WO2019182393A1

WO2019182393A1 - Compound having novel structure, anti-inflammatory agent comprising same, and matrix metalloprotease-9 inhibitor comprising same

Info

Publication number: WO2019182393A1
Application number: PCT/KR2019/003343
Authority: WO
Inventors: 장용민; 김희경
Original assignee: 경북대학교 산학협력단
Priority date: 2018-03-22
Filing date: 2019-03-22
Publication date: 2019-09-26
Also published as: KR102068727B1; KR20190111376A

Abstract

In a compound having a novel structure, an anti-inflammatory agent comprising same, and a matrix metalloprotease-9 inhibitor comprising same of the present invention, the compound of the present invention has the structure represented by chemical formula 1 according to the present invention.

Description

Compounds with Novel Structure, Anti-Inflammatory and Substance Metal Protease-9 Inhibitors Comprising the Same

The present invention relates to a compound having a novel structure, more specifically, a compound having a novel structure having a high self-relaxation rate and capable of targeting and treating an inflammatory site, and at the same time capable of diagnosing and treating an inflammatory target, an anti-inflammatory agent comprising the same And substrate metal protease-9 inhibitors.

Extracellular matrix (ECM) is a multifunctional conjugate composed of insoluble fibrous proteins such as proteoglycans and gelatin, keratin, complexed with proteins that contribute to the structural integrity of cells and tissues in the organ system. ECM molecules such as type IV collagen, laminin and fibronectin make up the basement membrane that provides structural support to the vasculature, where various factors are involved in maintaining the integrity of the ECM and the tissues maintained by it, and in particular physiological environments Underneath, the ECM is adjusted to damage or destroy the structure of the tissue.

Matrix metalloprotease (MMP) is a family of zinc-dependent enzymes that degrade extracellular matrix. In particular, MMP-9 is an enzyme that decomposes the basal membrane of cells composed of ECM substances such as type IV collagen and laminin, and decomposes ECM substances in the basal membrane to help the transfer of inflammatory mediators into the cell, thereby inducing an inflammatory response. Contribute to worsening.

Therefore, in order to prevent and treat the exacerbation of the inflammatory response, an anti-inflammatory substance that can target the inflammatory site and effectively inhibit MMP-9 to block the progress of the inflammatory response is required.

One object of the present invention is to provide a compound having a novel structure.

Another object of the present invention is to provide an anti-inflammatory agent comprising the compound.

Another object of the present invention is to provide an MMP-9 inhibitor comprising the compound.

Compound for one object of the present invention has a structure represented by the formula (1).

[Formula 1]

In Formula 1, Linker represents *-(CH ₂ ) _x -A- (CH ₂ ) _y- *, x and y each independently represent an integer of 0 to 5, and A represents * -COO -*, * -CO- *, * -CONH- * or * -O- *.

In one embodiment, Formula 1 may be represented by the following formula (2).

[Formula 2]

In one embodiment, the compound may target the site of inflammation and have anti-inflammatory activity at the site of inflammation.

In this case, the compound may have anti-inflammatory activity by inhibiting matrix metalloproteinase-9 (MMP-9) at the site of inflammation.

In one embodiment, the compound may have a magnetic relaxation of 4.5 mM ^-1 s ^-1 to 5.5 mM ^-1 s ^{-1 in} a 1.5T magnetic resonance image (MRI).

In this case, the compound may target diagnosis and treatment of the site of inflammation.

In one embodiment, the compound may coordinate with at least one water molecule.

Anti-inflammatory agent for another object of the present invention comprises a compound having a structure represented by the formula (1), and target the inflammation site and has an anti-inflammatory activity at the inflammation site.

In one embodiment, Formula 1 may be represented by Formula 2.

In one embodiment, the anti-inflammatory agent may inhibit matrix metalloproteinase (MMP-9) at the site of inflammation.

In one embodiment, the anti-inflammatory agent may have a magnetic relaxation of 4.5 mM ^-1 s ^-1 to 5.5 mM ^-1 s ^-1 in 1.5T magnetic resonance imaging.

