WO2020139044A1 - Novel compound and pharmaceutical composition comprising same for enhancing anticancer activity - Google Patents

Novel compound and pharmaceutical composition comprising same for enhancing anticancer activity Download PDF

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Publication number
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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French (fr)
Korean (ko)
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박기청
정재호
김석모
유태희
윤여진
김병모
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홀로스메딕 주식회사
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Priority to BR112021012639-2A priority Critical patent/BR112021012639A2/en
Priority to EP19904270.6A priority patent/EP3903786A4/en
Priority to AU2019416623A priority patent/AU2019416623B2/en
Priority to US17/418,323 priority patent/US12139491B2/en
Priority to CN201980086606.2A priority patent/CN113260365A/en
Priority to CA3124938A priority patent/CA3124938C/en
Priority to JP2021536764A priority patent/JP7195027B2/en
Priority claimed from KR1020190176706A external-priority patent/KR102468480B1/en
Publication of WO2020139044A1 publication Critical patent/WO2020139044A1/en

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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.

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Abstract

The present invention relates to a novel compound and a pharmaceutical composition comprising same for enhancing anticancer activity, and more specifically, by comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof, the anticancer activity of an anticancer agent or radiation can be enhanced, and by suppressing the proliferation of cancer cells and inducing apoptosis thereof, cancer can be treated effectively. [Chemical formula 1] In the chemical formula 1: n is an integer of 0 to 4; R1 is hydrogen, C1-C10 alkyl, or aryl(C1-C4)alkyl; R3 is C1-C6 alkyl, wherein the R3, if a plurality thereof is present, are identical or different from each other; L1 is a direct bond or C1-C6 alkylene; R2 is hydrogen, C1-C10 alkyl, or aryl(C1-C4)alkyl; and R4 is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl, or aryl(C1-C4)alkyl, or R2 and R4 are connected to each other, forming a 4- to 7-membered ring.

Description

신규한 화합물 및 이를 포함하는 항암 활성 증진용 약학 조성물Novel compounds and pharmaceutical compositions for enhancing anticancer activity
본 발명은 신규한 화합물 및 이를 포함하는 항암 활성 증진용 약학 조성물에 관한 것이다.The present invention relates to a novel compound and a pharmaceutical composition for enhancing anticancer activity comprising the same.
암은 전세계적으로 가장 보편적인 사망 원인 중의 하나로, 사망 원인의 약 12%를 차지하고 있다.Cancer is one of the most common causes of death worldwide, accounting for about 12% of deaths.
대표적인 항암 요법인 화학 요법(chemotherapy)은, 단독으로 또는 방사능 요법과 같은 다른 치료법과 조합하여 현재 암을 치료하기 위한 가장 효율적인 치료법으로 사용되고 있다. 그러나, 화학 요법에서 암 치료 약물의 효능은 암세포를 죽일 수 있는 능력에 따르나, 약물 사용 시 암 세포뿐만 아니라 일반적인 세포에도 작용할 수 있다는 문제가 있다.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. However, 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.
한편, 암 줄기세포(cancer stem cell)가 무제한 재생 능력을 가진 암 세포로서, 줄기세포에서 종양이 기원할 것이라는 가설은 90년대 말 급성 골수성 백혈병에서 암 줄기세포가 될 수 있는 세포를 면역억제 쥐에 이식하여 사람의 백혈병이 쥐에서 재현됨이 발표되면서 확고하게 되었고, 이후 유방암에서 암 줄기세포를 증명하면서 고형 암종에서도 줄기세포의 존재를 확신하게 되었다.On the other hand, the hypothesis that 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.
암 줄기세포는 자기 재생 능력이 있고 다른 세포로 분화할 수 있는 능력도 지니는 세포로, 암 재발과 전이의 원인으로 작용한다. 특정 환자군은 암 줄기세포가 활성화되면서 강한 항암제 저항성을 나타내게 되어 기존 항암요법으로는 치료하기 어려운 난치성 암 환자로 분류된다. 악성 종양이 보이는 다양한 이질성은 줄기세포의 다양한 분화성과 일치하며, 많은 표적 치료에도 불구하고 끊임없이 발현되는 암 세포의 약물 저항성은 줄기세포의 기본 특성과 일치한다.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.
암 줄기세포는 새로운 표적 치료 분야가 될 수 있으며, 정상 줄기세포에는 손상을 주지 않으면서 암 줄기세포만을 표적으로 하는 치료를 효율적으로 수행하기 위해서는 암 줄기세포의 유지와 조절에 중요한 분자 생물학적인 특성이나 그 조절 경로에 대한 지식과 이해가 필요하다.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.
암 줄기세포 가설에 근거하여 여러 치료방법들이 고안되었는데, 그 중 많이 알려진 방법은 암 줄기세포의 자가재생 경로를 이용하는 방법이다. 이러한 치료에서 중요한 점은 정상 줄기세포의 자가재생은 유지하면서 암 줄기세포의 자가 재생만을 표적으로 해야 하는 것이다. 예로서 Notch 신호는 감마 세크레타제(gamma secretase)라는 효소에 의해 진행되는데, 이에 대한 억제제(gamma secretase inhibitor)를 Notch1이 과발현된 유방암에 사용하면 종양 억제 효과를 달성할 수 있다. Hedgehog 신호체계를 표적으로 할 경우에도 항암효과를 보인다는 최근 보고가 있는데, Hedgehog 억제제인 사이클로파민(cyclopamine)을 종양을 이종이식(tumor xenograft)한 동물에 투여했을 때 극적으로 종양이 위축되었다는 것이다. 그 밖에도, PI3K/AKT, MAPK, JAK2/STAT3 신호 기전(signaling pathway)과 관련 있다고 알려져 있다.Various treatment methods have been devised based on the cancer stem cell hypothesis, and a well-known method is a method of using a self-renewal pathway of cancer stem cells. An important point in this treatment is that only autologous regeneration of cancer stem cells should be targeted while maintaining autologous regeneration of normal stem cells. For example, the Notch signal is progressed by an enzyme called gamma secretase. When an inhibitor for this is used in breast cancer overexpressed with Notch1, tumor suppression effect can be achieved. Targeting the Hedgehog signaling system has also reported anti-cancer effects, and the tumor has contracted dramatically when the tumor was injected with a tumor xenograft administered with the Hedgehog inhibitor cyclopamine. In addition, it is known to be involved in PI3K/AKT, MAPK, and JAK2/STAT3 signaling pathways.
이와 같이 암 줄기세포의 직접적인 타겟 유전자를 억제하는 실험으로 암 줄기세포를 억제하거나 암 줄기세포의 상위 신호전달 단백질을 억제하여 암 줄기세포를 억제하는 연구들이 다수 진행되고 있다. 그러나 현재까지 암 줄기세포를 직접적으로 타겟팅하는 항암제나 천연물 유래 추출물의 연구는 거의 없는 실정이며, 대부분의 종양 환자에 있어서 종양유전자의 변이나 단백질의 변이로 인해 타겟팅 실험에 많은 어려움이 존재한다.In this way, as an experiment to suppress the target gene of cancer stem cells directly, many studies have been conducted to suppress cancer stem cells by inhibiting cancer stem cells or by suppressing the upper signaling protein of cancer stem cells. However, there have been few studies on anticancer agents or extracts derived from natural products that directly target cancer stem cells, and there are many difficulties in targeting experiments due to mutations in oncogenes or proteins in most tumor patients.
한편, 암 줄기세포가 갖는 항암제 저항성의 핵심 원인이 세포 내 칼슘이온의 수송과 저장에 관여하는 단백질인 'SERCA(sarco/endoplasmic reticulum calcium ATPase)'에 있다는 것을 밝힌 종래 연구 결과가 있다. On the other hand, there is a result of a conventional study that revealed that a key cause of cancer stem cell resistance to anticancer drugs is SERCA (sarco/endoplasmic reticulum calcium ATPase), a protein involved in the transport and storage of calcium ions in cells.
일반 암세포는 항암제를 투여하면 과도한 스트레스가 유발되고 소포체(endoplasmic reticulum, ER)에서 칼슘 이온이 과다 분비되며 분비된 칼슘이온이 미토콘드리아에 쌓이면서 암 세포의 자살로 이어지는 반면, 암 줄기세포는 항암제 투여 시 과도한 칼슘 이온의 분비를 줄이고, 동시에 과도하게 분비된 칼슘이온을 다시 소포체로 되돌려 넣을 수 있는 SERCA 발현을 늘려 칼슘이온 농도를 조절하면서 생존하는 것으로 밝혀졌다. 즉, SERCA 단백질은 소포체 스트레스 신호전달 과정에서 생존 신호전달을 위한 역할을 할 수 있다.When cancer cells are administered with an anticancer agent, excessive stress is induced, endoplasmic reticulum (ER) over-calculates calcium ions, and secreted calcium ions accumulate in the mitochondria, leading to suicide of cancer cells, whereas cancer stem cells are excessive It has been found that by reducing the secretion of calcium ions and simultaneously increasing the expression of SERCA capable of returning excessively secreted calcium ions back to the vesicles, the calcium ion concentration was found to survive. That is, the SERCA protein may play a role for survival signaling in the endoplasmic reticulum stress signaling process.
