WO2023120963A1 - Composition pharmaceutique pour la prévention ou le traitement du cancer du poumon comprenant un composé dérivé de carbazole en tant que principe actif - Google Patents

Composition pharmaceutique pour la prévention ou le traitement du cancer du poumon comprenant un composé dérivé de carbazole en tant que principe actif Download PDF

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WO2023120963A1
WO2023120963A1 PCT/KR2022/017159 KR2022017159W WO2023120963A1 WO 2023120963 A1 WO2023120963 A1 WO 2023120963A1 KR 2022017159 W KR2022017159 W KR 2022017159W WO 2023120963 A1 WO2023120963 A1 WO 2023120963A1
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acid
group
structural formula
pharmaceutical composition
lung cancer
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PCT/KR2022/017159
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English (en)
Korean (ko)
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김은경
송은주
추현아
신상철
정정현
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한국과학기술연구원
이화여자대학교 산학협력단
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Priority claimed from KR1020220144475A external-priority patent/KR20230094959A/ko
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Publication of WO2023120963A1 publication Critical patent/WO2023120963A1/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating lung cancer comprising a carbazole derivative compound as an active ingredient, and more particularly, to a pharmaceutical composition for preventing or treating lung cancer comprising a carbazole derivative compound acting as an inhibitor of USP47 as an active ingredient. It is about.
  • Ubiquitination and deubiquitination play various roles in cells, including protein degradation, signal transduction, cell cycle, DNA damage response, and autophagy.
  • E1 ubiquitin-activating enzyme
  • E2 ubiquitin-conjugating enzyme
  • E3 ubiquitin ligase
  • DUB deubiquitinatinase
  • USP7 is a target protein for various diseases as well as antiviral and anticancer drugs.
  • Global pharmaceutical companies such as Genentech, Novartis, and Schr ⁇ dinger are developing inhibitors targeting USP7, and some compounds have undergone preclinical trials. It has passed and is in clinical trials.
  • USP47 has the most similar amino acid sequence to USP7 and shows similarity in terms of biological and biochemical functions. Recently, inhibition of the function and growth of USP47 has been confirmed to inhibit the growth of acute myeloid leukemia, colorectal cancer, and cisplatin-resistant cancer cells. In addition, it has been identified as a target protein for lung-related diseases including lung cancer. As such, the development of inhibitors of USP47 associated with various cancers and diseases is very insufficient, and in particular, inhibitory compounds targeting only USP47 are not known.
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating lung cancer comprising, as an active ingredient, a carbazole derivative capable of inhibiting the growth of lung cancer cells by inhibiting the activity of USP47 protein or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for preventing or treating lung cancer comprising a carbazole derivative represented by Structural Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient is provided;
  • n is an integer from 1 to 10;
  • n is an integer from 0 to 3;
  • Ar 1 is a hydrogen atom, a substituted or unsubstituted C1 to C7 alkyl group, a substituted or unsubstituted C1 to C7 alkylcarbonyl group, a substituted or unsubstituted C3 to C10 cycloalkyl group, or a substituted or unsubstituted C6 to C10 aryl group am.
  • Ar 1 may be a hydrogen atom, a substituted or unsubstituted C1 to C4 alkyl group, or a substituted or unsubstituted or substituted or unsubstituted phenyl group.
  • the carbazole derivative represented by Structural Formula 1 may be represented by Structural Formula 2 below.
  • n is an integer from 1 to 6;
  • n 0 or 1
  • R 1 is a hydrogen atom, a hydroxyl group, a C1 to C7 alkyl group, or a C1 to C7 alkoxy group.
  • the carbazole derivative represented by Structural Formula 2 may be represented by Structural Formula 3 below.
  • n is an integer from 2 to 4.
  • R 1 is a hydroxy group or a C1 to C3 alkoxy group.
  • the compound represented by Structural Formula 1 may be any one selected from compounds 1 to 13 below.
  • the compound represented by Structural Formula 1 may be Compound 1 below.
  • the pharmaceutical composition may be used for inhibiting USP47 protein activity.
  • the pharmaceutically acceptable salts are selected from hydrochloric acid, hydrobromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid and methanesulfonic acid. It may be a salt formed using any one selected inorganic acid or organic acid.
