WO2020139044A1 - Nouveau composé et composition pharmaceutique le comprenant pour renforcer l'activité anticancéreuse - Google Patents

Nouveau composé et composition pharmaceutique le comprenant pour renforcer l'activité anticancéreuse Download PDF

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WO2020139044A1
WO2020139044A1 PCT/KR2019/018660 KR2019018660W WO2020139044A1 WO 2020139044 A1 WO2020139044 A1 WO 2020139044A1 KR 2019018660 W KR2019018660 W KR 2019018660W WO 2020139044 A1 WO2020139044 A1 WO 2020139044A1
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alkyl
cancer
group
aryl
hydrogen
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PCT/KR2019/018660
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Korean (ko)
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박기청
정재호
김석모
유태희
윤여진
김병모
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홀로스메딕 주식회사
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Priority to AU2019416623A priority Critical patent/AU2019416623B2/en
Priority to US17/418,323 priority patent/US20220064171A1/en
Priority to BR112021012639-2A priority patent/BR112021012639A2/pt
Priority to JP2021536764A priority patent/JP7195027B2/ja
Priority to CN201980086606.2A priority patent/CN113260365A/zh
Priority to EP19904270.6A priority patent/EP3903786A4/fr
Priority to CA3124938A priority patent/CA3124938A1/fr
Priority claimed from KR1020190176706A external-priority patent/KR102468480B1/ko
Publication of WO2020139044A1 publication Critical patent/WO2020139044A1/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
    • A61K31/495—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 novel compound and a pharmaceutical composition for enhancing anticancer activity comprising the same.
  • Cancer is one of the most common causes of death worldwide, accounting for about 12% of deaths.
  • Chemotherapy a representative anti-cancer therapy, is currently used as the most effective treatment for treating cancer, either alone or in combination with other treatments such as radiotherapy.
  • the efficacy of a cancer treatment drug in chemotherapy depends on its ability to kill cancer cells, but there is a problem that it can act on not only cancer cells but also normal cells when using the drug.
  • a cancer stem cell is a cancer cell with unlimited regenerative capacity and that the tumor will originate from the stem cell
  • cells that can become cancer stem cells in acute myeloid leukemia in the late 90's were given to immunosuppressed mice. After transplantation, it was confirmed that human leukemia was reproduced in rats, and afterwards, cancer stem cells were demonstrated in breast cancer, and the presence of stem cells in solid carcinoma was confirmed.
  • Cancer stem cells are cells that have the ability to self-renew and differentiate into other cells, and act as a cause of cancer recurrence and metastasis. Certain groups of patients are classified as patients with refractory cancer, which are difficult to treat with conventional anticancer therapy because cancer stem cells are activated and exhibit strong anticancer drug resistance. The diverse heterogeneity of malignant tumors is consistent with the differentiation of stem cells, and the drug resistance of cancer cells, which are constantly expressed despite many targeted treatments, is consistent with the basic properties of stem cells.
  • Cancer stem cells can be a new targeted therapeutic field, and in order to efficiently perform treatment targeting only cancer stem cells without damaging normal stem cells, molecular biological properties important for the maintenance and control of cancer stem cells, It requires knowledge and understanding of the control pathways.
  • SERCA sarco/endoplasmic reticulum calcium ATPase
  • the present invention aims to provide novel compounds.
  • An object of the present invention is to provide a pharmaceutical composition for enhancing anticancer activity.
  • n is an integer from 0 to 4.
  • R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl
  • R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
  • L 1 is a direct bond or C1 to C6 alkylene
  • R 2 is hydrogen, C1 to C10 alkyl or aryl (C1 to C4)alkyl
  • R 4 is hydrogen, C1 to C4 alkyl, C3 to C8 cycloalkyl or aryl (C1 to C4)alkyl
  • R 2 and R 4 form a 4 to 7-membered ring and are connected to each other;
  • the alkyl of R 1 to R 4, the arylalkyl of R 1 , R 2 and R 4 , the cycloalkyl of R 4 , and the alkylene of L 1 are each independently a C1 to C6 alkyl group, halo group, aryl group When substituted with a substituent of a group, haloalkyl group, nitro group, cyano group, alkylthio group or arylalkylthio group or unsubstituted, and substituted with a plurality of substituents, they are the same or different from each other.
  • n is an integer from 0 to 2;
  • R 1 is C 1 to C 6 alkyl or aryl (C 1 to C 2) alkyl;
  • L 1 is C1 to C4 alkylene
  • R 2 is hydrogen, C1 to C6 alkyl or aryl (C1 to C2)alkyl
  • R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl (C1 to C2)alkyl
  • n is an integer from 0 to 1;
  • R 1 is C1 to C6 alkyl, phenylmethyl or phenylethyl
  • L 1 is C1 to C2 alkylene
  • R 2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl
  • R 4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl
  • a pharmaceutical composition for enhancing anticancer activity comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • n is an integer from 0 to 4.
  • R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl
  • R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
  • L 1 is a direct bond or C1 to C6 alkylene
  • R 2 is hydrogen, C1 to C10 alkyl or aryl (C1 to C4)alkyl
  • R 4 is hydrogen, C1 to C4 alkyl, C3 to C8 cycloalkyl or aryl (C1 to C4)alkyl
  • R 2 and R 4 form a 4 to 7-membered ring and are connected to each other;
  • the alkyl of R 1 to R 4, the arylalkyl of R 1 , R 2 and R 4 , the cycloalkyl of R 4 , and the alkylene of L 1 are each independently a C1 to C6 alkyl group, halo group, aryl group When substituted with a substituent of a group, haloalkyl group, nitro group, cyano group, alkylthio group or arylalkylthio group or unsubstituted, and substituted with a plurality of substituents, they are the same or different from each other.