In this case, the anti-inflammatory agent may target diagnosis and treatment of the inflammatory site.

Substrate metal protease-9 (MMP-9) inhibitors for still another object of the present invention includes a compound having a structure represented by the formula (1).

In one embodiment, Formula 1 may be represented by Formula 2.

In one embodiment, the substrate metal protease-9 inhibitor may inhibit substrate metal protease-9 at an inflammation site.

According to the compound of the present invention, an anti-inflammatory agent and an MMP-9 inhibitor comprising the present invention, the present invention targets an inflammatory site and has anti-inflammatory activity at the inflammatory site, and at the same time has a self-relaxing property to target the inflammatory site. Compounds may be provided. The compound of the present invention exhibits higher self-relaxation rate and excellent kinematic stability than the conventional clinical MRI contrast medium. In particular, the compound of the present invention can enhance the signal intensity of the inflammation site over a longer period of time than the conventional contrast medium, and thus can be used as a target for diagnosis of the inflammation site. It is possible. In addition, the compound of the present invention can inhibit the MMP-9 activity that progresses and exacerbates the inflammatory response at the site of inflammation can be used as an MMP-9 inhibitor, and the compound of the present invention can also inhibit the site of inflammation through MMP-9 inhibition It can be used as an anti-inflammatory agent because it can exhibit anti-inflammatory activity. In other words, the compounds of the present invention can be used as anti-inflammatory and MMP-9 inhibitors capable of targeted diagnosis and at the same time treatment of inflammatory sites of inflammatory diseases such as rheumatoid arthritis.

1 is a view for explaining the kinematic stability of the compound of the present invention.

Figure 2a is a view for explaining the result of inflammatory target ability evaluation of the compound of the present invention.

FIG. 2B is a diagram for explaining the results of evaluation of inflammation target ability of a commercial contrast agent Gadovist ^® .

FIG. 2C is a CNR graph to illustrate the inflammatory target ability results of the compounds of the invention and the commercial contrast agent Gadovist ^® .

3 is a view for explaining the anti-inflammatory properties of the compound of the present invention.

Hereinafter, with reference to the accompanying drawings will be described in detail an embodiment of the present invention. As the inventive concept allows for various changes and numerous embodiments, particular embodiments will be illustrated in the drawings and described in detail in the text. However, this is not intended to limit the present invention to a specific disclosed form, it should be understood to include all modifications, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the drawings, similar reference numerals are used for similar elements.

The terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be limiting of the invention. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this application, the terms "comprises" or "having" are intended to indicate that there is a feature, step, operation, component, part, or combination thereof described on the specification, and one or more other features or steps. It is to be understood that the present invention does not exclude, in advance, the possibility of the presence or the addition of an operation, a component, a part, or a combination thereof.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art. Terms such as those defined in the commonly used dictionaries should be construed as having meanings consistent with the meanings in the context of the related art and shall not be construed in ideal or excessively formal meanings unless expressly defined in this application. Do not.

The compound of the present invention has a structure represented by the following formula (1).

[Formula 1]

In Formula 1, Linker represents *-(CH ₂ ) _x -A- (CH ₂ ) _y- *, x and y each independently represent an integer of 0 to 5, and A represents * -COO -*, * -CO- *, * -CONH- * or * -O- *. In this case, * means a binding site.

In the compound of the present invention represented by Chemical Formula 1, gadolinium (Gd) may be coordinated with at least one water molecule. In this case, gadolinium in the compound may form a coordination bond with the oxygen atom of Linker A.

For example, the compound of the present invention represented by Chemical Formula 1 may be a compound represented by the following Chemical Formula 2.

