WO2023090908A1 - Nouveau dérivé de flavonoïde et composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement d'une maladie métabolique - Google Patents

Nouveau dérivé de flavonoïde et composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement d'une maladie métabolique Download PDF

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WO2023090908A1
WO2023090908A1 PCT/KR2022/018229 KR2022018229W WO2023090908A1 WO 2023090908 A1 WO2023090908 A1 WO 2023090908A1 KR 2022018229 W KR2022018229 W KR 2022018229W WO 2023090908 A1 WO2023090908 A1 WO 2023090908A1
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formula
hydroxy
nmr
mhz
meoh
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PCT/KR2022/018229
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English (en)
Korean (ko)
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변영주
안명환
김세윤
박승은
최지연
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고려대학교 세종산학협력단
한국과학기술원
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Priority claimed from KR1020220154592A external-priority patent/KR20230074404A/ko
Publication of WO2023090908A1 publication Critical patent/WO2023090908A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones

Definitions

  • the present invention relates to a novel flavonoid derivative, and more particularly, to a flavonoid derivative compound exhibiting efficacy in the prevention or treatment of metabolic diseases by inhibiting inositol kinases IPMK and IP6K, and prevention and treatment of metabolic diseases containing the same as an active ingredient It relates to a pharmaceutical composition for treatment.
  • Inositol phosphates have been recognized as secondary messengers involved in various biological processes ranging from cell growth to death.
  • inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5PP-IP5, abbreviation 5-IP7) are 1 or a 'high energy' diphosphate group at position 5.
  • 5-IP7 In mammals, including humans, the biosynthesis of 5-IP7 is catalyzed by three isoforms (IP6K1, IP6K2, and IP6K3) of the IP6 kinase (IP6K) family. 5-IP7 is created. It has been reported that metabolic changes that improve obesity and diabetes appear in the IP6K knockout model.
  • IPMK Mammalian inositol polyphosphate multikinase
  • IP4 Ins(1,3,4,5)P 4 and Ins(1,4,5,6)P 4
  • IP5 Ins(1, 3, 4,5,6)P 5
  • IPMK Mammalian inositol polyphosphate multikinase
  • IPMK deletion significantly reduces cellular levels of downstream IPs such as IP5 and IP7.
  • IPMK can phosphorylate PIP2 at the C-3 position to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3).
  • IPMK-deficient MEFs produced about 50% less PIP3 than wild-type MEFs and showed significantly less PIP3-dependent Akt phosphorylation and downstream signaling activity, suggesting that IPMK acts as a PI3-kinase for cell growth, inflammation and metabolism in mammalian cells. that control signal transduction.
  • Non-Patent Document 1 Britton RG, Horner-Glister E, Pomenya OA, et al. Synthesis and biological evaluation of novel flavonols as potential anti-prostate cancer agents. Eur J Med Chem 2012;54:952-958.
  • Non-Patent Document 2 Vasselin DA, Westwell AD, Matthews CS, et al. Structural studies on bioactive compounds. Synthesis and biological properties of fluoro-, methoxyl-, and amino-substituted 3-phenyl-4h-1-benzopyran-4-ones and a comparison of their antitumor activities with the activities of related 2-phenylbenzothiazoles. J Med Chem 2006;49:3973-3981.
  • the present inventors completed the present invention by designing, synthesizing, and evaluating flavonoid-based analogs having modifications in the A-ring to identify IP6K2 inhibitors that are superior to natural flavonoids, and identifying novel flavonoid derivatives exhibiting strong IP6K2 inhibitory effects.
  • an object of the present invention is to provide novel flavonoid derivatives exhibiting efficacy in the prevention or treatment of metabolic diseases including obesity and diabetes.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases comprising the novel flavonoid derivative as an active ingredient.
  • the present inventors confirmed that the flavonoid derivatives represented by the following [Formula 1a] and [Formula 1b] effectively inhibit the activity of IPMK and IP6K, which are key factors inducing metabolic diseases, and based on this, the present invention was completed. .
  • the present invention relates to a novel flavonoid derivative exhibiting efficacy in preventing or treating metabolic diseases and a pharmaceutical composition for preventing or treating metabolic diseases comprising the same as an active ingredient.
  • One aspect of the present invention relates to flavonoid derivatives represented by the following [Formula 1a] and [Formula 1b]:
  • R' is , , , and any one selected from
  • R 1 and R 2 are the same as or different from each other, and are each independently any one selected from hydrogen, halogen, -OH, -COOH, -CF 3 , -Ph, -OPh, and an alkyl group having 1 to 4 carbon atoms, and
  • X, Y and Z are each independently selected from hydrogen and -OH.
  • the range of the flavonoid derivative represented by [Formula 1a] or [Formula 1b] is not limited thereby, but may be any one selected from flavonoid derivatives represented by [Formula 2] to [Formula 27]. there is.
