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WO2019027203A1 - Stéréoisomère à base de dihydroxyphényle ayant une activité d'inhibition de hsp90 et son utilisation médicale - Google Patents

Stéréoisomère à base de dihydroxyphényle ayant une activité d'inhibition de hsp90 et son utilisation médicale Download PDF

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Publication number
WO2019027203A1
WO2019027203A1 PCT/KR2018/008613 KR2018008613W WO2019027203A1 WO 2019027203 A1 WO2019027203 A1 WO 2019027203A1 KR 2018008613 W KR2018008613 W KR 2018008613W WO 2019027203 A1 WO2019027203 A1 WO 2019027203A1
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WIPO (PCT)
Prior art keywords
cancer
hsp90
stereoisomer
group
alkoxy
Prior art date
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Ceased
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PCT/KR2018/008613
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English (en)
Korean (ko)
Inventor
서영호
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Industry Academic Cooperation Foundation of Keimyung University
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Industry Academic Cooperation Foundation of Keimyung University
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Priority claimed from KR1020180087930A external-priority patent/KR20190014474A/ko
Application filed by Industry Academic Cooperation Foundation of Keimyung University filed Critical Industry Academic Cooperation Foundation of Keimyung University
Publication of WO2019027203A1 publication Critical patent/WO2019027203A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the present invention relates to dihydroxyphenyl-based stereoisomers having HSP90 inhibitory activity and their medical uses.
  • the Hsp90 protein is one of the most abundant chaperones within eukaryotic cells, and is responsible for the stabilization and regulation of various proteins involved in cell growth differentiation, survival.
  • the substrate protein of Hsp90 called the client protein, contains over 50 cancer-causing proteins. When Hsp90 activity is inhibited, the Hsp90 client proteins are degraded by the proteasome.
  • Hsp90 activity inhibitor can attenuate various cancer-inducing proteins at the same time, and thus has attracted much attention as an anticancer agent that can be applied to a wide variety of cancers.
  • Hsp90 has been shown to be effective in the treatment of cancer with resistance, since it simultaneously reduces various cancer-inducing proteins.
  • Hsp90 inhibitor may be used as a therapeutic agent for degenerative neurological diseases, because proteins that cause degenerative neuropathy are also present in the Hsp90 client proteins.
  • the Hsp90 inhibitor started from the development of the natural substance geldanamycin (GA). GA has been shown to induce the degradation of the client protein Src through inhibition of Hsp90 in 1994. Since then, inhibitors targeting Hsp90 have been actively developed. However, GA has a strong anticancer effect, but has problems of liver toxicity, solubility and stability. In order to compensate for this, the GA derivatives, Tanespimycin (17-AAG), alvespimycin (17-DMAG) and retaspimycin have been developed but their structural characteristics have not solved the problem. Since then, research on Hsp90 inhibitors of various structures has been conducted at the clinical stage, but since FDA-approved drugs have not yet been developed, it is necessary to develop new, more potent compounds.
  • the present invention provides dihydroxyphenyl-based stereoisomers represented by the following formula (1).
  • R 1 is any one selected from the group consisting of halogen, C 1 -C 4 alkyl and C 1 -C 4 alkoxy,
  • R 2 is any one selected from the group consisting of C 3 -C 6 cycloalkyl, phenyl, halogen, C 1 -C 4 alkyl and C 1 -C 4 alkoxy,
  • R 3 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  • the present invention provides a pharmaceutical composition for preventing or treating Heat Shock Protein 90 (Hsp90) -mediated disease, which comprises the dihydroxyphenyl stereoisomer represented by Formula 1 as an active ingredient.
  • Hsp90 Heat Shock Protein 90
  • the present invention also provides a health food for preventing or ameliorating a heat shock protein 90 (Hsp90) mediated disease comprising the dihydroxyphenyl stereoisomer represented by the above formula (1) as an active ingredient.
  • Hsp90 heat shock protein 90
  • the present invention relates to a dihydroxyphenyl-based stereoisomer having Hsp90 inhibitory activity, and a pharmaceutical composition or health functional food comprising the same, wherein the stereoisomer is excellent in an unexpectedly superior 30 times or more
  • the Hsp90 inhibitory effect can be confirmed. Therefore, it can be effectively used as a pharmaceutical composition for preventing or treating Hsp90-mediated diseases selected from the group consisting of cancer diseases, degenerative neurological diseases and viral infections, or health functional foods for prevention or improvement.