  • n is an integer from 0 to 2;
  • R 1 is C 1 to C 6 alkyl or aryl (C 1 to C 2) alkyl;
  • L 1 is C1 to C4 alkylene
  • R 2 is hydrogen, C1 to C6 alkyl or aryl (C1 to C2)alkyl
  • R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl (C1 to C2)alkyl
  • the R 2 and R 4 form a 4 to 7-membered ring and are connected to each other, a pharmaceutical composition.
  • n is an integer from 0 to 1;
  • R 1 is C1 to C6 alkyl, phenylmethyl or phenylethyl
  • L 1 is C1 to C2 alkylene
  • R 2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl
  • R 4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl
  • the R 2 and R 4 form a 5 to 6 membered ring and are connected to each other, a pharmaceutical composition.
  • anti-cancer activity enhancement is an anti-cancer agent or radiation anti-cancer activity enhancement, pharmaceutical composition.
  • the anticancer agent is at least one of a taxane-based anticancer agent and a camptothecin-based anticancer agent.
  • taxane-based anticancer agent is at least one selected from the group consisting of paclitaxel, docetaxel and cabazitaxel.
  • camptothecin-based anti-cancer agent is at least one selected from the group consisting of irinotecan, topotecan and belotane.
  • the resistant cancer is thyroid cancer, stomach cancer, colon cancer, ovarian cancer, At least one selected from the group consisting of breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, pancreatic cancer, head and neck cancer, rectal cancer, colon cancer, esophageal cancer and prostate cancer.
  • composition according to the above 4 further comprising an anti-cancer agent.
  • the anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nilotinib, semasanib, conservitinib, ax Citinib, Macitinib, Cediranib, Restautinib, Trastuzumab, Gefitinib, Bortezomib, Sunitinib, Pazopanib, Toseranib, Nintedanib, Legorafenib, Semoxazanib, Tiboza Nip, ponatinib, carbozantinib carboplatin, sorafenib, lenbatinib, bevacizumab, cisplatin, cetuximab, biscumalbum, asparaginase, tretinoin, hydroxy
  • composition of 15 above wherein the anticancer agent is contained in a molar concentration ratio of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and a ratio of 1:0.001 to 1:1000.
  • a method of treating cancer comprising administering to a subject with resistant cancer a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
  • n is an integer from 0 to 4.
  • R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl
  • R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
  • L 1 is a direct bond or C1 to C6 alkylene
  • R 2 is hydrogen, C1 to C10 alkyl or aryl (C1 to C4)alkyl
  • R 4 is hydrogen, C1 to C4 alkyl, C3 to C8 cycloalkyl or aryl (C1 to C4)alkyl
  • R 2 and R 4 form a 4 to 7-membered ring and are connected to each other;
  • the alkyl of R 1 to R 4, the arylalkyl of R 1 , R 2 and R 4 , the cycloalkyl of R 4 , and the alkylene of L 1 are each independently a C1 to C6 alkyl group, halo group, aryl group When substituted with a substituent of a group, haloalkyl group, nitro group, cyano group, alkylthio group or arylalkylthio group or unsubstituted, and substituted with a plurality of substituents, they are the same or different from each other.
  • n is an integer from 0 to 2;
  • R 1 is C 1 to C 6 alkyl or aryl (C 1 to C 2) alkyl;
  • L 1 is C1 to C4 alkylene
  • R 2 is hydrogen, C1 to C6 alkyl or aryl (C1 to C2)alkyl
  • R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl (C1 to C2)alkyl
  • the R 2 and R 4 form a 4-6 membered ring and are linked to each other, a method for treating cancer.
  • n is an integer of 0 to 1;
  • R 1 is C1 to C6 alkyl, phenylmethyl or phenylethyl
  • L 1 is C1 to C2 alkylene
  • R 2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl
  • R 4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl
  • the R 2 and R 4 form a 5 to 6 membered ring and are linked to each other, a method for treating cancer.
  • the resistant cancer is selected from the group consisting of thyroid cancer, gastric cancer, colon cancer, ovarian cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, pancreatic cancer, head and neck cancer, rectal cancer, colon cancer, esophageal cancer and prostate cancer. At least one method of treating cancer.
  • n is an integer from 0 to 4.
  • R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl
  • R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
  • L 1 is a direct bond or C1 to C6 alkylene
  • R 2 is hydrogen, C1 to C10 alkyl or aryl (C1 to C4)alkyl
  • R 4 is hydrogen, C1 to C4 alkyl, C3 to C8 cycloalkyl or aryl (C1 to C4)alkyl
  • R 2 and R 4 form a 4 to 7-membered ring and are connected to each other;
  • the alkyl of R 1 to R 4, the arylalkyl of R 1 , R 2 and R 4 , the cycloalkyl of R 4 , and the alkylene of L 1 are each independently a C1 to C6 alkyl group, halo group, aryl group When substituted with a substituent of a group, haloalkyl group, nitro group, cyano group, alkylthio group or arylalkylthio group or unsubstituted, and substituted with a plurality of substituents, they are the same or different from each other.