  • the pharmaceutical composition may be any one formulation selected from extracts, powders, granules, tablets and capsules.
  • the pharmaceutical composition for preventing or treating lung cancer of the present invention can inhibit the growth of lung cancer cells by inhibiting the activity of USP47 protein.
  • Figure 8 shows the results of cancer growth rate delay analysis of Compound 1 for the H358 cell line.
  • Figure 9 shows the toxicity analysis results according to the change in body weight of the experimental animals.
  • substituted means that at least one hydrogen atom is deuterium, a C1 to C30 alkyl group, a C3 to C30 cycloalkyl group, a C2 to C30 heterocycloalkyl group, a C1 to C30 halogenated alkyl group, a C6 to C30 aryl group, a C1 to C30 heteroaryl group, C1 to C30 alkoxy group, C3 to C30 cycloalkoxy group, C1 to C30 heterocycloalkoxy group, C2 to C30 alkenyl group, C2 to C30 alkynyl group, C6 to C30 aryloxy group, C1 to C30 heteroaryloxy group, silyloxy Group (-OSiH 3 ), -OSiR 1 H 2 (R 1 is a C1 to C30 alkyl group or C6 to C30 aryl group), -OSiR 1 R 2 H (R 1 and R 2 are each independently a C1 to
  • two adjacent substituents among the substituents may be fused to form a saturated or unsaturated ring.
  • the carbon number range of the alkyl group or aryl group in the "substituted or unsubstituted alkyl group” or “substituted or unsubstituted aryl group” is the alkyl when viewed as unsubstituted without considering the part where the substituent is substituted. It means the total number of carbon atoms constituting the moiety or aryl moiety.
  • a phenyl group in which a butyl group is substituted at the para position corresponds to an aryl group having 6 carbon atoms substituted with a butyl group having 4 carbon atoms.
  • hydrogen atom means single hydrogen, double hydrogen, or tritium unless otherwise defined.
  • alkyl (alkyl) group means an aliphatic hydrocarbon group unless otherwise defined.
  • alkyl group may be a "saturated alkyl group" that does not contain any double or triple bonds.
  • the alkyl group may also be an "unsaturated alkyl group" containing at least one double bond or triple bond.
  • Alkyl groups whether saturated or unsaturated, may be branched, straight-chain or cyclic.
  • the C1 to C4 alkyl group has 1 to 4 carbon atoms in the alkyl chain, i.e. the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl. indicates being
  • the alkyl group is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, a hexyl group, an ethenyl group, a propenyl group, a butenyl group, a cyclopropyl group, a cyclo A butyl group, a cyclopentyl group, a cyclohexyl group, etc. are meant.
  • the term 'comprising as an active ingredient' in the present specification means including a sufficient amount to achieve the efficacy or activity of a carbazole derivative or a pharmaceutically acceptable salt thereof.
  • the carbazole derivative or a pharmaceutically acceptable salt thereof may be used at a concentration of 10 to 1500 ⁇ g/ml, preferably 100 to 1000 ⁇ g/ml, but the scope of the present invention is not limited thereto and the present invention
  • the upper limit of the amount of the carbazole derivative included in the pharmaceutical composition of the present invention can be selected and implemented within an appropriate range by those skilled in the art.
  • the pharmaceutical composition for preventing or treating lung cancer of the present invention is a carbazole derivative represented by Structural Formula 1 below or a pharmaceutically acceptable salt thereof.
  • n is an integer from 1 to 10;
  • n is an integer from 0 to 3;
  • Ar 1 is a hydrogen atom, a substituted or unsubstituted C1 to C7 alkyl group, a substituted or unsubstituted C1 to C7 alkylcarbonyl group, a substituted or unsubstituted C3 to C10 cycloalkyl group, or a substituted or unsubstituted C6 to C10 aryl group am.
  • Ar 1 may be a hydrogen atom, a substituted or unsubstituted C1 to C4 alkyl group, or a substituted or unsubstituted or substituted or unsubstituted phenyl group.
  • the carbazole derivative represented by Structural Formula 1 may be a carbazole derivative represented by Structural Formula 2 below.
  • n is an integer from 1 to 6;
  • n 0 or 1
  • R 1 is a hydrogen atom, a hydroxyl group, a C1 to C7 alkyl group, or a C1 to C7 alkoxy group.
  • the carbazole derivative represented by Structural Formula 2 may be a carbazole derivative represented by Structural Formula 3 below.
  • n is an integer from 2 to 4.
  • R 1 is a hydroxy group or a C1 to C3 alkoxy group.
