KR101010061B1 - Amphiphilic Porphyrin Derivatives, and the method for preparing the same - Google Patents

Abstract

The present invention relates to an amphipathic porphyrin derivative, a method for preparing the same, and an MRI contrast agent comprising the micelle formed by self-assembly of the porphyrin derivative and the porphyrin derivative, wherein the amphipathic porphyrin derivative according to the present invention may contain various metals. It has a high solubility in aqueous solution, and can be used as an effective MRI contrast agent, characterized by the ability to produce micelle particles composed of a single size of several tens of nanometers in an aqueous solution.

Description

Amphiphilic Porphyrin Derivatives, and the method for preparing the same

The present invention relates to an amphipathic porphyrin derivative, a method for preparing the same, an MRI contrast agent comprising the micelle formed by self-assembly of the porphyrin derivative and the porphyrin derivative, and the amphiphilic porphyrin derivative according to the present invention may contain various metals. It has a high solubility in aqueous solution, has the characteristic of producing micelle particles composed of a single size of several tens of nanometers in aqueous solution, and can be used as an effective MRI contrast agent.

Porphyrin derivatives according to the invention can be used as MRI contrast agents. Magnetic Resonance Imaging (MRI) is a method of obtaining anatomical, physiological and biochemical information of the body using the relaxation of the spin of hydrogen atoms in the magnetic field. Invasive and real-time imaging is one of the best imaging diagnostics to date.

In the field of life sciences and medicine, MRI uses various methods to increase image contrast by injecting a substance from outside, which is called a contrast agent. Contrast between tissues on an MRI image is a result of tissue-specific relaxation in which the nuclear spin of water molecules in the tissue returns to equilibrium, and contrast agents affect this relaxation. This results in a wider gap in relaxation between tissues and a change in the MRI signal, which sharpens the contrast between tissues.

Contrast agents differ in their utility and precision depending on their features, functions, and targets. Augmented contrast with contrast agents raises or lowers the periphery and image signal of certain living organs and tissues, allowing for clearer imaging. Contrast agents that make the image signal of the body part that wants to obtain MRI images relatively higher than the surroundings are called 'positive' contrast agents. Contrast contrast agents that make the relative lower than the surroundings are called 'negative' contrast agents. A 'positive' contrast agent is a contrast agent that relates to T1 relaxation, ie, a paper arm. This paper arm aligns the magnetization component Mz in the Z-axis direction of the spin with the Y-axis in the XY plane after the RF energy shock absorption from the X-axis, and releases energy to the outside and returns to its original value. Process, and this phenomenon is referred to as "T1 relaxation". The time until Mz returns to 63% of the initial value is called "T1 relaxation time". The shorter T1 relaxation is, the larger the MRI signal, and thus the shorter image acquisition time. 'Negative' contrast agents are contrast agents related to T2 relaxation and lateral relaxation. The magnetization component Mz in the Z-axis direction of the spin is aligned with the Y-axis in the XY plane after the RF energy shock absorption from the X-axis, and then the energy decays on itself or releases energy to the surrounding spindle and returns to its original value. In this case, the phenomenon in which the component My of the spin which has been spread evenly on the XY plane decays exponentially is expressed as "T2 relaxation". The time until My decays to 37% as the initial value is called "T2 relaxation time" and it is measured through the receiving coil installed on the Y axis as a function of the time that My decreases with time. It is called a free induction decay (FID). T2 short tissues appear dark on MRI.

Commercially available MRI contrast agents are paramagnetic compounds as 'positive' contrast agents and superparamagnetic nanoparticles as 'negative' contrast agents. Paramagnetic compounds that are 'positive' contrast agents are usually gadolinium ions (Gd 3+) or manganese ions (Mn).

2+) chelating compound, which accelerates the relaxation of both water to give a bright contrast image around the contrast medium. However, gadolinium ions are highly toxic and are used in the form of chelate compounds or compounds combined with high molecular materials to prevent this. Among them, Gd-DTPA is the most widely used, and its main medical applications are blood-brain diaphragm (BBB) damage, changes in the vascular system, and blood flow or perfusion conditions. This causes the problem that, because the contrast agent is in the form of a compound, it activates immune function in vivo or causes degradation in the liver, so that the residence time on the blood is short, about 20 minutes.