  • n is an integer from 0 to 2;
  • R 1 is C 1 to C 6 alkyl or aryl (C 1 to C 2) alkyl;
  • L 1 is C1 to C4 alkylene
  • R 2 is hydrogen, C1 to C6 alkyl or aryl (C1 to C2)alkyl
  • R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl (C1 to C2)alkyl
  • the R 2 and the R 4 form a 4-6 membered ring and are connected to each other.
  • n is an integer from 0 to 1;
  • R 1 is C1 to C6 alkyl, phenylmethyl or phenylethyl
  • L 1 is C1 to C2 alkylene
  • R 2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl
  • R 4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl
  • the R 2 and the R 4 form a 5 to 6 membered ring and are connected to each other.
  • the resistant cancer is selected from the group consisting of thyroid cancer, stomach cancer, colon cancer, ovarian cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, pancreatic cancer, head and neck cancer, rectal cancer, colon cancer, esophageal cancer and prostate cancer. Use, at least one.
  • composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof can enhance the anticancer activity of an anticancer agent or radiation, and can effectively inhibit cancer by inducing proliferation of cancer cells and cell death.
  • composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof overcomes the resistance of cancers having anti-cancer agents or radiation resistance, and can effectively treat resistant cancers.
  • Preparation Example 1-1 is a compound of Preparation Example 1-1 for cancer stem cell thyroid cancer cells derived from patients who have relapsed and metastasized after taking paclitaxel; Paclitaxel alone; Or after treating the combination of paclitaxel and the compound of Preparation Example 1-1, it shows the result of measuring the change in the number of cells according to the treatment time.
  • Figure 2 is a compound of Preparation Example 1-1 for cancer stem cell thyroid cancer cells derived from patients who have relapsed and metastasized after taking paclitaxel; Paclitaxel alone; Or after treating the combination of paclitaxel and the compound of Preparation Example 1-1, it shows the result of measuring the change in cell viability at different treatment concentrations.
  • FIG. 3 is oral administration of the compound of Preparation Example 1-1 alone to a mouse model in which a patient-derived cancer stem cell thyroid cancer cell is transplanted xenograft after metastasis of paclitaxel; Intraperitoneal injection of paclitaxel alone; Or after administering the compound of Preparation Example 1-1 orally and injecting paclitaxel intraperitoneally, it shows the result of measuring the change in tumor volume over time.
  • Preparation Example 1-1 for cancer stem cell gastric cancer cells derived from patients who have relapsed and metastasized after taking irinotecan; Irinotecan alone; Or after treating a combination of irinotecan and the compound of Preparation Example 1-1, it shows the result of measuring the change in the number of cells according to the treatment time.
  • FIG. 5 is oral administration of the compound of Preparation Example 1-1 alone to a mouse model in which cancer stem cell gastric cancer cells derived from a patient relapsed and metastasized after taking irinotecan are xenografted; Oral administration of irinotecan alone; Or after the oral administration of the compound of Preparation Example 1-1 and irinotecan, it shows the result of measuring the change in the volume of the tumor over time.
  • FIG. 6 is oral administration of the compound of Preparation Example 1-1 to a mouse model in which cancer stem cell gastric cancer cells derived from a patient relapsed and metastasized after taking irinotecan are xenografted; Oral administration of irinotecan alone; Or after the oral administration of the compound of Preparation Example 1-1 and irinotecan, it shows the result of measuring the change in the weight of the tumor over time.
  • FIG. 7 is oral administration of the compound of Preparation Example 1-1 alone to a mouse model in which cancer stem cell gastric cancer cells derived from a patient who has relapsed and metastasized after taking irinotecan are xenografted; Oral administration of irinotecan alone; Or after the oral administration of the compound of Preparation Example 1-1 and irinotecan, it shows the result of measuring the change in the weight of the mouse over time.
  • FIG. 9 is an oral administration of the compound of Preparation Example 1-1 to a mouse model in which a patient-derived cancer stem cell colorectal cancer cell that has relapsed and metastasized after irradiation is xenografted; Irradiation; Or after administering the compound of Preparation Example 1-1 orally and performing a combination of irradiation, it shows the result of measuring the change in the volume of the tumor over time.
  • FIG. 10 is an oral administration of the compound of Preparation Example 1-1 to a mouse model in which a patient-derived cancer stem cell colorectal cancer cell is transplanted xenograft after remission and metastasis after irradiation; Irradiation; Or after administering the compound of Preparation Example 1-1 orally and performing a combination of irradiation, it shows the result of measuring the change in the weight of the tumor over time.
  • FIG. 11 is an oral administration of the compound of Preparation Example 1-1 to a mouse model in which a patient-derived cancer stem cell colorectal cancer cell is transplanted xenograft after remission and metastasis after irradiation; Irradiation; Or after administering the compound of Preparation Example 1-1 orally and performing a combination of irradiation, it shows the result of measuring the change in body weight of the mouse over time.
  • FIG. 12 shows that SKOV3-TR, an epithelial ovarian cancer cell line, and SKOV3-TR, which are made of resistant cell lines resistant to paclitaxel anticancer agents, do not process anything (None) or treat ethanol (Preparation compound solvent), or Preparation Example 1 2 shows the results of confirming the morphology of cells after treatment of the compound.
  • FIG. 13 shows an image 72 hours after treatment with paclitaxel alone or a combination of paclitaxel and the compound of Preparation Example 1-2 in the SKOV3-TR cell line.
  • FIG. 14 shows an image 72 hours after treatment with paclitaxel alone or a combination of paclitaxel and the compound of Preparation Example 1-2 in the SKOV3 cell line.
