taken on major organs. The results are shown below. It is clear that the compound of the present invention has low toxicity and does not show neurotoxicity, and has excellent properties as a constituent lipid of liposomes for MRI contrast agents.
Compound: MTD (mg / kg); neurotoxicity (“-” indicates negative neurotoxicity, “+” indicates positive neurotoxicity)
Compound 103 _Gd (50 mg / kg): −

Claims (18)

The following general formula (I):

[Wherein, R represents an alkyl group or alkenyl group composed of 8 to 30 carbon atoms; X ¹ and X ² each independently represent a single bond, —O—, or —NZ ¹ — (Z ¹ represents a hydrogen atom; Or a lower alkyl group having 1 to 3 carbon atoms), but X ¹ and X ² do not simultaneously represent a single bond; X ³ represents —O— or —NZ ² — (Z ² hydrogen atom). Or represents a lower alkyl group having 1 to 3 carbon atoms; n represents an integer of 1 to 10; L represents a divalent linking group (L represents a carbon atom, a hydrogen atom, and a heteroatom (a heteroatom and Is an atom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom), and 0 to 9 oxygen atoms, 0 to 4 nitrogen atoms and 0 to 0 sulfur atoms constituting L 2 and the total number of carbon atoms and heteroatoms of L is 1-20) , X ^1, X ^2, and of X ³ at least one of an oxygen atom. Or a salt thereof. The compound or a salt thereof according to claim 1, wherein X ³ is an oxygen atom. The compound or a salt thereof according to claim 1 or 2, wherein L is a divalent linking group composed of an atom selected from the group consisting of a carbon atom, an oxygen atom, a nitrogen atom, and a hydrogen atom. The compound according to claim 1 or 2, wherein L is a divalent linking group composed of a carbon atom, an oxygen atom, and a hydrogen atom, or L is a divalent linking group composed of a carbon atom and a hydrogen atom. Its salt. The main chain of L (the main chain is an atomic group connecting X ² and X ³ in the shortest number), X ² , and the sum of the number of heteroatoms contained in X ³ are j and carbon contained in the main chain of L The compound or a salt thereof according to any one of claims 1 to 4, wherein a quotient obtained by dividing k by j when the number of atoms is k is 3 or less. The compound or a salt thereof according to claim 5, wherein a quotient obtained by dividing k by j is 2 or less. X ² is —O— or —NZ ¹ — (Z ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms), L is an alkylene group having 1 to 12 carbon atoms, or — ( CH ₂ CH ₂ Y) _m CH ₂ CH ₂ — (m represents an integer of 1 to 6, Y represents —O— or —NZ ³ — (Z ³ represents a hydrogen atom or a methyl group), and m represents The compound according to any one of claims 1 to 6, or a salt thereof, wherein when the number is 2 or more, the plurality of Ys may be the same or different. X ² is —O— or —NZ ¹ — (Z ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms), and L is — (CH ₂ CH ₂ Y) _m CH ₂ CH _2. -(M represents an integer of 1 to 6, Y represents -O- or -NZ ^3- (Z ³ represents a hydrogen atom or a methyl group), and when m is 2 or more, a plurality of Y are the same or different. The compound or its salt of any one of Claims 1-6 which is a coupling group represented by this. X ² is —O— or —NZ ¹ — (Z ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms), and L is — (CH ₂ CH ₂ O) ₁ CH ₂ CH The compound or a salt thereof according to any one of claims 1 to 6, which is a linking group represented by _2- (l represents an integer of 1 to 6). The compound or a salt thereof according to any one of claims 1 to 9, wherein R is a linear alkyl group or alkenyl group consisting of 10 to 22 carbon atoms, or a branched alkyl group or alkenyl group. . R is a linear or branched alkyl group consisting of 10 to 22 carbon atoms; X ¹ is a single bond; X ² is —O—; X ³ is —O—; n is 1, L is an alkylene group having 7 to 12 carbon atoms, or — (CH ₂ CH ₂ Y) _m CH ₂ CH ₂ — (m represents an integer of 1 to 6, Y represents —O— or 2. A linking group represented by —NZ ³ — (Z ³ represents a hydrogen atom or a methyl group), and when m is 2 or more, a plurality of Ys may be the same or different. Or a salt thereof. R is nC ₁₅ H ₃₁ or CH ₂ (CH (CH ₃ ) (CH ₂ ) ₃ ) ₃ CH (CH ₃ ) ₂ ; L is (CH ₂ ) ₁₂ , ((CH ₂ ) ₂ O) ₃ (CH ₂ ) ₂ , ((CH ₂ ) ₂ O) ₄ (CH ₂ ) ₂ , ((CH ₂ ) ₂ O) ₅ (CH ₂ ) ₂ , (CH ₂ ) ₂ NMe (CH ₂ ) ₂ Or a salt thereof. The chelate compound which consists of a compound of any one of Claims 1-12, and a metal ion, or its salt. The chelate compound or a salt thereof according to claim 13, wherein the metal ion is a metal ion of an element selected from atomic numbers 21-29, 31, 32, 37-39, 42-44, 49, and 57-83. The chelate compound or a salt thereof according to claim 13, wherein the metal ion is a paramagnetic element metal ion corresponding to atomic number 21-29, 42, 44, 57-71. The chelate compound or a salt thereof according to claim 13, wherein the metal ion is gadolinium (atomic number 64). The liposome which contains the compound or its salt of any one of Claims 1-16 as a membrane component. The liposome according to claim 17, comprising phosphatidylcholine and phosphatidylserine as membrane components.