암 줄기세포가 갖는 항암제 저항성을 나타나게 하는 원인인 SERCA 단백질을 타겟으로 하는 억제제로 작용할 수 있는 물질을 개발하여 암 줄기세포의 성장을 선택적으로 억제할 수 있다면, 항암 약물에 의한 화학 요법의 효능을 증가시켜 더 낮은 용량의 약물로도 우수한 항암 효과를 나타나게 할 수 있을 것이다.If you can selectively inhibit the growth of cancer stem cells by developing a substance that can act as an inhibitor targeting the SERCA protein, which causes cancer stem cells to exhibit anti-cancer drug resistance, increase the efficacy of chemotherapy by anticancer drugs This may lead to superior anticancer effects even with lower doses of the drug.
본 발명은 신규한 화합물을 제공하는 것을 목적으로 한다.The present invention aims to provide novel compounds.
본 발명은 항암 활성 증진용 약학 조성물을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a pharmaceutical composition for enhancing anticancer activity.
1. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염:1. A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2019018660-appb-img-000001
Figure PCTKR2019018660-appb-img-000001
상기 화학식 1에서, In Chemical Formula 1,
n은 0 내지 4의 정수이고;n is an integer from 0 to 4;
R 1은 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이고;R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl;
R 3은 C1 내지 C6의 알킬이고, 상기 R 3이 복수 개인 경우 이들은 서로 동일하거나 상이하며;R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
L 1은 직접결합이거나 C1 내지 C6의 알킬렌이고;L 1 is a direct bond or C1 to C6 alkylene;
R 2는 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이며, R 4는 수소, C1 내지 C4의 알킬, C3 내지 C8의 사이클로알킬 또는 아릴(C1 내지 C4)알킬이거나,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 2와 R 4가 4 내지 7원환을 이루며 서로 연결되고;R 2 and R 4 form a 4 to 7-membered ring and are connected to each other;
상기 R 1 내지 R 4의 알킬과, 상기 R 1, R 2 및 R 4의 아릴알킬, 상기 R 4의 사이클로알킬, 상기 L 1의 알킬렌은 각각 독립적으로 C1 내지 C6의 알킬기, 할로기, 아릴기, 할로알킬기, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환되고, 복수 개의 치환기로 치환되는 경우, 이들은 서로 동일하거나 상이함.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.
2. 위 1에 있어서, 상기 n은 0 내지 2의 정수이고;2. In the above 1, wherein n is an integer from 0 to 2;
상기 R 1은 C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이며;R 1 is C 1 to C 6 alkyl or aryl (C 1 to C 2) alkyl;
상기 L 1은 C1 내지 C4의 알킬렌이고;L 1 is C1 to C4 alkylene;
상기 R 2는 수소, C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이고, 상기 R 4는 수소, C1 내지 C4의 알킬, C3 내지 C6의 사이클로알킬 또는 아릴(C1 내지 C2)알킬이거나,R 2 is hydrogen, C1 to C6 alkyl or aryl (C1 to C2)alkyl, and R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl (C1 to C2)alkyl,
상기 R 2와 상기 R 4가 4 내지 6원환을 이루며 서로 연결되는, 화합물 또는 이의 약학적으로 허용 가능한 염.The compound or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 form a 4 to 6-membered ring and are linked to each other.
3. 위 1에 있어서, 상기 n은 0 내지 1의 정수이고;3. In the above 1, wherein n is an integer from 0 to 1;
상기 R 1은 C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이며;R 1 is C1 to C6 alkyl, phenylmethyl or phenylethyl;
상기 L 1은 C1 내지 C2의 알킬렌이고;L 1 is C1 to C2 alkylene;
상기 R 2는 수소, C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이고, 상기 R 4는 수소, C1 내지 C2의 알킬, C5 내지 C6의 사이클로알킬, 페닐메틸 또는 나프틸메틸이거나,R 2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl, and R 4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl,
상기 R 2와 상기 R 4가 5 내지 6원환을 이루며 서로 연결되는, 화합물 또는 이의 약학적으로 허용 가능한 염.The compound or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 form a 5 to 6 membered ring and are linked to each other.
4. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 항암 활성 증진용 약학 조성물:4. A pharmaceutical composition for enhancing anticancer activity comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2019018660-appb-img-000002
Figure PCTKR2019018660-appb-img-000002
상기 화학식 1에서, In Chemical Formula 1,
n은 0 내지 4의 정수이고;n is an integer from 0 to 4;
R 1은 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이고;R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl;
R 3은 C1 내지 C6의 알킬이고, 상기 R 3이 복수 개인 경우 이들은 서로 동일하거나 상이하며;R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
L 1은 직접결합이거나 C1 내지 C6의 알킬렌이고;L 1 is a direct bond or C1 to C6 alkylene;
R 2는 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이며, R 4는 수소, C1 내지 C4의 알킬, C3 내지 C8의 사이클로알킬 또는 아릴(C1 내지 C4)알킬이거나,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 2와 R 4가 4 내지 7원환을 이루며 서로 연결되고;R 2 and R 4 form a 4 to 7-membered ring and are connected to each other;
상기 R 1 내지 R 4의 알킬과, 상기 R 1, R 2 및 R 4의 아릴알킬, 상기 R 4의 사이클로알킬, 상기 L 1의 알킬렌은 각각 독립적으로 C1 내지 C6의 알킬기, 할로기, 아릴기, 할로알킬기, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환되고, 복수 개의 치환기로 치환되는 경우, 이들은 서로 동일하거나 상이함.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.
5. 위 4에 있어서, 상기 n은 0 내지 2의 정수이고;5. In the above 4, wherein n is an integer from 0 to 2;
상기 R 1은 C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이며;R 1 is C 1 to C 6 alkyl or aryl (C 1 to C 2) alkyl;
상기 L 1은 C1 내지 C4의 알킬렌이고;L 1 is C1 to C4 alkylene;
상기 R 2는 수소, C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이고, 상기 R 4는 수소, C1 내지 C4의 알킬, C3 내지 C6의 사이클로알킬 또는 아릴(C1 내지 C2)알킬이거나,R 2 is hydrogen, C1 to C6 alkyl or aryl (C1 to C2)alkyl, and R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl (C1 to C2)alkyl,
상기 R 2와 상기 R 4가 4 내지 7원환을 이루며 서로 연결되는, 약학 조성물.The R 2 and R 4 form a 4 to 7-membered ring and are connected to each other, a pharmaceutical composition.
6. 위 4에 있어서, 상기 n은 0 내지 1의 정수이고;6. In the above 4, wherein n is an integer from 0 to 1;
상기 R 1은 C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이며;R 1 is C1 to C6 alkyl, phenylmethyl or phenylethyl;
상기 L 1은 C1 내지 C2의 알킬렌이고;L 1 is C1 to C2 alkylene;
상기 R 2는 수소, C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이고, 상기 R 4는 수소, C1 내지 C2의 알킬, C5 내지 C6의 사이클로알킬, 페닐메틸 또는 나프틸메틸이거나,R 2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl, and R 4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl,
상기 R 2와 상기 R 4가 5 내지 6원환을 이루며 서로 연결되는, 약학 조성물.The R 2 and R 4 form a 5 to 6 membered ring and are connected to each other, a pharmaceutical composition.
7. 위 4에 있어서, 상기 항암 활성 증진은 항암제 또는 방사선의 항암 활성 증진인, 약학 조성물.7. The method of 4 above, wherein the anti-cancer activity enhancement is an anti-cancer agent or radiation anti-cancer activity enhancement, pharmaceutical composition.
8. 위 7에 있어서, 상기 항암제는 탁센 계열 항암제 및 캄프토테신 계열 항암제 중 적어도 하나인, 약학 조성물.8. The pharmaceutical composition of 7 above, wherein the anticancer agent is at least one of a taxane-based anticancer agent and a camptothecin-based anticancer agent.
9. 위 8에 있어서, 상기 탁센 계열 항암제는 파클리탁셀, 도세탁셀 및 카바지탁셀로 이루어진 군에서 선택된 적어도 하나인, 약학 조성물.9. The pharmaceutical composition of 8 above, wherein the taxane-based anticancer agent is at least one selected from the group consisting of paclitaxel, docetaxel and cabazitaxel.
10. 위 8에 있어서, 상기 캄프토테신 계열 항암제는 이리노테칸, 토포테칸 및 벨로테칸으로 이루어진 군에서 선택된 적어도 하나인, 약학 조성물.10. The pharmaceutical composition of 8 above, wherein the camptothecin-based anti-cancer agent is at least one selected from the group consisting of irinotecan, topotecan and belotane.
11. 위 4에 있어서, 내성암에 대한 항암 활성 증진용인 약학 조성물.11. The pharmaceutical composition according to the above 4, which is for enhancing anticancer activity against resistant cancer.
12. 위 11에 있어서, 상기 내성암은 탁센 계열 항암제 및 캄프토테신 계열 항암제 중 적어도 하나에 대한 내성암인, 약학 조성물.12. The pharmaceutical composition of 11 above, wherein the resistant cancer is resistant to at least one of taxane-based anti-cancer agents and camptothecin-based anti-cancer agents.
13. 위 11에 있어서, 상기 내성암은 방사선에 대한 내성암인, 약학 조성물.13. The pharmaceutical composition of 11 above, wherein the resistant cancer is radiation resistant cancer.
14. 위 11에 있어서, 상기 내성암은 갑성선암, 위암, 대장암, 난소암, 유방암, 폐암, 카포시 육종, 자궁경부암, 췌장암, 두경부암, 직장암, 결장암, 식도암 및 전립선암으로 이루어진 군에서 선택된 적어도 하나인, 약학 조성물.14. In the above 11, 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.