  • Figure 16 None in SKOV3 cell line; ethanol; And 2 ⁇ M of each of the compounds of the preparation example, and showing the number of cells after 72 hours.
  • Figure 17 None in SKOV3-TR cell line; ethanol; DMSO (paclitaxel solvent); Paclitaxel alone; And paclitaxel and the compound of the preparation example (2 ⁇ M), and the number of cells after 72 hours was treated.
  • the compound of Formula 1 and/or a pharmaceutically acceptable salt thereof of the present invention shows an inhibitory effect of the SERCA protein responsible for survival signaling in vesicle stress signaling.
  • the present invention provides a compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof:
  • R 1 may be hydrogen, C 1 to C 10 alkyl, or aryl (C 1 to C 4) alkyl.
  • R 1 may be C1 to C6 alkyl or aryl (C1 to C2) alkyl.
  • R 1 may be C1 to C6 alkyl, phenylmethyl or phenylethyl.
  • alkyl and arylalkyl of R 1 are each independently substituted or substituted with a C 1 to C 6 alkyl, halo group, aryl group, haloalkyl, nitro group, cyano group, alkylthio group, or arylalkylthio group substituent. Can be converted. If the alkyl and / or aryl of R 1 in formula (1) is replaced by a plurality of substituent, each substituent may be the same or different from each other.
  • R 1 is arylalkyl in the general formula (1) may be one the group or a phenyl group substituted with an alkyl group, a haloalkyl group, a haloalkyl group, a cyano group, a nitro in the para position.
  • alkyl refers to a straight or branched chain unsubstituted or substituted saturated hydrocarbon group, such as methyl, ethyl, propyl, isopropyl, isobutyl, sec butyl, tert butyl, pentyl, hexyl, heptyl, octyl, nonyl , Decyl, undecyl, tridecyl, pentadecyl and heptadecyl, and the like.
  • C1 to C10 alkyl means alkyl having an alkyl unit having 1 to 10 carbon atoms, and when C1 to C10 alkyl is substituted, the number of carbon atoms in the substituent is not included.
  • aryl refers to a wholly or partially unsaturated substituted or unsubstituted monocyclic or polycyclic carbon ring, and may be, for example, substituted or unsubstituted phenyl.
  • arylalkyl means alkyl substituted with an aryl group, and may be, for example, benzyl (phenylmethyl), phenylethyl or phenylpropyl.
  • Aryl (C1 to C4) alkyl means C1 to C4 alkyl substituted with an aryl group.
  • R 3 may be C1 to C6, C1 to C4, or C1 to C2 alkyl.
  • the alkyl of R 3 in Formula 1 may be substituted or unsubstituted with a substituent of C1 to C6 alkyl, halo group, aryl group, haloalkyl, nitro group, cyano group, alkylthio group or arylalkylthio group.
  • a substituent of C1 to C6 alkyl, halo group, aryl group, haloalkyl, nitro group, cyano group, alkylthio group or arylalkylthio group When alkyl of R 3 in Formula 1 is substituted with a plurality of substituents, each of the substituents may be the same or different from each other.
  • n may be an integer from 0 to 4, 0 to 2, or 0 to 1. When n in Formula 1 is 0, it means that R 3 is not substituted.
  • R 2 may be hydrogen, C 1 to C 10 alkyl, or aryl (C 1 to C 4) alkyl.
  • R 2 may be hydrogen, C 1 to C 6 alkyl, or aryl (C 1 to C 2) alkyl.
  • R 2 may be hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl.
  • alkyl and arylalkyl of R 2 are each independently substituted or substituted with a C 1 to C 6 alkyl, halo group, aryl group, haloalkyl, nitro group, cyano group, alkylthio group, or arylalkylthio group substituent. Can be converted.
  • the respective substituents may be the same or different from each other.
  • R 2 in Formula 1 is arylalkyl, an alkyl group, halo group, haloalkyl group, cyano group, nitro group, or phenyl group may be substituted at the para position.
  • R 4 may be hydrogen, C 1 to C 4 alkyl, C 3 to C 8 cycloalkyl, or aryl (C 1 to C 4) alkyl.
  • R 4 may be hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl(C1 to C2)alkyl.
  • R 4 may be hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl.
  • cycloalkyl refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group, for example, cycloalkyl can be mono or bicycle.
  • alkyl, arylalkyl and cycloalkyl of R 4 are each independently a substituent of C1 to C6 alkyl, halo group, aryl group, haloalkyl, nitro group, cyano group, alkylthio group or arylalkylthio group. It may be substituted or unsubstituted.
  • the alkyl, arylalkyl and/or cycloalkyl of R 4 in Formula 1 is substituted with a plurality of substituents, the respective substituents may be the same or different from each other.
  • R 4 when R 4 is alkyl, an alkylthio group or an arylalkylthio group may be substituted.
  • the alkylthio group may be methylthio group, ethylthio group, or the like.
  • the arylalkylthio group may be a phenylthio group, a benzylthio group, and the like.
  • R 2 and R 4 form a 4 to 7-membered ring, a 4 to 6-membered ring, or a 5 to 6-membered ring and may be connected to each other. That is, R 2 and R 4 may be connected to form a square to hexagonal ring, a square to hexagonal ring, or a pentagonal to hexagonal ring.
  • the 4 to 7-membered ring to which R 2 and R 4 are connected may contain 3 to 6 carbons.