  • flavonoid derivatives represented by [Formula 1a] or [Formula 1b] are represented by the following [Formula 2], [Formula 3], [Formula 4], [Formula 5], [Formula 23], and [Formula 24] ] may be any one selected from flavonoid derivatives represented by
  • the flavonoid derivatives represented by [Formula 2], [Formula 3], [Formula 4], [Formula 5], [Formula 23], and [Formula 24] according to the present invention have a carboxylic acid (- COOH) substituted, and exhibits excellent IP6K2 inhibitory activity.
  • the flavonoid derivatives represented by [Formula 2] to [Formula 27] according to the present invention can be specifically prepared through the following synthesis process, and the following [1] is a flavonoid represented by [Formula 1a] according to the present invention It is a flow chart schematically showing the synthesis process of the derivative, and [2] below is a flow chart schematically showing the synthesis process of the flavonoid derivative represented by [Formula 1b] according to the present invention.
  • the flavonoid derivative according to the present invention may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
  • an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
  • free acid inorganic acids and organic acids can be used.
  • the pharmaceutically acceptable salts of the flavonoid derivatives of the present invention are hydrochloride, bromate, sulfate, phosphate, citrate, acetate, trifluoroacetate, lactate, tartrate, maleate, fumarate, gluconate. , methanesulfonate, glycolate, succinate, 4-toluenesulfonate, gluturonate, embonate, glutamate, or aspartate, but may be selected from the group consisting of, but is not limited thereto, and is commonly used in the art. Salts formed using the various inorganic and organic acids used are all included.
  • the flavonoid derivative according to the present invention may also exist in the form of a solvate (for example, a hydrate).
  • Another aspect of the present invention relates to a pharmaceutical composition for preventing or treating metabolic diseases containing the flavonoid derivative represented by [Formula 1a] or [Formula 1b], a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
  • the flavonoid derivative represented by [Formula 1a] or [Formula 1b], a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. will be.
  • the composition controls intracellular signal transduction by IPMK and IP6K, and inhibits the activity of IPMK and IP6K.
  • metabolic disease is a general term for diseases caused by an imbalance of carbohydrates, lipids, proteins, vitamins, minerals, and water. include obesity and diabetes.
  • the metabolic disease may be obesity, hypertension, arteriosclerosis, hyperlipidemia, liver disease, cardiomyopathy, myocardial infarction, cerebral infarction, sarcopenia, hyperinsulinemia, hyperglycemia, diabetes or insulin resistance disease, but is not limited thereto.
  • prevention refers to any activity that suppresses or delays the progression of metabolic diseases by administration of the pharmaceutical composition according to the present invention.
  • treatment refers to all activities in which symptoms of metabolic diseases are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.
  • the component is included in an amount necessary or sufficient to realize a desired biological effect.
  • the amount to be included as an active ingredient is an amount to treat a target disease, and may be determined in consideration of matters that do not cause other toxicity, for example, the disease or condition to be treated, the type of composition to be administered, It can vary according to various factors such as the size of the subject, or the severity of the disease or condition. Effective amounts of individual compositions can be determined empirically without undue experimentation by those skilled in the art to which this invention pertains.
  • the pharmaceutically acceptable salt can be prepared by a conventional method in the art, for example, a salt with an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, or with organic acids such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid or acetylsalicylic acid (aspirin), or It means that it reacts with alkali metal ions such as sodium and potassium to form metal salts thereof, or reacts with ammonium ions to form another type of pharmaceutically acceptable salt.
  • an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, or with organic acids such as formic acid, acetic acid, oxalic acid, benzoic acid
  • pharmaceutically acceptable means a property that does not impair the biological activity and physical properties of a compound.
  • the pharmaceutical composition according to the present invention includes the above-described flavonoid derivative as an active ingredient, and may further include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is one commonly used in formulation, and includes, but is not limited to, saline, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposome, etc. It is not, and if necessary, other conventional additives such as antioxidants and buffers may be further included.
  • diluents, dispersants, surfactants, binders, lubricants, etc. may be additionally added to formulate formulations for injections such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
  • a suitable pharmaceutically acceptable carrier and formulation it can be preferably formulated according to each component using the method disclosed in Remington's literature.