Manganese-enhanced MRI (MEMRI) using manganese ions (Mn2 +) as a T1 contrast agent has been used to study anatomical structures and cell functions in various areas such as brain science (Lin YJ, Koretsky AP). , Manganese

ion enhances T1-weighted MRI during brain activation: an approach to direct imaging of brain function, Magn. Reson. Med. 1997; 38: 378-388). In the case of MEMRI using manganese ions as contrast medium, despite the excellent contrast properties, MnCl2 has a high permeation rate (> 88 ~ 175 mg / kg) and due to the toxicity caused by accumulation of manganese ions in tissues, In addition, the utilization of the human brain has inherent limitations due to its toxicity and the possibility of accumulation in the body.

Currently, Mn-DPDP (teslascan) is known in general as a manganese ion contrast medium used for contrasting human liver as a contrast agent using manganese. When Mn-DPDP is administered to the body, Zn substitutes for Mn to form Zn-DPDP and is excreted through the kidneys. Mn2 + circulates with blood and is absorbed into the liver, kidneys, and pancreas to act as a contrast agent. This also requires a slow infusion method of 2-3 ml / hr due to the toxicity of Mn2 +. Normally, 5 μmol / kg body weight (0.5 ml / kg body weight) is the amount that can be used in humans, which is not enough for the brain or other organs. (ref.Rofsky NM, Weinreb JC, Bernardino ME et al. Hepatocellular tumors: characterization with Mn-DPDP-enhanced MR imaging. Radiology 188: 53, 1993). T1 contrast using 'positive' contrast agent is suitable for studying anatomical structure and cell function of tissue without distortion of image, and has been widely used in MRI because of its high resolution. Since 'positive' contrast agents are based on paramagnetic metal ions or their complexes, their application limits to humans due to toxicity and their residence time in the blood are short, and they are attached to target-oriented substances due to steric hindrance by ligand molecules of the complexes. Make it hard to do

In order to overcome such problems of the prior art, US Patent US 2003/0215392 A1 discloses a study result of maintaining the shape of the particles while increasing the local concentration by concentrating gadolinium ions in the polymer nanostructure. However, since the particles are large in size and gadolinium ions are bound to the polymer nanostructure, they can be easily separated from the surface of the particles, and the cell permeability is not high.

Superparamagnetic nanoparticles are used as 'negative' contrast agents, and a typical example is superparamagnetic iron oxide (SPIO). US Pat. No. 4,951,675 uses biocompatible superparamagnetic particles as T2 contrast agent for magnetic resonance imaging. US Pat. No. 6,274,121 uses superparamagnetic particles and tissue-specific binding materials on the surface of the particles for diagnostic purposes. Or paramagnetic particles made of an inorganic or organic material comprising a binding site capable of coupling with a pharmaceutically active material.

Since superparamagnetic iron oxides in the form of nanoparticles are in the form of particles ranging in size from several hundreds to hundreds of nm, the retention time in vivo reaches several hours, which is much longer than the in vivo retention time of the compound. Because of the ability to bind to and the target material, it has attracted much attention as a target-oriented contrast agent. However, in the case of superparamagnetic nanoparticles, the T2 relaxation time is shortened due to its magnetic properties. As a side effect, the magnetic field is formed in the MRI to disturb the image. In the case of T2-weighted images, the contrasted areas are highlighted in black, which can be confused with areas that already appear black, such as bleeding in the body, petrification of the body, and accumulation of heavy metals.

In addition, due to its own magnetism, the magnetic field in the vicinity of the contrast medium (blooming effect) causes a signal loss (signal loss) or distortion in the background image, there is a problem that can not obtain an image close to the anatomical image.

Currently, injection formulations for delivering poorly soluble drugs, contrast agents, oils, etc. into cells or the body include biodegradable polymer nanoparticles prepared using self-assembling polymer micelles and self-emulsifying diffusion methods made from amphipathic block copolymers. , A polymer nanoparticle made by ionic bonds between ionic polymers, polymer nanoparticles using dendrimers, liposomes of 100-800 nm microspheres consisting of one or more phospholipid bilayers, and oils. Oil-in-water emulsions (R. Duncan, Nat. Rev. Drug Discovery 2 (2003) 347-360; A. Potineni, et al., J. Controlled Release 86 (2003) 223-234; K. Kataoka, et. al., Adv. Drug Deliv. Rev. 47 (2001) 113131; HS Yoo, et al., J. Controlled Release 96 (2004) 273-283; A. Gabizon, et al., Cancer Res. 54 (1994) 987-992), the polymer micelles and liposomes of the formulations Lee active drug, in particular, I have been widely studied in vivo delivery formulations of poorly soluble anticancer agents.