15. 위 4에 있어서, 항암제를 더 포함하는 약학 조성물.15. The pharmaceutical composition according to the above 4, further comprising an anti-cancer agent.
16. 위 15에 있어서, 상기 항암제는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 마시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 파조파닙, 토세라닙, 닌테다닙, 레고라페닙, 세막사닙, 티보자닙, 포나티닙, 카보잔티닙 카보플라틴, 소라페닙, 렌바티닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 5-플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 케페시타빈, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 올라파립, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴, 보리노스텟, 엔티노스텟 및 카르무스틴으로 이루어진 군에서 선택된 적어도 하나를 포함하는, 약학 조성물.16. The method of 15 above, wherein 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, hydroxycarbamide, dasatinib, estra Mustin, gemtuzumab ozogamycin, britumomab tucetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium chitosan nitrate, gemcitabine, doxyple Luridine, pemetrexed, tegapur, capecitabine, gimeracin, oteracyl, azacitidine, methotrexate, uracil, cytarabine, 5-fluorouracil, fludagabine, enositabine, flutamide , Kefecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmophor, raltitrexed, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinbla Stin, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsiroli Mousse, temozolomide, busulfan, ifosfamide, cyclophosphamide, melphalan, altretmine, dacarbazine, chiotepa, nimustine, chlorambucil, mitoractol, leucovorin, tretonin, exme Stan, aminoglutethimide, anagrelide, olaparib, navelvin, padrazol, tamoxifen, toremifen, testolactone, anastrozole, letrozole, borozol, bicalutamide, lomustine, borino A pharmaceutical composition comprising at least one selected from the group consisting of stet, entinosted and carmustine.
17. 위 15에 있어서, 상기 항암제는 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염과 1:0.001 내지 1:1000의 몰 농도비로 포함되는, 약학 조성물.17. The pharmaceutical 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.
18. 내성암이 있는 대상에게 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 치료적 유효량을 투여하는 단계를 포함하는 암 치료 방법:18. 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:
[화학식 1][Formula 1]
Figure PCTKR2019018660-appb-img-000003
Figure PCTKR2019018660-appb-img-000003
상기 화학식 1에서, In Chemical Formula 1,
n은 0 내지 4의 정수이고;n is an integer from 0 to 4;
R 1은 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이고;R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl;
R 3은 C1 내지 C6의 알킬이고, 상기 R 3이 복수 개인 경우 이들은 서로 동일하거나 상이하며;R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
L 1은 직접결합이거나 C1 내지 C6의 알킬렌이고;L 1 is a direct bond or C1 to C6 alkylene;
R 2는 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이며, R 4는 수소, C1 내지 C4의 알킬, C3 내지 C8의 사이클로알킬 또는 아릴(C1 내지 C4)알킬이거나,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 2와 R 4가 4 내지 7원환을 이루며 서로 연결되고;R 2 and R 4 form a 4 to 7-membered ring and are connected to each other;
상기 R 1 내지 R 4의 알킬과, 상기 R 1, R 2 및 R 4의 아릴알킬, 상기 R 4의 사이클로알킬, 상기 L 1의 알킬렌은 각각 독립적으로 C1 내지 C6의 알킬기, 할로기, 아릴기, 할로알킬기, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환되고, 복수 개의 치환기로 치환되는 경우, 이들은 서로 동일하거나 상이함.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.
19. 위 18에 있어서, 상기 n은 0 내지 2의 정수이고;19. In the above 18, n is an integer from 0 to 2;
상기 R 1은 C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이며;R 1 is C 1 to C 6 alkyl or aryl (C 1 to C 2) alkyl;
상기 L 1은 C1 내지 C4의 알킬렌이고;L 1 is C1 to C4 alkylene;
상기 R 2는 수소, C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이고, 상기 R 4는 수소, C1 내지 C4의 알킬, C3 내지 C6의 사이클로알킬 또는 아릴(C1 내지 C2)알킬이거나,R 2 is hydrogen, C1 to C6 alkyl or aryl (C1 to C2)alkyl, and R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl (C1 to C2)alkyl,
상기 R 2와 상기 R 4가 4 내지 6원환을 이루며 서로 연결되는, 암 치료 방법.The R 2 and R 4 form a 4-6 membered ring and are linked to each other, a method for treating cancer.
20. 위 18에 있어서, 상기 n은 0 내지 1의 정수이고;20. In the above 18, the n is an integer of 0 to 1;
상기 R 1은 C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이며;R 1 is C1 to C6 alkyl, phenylmethyl or phenylethyl;
상기 L 1은 C1 내지 C2의 알킬렌이고;L 1 is C1 to C2 alkylene;
상기 R 2는 수소, C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이고, 상기 R 4는 수소, C1 내지 C2의 알킬, C5 내지 C6의 사이클로알킬, 페닐메틸 또는 나프틸메틸이거나,R 2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl, and R 4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl,
상기 R 2와 상기 R 4가 5 내지 6원환을 이루며 서로 연결되는, 암 치료 방법.The R 2 and R 4 form a 5 to 6 membered ring and are linked to each other, a method for treating cancer.
21. 위 18에 있어서, 상기 내성암은 탁산 계열 항암제 및 캄토테신 계열 항암제 중 적어도 하나에 대한 내성암인, 암 치료 방법.21. The method of 18, wherein the resistant cancer is resistant to at least one of taxane-based anti-cancer agents and camptothecin-based anti-cancer agents.
22. 위 18에 있어서, 상기 내성암은 방사선에 대한 내성암인, 암 치료 방법.22. The method of 18, wherein the resistant cancer is radiation resistant cancer.
23. 위 18에 있어서, 상기 내성암은 갑성선암, 위암, 대장암, 난소암, 유방암, 폐암, 카포시 육종, 자궁경부암, 췌장암, 두경부암, 직장암, 결장암, 식도암 및 전립선암으로 이루어진 군에서 선택된 적어도 하나인, 암 치료 방법.23. In the above 18, 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.
24. 내성암 치료에 사용하기 위한 하기 화학식 1로 표시되는 화합물의 용도:24. Use of a compound represented by Formula 1 for use in the treatment of resistant cancer:
[화학식 1][Formula 1]
Figure PCTKR2019018660-appb-img-000004
Figure PCTKR2019018660-appb-img-000004
상기 화학식 1에서, In Chemical Formula 1,
n은 0 내지 4의 정수이고;n is an integer from 0 to 4;
R 1은 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이고;R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl;
R 3은 C1 내지 C6의 알킬이고, 상기 R 3이 복수 개인 경우 이들은 서로 동일하거나 상이하며;R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
L 1은 직접결합이거나 C1 내지 C6의 알킬렌이고;L 1 is a direct bond or C1 to C6 alkylene;
R 2는 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이며, R 4는 수소, C1 내지 C4의 알킬, C3 내지 C8의 사이클로알킬 또는 아릴(C1 내지 C4)알킬이거나,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 2와 R 4가 4 내지 7원환을 이루며 서로 연결되고;R 2 and R 4 form a 4 to 7-membered ring and are connected to each other;
상기 R 1 내지 R 4의 알킬과, 상기 R 1, R 2 및 R 4의 아릴알킬, 상기 R 4의 사이클로알킬, 상기 L 1의 알킬렌은 각각 독립적으로 C1 내지 C6의 알킬기, 할로기, 아릴기, 할로알킬기, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환되고, 복수 개의 치환기로 치환되는 경우, 이들은 서로 동일하거나 상이함.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.
25. 위 24에 있어서, 상기 n은 0 내지 2의 정수이고;25. In the above 24, wherein n is an integer from 0 to 2;
상기 R 1은 C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이며;R 1 is C 1 to C 6 alkyl or aryl (C 1 to C 2) alkyl;
상기 L 1은 C1 내지 C4의 알킬렌이고;L 1 is C1 to C4 alkylene;
상기 R 2는 수소, C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이고, 상기 R 4는 수소, C1 내지 C4의 알킬, C3 내지 C6의 사이클로알킬 또는 아릴(C1 내지 C2)알킬이거나,R 2 is hydrogen, C1 to C6 alkyl or aryl (C1 to C2)alkyl, and R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl (C1 to C2)alkyl,
상기 R 2와 상기 R 4가 4 내지 6원환을 이루며 서로 연결되는, 용도.The R 2 and the R 4 form a 4-6 membered ring and are connected to each other.
26. 위 24에 있어서, 상기 n은 0 내지 1의 정수이고;26. In the above 24, wherein n is an integer from 0 to 1;
상기 R 1은 C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이며;R 1 is C1 to C6 alkyl, phenylmethyl or phenylethyl;
상기 L 1은 C1 내지 C2의 알킬렌이고;L 1 is C1 to C2 alkylene;
상기 R 2는 수소, C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이고, 상기 R 4는 수소, C1 내지 C2의 알킬, C5 내지 C6의 사이클로알킬, 페닐메틸 또는 나프틸메틸이거나,R 2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl, and R 4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl,
상기 R 2와 상기 R 4가 5 내지 6원환을 이루며 서로 연결되는, 용도.The R 2 and the R 4 form a 5 to 6 membered ring and are connected to each other.