[Formula 2]

The compounds of the present invention have a target for the site of inflammation and can exhibit an anti-inflammatory effect at the site of inflammation. Specifically, the compound of the present invention may exhibit anti-inflammatory activity by targeting the inflammation site and inhibiting matrix metalloprotease-9 (MMP-9), which is an inflammation mediator at the inflammation site. MMP-9 is an enzyme that is induced by inflammatory stimuli and breaks down the basement membrane of cells composed of type IV collagen and laminin to help the transfer of inflammation mediators. By inhibiting the expression of -9, it is possible to prevent the onset, progression and duration of the inflammatory response thereby. That is, the compound of the present invention has inhibitory activity against MMP-9, and thus the compound of the present invention can be used as an MMP-9 inhibitor.

In addition, the compounds of the present invention have excellent self-relaxation properties. Magnetic relaxation characteristic refers to a characteristic that can show contrast enhancement in a magnetic resonance image (MRI). MRI is a method of obtaining the anatomical, physiological and biochemical information images of the body by relaxing the spin of hydrogen atoms in a magnetic field.In addition, MRI is used to increase image contrast by injecting an external substance during MRI measurement. The material to be referred to is a contrast agent. The relaxation effect of water molecules in the tissue nuclear spins back to equilibrium varies from tissue to tissue, resulting in contrast between tissues. Contrast agents affect these relaxations, widening the relaxation between tissues and causing changes in MRI signals. To make the contrast between organizations clearer. The contrast agent must be thermodynamically stable, water soluble, and have a self-relaxation property with high water in combination with at least one molecule of water. Since the compound of the present invention is capable of coordinating with at least one or more water molecules and having self-relaxation properties, the image contrast may be improved by combining with at least one or more water molecules in the human body to increase the hydrogen atom relaxation rate in the water molecules. . Therefore, the compound of the present invention may be used as a contrast agent for MRI, wherein the compound of the present invention may be a positive contrast agent that relatively increases the image signal of the desired body part on the MRI. The compounds of the present invention can exhibit good magnetic relaxation, for example, from 4.5 mM ⁻¹ s ⁻¹ to 5.5 mM ⁻¹ s ⁻¹ in 1.5T magnetic resonance imaging.

In addition, as described above, since the compound of the present invention can target an inflammatory site, the compound of the present invention can be used as a contrast agent to target an inflammatory site such as an inflammatory disease such as rheumatoid arthritis and diagnose the same. . In addition, the compound of the present invention may exhibit anti-inflammatory activity by inhibiting MMP-9 at the site of inflammation, and thus may be treatable at the same time as the diagnosis of the site of inflammation. That is, the compound of the present invention may be a compound capable of simultaneous diagnosis / treatment of an inflammatory target, capable of targeting and diagnosing an inflammation site and simultaneously treating the inflammation site by having an anti-inflammatory activity of the inflammation site. Compounds can be provided for multifunctional anti-inflammatory agents and MMP-9 inhibitors that are capable of simultaneously diagnosing and treating inflammatory targets.

Hereinafter, the compounds of the present invention, methods for preparing the same, and anti-inflammatory agents will be described.

본 발명의 화합물의 합성Synthesis of Compounds of the Invention

(1) 리간드의 합성(1) Synthesis of Ligand

To prepare a compound of the present invention, first, a ligand having a cyclic structure was synthesized. Specifically, tri-tert-butyl 2,2 ', 2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate , 2 ', 2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate) (5 g, 9.72 mmol) was dissolved in 160 mL of acetonitrile (ACN) Potassium hydrogen carbonate (KHCO ₃ ) (2.96 g, 29.69 mmol) was added and stirred for 30 minutes. Then, ethyl bromoacetate (1.18 mL, 10.69 mmol) was added, and heated to 60 ° C. for 24 hours. The insoluble reactant was then filtered and all solvents of the reactant were removed. Subsequently, after dissolving in dichloromethane (DCM), the insoluble reactant was filtered and the solvent of the reactant was removed and dried in vacuo to give tri-tert-butyl 2,2 ', 2''as a slightly yellowish solid. -(10- (2-ethoxy-2-oxoethyl) -1,4,7,10-teazacyclododecane-1,4,7-triyl) triacetate (tri-tert-butyl 2,2 ', 2''-(10- (2-ethoxy-2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate) (hereinafter compound (1)) was obtained. (Yield 5.8 g (99%)).