  • the compound represented by Structural Formula 1 may be any one selected from compounds 1 to 13 below.
  • the compound represented by Structural Formula 1 may be Compound 1 below.
  • the pharmaceutical composition may be used for inhibiting USP47 protein activity.
  • the pharmaceutically acceptable salts are selected from hydrochloric acid, hydrobromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid and methanesulfonic acid. It may be a salt formed using any one selected inorganic acid or organic acid.
  • the pharmaceutical composition of the present invention may be prepared using pharmaceutically suitable and physiologically acceptable adjuvants in addition to the above active ingredients, and the adjuvants include excipients, disintegrants, sweeteners, binders, coating agents, expanding agents, lubricants, and lubricants. agents or flavoring agents may be used.
  • the pharmaceutical composition may be preferably formulated as a pharmaceutical composition by including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients for administration.
  • Formulations of the pharmaceutical composition may be granules, powders, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, drops, or injectable solutions.
  • the active ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable binders, lubricants, disintegrants and coloring agents may also be included in the mixture.
  • Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tracacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • acceptable pharmaceutical carriers are sterile and biocompatible, and include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers, and bacteriostatic agents may be added if necessary.
  • diluents, dispersants, surfactants, binders, and lubricants may be additionally added to prepare formulations for injections such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc., preferably oral administration.
  • the suitable dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, administration method, patient's age, weight, sex, medical condition, food, administration time, administration route, excretion rate and reaction sensitivity, usually This allows the skilled physician to readily determine and prescribe dosages effective for the desired treatment or prophylaxis.
  • the daily dose of the pharmaceutical composition of the present invention is 0.001-10 g/kg.
  • the pharmaceutical composition of the present invention may be prepared in a unit dose form by formulation using a pharmaceutically acceptable carrier and/or excipient, or prepared by putting it into a multi-dose container.
  • the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally contain a dispersing agent or stabilizer.
  • the present invention provides a pharmaceutical composition containing the carbazole derivative represented by Structural Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the purpose of preventing or treating lung cancer.
  • a target compound was prepared in the same manner as in Preparation Example 1, except that 1,4-dibromobutane was used instead of 1,3-dibromopropane.
  • a target compound was prepared in the same manner as in Preparation Example 1, except that 1,5-dibromopentane was used instead of 1,3-dibromopropane.
  • a target compound was prepared in the same manner as in Preparation Example 1, except that 1,6-dibromohexane was used instead of 1,3-dibromopropane.
  • the target compound 9-(3- 204.6 mg (0.53 mmol, 77% yield) of (4-benzylpiperazin-1-yl)propyl)-9H-carbazole was obtained.
  • the carbazole derivative represented by Structural Formula 1 according to the present invention can be formulated in various forms depending on the purpose.
  • a formulation method containing the carbazole derivative represented by [Formula 1] or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient will be exemplified.
  • these formulation examples are only for exemplifying the present invention, and the scope of the present invention is not limited thereto.
  • An injection was prepared by containing 100 mg of the compound of Example as an active ingredient, 180 mg of mannitol, 26 mg of Na 2 HPO 4 12H 2 O, and 2974 mg of distilled water as additional materials.
  • the activity of the deubiquitination enzyme was measured using an artificial substrate, UB-AMC.
  • UB an artificial substrate
  • 7-amido-4-methylcoumarin (AMC) a fluorescent substance
  • the size of the fluorescence wavelength of the separated AMC (7-amido-4-methylcoumarin) was measured.
  • the fluorescence emission wavelength (Emission) to be measured is 460 nm