27. 위 24에 있어서, 상기 내성암은 탁산 계열 항암제 및 캄토테신 계열 항암제 중 적어도 하나에 대한 내성암인, 용도.27. The use according to the above 24, wherein the resistant cancer is resistant to at least one of taxane-based anti-cancer agents and camptothecin-based anti-cancer agents.
28. 위 24에 있어서, 상기 내성암은 방사선에 대한 내성암인, 용도.28. The use according to the above 24, wherein the resistant cancer is radiation resistant cancer.
29. 위 24에 있어서, 상기 내성암은 갑성선암, 위암, 대장암, 난소암, 유방암, 폐암, 카포시 육종, 자궁경부암, 췌장암, 두경부암, 직장암, 결장암, 식도암 및 전립선암으로 이루어진 군에서 선택된 적어도 하나인, 용도.29. In the above 24, 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.
본 발명 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물은 항암제 또는 방사선의 항암 활성을 증진시킬 수 있으며, 암세포의 증식 억제 및 세포 사멸 등을 유도하여 효과적으로 암을 치료할 수 있다.The 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.
본 발명 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물은 항암제 또는 방사선에 대한 내성을 갖는 암의 내성을 극복하고, 효과적으로 내성암을 치료할 수 있다.The 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.
도 1은 파클리탁셀의 복용 후 재발 및 전이된 환자 유래 암 줄기세포성 갑상선 암 세포에 대하여 제조예 1-1의 화합물 단독; 파클리탁셀 단독; 또는 파클리탁셀과 제조예 1-1의 화합물의 조합을 처리한 뒤, 처리 시간에 따른 세포 수의 변화를 측정한 결과를 나타낸 것이다.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.
도 2는 파클리탁셀의 복용 후 재발 및 전이된 환자 유래 암 줄기세포성 갑상선 암 세포에 대하여 제조예 1-1의 화합물 단독; 파클리탁셀 단독; 또는 파클리탁셀과 제조예 1-1의 화합물의 조합을 처리한 뒤, 처리 농도에 다른 세포 생존율의 변화를 측정한 결과를 나타낸 것이다.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.
도 3은 파클리탁셀의 복용 후 재발 및 전이된 환자 유래 암 줄기세포성 갑상선 암 세포를 이종 이식한 마우스 모델에 제조예 1-1의 화합물 단독을 경구 투여; 파클리탁셀 단독을 복강 내 주사; 또는 제조예 1-1의 화합물을 경구 투여하고 파클리탁셀을 복강 내 주사한 뒤, 시간의 경과에 따른 종양의 부피 변화를 측정한 결과를 나타낸 것이다.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.
도 4는 이리노테칸의 복용 후 재발 및 전이된 환자 유래 암 줄기세포성 위암 세포에 대하여 제조예 1-1의 화합물 단독; 이리노테칸 단독; 또는 이리노테칸과 제조예 1-1의 화합물의 조합을 처리한 뒤, 처리 시간에 따른 세포 수의 변화를 측정한 결과를 나타낸 것이다.4 is a compound of 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.
도 5는 이리노테칸의 복용 후 재발 및 전이된 환자 유래 암 줄기세포성 위암 세포를 이종 이식한 마우스 모델에 제조예 1-1의 화합물 단독을 경구 투여; 이리노테칸 단독을 경구 투여; 또는 제조예 1-1의 화합물과 이리노테칸을 경구 투여한 뒤, 시간의 경과에 따른 종양의 부피 변화를 측정한 결과를 나타낸 것이다.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.
도 6은 이리노테칸의 복용 후 재발 및 전이된 환자 유래 암 줄기세포성 위암 세포를 이종 이식한 마우스 모델에 제조예 1-1의 화합물 단독을 경구 투여; 이리노테칸 단독을 경구 투여; 또는 제조예 1-1의 화합물과 이리노테칸을 경구 투여한 뒤, 시간의 경과에 따른 종양의 무게 변화를 측정한 결과를 나타낸 것이다.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.
도 7은 이리노테칸의 복용 후 재발 및 전이된 환자 유래 암 줄기세포성 위암 세포를 이종 이식한 마우스 모델에 제조예 1-1 의 화합물 단독을 경구 투여; 이리노테칸 단독을 경구 투여; 또는 제조예 1-1의 화합물과 이리노테칸을 경구 투여한 뒤, 시간의 경과에 따른 마우스의 몸무게 변화를 측정한 결과를 나타낸 것이다.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.
도 8은 방사선 조사 후 재발 및 전이된 환자 유래 암 줄기세포성 대장암 세포에 대하여 제조예 1-1의 화합물 단독 처리; 방사선 조사; 또는 제조예 1-1의 화합물의 처리와 방사선 조사의 조합을 수행한 뒤, 처리 시간에 따른 세포 수의 변화를 측정한 결과를 나타낸 것이다.8 is a treatment with a compound of Preparation Example 1-1 for cancer stem cell colorectal cancer cells derived from patients who have relapsed and metastasized after irradiation; Irradiation; Or after performing the combination of the treatment of the compound of Preparation Example 1-1 and irradiation, it shows the result of measuring the change in the number of cells according to the treatment time.
도 9는 방사선 조사 후 재발 및 전이된 환자 유래 암 줄기세포성 대장암 세포를 이종 이식한 마우스 모델에 제조예 1-1의 화합물 단독을 경구 투여; 방사선을 조사; 또는 제조예 1-1의 화합물을 경구 투여하고 방사선 조사의 조합을 수행한 뒤, 시간의 경과에 따른 종양의 부피 변화를 측정한 결과를 나타낸 것이다.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.
도 10은 방사선 조사 후 재발 및 전이된 환자 유래 암 줄기세포성 대장암 세포를 이종 이식한 마우스 모델에 제조예 1-1의 화합물 단독을 경구 투여; 방사선을 조사; 또는 제조예 1-1의 화합물을 경구 투여하고 방사선 조사의 조합을 수행한 뒤, 시간의 경과에 따른 종양의 무게 변화를 측정한 결과를 나타낸 것이다.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.
도 11은 방사선 조사 후 재발 및 전이된 환자 유래 암 줄기세포성 대장암 세포를 이종 이식한 마우스 모델에 제조예 1-1의 화합물 단독을 경구 투여; 방사선을 조사; 또는 제조예 1-1의 화합물을 경구 투여하고 방사선 조사의 조합을 수행한 뒤, 시간의 경과에 따른 마우스의 몸무게 변화를 측정한 결과를 나타낸 것이다.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.
도 12는 상피성 난소암 세포주인 SKOV3와 파클리탁셀 항암제에 저항성을 갖는 내성 세포주로 제작된 SKOV3-TR 각각에 아무것도 처리하지 않거나(None), 에탄올(제조예 화합물 용매)을 처리하거나, 제조예 1-2의 화합물을 처리한 후 세포의 형태를 확인한 결과를 나타낸 것이다.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.
도 13은 SKOV3-TR 세포주에 파클리탁셀 단독 또는 파클리탁셀과 제조예 1-2의 화합물의 조합을 처리하고 72시간 후의 이미지를 나타낸다. 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.
도 14는 SKOV3 세포주에 파클리탁셀 단독 또는 파클리탁셀과 제조예 1-2의 화합물의 조합을 처리하고 72시간 후의 이미지를 나타낸다.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.
도 15는 SKOV3-TR 세포주에서 None; 에탄올; 및 제조예의 화합물들 각각을 2μM씩 처리하고 72시간 후의 세포수를 나타낸 것이다.15 shows None in SKOV3-TR cell line; ethanol; And 2 μM of each of the compounds of the preparation example, and showing the number of cells after 72 hours.
도 16은 SKOV3 세포주에서 None; 에탄올; 및 제조예의 화합물들 각각을 2μM씩 처리하고 72시간 후의 세포수를 나타낸 것이다.Figure 16 None in SKOV3 cell line; ethanol; And 2 μM of each of the compounds of the preparation example, and showing the number of cells after 72 hours.
도 17은 SKOV3-TR 세포주에서 None; 에탄올; DMSO (파클리탁셀 용매); 파클리탁셀 단독; 및 파클리탁셀 및 제조예의 화합물들 각각(2μM)의 조합을 처리하고 72시간 후의 세포수를 나타낸 것이다.Figure 17 None in SKOV3-TR cell line; ethanol; DMSO (paclitaxel solvent); Paclitaxel alone; And paclitaxel and the compound of the preparation example (2 μM), and the number of cells after 72 hours was treated.
도 18은 SKOV3 세포주에서 None; 에탄올; DMSO; 파클리탁셀 단독; 및 파클리탁셀 및 제조예의 화합물들 각각(2μM)의 조합을 처리하고 72시간 후의 세포수를 나타낸 것이다.18 shows None in the SKOV3 cell line; ethanol; DMSO; Paclitaxel alone; And paclitaxel and the compound of the preparation example (2 μM), and the number of cells after 72 hours was treated.
본 발명의 하기 화학식 1의 화합물 및/또는 이의 약학적으로 허용 가능한 염은 소포체 스트레스 신호전달에서 생존 신호전달을 담당하는 SERCA 단백질의 억제 효과를 나타내는 것이다.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.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다:The present invention provides a compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2019018660-appb-img-000005
.
Figure PCTKR2019018660-appb-img-000005
.
화학식 1에서 R 1은 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬일 수 있다.In Formula 1, R 1 may be hydrogen, C 1 to C 10 alkyl, or aryl (C 1 to C 4) alkyl.