  • Figure 1 shows the chiral HPLC separation results to identify the stereoisomers of Compound 17.
  • FIG. 2 shows the effect of inhibiting H1975 cell proliferation through the regulation of Hsp90 client protein of the stereoisomer of compound 17, Peak 1, wherein FIG. 2 (A) is the MTS analysis result and FIG. 2 (B) is the Western blot analysis result.
  • the inventors of the present invention have found that when a compound showing heat shock protein 90 (Heat Shock Protein 90, Hsp90) inhibitory effect is produced, the stereoisomer represented by the following formula 1 has an excellent Hsp90 inhibitory effect To complete the present invention.
  • R 1 is any one selected from the group consisting of halogen, C 1 -C 4 alkyl and C 1 -C 4 alkoxy,
  • R 2 is any one selected from the group consisting of C 3 -C 6 cycloalkyl, phenyl, halogen, C 1 -C 4 alkyl and C 1 -C 4 alkoxy,
  • R 3 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  • the stereoisomer may be a dihydroxyphenyl-based stereoisomer represented by the following general formula (2).
  • the present invention can provide a pharmaceutical composition for preventing or treating Heat Shock Protein 90 (Hsp90) -mediated disease comprising dihydroxyphenyl based stereoisomer represented by the following formula (1) as an active ingredient:
  • Hsp90 Heat Shock Protein 90
  • R 1 is any one selected from the group consisting of halogen, C 1 -C 4 alkyl and C 1 -C 4 alkoxy,
  • R 2 is any one selected from the group consisting of C 3 -C 6 cycloalkyl, phenyl, halogen, C 1 -C 4 alkyl and C 1 -C 4 alkoxy,
  • R 3 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  • the stereoisomer may be a compound represented by the following formula (2).
  • the pharmaceutical composition may be a pharmaceutical composition for preventing or treating Heat Shock Protein 90 (Hsp90) mediated diseases.
  • Hsp90 Heat Shock Protein 90
  • the heat shock protein 90-mediated disease is any one or more diseases selected from the group consisting of cancer diseases, degenerative neurological diseases, and viral infections.
  • cancer diseases include cancer of the non-small cell lung, breast, ovarian, uterine, pancreatic, lung, stomach, liver, but are not limited to, cancer, rectal cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and blood cancer.
  • the degenerative neurological disorder may be selected from the group consisting of stroke, paralysis, memory loss, memory impairment, dementia, forgetfulness, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeld-Kacob disease, Huntington's disease, But the present invention is not limited thereto.
  • compositions according to the present invention may further comprise suitable carriers, excipients or diluents conventionally used in the production of pharmaceutical compositions.
  • Examples of carriers, excipients or diluents usable in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.
  • the pharmaceutical composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method .
  • a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used.
  • Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose sucrose), lactose, gelatin, and the like.
  • lubricants such as magnesium stearate and talc may also be used.
  • liquid preparation for oral use include suspensions, solutions, emulsions, and syrups.
  • excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included .
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like.
  • the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
  • the dosage of the pharmaceutical composition according to the present invention may be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like.
  • the dosage amounts are not intended to limit the scope of the invention in any manner.
  • the pharmaceutical composition may be administered to mammals such as rats, mice, livestock, humans, and the like in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intratracheal, intrauterine or intracerebroventricular injections.
  • the present invention provides a health functional food for preventing or ameliorating a heat shock protein 90 (Hsp90) mediated disease comprising the dihydroxyphenyl based stereoisomer represented by the above formula (1) or (2) as an active ingredient.
  • Hsp90 heat shock protein 90
  • the health functional food may be provided in the form of powder, granules, tablets, capsules, syrups or beverages.
  • the health functional food may be used together with other food or food additives other than the compound represented by the formula (1) Can be suitably used according to the method of
  • the amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.