The first problem to be solved by the present invention is to provide an amphiphilic porphyrin derivative which may contain a variety of metals, high solubility in aqueous solution, and can impart a variety of functionalities according to the change of hydrophobic and hydrophilic molecules.

The second object of the present invention is to provide a method for preparing the amphipathic porphyrin derivative.

The third object of the present invention is to provide a micelle having a uniform size of several tens of nanometers formed by self-assembly of the porphyrin derivative in an aqueous solution.

A fourth object of the present invention is to provide an MRI contrast agent comprising a porphyrin derivative which is a metal chelate and has the characteristics of a nanoassembly.

The present invention provides a porphyrin derivative represented by the following formula (1) in order to solve the first problem:

(1)

(One)

Wherein M is H ₂ or a metal atom, R ₁ , R ₂ , R ₃ are each H or OR ₅ , R ₅ is an alkyl group of C ₁ -C ₁₂ , and R ₄ is a dendron consisting of oligoethylene being).

According to a preferred embodiment of the present invention, when M in the formula (1), it may be selected from the group consisting of Mn, Cu, Co, Zn, Ni, Pd, Pt.

According to another preferred embodiment of the present invention, the porphyrin derivative according to the present invention is preferably a compound represented by the following formula (2) or (3):

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The present invention provides a method for preparing a porphyrin derivative of formula (2) by the following scheme (1) to solve the second problem:

Scheme 1

(a) MnCl₂·4H₂O, N,N-디메틸포름아미드, 160℃, 12 h

(a) MnCl ₂ · 4H ₂ O, N, N-dimethylformamide, 160 ° C., 12 h

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According to one embodiment of the present invention, the compound of formula (4) may be prepared according to the following scheme (2).

Scheme 2

b) THF, 0 ° C, NaH, 3 days at room temperature

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In addition, according to an embodiment of the present invention, the compound of formula (5) may be prepared according to the following scheme (3).

Scheme 3

c) THF, LiAlH ₄ , 0 ° C. → room temperature, 1 h

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In addition, according to an embodiment of the present invention, the compound of formula (7) may be prepared according to the following scheme (4).

Scheme 4

d) K ₂ CO ₃ , 18-crown-6 ether, THF, 1-bromooctane, 85 ° C., 25 h

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In addition, according to an embodiment of the present invention, the compound of formula (8) may be prepared according to the following scheme (5).

Scheme 5

e) dichloromethane, BF ₃ , chloranyl, 2-3 days

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In addition, according to an embodiment of the present invention, the compound of formula (6) may be prepared according to the following scheme (6).

Scheme 6

f) p-toluene sulfonylchloride, pyridine, dichloromethane, 0 ° C. to room temperature, 8 h

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In addition, according to an embodiment of the present invention, the compound of formula (9) may be prepared according to the following scheme (7).

Scheme 7

g) 1) BH ₃ , 0 ° C., 2-3 h, THF, 2) H ₂ O ₂ , 0 ° C., 1 h, 3) NaOH, 0 ° C., 1 h

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In addition, according to an embodiment of the present invention, the compound of formula (10) may be prepared according to the following scheme (8).

Scheme 8

h) NaH, THF, reflux, 24 h

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In addition, according to an embodiment of the present invention, the compound of formula (11) may be prepared according to the following scheme (9).

Scheme 9

i) 1) BH ₃ , 0 ° C., 2-3 h, THF, 2) H ₂ O ₂ , 0 ° C., 1 h, 3) NaOH, 0 ° C., 1 h

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In addition, according to an embodiment of the present invention, the compound of formula (12) may be prepared according to the following scheme (10).

Scheme 10

j) NaH, THF, reflux, 12 h

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In order to solve the third problem, the present invention provides a micelle (Micelle) formed by self-assembly of the porphyrin derivative in an aqueous solution. At this time, the size of the micelle is preferably 20 to 100 nm.

In order to solve the fourth problem, the present invention provides an MRI contrast agent comprising the porphyrin derivative.