화학식 1에서 R 1은 C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬일 수 있다.In Formula 1, R 1 may be C1 to C6 alkyl or aryl (C1 to C2) alkyl.
화학식 1에서 R 1은 C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸일 수 있다.In Formula 1, R 1 may be C1 to C6 alkyl, phenylmethyl or phenylethyl.
화학식 1에서 R 1의 알킬 및 아릴알킬은 각각 독립적으로 C1 내지 C6의 알킬, 할로기, 아릴기, 할로알킬, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환될 수 있다. 화학식 1에서 R 1의 알킬 및/또는 아릴알킬이 복수 개의 치환기로 치환되는 경우, 각 치환기들은 서로 동일하거나 상이할 수 있다.In Formula 1, 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.
화학식 1에서 R 1이 아릴알킬인 경우, 파라 위치에 알킬기, 할로기, 할로알킬기, 시아노기, 나이트로기 또는 페닐기가 치환된 것일 수 있다.If 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.
용어 “알킬”은 직쇄 또는 분지쇄의 비치환 또는 치환된 포화 탄화수소기를 의미하며, 예컨대, 메틸, 에틸, 프로필, 이소프로필, 이소부틸, sec 부틸, tert 부틸, 펜틸, 헥실, 헵틸, 옥틸, 노닐, 데실, 운데실, 트리데실, 펜타데실 및 헵타데실 등을 포함한다. C1 내지 C10의 알킬은 탄소수 1 내지 10의 알킬 유니트를 가지는 알킬을 의미하며, C1 내지 C10의 알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다.The term “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.
용어 “아릴”은 전체적으로 또는 부분적으로 불포화된 치환 또는 비치환된 모노사이클릭 또는 폴리사이클릭 탄소 고리를 의하며, 예컨대, 치환 또는 비치환된 페닐일 수 있다.The term “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.
용어 “아릴알킬”은 아릴기로 치환된 알킬을 의미하며, 예컨대, 벤질(페닐메틸), 페닐에틸 또는 페닐프로필일 수 있다. 아릴(C1 내지 C4)알킬은 아릴기로 치환된 C1 내지 C4의 알킬을 의미한다.The term “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.
화학식 1에서 R 3은 C1 내지 C6, C1 내지 C4 또는 C1 내지 C2의 알킬일 수 있다.In Formula 1, R 3 may be C1 to C6, C1 to C4, or C1 to C2 alkyl.
화학식 1에서 R 3의 알킬은 C1 내지 C6의 알킬, 할로기, 아릴기, 할로알킬, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환될 수 있다. 화학식 1에서 R 3의 알킬이 복수 개의 치환기로 치환되는 경우, 각 치환기들은 서로 동일하거나 상이할 수 있다.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. 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.
화학식 1에서 n은 0 내지 4, 0 내지 2 또는 0 내지 1의 정수일 수 있다. 화학식 1의 n이 0인 경우, R 3로 치환되지 않은 것을 의미한다.In Formula 1, 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.
화학식 1에서 R 2는 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬일 수 있다.In Formula 1, R 2 may be hydrogen, C 1 to C 10 alkyl, or aryl (C 1 to C 4) alkyl.
화학식 1에서 R 2는 수소, C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬일 수 있다.In Formula 1, R 2 may be hydrogen, C 1 to C 6 alkyl, or aryl (C 1 to C 2) alkyl.
화학식 1에서 R 2는 수소, C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸일 수 있다.In Formula 1, R 2 may be hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl.
화학식 1에서 R 2의 알킬 및 아릴알킬은 각각 독립적으로 C1 내지 C6의 알킬, 할로기, 아릴기, 할로알킬, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환될 수 있다. 화학식 1에서 R 2의 알킬 및/또는 아릴알킬이 복수 개의 치환기로 치환되는 경우, 각 치환기들은 서로 동일하거나 상이할 수 있다.In Formula 1, 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. When the alkyl and/or arylalkyl of R 2 in Formula 1 is substituted with a plurality of substituents, the respective substituents may be the same or different from each other.
화학식 1에서 R 2가 아릴알킬인 경우, 파라 위치에 알킬기, 할로기, 할로알킬기, 시아노기, 나이트로기 또는 페닐기가 치환된 것일 수 있다.When 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.
화학식 1에서 R 4는 수소, C1 내지 C4의 알킬, C3 내지 C8의 사이클로알킬 또는 아릴(C1 내지 C4)알킬일 수 있다.In Formula 1, 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.
화학식 1에서 R 4는 수소, C1 내지 C4의 알킬, C3 내지 C6의 사이클로알킬 또는 아릴(C1 내지 C2)알킬일 수 있다.In Formula 1, R 4 may be hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl(C1 to C2)alkyl.
화학식 1에서 R 4는 수소, C1 내지 C2의 알킬, C5 내지 C6의 사이클로알킬, 페닐메틸 또는 나프틸메틸일 수 있다.In Formula 1, R 4 may be hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl.
용어 "사이클로알킬"은 비방향족, 포화 또는 부분적으로 불포화 탄화수소 고리기를 의미하며, 예컨대, 사이클로알킬은 모노 또는 바이사이클일 수 있다.The term "cycloalkyl" refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group, for example, cycloalkyl can be mono or bicycle.
화학식 1에서 R 4의 알킬, 아릴알킬 및 사이클로알킬은 각각 독립적으로 C1 내지 C6의 알킬, 할로기, 아릴기, 할로알킬, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환될 수 있다. 화학식 1에서 R 4의 알킬, 아릴알킬 및/또는 사이클로알킬이 복수 개의 치환기로 치환되는 경우, 각 치환기들은 서로 동일하거나 상이할 수 있다.In Formula 1, 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. When 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.
화학식 1에서 R 4가 알킬인 경우, 알킬싸이오기 또는 아릴알킬싸이오기가 치환된 것일 수 있다.In Formula 1, when R 4 is alkyl, an alkylthio group or an arylalkylthio group may be substituted.
예를 들어, 알킬싸이오기는 메틸싸이오기, 에틸싸이오기 등일 수 있다.For example, the alkylthio group may be methylthio group, ethylthio group, or the like.
예를 들어, 아릴알킬싸이오기는 페닐싸이오기, 벤질싸이오기 등일 수 있다.For example, the arylalkylthio group may be a phenylthio group, a benzylthio group, and the like.
화학식 1에서 R 2 및 R 4는 4 내지 7원환, 4 내지 6원환 또는 5 내지 6원환을 이루며 서로 연결될 수 있다. 즉, R 2 및 R 4는 연결되어 사각 내지 칠각고리, 사각 내지 육각고리 또는 오각 내지 육각고리를 형성하는 것일 수 있다.In Formula 1, 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.
R 2 및 R 4가 연결된 4 내지 7원환은 3 내지 6개의 탄소를 포함할 수 있다. The 4 to 7-membered ring to which R 2 and R 4 are connected may contain 3 to 6 carbons.
R 2 및 R 4가 연결된 4 내지 6원환은 3 내지 5개의 탄소를 포함할 수 있다.The 4 to 6-membered ring to which R 2 and R 4 are connected may contain 3 to 5 carbons.
R 2 및 R 4가 연결된 5 내지 6원환은 4 내지 5개의 탄소를 포함할 수 있다.The 5 to 6-membered ring to which R 2 and R 4 are connected may contain 4 to 5 carbons.
화학식 1에서 L 1은 직접결합이거나 C1 내지 C6, C1 내지 C4 또는 C1 내지 C2의 알킬렌일 수 있다.In Formula 1, L 1 may be a direct bond or C1 to C6, C1 to C4, or C1 to C2 alkylene.
용어 “알킬렌”은 직쇄형 또는 분지형의 탄화수소 사슬로부터 유도되는 2가의 잔기를 의미하며, 예컨대, 메틸렌기, 에틸렌기, 프로필렌기, 이소프로필렌기, n-부틸렌기, sec-부틸렌기, t-부틸렌기, n-펜틸렌기, n-헥실렌기 등일 수 있다.The term “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.
L 1의 알킬렌은 C1 내지 C6의 알킬기, 할로기, 아릴기, 할로알킬기, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환될 수 있다. 화학식 1에서 L- 1의 알킬렌이 복수 개의 치환기로 치환되는 경우, 각 치환기들은 서로 동일하거나 상이할 수 있다.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.
화학식 1에서 n은 0 내지 4의 정수이고; R 1은 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이고; R 3은 C1 내지 C6의 알킬이고, 상기 R 3이 복수 개인 경우 이들은 서로 동일하거나 상이하며; L 1은 직접결합이거나 C1 내지 C6의 알킬렌이고; R 2는 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이며, R 4는 수소, C1 내지 C4의 알킬, C3 내지 C8의 사이클로알킬 또는 아릴(C1 내지 C4)알킬이거나, R 2와 R 4가 4 내지 7원환을 이루며 서로 연결되고; 상기 R 1 내지 R 4의 알킬과, 상기 R 1, R 2 및 R 4의 아릴알킬, 상기 R 4의 사이클로알킬, 상기 L 1의 알킬렌은 각각 독립적으로 C1 내지 C6의 알킬기, 할로기, 아릴기, 할로알킬기, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환되고, 복수 개의 치환기로 치환되는 경우, 각 치환기들은 서로 동일하거나 상이할 수 있다.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, halo group, aryl group When a group, a haloalkyl group, a nitro group, a cyano group, an alkylthio group or an arylalkylthio group is substituted or unsubstituted, and substituted with a plurality of substituents, the respective substituents may be the same or different from each other.