  • the stereoisomers represented by the above formula (1) or (2) contained in the health functional food may be used in accordance with the effective dose of the pharmaceutical composition, but may be used for health and hygiene purposes or for long- It may be less than the above range, and since the active ingredient has no problem in terms of safety, it can be used in an amount exceeding the above range.
  • dihydroxyphenyl-based stereoisomers of the present invention include not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates which can be prepared by conventional methods.
  • the addition salt according to the present invention can be prepared by a conventional method.
  • the dihydroxyphenyl stereoisomer of the formula (1) or (2) is dissolved in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile Or the like, adding an excess amount of an organic acid, or adding an aqueous acid solution of an inorganic acid, followed by precipitation or crystallization.
  • a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.
  • the splitting pattern abbreviations are: s, singlet; d, doublet; t, triplet; q, quartet, dd, doublet of doublets; m, multiplet.
  • Sk-Br3 Kerman cell line bank
  • a breast cancer cell and H1975 cell (ATCC), a non-small cell lung cancer
  • 25 mM HEPES [4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid] (Streptomycin, 500 mg / mL), penicillin (100 units / mL) and 10% fetal bovine serum (L-glutamine) fetal bovine serum, FBS).
  • the cells were cultured in a humidified atmosphere of 37 ° C and 5% CO 2 .
  • H1975 cells were dispensed into a 96-well plate to 1500 cells per well, added to a volume of 100 ⁇ L, and then the cells were allowed to adhere overnight.
  • each compound was added to the wells at various concentrations and then the cells were incubated at 37 ⁇ for 3 days.
  • H1975 cells were plated at a density of 1x10 < 6 > / dish in a 100 mm culture dish and adhered overnight. Each compound was added to the cells at a concentration of 0.1 and 0.5 ⁇ M and the cells were further incubated for 24 hours. Cells were then harvested with cold lysis buffer (23 mM Tris-HCl pH 7.6, 130 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS) and 30 ⁇ g lysine / PAGE, and then transferred to a PVDF membrane (Bio-Rad).
  • cold lysis buffer 23 mM Tris-HCl pH 7.6, 130 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS
  • the membranes were blocked with TBST containing 5% skim milk and incubated with the appropriate antibodies (EGFR, p-EGFR, Her2, Met, Akt, Hsp90, Hsp70, and beta-Actin).
  • HFB buffer (20 mM HEPES pH 7.3, 50 mM KCl, 5 mM MgCl 2 , 20 mM Na 2 MoO 4 , 0.01% NP-40), 30 nM recombinant Hsp90 alpha full length protein, 5 nM (GA-FITC) inhibitor labeled with fluorescein isothiocyanate, 0.1 mg / mL bovine serum globulin (BGG), 2 mM 1,4-dithiothreitol (DTT) and various concentrations of compound was added.
  • the HFB buffer in all wells was brought to a final volume of 100 ⁇ L. Plates were incubated at 4 ° C for 16 hours and the polarization values of millipolarization units were measured at an emission wavelength of 495 nm and a radiation wavelength of 530 nm.
  • H1975 cells were treated with various concentrations of peak 1 for 3 days and cell proliferation level was confirmed.
  • the peak 1 compound effectively inhibited the growth of H1975 cells in a dose-dependent manner compared to the gefitinib and peak 2 compounds.
  • the cell biomarker of Hsp90 inhibition confirmed the differentiation of the client protein and the induction of Hsp70.
  • Peak 1 the anti-proliferative effect of the Peak 1 compound in cancer cells was a result of suppression of Hsp90, and Peak 1 was the most effective as compared with the test compound, iressa, peak 2 and geladinamycin (GA) And exhibited excellent anticancer activity.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Mycology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un nouveau stéréoisomère à base de dihydroxyphényle ayant une activité d'inhibition de Hsp90, et une composition pharmaceutique ou un aliment fonctionnel de santé le comprenant. Présentant un effet inhibiteur de Hsp90 qui est trop important à prédire, et qui est au moins 30 fois supérieur à un racémate de celui-ci, le stéréoisomère peut trouver des applications utiles dans une composition pharmaceutique pour la prévention ou le traitement d'une maladie médiée par Hsp90 choisie dans le groupe constitué par une maladie cancéreuse, une maladie neurodégénérative et une infection virale, ou dans un aliment fonctionnel de santé pour la prévention ou le soulagement d'une maladie médiée par Hsp90 choisie dans le groupe constitué par une maladie cancéreuse, une maladie neurodégénérative et une infection virale.
PCT/KR2018/008613 2017-08-02 2018-07-30 Stéréoisomère à base de dihydroxyphényle ayant une activité d'inhibition de hsp90 et son utilisation médicale Ceased WO2019027203A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2017-0097923 2017-08-02
KR20170097923 2017-08-02
KR1020180087930A KR20190014474A (ko) 2017-08-02 2018-07-27 Ｈｓｐ９０ 억제 활성을 갖는 디히드록시페닐계 입체이성질체 및 이의 의학적 용도
KR10-2018-0087930 2018-07-27