Subsequently, Compound (1) (3.2 g. 5.33 mmol) was dissolved in 7 mL methanol (MeOH), and then 6 mL of ethylenediamine was added and reacted at room temperature for about 4 days. It was then connected to a vacuum line and heated to about 55 ° C. and the solvent was removed to give an oily solid. This was washed several times with diethyl ether, dried in vacuo and dissolved in MeOH. The insoluble reactant was then filtered and tri-tert-butyl 2,2 ', 2''-(10- (2-) as a slightly yellowish colored solid via open column chromatography under DCM / MeOH conditions. ((2-aminoethyl) amino) -2-oxoethyl) -1,4,7,10-teazacyclododecane-1,4,7-triyl) triacetate (tri-tert-butyl 2,2 ', 2''-(10- (2-((2-aminoethyl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate, DO3A ^t (Bu ) ₃ -NH ₂ ) (hereinafter compound (2)) was obtained (yield: 1.87 g (57%)).

Synthesis reaction of the above compounds (1) and (2) can be represented by the following formula (1).

Scheme 1

In Scheme 1, 1 represents compound (1), and 2 represents compound (2).

(2) 본 발명의 실시예 1에 따른 화합물: GdL (6)의 합성(2) Compound according to Example 1 of the present invention: Synthesis of GdL (6)

Sulindac (1.7 g, 4.77 mmol) was dissolved in 40 mL tetrahydrofuran (THF) and N-hydroxysuccimide (NHS) was added and stirred for 30 minutes. N, N'-Dicyclohexylcarbodiimide (N, N'-Dicyclohexylcarbodiimide, DCC) was dissolved in 30 mL THF and slowly added to the reaction at 4 ℃ and reacted at room temperature for 24 hours. Subsequently, the insoluble reactants were filtered off, all solvent was removed, and the yellow solid was separated and purified through open column chromatography (DCM / MeOH, 99: 1) to give 2,5-dioxopyrrolidin-1-yl (Z). 2- (5-Fluoro-2-methyl-1- (4- (methylsulfinyl) benzylidene) -1H-inden-3-yl) acetate (2,5-dioxopyrrolidin-1-yl (Z)- 2- (5-fluoro-2-methyl-1- (4- (methylsulfinyl) benzylidene) -1H-inden-3-yl) acetate (hereinafter referred to as compound (3)) was obtained (yield: 1.17 g (51) %)).

Then, Compound (3) (2.5 g, 5.5 mmol) dissolved in 20 mL THF and Compound (2) (2.83 g, 4.6 mmol) dissolved in 20 mL MeOH were mixed and reacted at room temperature for 24 hours. Subsequently, after removing all solvents, extraction was performed under DCM / deionized water conditions. Then, the DCM layer was dehydrated with Na ₂ SO ₄ , and then the solvents were removed and yellow through open column chromatography (DCM / MeOH, 96: 4). The solid was separated and purified to give tri-tert-butyl 2,2 ', 2''-(10- (2-((2- (2- (5-fluoro-2-methyl-1- (4- (methyl) Sulfinyl) benzylidene) -1H-inden-3-yl) acetamido) ethyl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7- Triyl) (Z) -triacetate (tri-tert-butyl 2,2 ', 2''-(10- (2-((2- (2- (5-fluoro-2-methyl-1- (4) -(methylsulfinyl) benzylidene) -1H-inden-3-yl) acetamido) ethyl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) (Z) -triacetate (Hereinafter, compound (4) was obtained (yield: 2.46 g (51%).

Subsequently, Compound (4) (2.5 g, 2.95 mmol) was dissolved in DCM / TFA (1: 1, 40 mL) at 0 ° C., and then reacted at room temperature for 24 hours. The solvent was then removed, dissolved in 10 mL of MeOH and precipitated in 200 mL of diethyl ether. The precipitate is then filtered and prep. Separated using HPLC to give a yellow solid, (Z) -2,2 ', 2' '-(10- (2-((2- (2- (5-fluoro-2-methyl-1- (4- (Methylsulfinyl) benzylidene) -1H-inden-3-yl) acetamido) ethyl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4, 7-triyl) triacetic acid ((Z) -2,2 ', 2' '-(10- (2-((2- (2- (5-fluoro-2-methyl-1- (4- (methylsulfinyl) ) benzylidene) -1H-inden-3-yl) acetamido) ethyl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid) 5)) (yield: 0.45 g (22%)).