Amphiphilic porphyrin derivatives according to the present invention may contain various metals, have high solubility in aqueous solutions, and are characterized in that they can produce micelle particles composed of a single size of several tens of nanometers in aqueous solution, especially in the medical field. At the present time when early diagnosis of disease is important, the new type of nanoparticles according to the present invention, which is a metal chelate and has the characteristics of nanoassembly, is expected to have high marketability because it can be applied as a contrast agent.

Porphyrin derivatives of the present invention is characterized in that the compound represented by the following formula (1).

<Equation 1>

(1)

(One)

Wherein M is H ₂ or a metal atom, R ₁ , R ₂ , R ₃ are each H or OR ₅ , R ₅ is an alkyl group of C ₁ -C ₁₂ , and R ₄ is a dendron consisting of oligoethylene being).

According to a preferred embodiment of the present invention, when M in the formula (1), it may be selected from the group consisting of Mn, Cu, Co, Zn, Ni, Pd, Pt.

According to another preferred embodiment of the present invention, the porphyrin derivative according to the present invention may be a compound represented by the following formula (2) or (3).

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The porphyrin derivative is self-assembled in an aqueous solution to form a micelle of a certain size (Micelle), wherein the micelle size is preferably 20 to 100 nm, showing an EPR (Enhanced Permeation and Retention) effect in the size range. In addition, the porphyrin derivative according to the present invention is characterized by being applicable as an MRI contrast agent, in particular, a T1 contrast agent.

Hereinafter, examples of the present invention will be described in more detail, but the scope of the present invention is not limited to these examples.

Example 1

Example 1-1

5.3 g of Metallyl dichloride and 11.9 g of Tri (ethylene glycol) monomethyl ether were added to the reaction vessel, and 60 mL of tetrahydrofuran was added. 3.84 g of sodium hydride. It was added dropwise and maintained at 65 ℃ for 12 hours. 5 mL of water was added dropwise to the reaction vessel, tetrahydrofuran was evaporated and concentrated in vacuo, and the reaction mass was extracted with diethyl ether 100 mL and 100 mL water. This was carried out by column chromatography using ethyl acetate and methanol mixed solvent (100 / 0-80 / 20) to separate the reaction terminated material to obtain the compound of formula (12) in 35% yield. 1 H NMR (250 MHz, CDCl 3): d 5.18 (s, 2H; CH 2), 4.01 (s, 4H; CH 2 (CH 2 O) 2), 3.70-3.58 (m, 24H; OCH 2), 3.37 (s, 6H; OCH 3 ).

j) NaH, THF, reflux, 12 h

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Example 1-2

3.8 g of the compound of Formula 12 and 5 mL of tetrahydrofuran were placed in a reaction vessel, and the reaction vessel was cooled using ice water. 4 mL of Borane-tetrahydrofuran was added dropwise and stirred for 2 hours. 3 mol sodium hydroxide was added dropwise to the reaction vessel and stirred for 15 minutes. 4 mL of 30% hydrogen peroxide solution was added dropwise and stirred for 30 minutes. The reaction mass was extracted with 100 mL of potassium carbonate saturated solution and 100 mL of diethyl ether. This was carried out by column chromatography using a mixture of ethyl acetate and methanol (100 / 0-80 / 20) to separate the reaction was terminated to obtain the desired compound of formula (11) in a yield of 68%. 1 H NMR (250 MHz, CDCl 3): d3.74 (d, 2H; CH 2 OH), 3.65-3.60 (d, 4H; CH 2 (CH 2 O) 2), 3.65-3.60 (m, 24H; OCH 2), 3.38 (s, 6H; 0CH 3), 2.13 (m, 1H; CH).

i) 1) 1M BH ₃ , 0 ° C., 2-3 h, THF, 2) H ₂ O ₂ , 0 ° C., 1 h, 3) NaOH, 0 ° C., 1 h

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Example 1-3

1.7 g of metaldichloride and 8.9 g of the compound of the above formula (11) were added to a reaction vessel, 20 mL of tetrahydrofuran was added thereto, and 0.8 g of sodium hydride was added dropwise and maintained at 65 ° C for 24 hours. 2 mL of water was added dropwise to the reaction vessel, and tetrahydrofuran was evaporated and concentrated under vacuum. Then, the reaction mass was extracted with diethyl ether and 100 mL of diethyl ether. This was carried out by column chromatography using a mixture of ethyl acetate and methanol (100 / 0-80 / 20) to terminate the reaction to obtain a compound of the formula (10) in a yield of 28%. 1 H NMR (250 MHz, CDCl 3): d 5.18 (s, 2H; CH 2), 4.02 (s, 8H; CH 2 (CH 2 O) 2), 3.62-3.41 (m, 64H; OCH 2), 3.37 (s, 12H; OCH 3 ), 2.22-2.04 (m, 4H; CH (OCH 2) 2).