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WO2019027203A1 true WO2019027203A1 (fr) 2019-02-07

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190031620A1 (en) * 2016-01-29 2019-01-31 Industry Academic Cooperation Foundation Keimyung University Novel compound having hsp90 inhibitory activity or pharmaceutically acceptable salt thereof, and medical use thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006109075A2 (fr) * 2005-04-13 2006-10-19 Astex Therapeutics Limited Composes pharmaceutiques
WO2006117669A1 (fr) * 2005-05-03 2006-11-09 Pfizer Inc. Composes d'amide resorcinol
US20070265268A1 (en) * 2004-11-09 2007-11-15 Kyowa Hakko Kogyo Co., Ltd. Hsp90 Family protein Inhibitors
WO2008044041A1 (fr) * 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
WO2011154708A1 (fr) * 2010-06-11 2011-12-15 Chroma Therapeutics Ltd Dérivés de benzamide et leur utilisation comme inhibiteurs de hsp90

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070265268A1 (en) * 2004-11-09 2007-11-15 Kyowa Hakko Kogyo Co., Ltd. Hsp90 Family protein Inhibitors
WO2006109075A2 (fr) * 2005-04-13 2006-10-19 Astex Therapeutics Limited Composes pharmaceutiques
WO2006117669A1 (fr) * 2005-05-03 2006-11-09 Pfizer Inc. Composes d'amide resorcinol
WO2008044041A1 (fr) * 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
WO2011154708A1 (fr) * 2010-06-11 2011-12-15 Chroma Therapeutics Ltd Dérivés de benzamide et leur utilisation comme inhibiteurs de hsp90

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190031620A1 (en) * 2016-01-29 2019-01-31 Industry Academic Cooperation Foundation Keimyung University Novel compound having hsp90 inhibitory activity or pharmaceutically acceptable salt thereof, and medical use thereof
US10464907B2 (en) * 2016-01-29 2019-11-05 Industry Academic Cooperation Foundation Keimyung University Compound having HSP90 inhibitory activity or pharmaceutically acceptable salt thereof, and medical use thereof
US10889552B2 (en) 2016-01-29 2021-01-12 Oncozen Co.. Ltd. Dihydroxybenzamide compound having HSP90 inhibitory activity or pharmaceutically acceptable salt thereof, and medical use thereof

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