Then, Compound (5) (0.25 g, 0.368 mmol) was dissolved in deionized water, and then the pH of the solution was adjusted to 3 using 1 M NaOH. GdCl ₃ ㅇ H ₂ O (0.15 g, 0.405 mmol) was dissolved in 1 mL of water, and then added little by little. The pH of the reaction was adjusted to 7 using 1 M NaOH, and the reaction was carried out at a temperature of 55 ° C. for 18 hours. Subsequently, the solvent was removed and then prep. The yellow solid was separated and purified using HPLC to give the compound according to Example 1 of the present invention (hereinafter GdL (6)) (yield: 0.18 g (58%)).

Synthesis reaction of the compound according to Example 1 of the present invention, GdL (6) can be represented by the following scheme 2.

Scheme 2

In

Scheme

2, 2 represents compound (2), 3 represents compound (3), 4 represents compound (4), 5 represents compound (5), and 6 represents GdL (6).

(3) Comparative Compound of the Invention: Synthesis of GdL (10)

In addition, a comparative compound was prepared using Diflunisal as a comparative example of the present invention. Specifically, diflunisal (3 g, 12 mmol) was dissolved in 40 mL tetrahydrofuran (THF), and N-hydroxysuccinimide (NHS) was added and stirred for 30 minutes. Subsequently, N, N'-dicyclohexylcarbodiimide (DCC) dissolved in 30 mL THF was slowly added to the reaction at 4 ° C and reacted at room temperature for 24 hours. The insoluble reactant was then filtered and all solvent removed and white solid 2,5-dioxopyrrolidin-1-yl 2 'via open column chromatography (DCM / MeOH, 99: 1). , 4'-difluoro-4-hydroxy- [1,1'-biphenyl] -3-carboxylate (2,5-dioxopyrrolidin-1-yl 2 ', 4'-difluoro-4-hydroxy- [1,1'-biphenyl] -3-carboxylate) (hereinafter Compound (7)) was purified separately (yield: 2.36 g (57%)).

Subsequently, compound (7) (2.36 g, 6.8 mmol) dissolved in 20 mL THF and compound (2) (3.5 g, 5.7 mmol) dissolved in 20 mL MeOH were mixed and reacted at room temperature for 24 hours. Then, after removing all of the solvent, the extraction was carried out under DCM / deionized water conditions, the DCM layer was dehydrated with sodium sulfate (Na ₂ SO ₄ ) and then the solvent was removed. Thereafter, tri-tert-butyl 2,2 ', 2''-(10- (2-((2- (2', 4'-difluoro-4-hydroxy- [1,1'-biphenyl] -3-carboxamidoethyl) amino) -2-oxoethyl) -1,4,7,10- tetraazacyclodo Decane-1,4,7-triyl) triacetate (tri-tert-butyl 2,2 ', 2''-(10- (2-((2- (2', 4'-difluoro-4-hydroxy) -[1,1'-biphenyl] -3-carboxamido) ethyl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate) (hereinafter compound (8 )) Was isolated and purified (yield: 2.7 g (56%)).

Compound (8) (2.5 g, 2.95 mmol) was then dissolved in DCM / TFA (1: 1, 40 mL) at 0 ° C. and then reacted at room temperature for 24 hours. The solvent of the reaction was removed and then dissolved in 10 mL of MeOH and precipitated in 200 mL of diethyl ether. The precipitate was filtered off and then prep. White solid using HPLC, 2,2 ', 2' '-(10- (2-((2- (2', 4'-difluoro-4-hydroxy- [1,1'-biphenyl) ] -3-carboxamido) ethyl) amino) -2-oxoethyl) -1,4,7,10-teazacyclododecane-1,4,7-triyl) triacetic acid (2,2 ', 2 ''-(10- (2-((2- (2 ', 4'-difluoro-4-hydroxy- [1,1'-biphenyl] -3-carboxamido) ethyl) amino) -2-oxoethyl)- 1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (hereinafter referred to as compound (9)) was isolated. At this time, the yield was 1.91 g (95%).