h) NaH, THF, reflux, 24 h

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Example 1-4

9.3 g of the compound of Formula 10 and 6 mL of tetrahydrofuran were added to a reaction vessel, and the reaction vessel was cooled using ice water. 4 mL of Borane-tetrahydrofuran was added dropwise and stirred for 2 hours. 3 mol sodium hydroxide was added dropwise to the reaction vessel and stirred for 15 minutes. 4 mL of 30% hydrogen peroxide solution was added dropwise and stirred for 30 minutes. The reaction mass was extracted with 100 mL of potassium carbonate saturated solution and 100 mL of diethyl ether. This was carried out by column chromatography using a mixture of ethyl acetate and methanol (100 / 0-80 / 20) to separate the reaction was terminated to obtain the desired compound of formula (9) in 74% yield. 1 H NMR (250 MHz, CDCl 3): d3.86 (d, 2H; CH 2 OH), 2.95-3.59 (m, 64H; OCH 2), 3.38 (s, 12H; OCH 3), 2.01-2.14 (m, 3H; CH)

g) 1) BH ₃ , 0 ° C., 2-3 h, THF, 2) H ₂ O ₂ , 0 ° C., 1 h, 3) NaOH, 0 ° C., 1 h

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Examples 1-5

5.5 g of the compound of formula (9) and 3.8 g of para-toluenesulfonyyl chloride were added to a reaction vessel, and 50 mL of dichloromethane and 3 mL of pyridine were added dropwise and stirred at room temperature for 5 hours. The dichloromethane was concentrated by evaporation under vacuum, and then the reaction mass was extracted with diethyl ether with 100 mL of diethyl ether and 100 mL of water. The reaction mixture was separated by column chromatography using ethyl acetate and methanol mixed solvent (100 / 0-80 / 20) to obtain the desired compound of formula (6) in 78% yield in 1H NMR ( 400 MHz, CDCl 3): d 7.76 (d, 2H; CH, phenyl), 3.30 (d, 2H; CH, phenyl), 2.45 (s, 3H; CH 3), 4.10 (d, 2H; CH 2), 3.29-4.06 (m, 64H; OCH 2), 3.37 (s, 12H; OCH 3), 2.17-2.04 (m, 3H; CH).

f) p-toluene sulfonylchloride, pyridine, dichloromethane, room temperature, 5 h

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Example 2

Example 2-1

2.11 g of dipyrrolmethane, 1 g of 3,5-dihydroxybenzaldehyde and 1.19 g of terephalaldehydic acid methyl ester were added to a reaction vessel together with 850 mL of dichloromethane and stirred for 10 minutes. 2 mL of boron trifluoride was added thereto and stirred at room temperature for 24 hours. 10 g of chloranil was added thereto, followed by stirring for 12 hours. The dichloromethane solvent was concentrated by evaporation in a water bath. This was carried out by column chromatography using dichloromethane and methanol mixed solvent (100 / 0-95 / 5) to separate the reaction terminated material to obtain a compound of formula (8) in a yield of 10%. 1 H NMR (400 MHz, CDCl 3): d4.07 (s, 3H; OCH 3), 6.68 and 7.08 (s, 3H; C 6 H 3), 8.37-8.44 (q, 4H; C 6 H 4), 8.91-9.53 (m, 8H; pyrrole ring CH), 10.37 (s, 2H; meso-CH in Pzn).