  • the 4 to 6-membered ring to which R 2 and R 4 are connected may contain 3 to 5 carbons.
  • the 5 to 6-membered ring to which R 2 and R 4 are connected may contain 4 to 5 carbons.
  • L 1 may be a direct bond or C1 to C6, C1 to C4, or C1 to C2 alkylene.
  • alkylene refers to a divalent residue derived from a straight chain or branched hydrocarbon chain, such as methylene group, ethylene group, propylene group, isopropylene group, n-butylene group, sec-butylene group, t -Butylene group, n-pentylene group, n-hexylene group, and the like.
  • the alkylene of L 1 may be substituted or unsubstituted with a C1 to C6 alkyl group, halo group, aryl group, haloalkyl group, nitro group, cyano group, alkylthio group, or arylalkylthio group substituent. If in formula (1) alkylene L- 1 is substituted with plural substituents, respective substituents may be the same or different from each other.
  • N in Formula 1 is an integer from 0 to 4;
  • R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl;
  • R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
  • L 1 is a direct bond or C1 to C6 alkylene;
  • R 2 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl,
  • R 4 is hydrogen, C1 to C4 alkyl, C3 to C8 cycloalkyl or aryl(C1 to C4)alkyl, or R 2 and R 4 forms a 4 to 7 membered ring and is connected to each other;
  • the alkyl of R 1 to R 4, the arylalkyl of R 1 , R 2 and R 4 , the cycloalkyl of R 4 , and the alkylene of L 1 are each independently a C1 to C6 alkyl group, hal
  • N in Formula 1 is an integer from 0 to 2;
  • R 1 is hydrogen, C1 to C6 alkyl or aryl(C1 to C2)alkyl;
  • R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
  • L 1 is C1 to C4 alkylene;
  • R 2 is hydrogen, C1 to C6 alkyl or aryl(C1 to C2)alkyl,
  • R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl(C1 to C2)alkyl, or R 2 and R 4 forms a 4-6 membered ring and is connected to each other;
  • the alkyl of R 1 to R 4, the arylalkyl of R 1 , R 2 and R 4 , the cycloalkyl of R 4 , and the alkylene of L 1 are each independently a C1 to C6 alkyl group, halo group, aryl
  • N in Formula 1 is an integer from 0 to 1;
  • R 1 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl;
  • R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
  • L 1 is C1 to C2 alkylene;
  • R 2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl,
  • R 4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl, phenylethyl or naphthylmethyl, or R 2 and R 4 forms a 5-6 membered ring and is connected to each other;
  • the compound of Formula 1 may be Formula 2, Formula 5, Formula 8 to 9, and Formula 13 to 34 in Table 1 below.
  • Pharmaceutically acceptable salts can be, for example, acid addition salts or metal salts.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes It can be formed from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propyrate, oxalate, malonate, succinate, suberate, Sebacate, fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, methoxy Benzoate, phthalate, terephthalate, benzenesulfonate, ertuenesulf
  • the acid addition salt of the compound represented by the formula (1) can be obtained by dissolving the compound in an excess aqueous acid solution and precipitating the salt with a hydrating organic solvent such as methanol, ethanol, acetone or acetonitrile. .
  • a hydrating organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • the metal salt can be sodium, potassium or calcium salt.
  • Metal salts can be prepared using bases, for example, alkali metal or alkaline earth metal salts dissolve the compound in excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filter the compound salt at cost and evaporate the filtrate and/or Or it can be obtained by drying.
  • the compound of Formula 1 and/or a pharmaceutically acceptable salt thereof may serve as an inhibitor of the SERCA protein responsible for survival signaling in vesicle stress signaling.
  • the present invention provides a pharmaceutical composition for enhancing anticancer activity comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • the anti-cancer activity enhancement may be an anti-cancer agent or radiation enhancing anti-cancer activity.
  • composition of the present invention can enhance the effect on chemotherapy, chemotherapy, radiotherapy, or immunotherapy with anticancer agents.
  • a “anti-cancer treatment regimen” is a method for treating cancer, for example, surgical resection, chemotherapy with anti-cancer agents, radiation therapy, or immunotherapy.
  • treatment refers to any act of suspected disease and the symptoms of the developing individual are improved or beneficially altered.
  • composition of the present invention can be used as an anti-cancer adjuvant for anti-cancer therapy.
  • the anti-cancer agent may be at least one selected from the group consisting of taxane-based anti-cancer agents and camptothecin-based anti-cancer agents.
  • the taxane-based anticancer agent may be at least one selected from the group consisting of paclitaxel, docetaxel and cabazitaxel.
  • the camptothecin-based anticancer agent may be at least one selected from the group consisting of irinotecan, topotecan and belotecane.
  • composition of the present invention may be a pharmaceutical composition for enhancing anticancer activity against resistant cancer.
  • composition of the present invention can increase the susceptibility of cancer cells to anti-cancer treatment regimens, and can overcome the resistance of resistant cancers.
  • the term “increased susceptibility of cancer cells” is equal to or higher than the concentration showing the effect of suppressing growth, etc. against cancer cells that are not resistant, and showing the effect of suppressing the growth and apoptosis of cancer cells that acquired resistance. It means reaching the degree of ascending.
  • resistant cancer refers to a cancer in which the symptoms of cancer are not improved, alleviated, relieved or treated by anti-cancer therapy. Resistant cancer may be resistant to a specific anti-cancer treatment regimen from the beginning, or may not initially exhibit resistance, but may be resistant to the same treatment regimen due to gene mutations in cancer cells due to long-term treatment.