Subsequently, Compound (9) (0.25 g, 0.368 mmol) was dissolved in deionized water (DI water) and the pH of the solution was adjusted to 3 using 1 M NaOH. Then, gadolinium chloride hexahydrate (GdCl ₃ -6H ₂ O) (0.15 g, 0.405 mmol) was dissolved in 1 mL of water and added little by little. The pH of the reaction was adjusted to 7 with 1 M NaOH and reacted at 55 ° C. for 18 hours. Subsequently, the solvent was removed and then prep. Separation and purification using HPLC gave a comparative compound (hereinafter referred to as GdL (10)) as a white solid (yield: 0.21 g (68%)).

Synthesis reaction of a comparative compound according to a comparative example of the present invention can be represented by the following scheme 3.

Scheme 3

In Scheme 3, 2 represents compound (2), 7 represents compound (7), 8 represents compound (8), 9 represents compound (9), and 10 represents GdL (10).

특성 평가: 자기이완도Characteristic evaluation: self relaxation

The relaxation of the compound of the present invention prepared according to Example 1 of the present invention, GdL (6) was confirmed.

Magnetic relaxation is a quantification of the contrast enhancement of the contrast agent in magnetic resonance imaging (MRI), in which GdL (6) according to Example 1 of the present invention and a commercial contrast agent Gadovist ^® dissolved in PBS buffer solution (pH 7.4) Then, the magnetic relaxation rate was measured at room temperature (25 ° C.) 1.5T and compared with each other to evaluate whether the contrast enhancement effect of GdL (6) of the present invention is effective. The results are shown in Table 1.

Table 1 shows the results of the self-relaxation rate of GdL (6) and the commercial contrast agent Gadovist ^® according to Example 1 of the present invention.

Referring to Table 1, the self-relaxation rate of GdL (6) according to Example 1 of the present invention was r ₁ = 4.88 ± 0.21, r ₂ = 5.26 ± 0.20, and Gadovist ^® measured as a comparison group had r ₁ = 4.12 It can be confirmed that the value of ± 0.15, r ₂ = 4.55 ± 0.18. That is, it can be confirmed that the compound of the present invention exhibits a higher magnetic relaxation rate than Gadovist, a commercial contrast agent of GdL (6), which is high enough to be effective enough to be used as a contrast agent for obtaining an in vivo magnetic resonance image. It can be evaluated as having. That is, it can be confirmed that the compound of the present invention can be used as an excellent contrast agent.

특성 평가: 운동학적 안정성Characteristic evaluation: kinematic stability

In addition, the kinematic stability of the compound GdL (6) according to Example 1 of the present invention was confirmed. The kinematic stability of GdL (6) can be confirmed by the change of the self-relaxation rate with time. Specifically, zinc chloride (ZnCl ₂ ) is added to the solution in which GdL (6) is dissolved, followed by metal exchange between gadolinium and zinc ions. It was confirmed by inducing a transmetallation reaction and measuring its self-relaxation rate. At this time, it can be evaluated that the greater the change in the magnetic relaxation rate after the addition of zinc ions is unstable. In addition, the kinematic stability of four commercially available contrast agents (Dotarem ^® , Multihance ^® , Gadovist ^® and Primovist ^® ) with GdL (6) of the present invention was evaluated and compared with the GdL (6) of the present invention. The result is shown in FIG.