화학식 1에서 n은 0 내지 2의 정수이고; R 1은 수소, C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이며; R 3은 C1 내지 C6의 알킬이고, 상기 R 3이 복수 개인 경우 이들은 서로 동일하거나 상이하며; L 1은 C1 내지 C4의 알킬렌이고; R 2는 수소, C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이고, R 4는 수소, C1 내지 C4의 알킬, C3 내지 C6의 사이클로알킬 또는 아릴(C1 내지 C2)알킬이거나, R 2와 R 4가 4 내지 6원환을 이루며 서로 연결되고; 상기 R 1 내지 R 4의 알킬과, 상기 R 1, R 2 및 R 4의 아릴알킬, 상기 R 4의 사이클로알킬, 상기 L 1의 알킬렌은 각각 독립적으로 C1 내지 C6의 알킬기, 할로기, 아릴기, 할로알킬기, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환되고, 복수 개의 치환기로 치환되는 경우, 각 치환기들은 서로 동일하거나 상이할 수 있다.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 group When a group, a haloalkyl group, a nitro group, a cyano group, an alkylthio group or an arylalkylthio group is substituted or unsubstituted, and substituted with a plurality of substituents, the respective substituents may be the same or different from each other.
화학식 1에서 n은 0 내지 1의 정수이고; R 1은 수소, C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이며; R 3은 C1 내지 C6의 알킬이고, 상기 R 3이 복수 개인 경우 이들은 서로 동일하거나 상이하며; L 1은 C1 내지 C2의 알킬렌이고; R 2는 수소, C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이고, R 4는 수소, C1 내지 C2의 알킬, C5 내지 C6의 사이클로알킬, 페닐메틸, 페닐에틸 또는 나프틸메틸이거나, R 2와 R 4가 5 내지 6원환을 이루며 서로 연결되고; 상기 R 1 내지 R 4의 알킬, 상기 R 1, R 2 및 R 4의 페닐메틸, 페닐에틸 및 나프틸메틸, 상기 R 4의 사이클로알킬, 상기 L 1의 알킬렌은 각각 독립적으로 C1 내지 C6의 알킬기, 할로기, 아릴기, 할로알킬기, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환되고, 복수 개의 치환기로 치환되는 경우, 각 치환기들은 서로 동일하거나 상이할 수 있다.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 alkyl of R 1 to R 4 , the phenylmethyl, phenylethyl and naphthylmethyl of R 1 , R 2 and R 4 , the cycloalkyl of R 4 and the alkylene of L 1 are each independently of C1 to C6. When substituted or unsubstituted with a substituent of an alkyl group, halo group, aryl group, haloalkyl group, nitro group, cyano group, alkylthio group or arylalkylthio group, when substituted with a plurality of substituents, the respective substituents are the same or different from each other can do.
화학식 1의 화합물은 하기 표 1의 화학식 2, 화학식 5, 화학식 8 내지 9, 화학식 13 내지 34일 수 있다.The compound of Formula 1 may be Formula 2, Formula 5, Formula 8 to 9, and Formula 13 to 34 in Table 1 below.
화학식Chemical formula 화학구조Chemical structure 화학식Chemical formula 화학구조Chemical structure
22
Figure PCTKR2019018660-appb-img-000006
Figure PCTKR2019018660-appb-img-000006
 		55
Figure PCTKR2019018660-appb-img-000007
Figure PCTKR2019018660-appb-img-000007
88
Figure PCTKR2019018660-appb-img-000008
Figure PCTKR2019018660-appb-img-000008
 		99
Figure PCTKR2019018660-appb-img-000009
Figure PCTKR2019018660-appb-img-000009
1313
Figure PCTKR2019018660-appb-img-000010
Figure PCTKR2019018660-appb-img-000010
 		1414
Figure PCTKR2019018660-appb-img-000011
Figure PCTKR2019018660-appb-img-000011
1515
Figure PCTKR2019018660-appb-img-000012
Figure PCTKR2019018660-appb-img-000012
 		1616
Figure PCTKR2019018660-appb-img-000013
Figure PCTKR2019018660-appb-img-000013
1717
Figure PCTKR2019018660-appb-img-000014
Figure PCTKR2019018660-appb-img-000014
 		1818
Figure PCTKR2019018660-appb-img-000015
Figure PCTKR2019018660-appb-img-000015
1919
Figure PCTKR2019018660-appb-img-000016
Figure PCTKR2019018660-appb-img-000016
 		2020
Figure PCTKR2019018660-appb-img-000017
Figure PCTKR2019018660-appb-img-000017
2121
Figure PCTKR2019018660-appb-img-000018
Figure PCTKR2019018660-appb-img-000018
 		2222
Figure PCTKR2019018660-appb-img-000019
Figure PCTKR2019018660-appb-img-000019
2323
Figure PCTKR2019018660-appb-img-000020
Figure PCTKR2019018660-appb-img-000020
 		2424
Figure PCTKR2019018660-appb-img-000021
Figure PCTKR2019018660-appb-img-000021
2525
Figure PCTKR2019018660-appb-img-000022
Figure PCTKR2019018660-appb-img-000022
 		2626
Figure PCTKR2019018660-appb-img-000023
Figure PCTKR2019018660-appb-img-000023
2727
Figure PCTKR2019018660-appb-img-000024
Figure PCTKR2019018660-appb-img-000024
 		2828
Figure PCTKR2019018660-appb-img-000025
Figure PCTKR2019018660-appb-img-000025
2929
Figure PCTKR2019018660-appb-img-000026
Figure PCTKR2019018660-appb-img-000026
 		3030
Figure PCTKR2019018660-appb-img-000027
Figure PCTKR2019018660-appb-img-000027
3131
Figure PCTKR2019018660-appb-img-000028
Figure PCTKR2019018660-appb-img-000028
 		3232
Figure PCTKR2019018660-appb-img-000029
Figure PCTKR2019018660-appb-img-000029
3333
Figure PCTKR2019018660-appb-img-000030
Figure PCTKR2019018660-appb-img-000030
 		3434
Figure PCTKR2019018660-appb-img-000031
Figure PCTKR2019018660-appb-img-000031
약학적으로 허용 가능한 염은 예를 들어 산 부가염 또는 금속염일 수 있다. Pharmaceutically acceptable salts can be, for example, acid addition salts or metal salts.
산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 형성될 수 있다. 이러한 약학적으로 무독한 염은 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트, 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피을레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴- 1,4-디오에이트, 핵산-1，6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 를투엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β_하이드톡시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함할 수 있다. 예를 들어, 화학식 1로 표시되는 화합물의 산 부가염은 화합물을 과량의 산 수용액 중에 용해시키고, 염을 수화성 유기 용매, 예컨대 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜 수득할 수 있다.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, ertuenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β_hydroxybutyrate, glycol Rate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate. For example, 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. .
금속염은 나트륨, 칼륨 또는 칼슘염일 수 있다. 금속염은 염기를 사용하여 제조할 수 있으며, 예를 들어, 알칼리 금속 또는 알칼리 토금속 염은 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고 여액을 증발 및/또는 건조시켜 수득할 수 있다.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.
전술한 화학식 1의 화합물 및/또는 이의 약학적으로 허용 가능한 염은 소포체 스트레스 신호전달에서 생존 신호전달을 담당하는 SERCA 단백질의 억제제로서의 역할을 할 수 있다.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.
또한, 본 발명은 전술한 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 항암 활성 증진용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for enhancing anticancer activity comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염은 전술한 바와 동일하다.The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is the same as described above.
항암 활성 증진은 항암제 또는 방사선의 항암 활성 증진일 수 있다.The anti-cancer activity enhancement may be an anti-cancer agent or radiation enhancing anti-cancer activity.
본 발명 조성물은 항암제를 이용한 화학적 치료법, 방사선 치료법 또는 면역 치료법 등의 항암 치료 요법에 대한 효과를 증진시킬 수 있다.The composition of the present invention can enhance the effect on chemotherapy, chemotherapy, radiotherapy, or immunotherapy with anticancer agents.
“항암 치료 요법”은 암을 치료하기 위한 방법으로, 예컨대 외과적 절제 치료법, 항암제를 이용한 화학적 치료법, 방사선 치료법 또는 면역 치료법일 수 있다.A “anti-cancer treatment regimen” is a method for treating cancer, for example, surgical resection, chemotherapy with anti-cancer agents, radiation therapy, or immunotherapy.
용어 "치료"는 질병 의심 및 발병 개체의 증상이 호전 되거나 이롭게 변경되는 모든 행위를 의미한다.The term "treatment" refers to any act of suspected disease and the symptoms of the developing individual are improved or beneficially altered.
본 발명 조성물은 항암 치료 요법에 대한 항암 보조제로 사용될 수 있다.The composition of the present invention can be used as an anti-cancer adjuvant for anti-cancer therapy.
항암제는 탁센 계열 항암제 및 캄프토테신 계열 항암제로 이루어진 군에서 선택된 적어도 하나일 수 있다.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.
탁센 계열 항암제는 파클리탁셀, 도세탁셀 및 카바지탁셀로 이루어진 군에서 선택된 적어도 하나일 수 있다.The taxane-based anticancer agent may be at least one selected from the group consisting of paclitaxel, docetaxel and cabazitaxel.