  • the pharmaceutical composition of the present invention is not particularly limited in dosage form, but may be formulated as an injection, an inhalant, or an external skin preparation.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied) depending on the desired method, and the dosage depends on the patient's condition, body weight and disease. Depending on the degree, drug form, administration route and time, it can be appropriately selected by those skilled in the art.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, activity of the drug, It may be determined according to factors including sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concomitantly used drugs, and other factors well known in the medical field.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, body weight, absorption rate, inactivation rate and excretion rate of the active ingredient in the body, type of disease, and concomitant drugs, and generally 0.001 to 150 mg, preferably 0.01 to 100 mg per 1 kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, severity of obesity, gender, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.
  • the present invention relates to a novel flavonoid derivative compound, and the flavonoid derivative compound according to the present invention can effectively inhibit the activity of IPMK and IP6K, and can fundamentally prevent or treat metabolic diseases using a pharmaceutical composition containing the same. It is expected that there will be
  • 1a is a dose-response IPMK inhibitory activity result of a flavonoid derivative (Compound 20s) synthesized according to an embodiment of the present invention.
  • 1c is a dose-response IP6K2 inhibitory activity result by Experimental Example 1-2) of a flavonoid derivative (Compound 20s) synthesized according to an embodiment of the present invention.
  • FIG. 2 is an in silico molecular docking analysis result for a flavonoid derivative (Compound 20s) (FIG. 2a) and a control quercetin (FIG. 2b) synthesized according to an embodiment of the present invention.
  • Method A mobile phase was acetonitrile and water (55:45, v/v, 0.1% trifluoroacetic acid); Method B mobile phase was acetonitrile and water (50:50, v/v, 0.1% trifluoroacetic acid); Method C mobile phase was acetonitrile and water (45:55, v/v, 0.1% trifluoroacetic acid); Method D mobile phase was acetonitrile and water (40:60, v/v, 0.1% trifluoroacetic acid); Method E mobile phase was acetonitrile and water (35:65, v/v, 0.1% trifluoroacetic acid); Method F mobile phase was acetonitrile and water (30:70, v/v, 0.1% trifluoroacetic acid); Method G mobile phase was acetonitrile and water (25:75, v/v, 0.1% trifluoroacetic acid); Method H mobile phase was acetononitrile and water (55:45, v/v,
  • the crude material was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH or hexane/EtOAc) or washed with an organic solvent such as ether or hexane to give compounds 16a-16d and 20a-20s .
  • the IPMK/IP6K2 inhibitory activity of the flavonoid derivatives according to the present invention synthesized in the Synthesis Example was evaluated by an ADP-Glo kinase assay [using ADP-Glo Kinase Assay (Promega)].
  • the kinase reaction mixture was first shaken and incubated with the respective drugs (diluted in DMSO) at RT for 15 min for pre-incubation, followed by the addition of ATP (final 10 ⁇ M) to initiate the reaction.
  • 20 ng of human recombinant IPMK protein was used per 25 ⁇ L of IPMK reaction mixture (50 mM Hepes, pH 7.4, 10 mM MgCl 2 , 50 mM KCl, 10 ⁇ M IP(1,4,5,6) 4 ).
  • the kinase reaction was carried out at 37° C.
  • kinase assays were prepared in 384-well plates (using 20 ng of recombinant human IP6K2 protein as replicates) for IC 50 estimation of compounds.
  • 20 ng of human recombinant IP6K2 protein was used per 20 ⁇ L of the reaction mixture (50 mM Tris-HCl, pH 6.8, 10 mM MgCl 2 , 2.5 mM DTT, 0.02% Triton X-100, 10 ⁇ M IP6).
  • the kinase reaction was carried out for 1 hour at -25 °C with shaking at 300 rpm, and ADP production was measured using a Synergy Neo microplate reader (Biotek) according to the manufacturer's protocol.
  • IP6K2 human recombinant IP6K2 protein was used per 25 ⁇ L of IP6K2 reaction mixture (50 mM Tris-HCl, pH 6.9, 10 mM MgCl 2 , 2.5 mM DTT, 0.02% Triton X-100, 10 ⁇ M IP6).
  • Compound 23b [Formula 26] in which the methylpyrazole group was substituted showed a strong inhibitory effect on IPMK with an IC 50 value of 0.77 ⁇ M. This means that the heterocyclic substituent can increase the IPMK inhibitory effect.
  • compound 20s [formula 24] was confirmed to be the most potent inhibitor against IP6K2 with an IC 50 value of 0.55 ⁇ M (FIG. 1b).
  • IP6K2 homology model (UniProt: Q9UHH9) was downloaded from the AlphaFold2 structural database (https://alphafold.ebi.ac.uk) in PDB and FASTA formats.
  • both compound 20s and quercetin formed one hydrogen bond with Lys42 and one hydrogen bond with Leu209.
  • compound 20s formed an additional hydrogen bond with Asp383 through the -OH group of the A ring compared to quercetin.
  • the -COOH group in the B ring of compound 20s formed one hydrogen bond with Thr210 and an additional hydrogen bond with Gln260, while the 3-OH group of quercetin's C ring formed one hydrogen bond with Thr210. , Therefore, it was found that compound 20s is a more potent IP6K2 inhibitor than quercetin.