Referring to FIG. 1, it can be seen that GdL 6 according to Example 1 of the present invention exhibits a rate of change of self-relaxation between Dotarem ^® and Gadovist ^® among four commercially available contrast agents. That is, GdL (6) of the present invention compared to the relative stability is not only exhibit extremely high magnetic relaxation rate of change than the commercially available contrast agent of Primovist ^® and Multihance ^® of low linear structure, a commercially available contrast agent of a stable ring structure Dotarem ^® and Gadovist ^® It can be seen that similar high kinematic stability.

That is, it can be seen that the compound of the present invention exhibits excellent kinematic stability.

특성 평가: 염증 표적 능력Characterization: Inflammation target ability

In vivo inflammation targeting ability of GdL (6) according to Example 1 of the present invention is evaluated by confirming the in vivo distribution and inflammation target function of GdL (6) through in vivo MRI experiments in a thigh inflammation animal model This was compared with the result of Gadovist ^® , a commercial contrast medium. In vivo distribution and inflammatory target ability evaluation results of the GdL (6) and the commercial contrast agent Gadovist ^® of the present invention are shown in FIGS. 2A to 2C.

Figure 2a is a view for explaining the result of inflammatory target capacity evaluation of the compound of the present invention, Figure 2b is a view for explaining the result of inflammatory target ability evaluation of commercial contrast agent Gadovist ^® .

First, referring to FIGS. 2A and 2B, Gadovist ^® shows bright inflammation immediately after injection but gradually decreases in signal augmentation effect, whereas GdL (6) of the present invention has a steady signal augmentation effect for two hours or more immediately after injection. It can confirm that it shows.

In addition, referring to FIG. 2C, when the inflammatory targets of GdL (6) and Gadovist ^® of the present invention are shown in the CNR graph, the CNR immediately after the injection is similar, but the difference gradually increases over time, in particular, After 2 hours, the CNR of Gadovist ^® is drastically reduced to 30% or less, but the compound GdL (6) of the present invention exhibits about 50% signal amplification, which is twice as high as that of Gadovist ^®. You can check it.

That is, as shown in Figs. 2A to 2C, it can be seen that the compound GdL (6) of the present invention exhibits superior inflammation target ability than commercial contrast agents.

특성 평가: 항염 특성Characteristic evaluation: anti-inflammatory properties

In addition, the anti-inflammatory properties of the compound GdL (6) of the present invention were confirmed. Anti-inflammatory properties were performed in vitro , and specifically, cells were treated with lipopolysaccharide (LPS), which is an inflammation-inducing substance, to induce an inflammatory response, and then the cells were divided into two types of non-inflammatory. Non-steroidal anti-inflammatory drugs (NSAIDs) (Diflunisal and Sulindac) and compound GdL (6) of the invention, and comparative compound GdL (10) of the invention Treated with and confirmed the ability of MMP-9 inhibition to induce an inflammatory response in cells. The result is shown in FIG.

Referring to FIG. 3, first, when comparing Diflunisal and GdL (10), a comparative compound of the present invention prepared using Diflunisal than MMP-9 of Diflunisal, a commercial nonsteroidal anti-inflammatory material It can be seen that the degree of MMP-9 expression of GdL (10) increases. That is, it can be confirmed that the inhibitory ability of MMP-9 of the comparative compound GdL (10) is lower than the MMP-9 inhibitory ability of Diflunisal, which is a nonsteroidal anti-inflammatory substance.

On the other hand, when comparing Sulindac (Sulindac) and the compound GdL (6) of the present invention synthesized according to the present invention, the compound of the present invention GdL (6) is reduced MMP-9 expression compared to the sulindac It can be confirmed that this means that the compound GdL (6) of the present invention has an increased activity compared to the commercial nonsteroidal anti-inflammatory material, sulindac, and specifically has about 1.5 times improved inflammation inhibition ability than sulindac. In addition, it can be seen that the therapeutic effect to reduce the expressed inflammation close to 50%. This can be achieved by conjugating sulindac according to the present invention with a DO3A based gadolinium complex ligand, thereby providing a compound of novel structure with anti-inflammatory activity superior to that of conventional sulindac, in particular the compounds of the present invention It can be seen that the inflammatory response can be reduced by inhibiting MMP-9, which contributes to inflammation expression at the site of inflammation.