e) dichloromethane, BF ₃ , chloranyl, room temperature, 2-3 days

Example 2-2

0.89 g of the compound of formula (8), 2 g of potassium carbonate, and 0.76 g of 18-crown-6 ether are added to a reaction vessel, and 140 mL of tetrahydrofuran is added dropwise. 5 mL of 1-bromooctane is added and maintained at 80 ° C. for 25 hours. Tetrahydrofuran was evaporated by heating under vacuum, concentrated, and then the reaction mass was extracted with ethyl acetate and 100 mL of ethyl acetate and 100 mL of water. This was carried out by column chromatography using a mixture of hexane (Hexane) and ethyl acetate (65/35) to terminate the reaction to give a compound of the formula (7) in a yield of 71%. 1 H NMR (400 MHz, CDCl 3): d0.87 (t, 6H; CH 3), 1.27 (m, 24H; C 12 H 24), 4.15 (s, 3H; OCH 3), 5.35 (t, 4H; OCH 2), 6.90 (t , 1H; p-C6H3), 7.42 (d, 2H; o-C6H3), 8.35 and 8.47 (d, 4H; C6H4), 9.08-9.47 (m, 8H; pyrrole ring CH), 10.35 (s, 2H; meso -CH in Pzn).

d) K ₂ CO ₃ , 18-crown-6 ether, THF, 1-bromooctane, 85 ° C., 25 h

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Example 2-3

0.85 g of the compound of Chemical Formula (7) and 100 mL of tetrahydrofuran were placed in a reaction vessel, and cooled by ice bath. 57.6 mg of lithium aluminum hydride was added thereto, followed by stirring at room temperature for 1 hour. 5 mL of water was added, tetrahydrofuran was evaporated by heating in vacuo, and the reaction mass was extracted with ethyl acetate and 100 mL of ethyl acetate and 100 mL of water. This was carried out by column chromatography using dichloromethane and methanol mixed solvent (100 / 0-95 / 5) to separate the reaction terminated material to obtain the compound of formula (5) in 91% yield. 1 H NMR (400 MHz, CDCl 3): d 0.84 (t, 6H; CH 3), 1.25-1.39 (m, 60H; C 12 H 24), 1.88 (m, 4H; CH 2 in alkyl chain), 4.13 (t, 4H; Ar − OCH2), 5.02 (d, 2H; Ar-CH2), 6.91 (t, 1H; p-C6H3), 7.43 (d, 2H; o-C6H3), 7.75 and 8.24 (d, 4H; C6H4), 9.12-9.44 (m, 8H; pyrrole ring CH), 10.32 (s, 2H; meso-CH in Pzn).

c) THF, LiAlH ₄ , 0 ° C. → room temperature, 1 h

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Examples 2-4

70 mg of the compound of Formula (5) and 0.2 mL of the compound of Formula (6) were transferred to a reaction vessel, and 30 mL of tetrahydrofuran was added dropwise, followed by cooling with ice. 20 mg of 60% sodium hydride was added at once and transferred to room temperature and stirred for 3 days. After adding 2 mL of water, tetrahydrofuran was evaporated by heating under vacuum, the reaction mass was extracted with ethyl acetate and 100 mL of ethyl acetate and 100 mL of water. This was carried out by column chromatography using an ethyl acetate and methanol mixed solvent (100 / 0-80 / 20) to separate the reaction terminated material to obtain a compound of the formula (4) in 21% yield. 1 H NMR (400 MHz, CDCl 3): d 1.25-1.91 (m, 24H; CH 2 in alkyl chain), 0.86 (t, 6H; CH 3), 2.25-2.40 (m, 3H; CH), 3.33 (s, 12H; OCH3), 3.38-3.66 (m, 64H; OCH2), 3.8 1 (d, 2H; CH2O), 4.14 (t, 6H; CH2O), 4.88 (s, 2H; CH2O), 6.95 (s, 1H; C6H3) , 7.42 (s, 2H; C6H3) 7.78and 8.26 (d, 4H; C6H4), 9.09-9.41 (m, 8H; pyrrole ring CH), 10.31 (s, 2H; meso-CH in Pzn), -3.13 (s , 2H; NH).

b) THF, 0 ° C., NaH, room temperature, 3 days

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Example 2-5

4 mg of the compound of the formula (4) and manganese (ll) chloride tetrahydrate were transferred to a reaction vessel, and 20 mL of N, N-dimethylformamide was added dropwise. The reaction vessel was kept at 160 ° C for 12 hours. After cooling to room temperature, the reaction mass was extracted with ethyl acetate and 100 mL of ethyl acetate and 100 mL of water. This was carried out by column chromatography using a mixture of ethyl acetate and methanol (100 / 0-60 / 40) to finally obtain the compound of formula (2) in a yield of 49%. UV-Vis (CH 2 Cl 2): lmax 369, 471, 569, 601; (H 2 O): lmax 365, 461, 560, 596.