Abstract

La présente invention concerne un nouveau composé dérivé de flavonoïde. Le composé dérivé de flavonoïde selon la présente invention peut inhiber de manière efficace l'activité de IPMK et IP6K et il est attendu qu'une composition pharmaceutique le comprenant peut être utilisée pour prévenir ou traiter de manière fondamentale des maladies métaboliques.
PCT/KR2022/018229 2021-11-19 2022-11-17 Nouveau dérivé de flavonoïde et composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement d'une maladie métabolique WO2023090908A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2021-0160633 2021-11-19
KR20210160633 2021-11-19
KR10-2022-0154592 2022-11-17
KR1020220154592A KR20230074404A (ko) 2021-11-19 2022-11-17 신규 플라보노이드 유도체 및 이를 유효성분으로 포함하는 대사성 질환의 예방 또는 치료용 약학 조성물

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050049206A1 (en) * 2003-09-01 2005-03-03 Gong Bang Qiang Compositions of flavonoids and flavonoid-containing extracts and the treatment of diseases
US20120016016A1 (en) * 2009-03-13 2012-01-19 The Salk Institute For Biological Studies Methods and compositions for treating complications of diabetes and vascular diseases using flavones
KR20160068073A (ko) * 2014-12-04 2016-06-15 경희대학교 산학협력단 플라보노이드 화합물을 포함하는 항당뇨용 조성물

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050049206A1 (en) * 2003-09-01 2005-03-03 Gong Bang Qiang Compositions of flavonoids and flavonoid-containing extracts and the treatment of diseases
US20120016016A1 (en) * 2009-03-13 2012-01-19 The Salk Institute For Biological Studies Methods and compositions for treating complications of diabetes and vascular diseases using flavones
KR20160068073A (ko) * 2014-12-04 2016-06-15 경희대학교 산학협력단 플라보노이드 화합물을 포함하는 항당뇨용 조성물

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HU YUN, YANG YAQI, YU YANJUN, WEN GESI, SHANG NANA, ZHUANG WEI, LU DIHAN, ZHOU BINHUA, LIANG BAOXIA, YUE XIN, LI FENG, DU JUN, BU : "Synthesis and Identification of New Flavonoids Targeting Liver X Receptor β Involved Pathway as Potential Facilitators of Aβ Clearance with Reduced Lipid Accumulation", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 56, no. 15, 8 August 2013 (2013-08-08), US , pages 6033 - 6053, XP093068997, ISSN: 0022-2623, DOI: 10.1021/jm301913k *
KALKBRENNER, F. ET AL.: "In vitro inhibition and stimulation of purified prostaglandin endoperoxide synthase by flavonoids: structure-activity relationship", PHARMACOLOGY, vol. 44, no. 1, 1992, pages 1 - 12, XP009546653 *

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