That is, when sintering the above confirmed, the compound of the present invention exhibits excellent self-relaxation rate, strong contrast enhancement and long-term targetability at the site of inflammation even through animal model experiments of inflammatory disease, and through the kinematic stability test It can be confirmed that the stability is also excellent, and furthermore, the compounds of the present invention exhibit superior MMP-9 inhibitory properties and have effective anti-inflammatory activity properties than the existing anti-inflammatory materials.

Therefore, the compounds of the present invention can be used as an anti-inflammatory agent that can be used for both inflammation and diagnosis and treatment at the same time, which is capable of treating inflammation by targeting the inflammation site and diagnosing the site of inflammation and having excellent MMP-9 inhibitory ability. Can be.

While the foregoing has been described with reference to preferred embodiments of the present invention, those skilled in the art will be able to variously modify and change the present invention without departing from the spirit and scope of the invention as set forth in the claims below. It will be appreciated.

Claims

Compound having a structure represented by the following formula (1);

[Formula 1]

In Chemical Formula 1,

Linker represents *-(CH 2 ) x -A- (CH 2 ) y- *,

x and y each independently represent an integer of any one of 0 to 5,

A represents * -COO- *, * -CO- *, * -CONH- * or * -O- *.
The method of claim 1,

Formula 1 is represented by the following formula (2), a compound;

[Formula 2]
The method of claim 1,

The compound is characterized in that it targets the site of inflammation and has anti-inflammatory activity at the site of inflammation,

compound.
The method of claim 3,

The compound is characterized by having anti-inflammatory activity by inhibiting matrix metalloproteinase-9 (MMP-9) at the site of inflammation,

compound.
The method of claim 1,

The compound is characterized in that having a magnetic relaxation of 4.5 mM -1 s -1 to 5.5 mM -1 s -1 in 1.5T magnetic resonance image (MRI),

compound.
The method of claim 1,

The compound is characterized in that the target diagnosis and treatment of the site of inflammation,

compound.
The method of claim 1,

Wherein said compound is coordinated with at least one water molecule,

compound.
An anti-inflammatory agent comprising a compound having a structure represented by the following formula (1), characterized in that it targets an inflammation site and has anti-inflammatory activity at the inflammation site;

[Formula 1]

In Chemical Formula 1,

Linker represents *-(CH 2 ) x -A- (CH 2 ) y- *,

x and y each independently represent an integer of any one of 0 to 5,

A represents * -COO- *, * -CO- *, * -CONH- * or * -O- *.
The method of claim 8,

Formula 1 is represented by the following formula 2, anti-inflammatory agent;

[Formula 2]
The method of claim 8,

The anti-inflammatory agent is characterized in that to inhibit the matrix metalloproteinase-9 (MMP-9) at the site of inflammation,

Anti-inflammatory.
The method of claim 8,

The anti-inflammatory agent is characterized in that the magnetic relaxation of 4.5 mM -1 s -1 to 5.5 mM -1 s -1 in 1.5T magnetic resonance imaging,

Anti-inflammatory.
The method of claim 11,

The anti-inflammatory agent is characterized in that the target diagnosis and treatment of the inflammation site,

Anti-inflammatory.
The method of claim 8,

Compound represented by the formula (1) is characterized in that the coordination with at least one water molecule,

Anti-inflammatory.
A substrate metal protease-9 inhibitor comprising a compound having a structure represented by Formula 1 below;

[Formula 1]

In Chemical Formula 1,

Linker represents *-(CH 2 ) x -A- (CH 2 ) y- *,

x and y each independently represent an integer of any one of 0 to 5,

A represents * -COO- *, * -CO- *, * -CONH- * or * -O- *.
The method of claim 14,

Formula 1 is represented by the following formula 2, anti-inflammatory agent;

[Formula 2]
The method of claim 14,

The matrix metalloproteinase-9 inhibitor is characterized in that to inhibit the matrix metalloproteinase-9 at the site of inflammation,

Matrix metalloproteinase-9 inhibitors.