캄프토테신 계열 항암제는 이리노테칸, 토포테칸 및 벨로테칸으로 이루어진 군에서 선택된 적어도 하나일 수 있다.The camptothecin-based anticancer agent may be at least one selected from the group consisting of irinotecan, topotecan and belotecane.
본 발명 조성물은 내성암에 대한 항암 활성 증진용인 약학 조성물일 수 있다. The composition of the present invention may be a pharmaceutical composition for enhancing anticancer activity against resistant cancer.
본 발명 조성물은 항암 치료 요법에 대한 암 세포의 감수성을 증가시킬 수 있으며, 내성암의 내성을 극복할 수 있다.The 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.
용어 “암세포의 감수성 증가”는 내성이 없는 암 세포에 대해 성장 억제 등의 효과를 보이는 농도와 비교하여, 내성을 획득한 암 세포의 성장 억제 및 세포 사멸 등의 효과를 보이는 농도가 동등하거나 그 이상으로 상승시키는 정도에 이르는 것을 의미한다.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.
용어 "내성암"이란 항암 치료 요법에 의하여 암의 증세가 호전, 완화, 경감 또는 치료 증상을 나타내지 않는 암을 의미한다. 내성암은 특정의 항암 치료 요법에 대하여 처음부터 내성을 가지는 것일 수도 있고, 최초에는 내성을 나타내지 않았으나 긴 시간의 치료로 인한 암세포 내의 유전자 변이 등으로 인해 동일한 치료 요법에 대한 내성이 나타난 것일 수도 있다.The term "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.
내성암은 방사선 조사를 통한 방사선 치료 요법에 대하여 내성을 가진 암, 즉 방사선에 대한 내성암일 수 있다.The resistant cancer may be a cancer resistant to radiation therapy through radiation, that is, a cancer resistant to radiation.
내성암은 항암제를 이용한 화학 치료 요법에 대하여 내성을 가진 암, 즉 항암제에 대한 내성암일 수 있다.Resistant cancer may be a cancer resistant to chemotherapy using an anticancer agent, that is, a cancer resistant to an anticancer agent.
예를 들어, 항암제에 대한 내성암은 탁센 계열 항암제 및 캄프토테신 계열 항암제 중 적어도 하나에 대한 내성암일 수 있다.For example, 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.
탁센 계열 항암제에 대한 내성암은 NF-κB나 GRP78 등과 같은 생존 신호전달 단백질에 의해 탁센 계열 항암제에 의한 암세포 사멸 효과가 저해되어 발생되는 것일 수 있다. 이 경우 본 발명 약학 조성물은 NF-κB나 GRP78 등과 같은 생존 신호전달 단백질의 발현이나 활성을 억제시킴으로써, 탁센 계열 항암제에 대한 내성을 극복하는 것으로 보인다. 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-κB or GRP78. In this case, 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-κB or GRP78.
캄프토테신 계열 항암제에 대한 내성암은 PARP나 NF-κB 등과 같은 생존 신호전달 단백질에 의해 캄프토테신 계열 항암제에 의한 암세포 사멸 효과가 저해되어 발생되는 것일 수 있다. 이 경우 본 발명 약학 조성물은 PARP나 NF-κB 등과 같은 생존 신호전달 단백질의 발현이나 활성을 억제시킴으로써, 캄프토테신 계열 항암제에 대한 내성을 극복하는 것으로 보인다.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-κB. In this case, 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-κB.
탁센 계열 항암제 및/또는 캄프토테신 계열 항암제에 대한 내성암은 소포체 스트레스 신호전달에서 생존 신호전달을 담당하는 SERCA 단백질의 과발현 및/또는 과도한 활성화에 의해 암세포 사멸 효과가 저해되어 발생되는 것일 수 있다. 즉, SERCA 단백질의 저해제로서 SERCA 단백질의 발현이나 활성을 억제시킬 수 있는 본 발명 약학 조성물은 탁센 계열 항암제 및/또는 캄프토테신 계열 항암제에 대한 내성을 극복할 수 있다.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.
탁센 계열 항암제 및 캄프토테신 계열 항암제에 대해서는 전술한 바와 동일하다.The taxane-based anticancer agent and camptothecin-based anticancer agent are the same as described above.
내성암은 갑성선암, 위암, 대장암, 난소암, 유방암, 폐암, 카포시 육종, 자궁경부암, 췌장암, 두경부암, 직장암, 결장암, 식도암 및 전립선암으로 이루어진 군에서 선택된 적어도 하나일 수 있다. 이들은 탁센 계열 항암제 및 캄프토테신 계열 항암제 중 적어도 하나 의해 내성이 유발된 암일 수 있다.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.
본 발명 조성물은 항암제와 함께 병용 투여될 수 있고, 이 경우 항암제 또는 방사선에 대한 내성을 극복시키는 항암 증강효과(adjuvant effect)를 나타낼 수 있다.The 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.
본 발명 조성물은 화학식 1로 표현되는 화합물 또는 이의 약학적으로 허용되는 염;과 항암제를 더 포함할 수 있다.The composition of the present invention may further include a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and an anticancer agent.
이때, 추가로 포함되는 항암제는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 마시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 파조파닙, 토세라닙, 닌테다닙, 레고라페닙, 세막사닙, 티보자닙, 포나티닙, 카보잔티닙 카보플라틴, 소라페닙, 렌바티닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 5-플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 케페시타빈, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 올라파립, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴, 보리노스텟, 엔티노스텟 및 카르무스틴으로 이루어진 군에서 선택된 적어도 하나일 수 있다.At this time, 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, hydroxycarbamide, dasatinib, estramustine , Gemtuzumab ozogamycin, britumomab tucetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium chitosan, gemcitabine, doxyfluridine , Pemetrexed, tegapur, capecitabine, gimeracin, oteracyl, azacitidine, methotrexate, uracil, cytarabine, 5-fluorouracil, fludagabine, enositabine, flutamide, ke Pecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmophor, raltitrexed, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, Teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus, Temozolomide, busulfan, iphosphamide, cyclophosphamide, melphalan, altretmine, dacarbazine, chiotepa, nimustine, chlorambucil, mitoractol, leucovorin, tretonin, exmestan, Aminoglutethimide, anagrelide, olaparib, navelbin, padrazol, tamoxifen, toremifene, testolactone, anastrozole, letrozole, borozol, bicalutamide, lomustine, boronosted, It may be at least one selected from the group consisting of entinosted and carmustine.
본 발명 조성물은 화학식 1로 표현되는 화합물 또는 이의 약학적으로 허용되는 염 외에, 탁센 계열 항암제 및 캄프토테신 계열 항암제 중 적어도 하나를 더 포함할 수 있다.The 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.
예를 들어, 본 발명 조성물은 파클리탁셀, 도세탁셀 및 카바지탁셀로 이루어진 군에서 선택된 적어도 하나를 더 포함할 수 있다.For example, the composition of the present invention may further include at least one selected from the group consisting of paclitaxel, docetaxel and cabazitaxel.
예를 들어, 본 발명 조성물은 이리노테칸, 토포테칸 및 벨로테칸으로 이루어진 군에서 선택된 적어도 하나를 더 포함할 수 있다.For example, the composition of the present invention may further include at least one selected from the group consisting of irinotecan, topotecan and belotane.
예를 들어, 본 발명 조성물은 파클리탁셀, 도세탁셀, 카바지탁셀, 이리노테칸, 토포테칸 및 벨로테칸으로 이루어진 군에서 선택된 적어도 하나를 더 포함할 수 있다.For example, the composition of the present invention may further include at least one selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, irinotecan, topotecan, and velotecan.
본 발명 조성물은 화학식 1로 표현되는 화합물 또는 이의 약학적으로 허용되는 염;과 탁센 계열 항암제 및 캄프토테신 계열 항암제 중 적어도 하나; 외에도 다른 항암제를 더 포함할 수 있다.The 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.
탁센 계열 항암제 및 캄프토테신 계열 항암제 외에 다른 항암제는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 마시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 파조파닙, 토세라닙, 닌테다닙, 레고라페닙, 세막사닙, 티보자닙, 포나티닙, 카보잔티닙 카보플라틴, 소라페닙, 렌바티닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 5-플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 케페시타빈, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 올라파립, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴, 보리노스텟, 엔티노스텟 및 카르무스틴으로 이루어진 군에서 선택된 적어도 하나 이상일 수 있다.In addition to taxane-based anti-cancer drugs and camptothecin-based anti-cancer drugs, other 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, cetuximab, biscumalbum, asparaginase, tretinoin, hydroxycarbamide, dasatti Nip, Estramustine, gemtuzumab ozogamycin, ibritomomabtucetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine , Doxyfluridine, pemetrexed, tegapur, capecitabine, gimeracin, oteracyl, azacitidine, methotrexate, uracil, cytarabine, 5-fluorouracil, fludagabine, enocitabine, Flutamide, kefecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmophor, raltitrexed, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, isida Rubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, busulfan, Iphosphamide, cyclophosphamide, melphalan, altretmine, dacarbazine, chiotepa, nimustine, chlorambucil, mitoractol, leucovorin, tretonin, exemestane, aminoglutethimide, ana Grelide, olaparib, navelvin, padrazol, tamoxifen, toremifene, testolactone, anastrozole, letrozole, borozol, bicalutamide, lomustine, vorinostat, entinostat and carmustine It may be at least one selected from the group consisting of.