  • the excitation wavelength (Excitation) was measured based on 380 nm. Fluorescence change was measured using SpectraMax M3 plate reader, which is an equipment capable of measuring these two wavelengths.
  • 50 nM of purified USP47 protein in aqueous solution was preserved in a buffer solution (150 mM sodium chloride, 20 mM HEPES-hydrochloric acid buffer, pH 7.5, 150 mM dithiothreitol) to stabilize the protein.
  • a buffer solution 150 mM sodium chloride, 20 mM HEPES-hydrochloric acid buffer, pH 7.5, 150 mM dithiothreitol
  • Step 2 Measurement of enzymatic activity inhibitory ability of USP47 according to the concentration of K-552 compound
  • step 1 Based on the initial experimental results obtained in step 1 above, the difference in activity of USP47 protein according to the concentration of compound 1 was confirmed.
  • the enzymatic activity of the USP47 protein was measured at various concentrations (100, 50, 10, 5, 1, 0.5, 0.1, 0.01 ⁇ M) of compound 1 in the same manner as in step 1, and the results are shown in FIG. 2 .
  • Compound 1 of the present invention has high inhibitory activity on the enzymatic activity of USP47 protein in a concentration-dependent manner.
  • Test Example 2 Activity assay for cell-based USP47 and USP7
  • activity probe assay was used.
  • A549 lung cancer cell line was treated with Compound 1 at a concentration between 25 ⁇ M and 100 ⁇ M for 6 hours.
  • cells were treated with P50429, known as an inhibitor of USP47 and USP7 at a concentration of 25 ⁇ M for 6 hours, and the effects were compared.
  • Each drug-treated cell was obtained and lysed in protein lysis buffer (20 mM Tris-Cl (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 50 mM NaF, 5 mM Protein was prepared using beta-glycero phosphate, 1 mM Na3VO4, and 1X protease inhibitor (cComplete, EDTA-free; Roche, Basel, Switzerland) 60 ⁇ g of cellular protein was prepared using HA-Ub-PA (UBIQ, ubiq-078).
  • protein lysis buffer (20 mM Tris-Cl (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 50 mM NaF, 5 mM Protein was prepared using beta-glycero phosphate
  • FIG. 3 The result of analysis by Western blotting according to this is shown in FIG. 3 .
  • the band to which the HA-Ub probe was bound appeared well in Western blotting using USP47 and USP7 antibodies, but in the case of treatment with P50429, the probe was not bound. I was able to confirm.
  • the compound 1 when the compound 1 was treated, it was confirmed that the activity of USP47 was inhibited, as the band bound to the HA-Ub probe was significantly reduced compared to the control group in the USP47 blot.
  • USP7 it was found that the activity of USP7 was not affected as the binding with the HA-Ub probe was maintained.
  • A549 lung cancer cells were treated with Compound 1 for 48 hours, and then the cells were cultured for 8 days while exchanging the medium every 2 days.
  • the cells were washed with PBS, fixed with 4% paraformaldehyde, treated with ice-cold methanol for 20 minutes, and then stained with crystal violet for 30 minutes.
  • a graph in which the number was counted is shown in FIG. 6 . According to this, it was found that colony formation of lung cancer cells was reduced in a concentration-dependent manner when Compound 1 was treated.
  • Compound 1 was intraperitoneally administered at a concentration of 30 mg/kg once a day for 21 days. During the drug administration period, cancer volume was measured once a day to confirm the delay in cancer growth rate due to drug administration, and body weights of the experimental animals were measured to indirectly confirm the toxicity caused by drug administration.
  • the cancer growth rate delay analysis results of Compound 1 on the H358 cell line are shown in FIG. 8
  • the results of toxicity analysis according to changes in body weight of experimental animals are shown in FIG. 9 .
  • the cancer growth rate delay analysis results of Compound 1 for the Calu-1 cell line are shown in FIG. 10, and the toxicity analysis results according to the body weight change of the experimental animals are shown in FIG. According to this, when Calu-1 cancer cells were transplanted into mice and Compound 1 was administered, the growth of cancer cells was delayed in the group administered with Compound 1 compared to the control group, and there was no difference in body weight change between the two groups during the administration period. It was indirectly confirmed that the administration did not stress the experimental animals and was non-toxic.
  • the pharmaceutical composition for preventing or treating lung cancer of the present invention can inhibit the growth of lung cancer cells by inhibiting the activity of USP47 protein.