  • the resistant cancer may be a cancer resistant to radiation therapy through radiation, that is, a cancer resistant to radiation.
  • Resistant cancer may be a cancer resistant to chemotherapy using an anticancer agent, that is, a cancer resistant to an anticancer agent.
  • the cancer resistant to the anticancer agent may be a cancer resistant to at least one of the taxane-based anticancer agent and the camptothecin-based anticancer agent.
  • Resistant cancer to taxane-based anticancer agents may be generated by inhibiting cancer cell killing effects by taxane-based anticancer agents by survival signaling proteins such as NF- ⁇ B or GRP78.
  • the pharmaceutical composition of the present invention seems to overcome resistance to taxane-based anti-cancer agents by inhibiting the expression or activity of survival signaling proteins such as NF- ⁇ B or GRP78.
  • Resistant cancer to camptothecin-based anticancer agents may be caused by inhibition of cancer cell killing effects by camptothecin-based anticancer agents by survival signaling proteins such as PARP or NF- ⁇ B.
  • the pharmaceutical composition of the present invention seems to overcome resistance to camptothecin-based anticancer agents by inhibiting the expression or activity of survival signaling proteins such as PARP or NF- ⁇ B.
  • the cancer resistant to taxane-based anti-cancer agents and/or camptothecin-based anti-cancer agents may be generated by inhibiting cancer cell killing effects by over-expression and/or excessive activation of the SERCA protein responsible for survival signaling in endoplasmic reticulum stress signaling. That is, the pharmaceutical composition of the present invention capable of inhibiting the expression or activity of the SERCA protein as an inhibitor of the SERCA protein can overcome resistance to taxane-based anti-cancer agents and/or camptothecin-based anti-cancer agents.
  • taxane-based anticancer agent and camptothecin-based anticancer agent are the same as described above.
  • Resistant cancer may be at least one selected from the group consisting of thyroid cancer, stomach cancer, colon cancer, ovarian cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, pancreatic cancer, head and neck cancer, rectal cancer, colon cancer, esophageal cancer, and prostate cancer. These may be cancers caused by resistance by at least one of taxane-based anti-cancer agents and camptothecin-based anti-cancer agents.
  • composition of the present invention may be administered in combination with an anticancer agent, and in this case, may exhibit an anticancer adjuvant effect that overcomes resistance to anticancer agents or radiation.
  • composition of the present invention may further include a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and an anticancer agent.
  • the additional anticancer agent included nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nilotinib, semasanib, bosutinib, axitinib , Macitinib, cediranib, restautinib, trastuzumab, gefitinib, bortezomib, sunitinib, pazopanib, toseranib, nintedanib, regorafenib, cemaksanib, tibozanib, Ponatinib, carbozantinib carboplatin, sorafenib, renbatinib, bevacizumab, cisplatin, cetuximab, biscumalbum, asparaginase, tretinoin,
  • composition of the present invention may further include at least one of a taxane-based anticancer agent and a camptothecin-based anticancer agent, in addition to the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • composition of the present invention may further include at least one selected from the group consisting of paclitaxel, docetaxel and cabazitaxel.
  • composition of the present invention may further include at least one selected from the group consisting of irinotecan, topotecan and belotane.
  • composition of the present invention may further include at least one selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, irinotecan, topotecan, and velotecan.
  • composition of the present invention is a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; and at least one of a taxane-based anticancer agent and a camptothecin-based anticancer agent; In addition, other anticancer agents may be further included.
  • anti-cancer drugs include nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nilotinib, semasanib, and conservative Tinib, axitinib, macitinib, cediranib, restautinib, trastuzumab, gefitinib, bortezomib, sunitinib, pazopanib, toseranib, nintdanib, regorafenib, cemakanib , Tivozanib, ponatinib, carbozantinib carboplatin, sorafenib, renbatinib, bevacizumab, cisplatin, cetuxim
  • composition of the present invention may exhibit a better anti-cancer activity-enhancing effect by further comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; and at least one of taxane-based anti-cancer agents and camptothecin-based anti-cancer agents; and other anti-cancer agents. have.
  • the pharmaceutical composition of the present invention is a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and an anti-cancer agent from 1:0.001 to 1:1000, 1:0.01 to 1:100, 1:0.1 to 1:50 or 1:0.1 to 1:20 molar concentration ratio.
  • the pharmaceutical composition of the present invention may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages.
  • the pharmaceutical composition of the present invention may be used by formulating in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and injections.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers can be binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, fragrances, etc., when administered orally, in the case of injections, buffers, preservatives, painless agents, Solubilizers, isotonic agents, stabilizers, etc. can be used in combination, and for topical administration, bases, excipients, lubricants, preservatives, etc. can be used.
  • the formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier, for example, tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., when administered orally. It may be prepared in the form, and in the case of an injection, it may be prepared in unit dosage ampoules or multiple dosage forms. In addition, the formulation of the pharmaceutical composition of the present invention may be prepared as a solution, suspension, tablet, capsule, sustained release preparation, and the like.
  • a pharmaceutically acceptable carrier for example, tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc.
  • Carriers, excipients and diluents for formulation are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers or preservatives.
  • the route of administration of the pharmaceutical composition of the present invention is not limited to these, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or Workplace included.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, an external skin or intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection may be selected.
  • the dosage of the pharmaceutical composition of the present invention varies depending on the patient's condition and body weight, the degree of disease, the drug form, the route and duration of administration, and may be appropriately selected by those skilled in the art.
