WO2019182393A1 - Composé ayant une nouvelle structure, agent anti-inflammatoire le comprenant, et inhibiteur de métalloprotéase-9 de matrice le comprenant - Google Patents

Composé ayant une nouvelle structure, agent anti-inflammatoire le comprenant, et inhibiteur de métalloprotéase-9 de matrice le comprenant Download PDF

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Publication number
WO2019182393A1
WO2019182393A1 PCT/KR2019/003343 KR2019003343W WO2019182393A1 WO 2019182393 A1 WO2019182393 A1 WO 2019182393A1 KR 2019003343 W KR2019003343 W KR 2019003343W WO 2019182393 A1 WO2019182393 A1 WO 2019182393A1
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Prior art keywords
compound
inflammatory
formula
inflammation
present
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PCT/KR2019/003343
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English (en)
Korean (ko)
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장용민
김희경
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경북대학교 산학협력단
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Publication of WO2019182393A1 publication Critical patent/WO2019182393A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings

Definitions

  • 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 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 is a family of zinc-dependent enzymes that degrade extracellular matrix.
  • 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.
  • 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).
  • 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- *.
  • Formula 1 may be represented by the following formula (2).
  • the compound may target the site of inflammation and have anti-inflammatory activity at the site of inflammation.
  • the compound may have anti-inflammatory activity by inhibiting matrix metalloproteinase-9 (MMP-9) at the site of inflammation.
  • MMP-9 matrix metalloproteinase-9
  • 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).
  • MRI magnetic resonance image
  • the compound may target diagnosis and treatment of the site of inflammation.
  • 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.
  • Formula 1 may be represented by Formula 2.
  • the anti-inflammatory agent may inhibit matrix metalloproteinase (MMP-9) at the site of inflammation.
  • MMP-9 matrix metalloproteinase
  • 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.
  • 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).
  • Formula 1 may be represented by Formula 2.
  • the substrate metal protease-9 inhibitor may inhibit substrate metal protease-9 at an inflammation site.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound of the present invention has a structure represented by the following 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- *.
  • * means a binding site.
  • gadolinium may be coordinated with at least one water molecule.
  • gadolinium in the compound may form a coordination bond with the oxygen atom of Linker A.
  • the compound of the present invention represented by Chemical Formula 1 may be a compound represented by the following Chemical 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.
  • 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.
  • MMP-9 matrix metalloprotease-9
  • MMP-9 matrix metalloprotease-9
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • ACN acetonitrile
  • KHCO 3 Potassium hydrogen carbonate
  • GdL (6) can be represented by the following scheme 2.
  • 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.
  • THF tetrahydrofuran
  • NHS N-hydroxysuccinimide
  • DCC N, N'-dicyclohexylcarbodiimide
  • Synthesis reaction of a comparative compound according to a comparative example of the present invention can be represented by the following scheme 3.
  • 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.
  • 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.
  • 1 is a view for explaining the kinematic stability of the compound of the present invention.
  • 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.
  • the compound of the present invention exhibits excellent kinematic stability.
  • 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 ® .
  • 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 ® .
  • Gadovist ® shows bright inflammation immediately after injection but gradually decreases in signal augmentation effect
  • 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.
  • the compound GdL (6) of the present invention exhibits superior inflammation target ability than commercial contrast agents.
  • 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.
  • 3 is a view for explaining the anti-inflammatory properties of the compound of 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%.
  • 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
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  • Radiology & Medical Imaging (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un composé ayant une nouvelle structure, un agent anti-inflammatoire le comprenant, et un inhibiteur de métalloprotéase-9 de matrice le comprenant, le composé selon la présente invention a la structure représentée par la formule chimique 1.
PCT/KR2019/003343 2018-03-22 2019-03-22 Composé ayant une nouvelle structure, agent anti-inflammatoire le comprenant, et inhibiteur de métalloprotéase-9 de matrice le comprenant WO2019182393A1 (fr)

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KR1020180033430A KR102068727B1 (ko) 2018-03-22 2018-03-22 신규한 구조를 갖는 화합물, 이를 포함하는 항염증제 및 기질 금속 단백질분해효소-9 억제제
KR10-2018-0033430 2018-03-22

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KR102232979B1 (ko) 2018-03-22 2021-03-29 경북대학교 산학협력단 Do3a 가돌리늄 착물의 신규한 구조를 갖는 화합물, 이를 포함하는 항염증제 및 조영제
KR20230154685A (ko) * 2022-05-02 2023-11-09 (주)에트노바테라퓨틱스 가돌리늄 착물을 함유하는 do3a 기반의 혈전억제제 또는 혈액용해제

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KR20140125896A (ko) * 2013-04-18 2014-10-30 경북대학교 산학협력단 Do3a-디아미노바이페닐 화합물 및 이를 리간드로 포함하는 가돌리늄 착물

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WO2014068461A2 (fr) 2012-11-02 2014-05-08 Mahesh Kandula Compositions et méthodes de traitement d'une inflammation aiguë

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KR20140125896A (ko) * 2013-04-18 2014-10-30 경북대학교 산학협력단 Do3a-디아미노바이페닐 화합물 및 이를 리간드로 포함하는 가돌리늄 착물

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LEUNG, A. H. H.: "Inflammation targeted Gd3+ -based MRI contrast agents imaging tumor and rheumatoid arthritis models", BIOCONJUGATE CHEMISTRY, vol. 25, no. 6, 2014, pages 1112 - 1123, XP055637370 *
SUNG, B. K.: "Gadolinium-complexes of D03A conjugates as inflammation targeted magnetic resonance imaging contrast agents", THE GRADUATE SCHOOL OF KYUNGPOOK NATIONAL UNIVERSITY, February 2018 (2018-02-01), pages 1 - 37 *
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KR20190111376A (ko) 2019-10-02
KR102068727B1 (ko) 2020-01-21

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