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Abstract

La présente invention concerne une composition pharmaceutique pour la prévention ou le traitement du cancer du poumon, la composition comprenant un dérivé de carbazole représenté par la formule structurale 1, ou un sel pharmaceutiquement acceptable de celui-ci, en tant que principe actif.
PCT/KR2022/017159 2021-12-21 2022-11-03 Composition pharmaceutique pour la prévention ou le traitement du cancer du poumon comprenant un composé dérivé de carbazole en tant que principe actif WO2023120963A1 (fr)

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KR10-2021-0184299 2021-12-21
KR20210184299 2021-12-21
KR10-2022-0144475 2022-11-02
KR1020220144475A KR20230094959A (ko) 2021-12-21 2022-11-02 카바졸 유도체 화합물을 유효성분으로 포함하는 폐암 예방 또는 치료용 약학 조성물

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009074809A1 (fr) * 2007-12-13 2009-06-18 University Of Dundee Ligands des récepteurs sigma et inhibiteurs d'ikk / nf-kb pour traitement médical
CN111217741A (zh) * 2019-03-01 2020-06-02 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） 氟取代单咔唑类衍生物、其制备方法及应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009074809A1 (fr) * 2007-12-13 2009-06-18 University Of Dundee Ligands des récepteurs sigma et inhibiteurs d'ikk / nf-kb pour traitement médical
CN111217741A (zh) * 2019-03-01 2020-06-02 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） 氟取代单咔唑类衍生物、其制备方法及应用

Non-Patent Citations (3)

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Title
CHO JINHONG, PARK JINYOUNG, SHIN SANG CHUL, JANG MIHUE, KIM JAE-HONG, KIM EUNICE EUNKYEONG, SONG EUN JOO: "USP47 Promotes Tumorigenesis by Negative Regulation of p53 through Deubiquitinating Ribosomal Protein S2", CANCERS, vol. 12, no. 5, pages 1137, XP093073312, DOI: 10.3390/cancers12051137 *
LI NA; QU GUOJING; XUE JINGNA; LI XIAO; ZHAO XUAN; YAN YEHAO; GAO DONGFANG; ZHANG LU; WANG PENG; ZHANG MING; ZHAO BAOXIANG; MIAO J: "Discovery of a new autophagy inducer for A549 lung cancer cells", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 27, no. 13, 1 January 1900 (1900-01-01), AMSTERDAM, NL, pages 2845 - 2856, XP085704944, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2019.05.015 *
PATI MARIA LAURA, HORNICK JOHN R., NISO MAURO, BERARDI FRANCESCO, SPITZER DIRK, ABATE CARMEN, HAWKINS WILLIAM: "Sigma-2 receptor agonist derivatives of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) induce cell death via mitochondrial superoxide production and caspase activation in pancreatic cancer", BMC CANCER, vol. 17, no. 1, 1 December 2017 (2017-12-01), XP093073311, DOI: 10.1186/s12885-016-3040-4 *

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