(a) MnCl ₂ · 4H ₂ O, N, N-dimethylformamide, 160 ° C., 12 h

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As a result of measuring the T1 relaxation time of water molecules using this micelle structure, the relaxation time of 80.3 ms was shown at a concentration of 2.5 mM. In general, it is much shorter than the relaxation time of water molecules, indicating that it can be used as an MRI contrast agent. In addition, through the formation of micelles (Micelle) structure can be expected EPR (Enhanced Permeation and Retention) effect. In general, neoplasms grow in tumor tissues or tissues that are inflamed. Neovascular tissues have a certain size or more defects in blood vessels because of relatively slow development of vascular endothelial cells. Accordingly, substances of a certain size, such as micelle structures, tend to selectively accumulate in the drug tissue or inflammatory tissue. Currently, T2 contrast agents using nanoparticles are attempting selective delivery to tumor tissues using this principle, but most of T1 contrast agents are chelates of paramagnetic metal ions as low molecular weight compounds. The present invention proposes a material that can be applied as a T1 contrast agent while having properties as nanoparticles.

1 is a SEM photograph showing a micelle formed by porphyrin derivative self-assembly in an aqueous solution according to the present invention

Claims (16)

Porphyrin derivatives represented by the following formula (1):

(One) Wherein M is H ₂ or a metal atom, R ₁ , R ₂ , R ₃ are each H or OR ₅ , R ₅ is an alkyl group of C ₁ -C ₁₂ , and R ₄ is a dendron consisting of oligoethylene being). The porphyrin derivative according to claim 1, wherein M is selected from the group consisting of Mn, Mn, Cu, Co, Zn, Ni, Pd, and Pt. The porphyrin derivative according to claim 1, which is a compound represented by the following formula (2) or (3):

Process for preparing a porphyrin derivative of formula (2) by the following scheme (1): Scheme 1

(a) MnCl ₂ · 4H ₂ O, N, N-dimethylformamide, 160 ° C., 12 h The method of claim 4, wherein the compound of formula (4) is prepared according to the following scheme (2): Scheme 2

b) THF, 0 ° C, NaH, 3 days at room temperature A process for preparing a porphyrin derivative according to claim 5, wherein the compound of formula (5) is prepared according to the following scheme (3): Scheme 3

c) THF, LiAlH ₄ , 0 ° C. → room temperature, 1 h A process for preparing a porphyrin derivative according to claim 6, wherein the compound of formula (7) is prepared according to the following scheme (4): Scheme 4

d) K ₂ CO ₃ , 18-crown-6 ether, THF, 1-bromooctane, 85 ° C., 25 h A process for preparing a porphyrin derivative according to claim 7, wherein the compound of formula (8) is prepared according to the following scheme (5): Scheme 5

e) dichloromethane, BF ₃ , chloranyl, 2-3 days A process for preparing a porphyrin derivative according to claim 8, wherein the compound of formula (6) is prepared according to the following scheme (6): Scheme 6

f) p-toluene sulfonylchloride, pyridine, dichloromethane, 0 ° C. to room temperature, 8 h A process for preparing a porphyrin derivative according to claim 9, wherein the compound of formula (9) is prepared according to the following scheme (7): Scheme 7

g) 1) BH ₃ , 0 ° C., 2-3 h, THF, 2) H ₂ O ₂ , 0 ° C., 1 h, 3) NaOH, 0 ° C., 1 h A process for preparing a porphyrin derivative according to claim 10, wherein the compound of formula (10) is prepared according to the following scheme (8): Scheme 8

h) NaH, THF, reflux, 24 h 12. The process of claim 11, wherein the compound of formula (11) is prepared according to the following scheme (9): Scheme 9

i) 1) BH ₃ , 0 ° C., 2-3 h, THF, 2) H ₂ O ₂ , 0 ° C., 1 h, 3) NaOH, 0 ° C., 1 h The process for preparing a porphyrin derivative according to claim 12, wherein the compound of formula (12) is prepared according to the following Scheme (10): Scheme 10

j) NaH, THF, reflux, 12 h Micelle formed by self-assembling the porphyrin derivative according to any one of claims 1 to 3 in an aqueous solution. 15. The micelles of claim 14 wherein the micelles are between 20 and 100 nm in size. MRI contrast agent comprising a porphyrin derivative according to any one of claims 1 to 3.

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