  • the pharmaceutical composition of the present invention may be administered at 0.0001 to 1000 mg/kg or 0.001 to 500 mg/kg per day.
  • the pharmaceutical composition of the present invention may be administered once a day, or may be divided into several times. The above dosage does not limit the scope of the present invention in any way.
  • the present invention provides the use of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the treatment of resistant cancer.
  • Resistant cancer the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is the same as the above, detailed description is omitted.
  • the present invention provides a method for treating cancer comprising administering a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject with resistant cancer.
  • administration refers to the introduction of a given substance into an individual in a suitable way.
  • Resistant cancer the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is the same as the above, detailed description is omitted.
  • Subject with resistant cancer refers to an individual who develops or has a high likelihood of developing resistant cancer and needs appropriate treatment.
  • an anti-cancer therapy for example, surgical resection therapy, chemotherapy with an anti-cancer agent, It may be an individual who has undergone radiation therapy or immunotherapy, but has developed resistance to it and has relapsed.
  • Subjects with resistant cancer may include humans, cows, dogs, guinea pigs, rabbits, chickens or insects.
  • the present invention comprises the steps of administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject with resistant cancer; And irradiating radiation.
  • Resistant cancer a subject with resistant cancer, a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof is the same as described above, and detailed description is omitted.
  • Irradiation may be applied to any radiation method that has been conventionally used for radiation treatment of cancer or a radiation method for cancer to be developed in the future.
  • the synergistic effect is given to the growth inhibition and/or the induction of death of cancer cells or cancer stem cells, thereby effectively preventing or preventing cancer. Not only can it be treated, it can further prevent radiation resistance, cancer metastasis, or cancer recurrence.
  • 2-ethyl benzofuran (1.0 eq.) was added to methylene chloride (MC), cooled to 0 °C, maintained at 0 °C, and tin (IV) chloride (1.5 eq.) and dichloromethyl methyl ether (1.5 eq.) were added. After the order was added, the mixture was stirred for 1 hour. The reaction was confirmed, and the reaction was terminated using an aqueous solution of ammonium chloride and methylene chloride. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica chromatography to obtain 2-ethylbenzofuran-3-carbaldehyde.
  • benzyl 1-((tert-butoxycarbonyl)glycyl)-4-((2-ethylbenzofuran-3-yl)methyl)piperazine-2-carboxylate obtained through step 8 at room temperature was dichloromethane (5.0 Volume), trichloroacetic acid (2.0 vol) was added and stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was neutralized with an aqueous sodium bicarbonate solution, and extracted with methylene chloride. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain benzyl 4-((2-ethylbenzofuran-3-yl)methyl)-1-glycylpiperazine-2-carboxylate.
  • step 1 Synthesis in the same manner as in Production Example 1-1, in step 1 (Scheme 1), instead of ethyl iodide as a reactant, methyl iodide was used to obtain a compound of Formula 28.
  • step 1 Synthesis in the same manner as in Production Example 1-1, in step 1 (Scheme 1), instead of ethyl iodide as a reactant, hexyl bromide was used to obtain a compound of Formula 30.
  • step 1 Synthesis in the same manner as in Preparation Example 1-1, in step 1 (Scheme 1), instead of ethyl iodide as a reactant, benzyl bromide was used to obtain a compound of Formula 31.
  • step 1 Synthesis in the same manner as in Production Example 1-1, in step 1 (Reaction Scheme 1), 4-chlorobenzyl bromide was used instead of ethyl iodide as a reactant to obtain a compound of Formula 32.
  • step 1 Synthesis in the same manner as in Preparation Example 1-1, in step 1 (Scheme 1), instead of ethyl iodide, a reactant, phenylethyl bromide was used to obtain a compound of Formula 34.
  • the change in cell viability according to the treatment concentration of paclitaxel, the compound of Preparation Example 1-1, and the compound combination of paclitaxel and Preparation Example 1-1 is shown in FIG. 1.
  • the change in cell viability according to the treatment concentration of the paclitaxel, the compound of Preparation Example 1-1, and combinations thereof was measured and the results are shown in FIG. 2.
  • the patient-derived cancer stem cell thyroid cancer cells that were relapsed and metastasized were cultured in-vitro, and then cells cultured in the sub left flank of BALB/c nude female mice were 2.0 X 10 7 cells/mouse. It was injected to be.
  • mice After 7 days, after grouping 10 animals, each group was administered orally with the compound of Preparation Example 1-1 (60 mg/kg) alone; Intraperitoneal injection of paclitaxel (25 mg/kg) alone; Alternatively, after oral administration of the compound of Preparation Example 1-1 (27 mg/kg) and intraperitoneal injection of paclitaxel (11 mg/kg), mice are euthanized and the volume change of the tumor is measured daily using a caliper for 60 days. The results are shown in Fig. 3. The tumor volume was evaluated using Equation 1 below.
  • Tumor volume L ⁇ S 2 /2
  • L means the longest diameter and S means the shortest diameter.
  • the patient-derived cancer stem cell colorectal cancer cells which were relapsed and metastasized, were cultured in vitro, and cells cultured under the upper left flank of BALB/c nude female mice were 2.0 X 10 7 cells/mouse. It was injected to be.
  • each group was administered orally with the compound of Preparation Example 1-1 (60 mg/kg); Faxitron X-ray (Faxitro Bioptics, AZ, USA) examined at a intensity of 5 Gy;
  • the compound of Preparation Example 1-1 27 mg/kg was administered orally and the X-ray was irradiated to a strength of 5 Gy, the mice were euthanized and the volume change of the tumor was measured daily using a caliper for 40 days. , The results are shown in FIG. 9.
  • the tumor volume was calculated by Equation 1 above.
  • the weight of the tumor was measured, and the result is shown in FIG. 10, and the weight of the mouse was measured for 41 days, and the result is shown in FIG. 11.
  • Preparation Example Compound a compound or a salt prepared by Preparation Examples 1-1 to 31 (hereinafter, Preparation Example Compound) was used, and derived from SKOV3, an epithelial ovarian cancer cell line, and Then, a cell experiment was conducted on SKOV3-TR, which was made of a resistant cell line resistant to paclitaxel anticancer agents.
  • each of the compounds of the preparation example was pretreated for 4 hours at 2 ⁇ M, followed by treatment of paclitaxel with 5 ⁇ M in the SKOV3-TR cell line and 0.2 ⁇ M in the SKOV3 cell line.
  • the number of living cells was measured through Image J analysis 72 hours after paclitaxel or preparation compounds were treated alone or in combination with each of paclitaxel and preparation compounds.
  • FIG. 12 shows images captured 24 hours, 48 hours, and 72 hours after the treatment of None, ethanol, and the compound of Preparation Example 1-2 (L19001, 2 ⁇ M).
  • the effects of paclitaxel on cancer cell death were evaluated after pretreatment of the compounds of the preparations 4 hours before treatment with paclitaxel.
  • paclitaxel treatment it was confirmed that the number of living cells decreased due to cell death induction and cell growth inhibition in SKOV3-TR and SKOV3.
  • the cell number was measured after 72 hours after treating each of the compounds of the preparation example with SKOV3-TR and SKOV3 cell lines by 2 ⁇ M.
  • the cell viability was not significantly affected in SKOV3-TR and SKOV3.
  • 15 and 16 show the number of cells after 72 hours after treatment of None, ethanol, and compounds of the preparation example in the SKOV3-TR and SKOV3 cell lines.
  • the effect of paclitaxel on cancer cell death was evaluated after pretreatment with 2 ⁇ M of the preparation compounds 4 hours before treatment with paclitaxel.
  • the number of cells decreased due to the cell death induction and cell growth inhibition phenomenon in SKOV3-TR and SKOV3 when paclitaxel treatment was performed after pretreatment of the preparation example compounds.
  • the phenomenon in which the number of cells decreases by pretreatment of the preparation compounds is more pronounced without exception.
  • 17 and 18 show the number of cells 72 hours after paclitaxel treatment after pretreatment with each of None, DMSO, ethanol, paclitaxel alone and the compounds of Preparation Examples in the SKOV3-TR and SKOV3 cell lines.

Abstract

La présente invention concerne un nouveau composé et une composition pharmaceutique le comprenant pour renforcer l'activité anticancéreuse, et plus spécifiquement, un composé représenté par la formule chimique 1 ou un sel pharmaceutiquement acceptable de celui-ci, qui permet de traiter efficacement le cancer en renforçant l'activité anticancéreuse d'un agent ou d'un rayonnement anticancéreux, en supprimant la prolifération de cellules cancéreuses et en induisant l'apoptose de celles-ci. [[Formule chimique 1] Dans la formule chimique 1 : n est un nombre entier de 0 à 4; R1 représente hydrogène, un alkyle en C1-C10 ou un arylalkyle en C1-C4; R3 représente un alkyle en C1-C6, les radicaux R3, si une pluralité de ceux-ci sont présents, étant identiques ou différents les uns des autres; L1 représente une liaison directe ou un alkylène en C1-C6; R2 représente un atome d'hydrogène, un alkyle en C1-C10 ou un arylalkyle en C1-C4; et R4 représente un atome d'hydrogène, un alkyle en C1-C4, un cycloalkyle en C3-C8 ou un arylalkyle en C1-C4, ou bien R2 et R4 sont liés l'un à l'autre et forment un cycle à 4 à 7 chaînons.
PCT/KR2019/018660 2018-12-27 2019-12-27 Nouveau composé et composition pharmaceutique le comprenant pour renforcer l'activité anticancéreuse WO2020139044A1 (fr)

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AU2019416623A AU2019416623B2 (en) 2018-12-27 2019-12-27 Novel compound and pharmaceutical composition comprising same for enhancing anticancer activity
US17/418,323 US20220064171A1 (en) 2018-12-27 2019-12-27 Novel compound and pharmaceutical composition comprising same for enhancing anticancer activity
BR112021012639-2A BR112021012639A2 (pt) 2018-12-27 2019-12-27 Novo composto e composição farmacêutica compreendendo o mesmo para intensificar atividade anticâncer
JP2021536764A JP7195027B2 (ja) 2018-12-27 2019-12-27 新規の化合物およびこれを含む抗癌活性増進用薬学組成物
CN201980086606.2A CN113260365A (zh) 2018-12-27 2019-12-27 新型化合物及包含其的用于增强抗癌活性的药学组合物
EP19904270.6A EP3903786A4 (fr) 2018-12-27 2019-12-27 Nouveau composé et composition pharmaceutique le comprenant pour renforcer l'activité anticancéreuse
CA3124938A CA3124938A1 (fr) 2018-12-27 2019-12-27 Nouveau compose et composition pharmaceutique le comprenant pour renforcer l'activite anticancereuse

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