본 발명 조성물은 화학식 1로 표현되는 화합물 또는 이의 약학적으로 허용되는 염;과 탁센 계열 항암제 및 캄프토테신 계열 항암제 중 적어도 하나;외에 다른 항암제를 더 포함함으로써 보다 더 우수한 항암 활성 증진 효과를 나타낼 수 있다.The 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.
본 발명 약학 조성물은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염과 항암제를 1:0.001 내지 1:1000, 1:0.01 내지 1:100, 1:0.1 내지 1:50 또는 1:0.1 내지 1:20 몰 농도비로 포함할 수 있다.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.
본 발명 약학 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태일 수 있다.The pharmaceutical composition of the present invention may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages.
본 발명의 약학 조성물은 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 주사제의 형태로 제형화하여 사용될 수 있다.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.
본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용 가능한 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등일 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다.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.
본 발명 약학 조성물의 제형은 약학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있으며, 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조될 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조될 수 있다. 또한, 본 발명 약학 조성물의 제형은 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제조될 수 있다.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.
제제화를 위한 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 광물유, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 또는 방부제 등일 수 있다.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.
본 발명 약학 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다.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.
본 발명 약학 조성물은 경구 또는 비경구로 투여될 수 있으며, 비경구 투여 시 피부 외용 또는 복강내주사, 직장내주사, 피하주사, 정맥주사, 근육내 주사 또는 흉부내 주사 주입방식이 선택될 수 있다.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.
본 발명 약학 조성물의 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 예를 들어, 본 발명 약학 조성물은 1일 0.0001 내지 1000mg/kg 또는 0.001 내지 500mg/kg으로 투여될 수 있다. 본 발명 약학 조성물의 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.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. For example, 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.
또한, 본 발명은 내성암 치료에 사용하기 위한 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 용도를 제공한다.In addition, 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.
내성암, 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염은 전술한 내용과 동일하여, 구체적인 설명은 생략한다.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.
또한, 본 발명은 내성암이 있는 대상에게 전술한 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 치료적 유효량을 투여하는 단계를 포함하는 암 치료 방법을 제공한다.In addition, 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.
용어 "투여"는 적절한 방법으로 개체에게 소정의 물질을 도입하는 것을 의미한다.The term "administration" refers to the introduction of a given substance into an individual in a suitable way.
내성암, 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염은 전술한 내용과 동일하여, 구체적인 설명은 생략한다.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.
“내성암이 있는 대상”은 내성암 암이 발병하였거나 발병 가능성이 높아 적절한 치료를 필요로 하는 개체를 의미하는 것으로, 항암 치료 요법으로, 예를 들면, 외과적 절제 치료법, 항암제를 이용한 화학적 치료법, 방사선 치료법 또는 면역 치료법을 받았지만, 이에 대하여 내성을 가져 재발한 개체일 수 있다.“Subject with resistant cancer” refers to an individual who develops or has a high likelihood of developing resistant cancer and needs appropriate treatment. As 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.
내성암이 있는 대상은 인간, 소, 개, 기니피그, 토끼, 닭 또는 곤충 등을 포함할 수 있다.Subjects with resistant cancer may include humans, cows, dogs, guinea pigs, rabbits, chickens or insects.
또한, 본 발명은 내성암이 있는 대상에게 전술한 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 투여하는 단계; 및 방사선을 조사하는 단계;를 포함하는 방사선 치료 방법을 제공한다.In addition, 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.
내성암, 내성암이 있는 대상, 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염은 전술한 내용과 동일하여, 구체적인 설명은 생략한다.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.
방사선 조사는 암의 방사선 치료를 위해 종래 사용되었던 임의의 방사선 조사 방법 또는 추후 개발되는 암에 대한 방사선 조사 방법이 모두 적용될 수 있다.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.
본 발명 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 투여와 방사선 조사를 병용 하는 경우 암 세포 또는 암 줄기세포의 성장 억제 및/또는 사멸 유도에 상승적인 효과를 부여하여 암을 효과적으로 예방 또는 치료할 수 있을 뿐만 아니라, 더 나아가서는 방사선에 대한 내성이나, 암의 전이 또는 암의 재발을 방지할 수 있다.When the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof is used in combination with irradiation, 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.
이하, 본 발명을 구체적으로 설명하기 위해 실시예를 들어 상세하게 설명하기로 한다.Hereinafter, examples will be described in detail to specifically describe the present invention.
제조예Manufacturing example
1. 제조예1-1: C101, L190311. Preparation Example 1-1: C101, L19031
아래 기재된 10 단계 반응을 거쳐 2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione(C101)을 제조하였다. 각 단계에서의 합성 방법을 아래에서 구체적으로 설명한다.Through the 10-step reaction described below, 2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione(C101) was prepared. The synthesis method at each step is specifically described below.
1) 단계 11) Step 1
[반응식 1][Scheme 1]
Figure PCTKR2019018660-appb-img-000032
Figure PCTKR2019018660-appb-img-000032
반응식 1과 같이 벤조퓨란(1.0당량)을 테트라하이드로퓨란 용매하에서 -78℃로 냉각하고 2.5M n-부틸리튬(1.2당량) 용액을 첨가하였다. -78℃를 유지하면서 1시간 교반하고 에틸아이오다이드(2.0당량)를 적가한 후, 0℃에서 1시간 교반하였다. 반응완결을 확인하고, 암모늄클로라이드수용액과 에틸아세테이트를 사용하여 반응을 종료하였다. 유기층을 증류수로 세정하고, 무수 마그네슘설페이트로 건조 후, 감압농축하였다. 잔사를 실리카크로마토그래피로 정제하여 2-에틸 벤조퓨란을 수득하였다.As shown in Scheme 1, benzofuran (1.0 eq.) was cooled to -78°C in a tetrahydrofuran solvent, and a 2.5M n-butyllithium (1.2 eq.) solution was added. The mixture was stirred for 1 hour while maintaining -78°C, ethyl iodide (2.0 eq) was added dropwise, and then stirred at 0°C for 1 hour. The reaction was confirmed, and the reaction was terminated using an aqueous solution of ammonium chloride and ethyl acetate. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica chromatography to obtain 2-ethyl benzofuran.
2) 단계 22) Step 2
[반응식 2][Scheme 2]
Figure PCTKR2019018660-appb-img-000033
Figure PCTKR2019018660-appb-img-000033
2-에틸 벤조퓨란(1.0당량)을 메틸렌클로라이드(MC)에 투입한 후, 0℃로 냉각하고, 0℃를 유지하며 틴(Ⅳ)클로라이드(1.5당량), 디클로로메틸 메틸에테르(1.5당량)를 순서대로 투입한 후, 1시간 교반하였다. 반응완결을 확인하고, 암모늄클로라이드수용액과 메틸렌클로라이드를 사용하여 반응을 종료하였다. 유기층을 증류수로 세정하고, 무수 마그네슘설페이트로 건조하고, 감압농축하였다. 잔사를 실리카크로마토그래피로 정제하여 2-ethylbenzofuran-3-carbaldehyde 를 수득하였다.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.
3) 단계 33) Step 3
[반응식 3][Scheme 3]
Figure PCTKR2019018660-appb-img-000034
Figure PCTKR2019018660-appb-img-000034
piperazine-2-carboxylic acid (1.0당량), 다이옥세인 및 증류수를 넣고, 5℃ 이하로 냉각하였다. 그 후, di-tert-butyl dicarbonate (1.1당량)를 10℃ 이하를 유지하며 투입하였다. 실온에서 5시간 교반 후, 소듐카보네이트(1.1당량)를 투입하고 5분간 교반하였다. 9-Fluorenylmethyl chloroformate (1.2당량)를 투입하고, 철야 교반 후, 감압농축 하였다. 잔사에 에틸아세테이트와 1M 염산을 넣고 pH를 2~3으로 하고, 잔사가 모두 풀릴 때까지 세차게 교반하였다. 유기층을 brine으로 세정하고, 무수 마그네슘설페이트로 건조 후, 감압 농축하였다. EA로 재결정하여 흰색 고체가루인 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid를 수득하였다.Piperazine-2-carboxylic acid (1.0 eq), dioxane and distilled water were added and cooled to 5°C or lower. Subsequently, di-tert-butyl dicarbonate (1.1 eq.) was added while maintaining below 10°C. After stirring at room temperature for 5 hours, sodium carbonate (1.1 eq.) was added and stirred for 5 minutes. 9-Fluorenylmethyl chloroformate (1.2 eq) was added, stirred overnight, and concentrated under reduced pressure. Ethyl acetate and 1M hydrochloric acid were added to the residue, and the pH was adjusted to 2-3, and the residue was stirred vigorously until all was released. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Recrystallization from EA gave white solid powder, 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid.
4) 단계 44) Step 4
[반응식 4][Scheme 4]
Figure PCTKR2019018660-appb-img-000035
Figure PCTKR2019018660-appb-img-000035
1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, 벤질 알코올(1.02당량)과 트리페닐포스핀(1.02당량)의 무수 메틸렌클로라이드로 용액을 질소기류하에서 0℃로 냉각하였다. 0℃이하를 유지하며 Diethyl Azodicarboxylate (DEAD)(1.02당량)를 투입하고 1시간 교반하였다. 물을 투입하여 20분간 세차게 교반 후, 유기층을 무수 마그네슘설페이트로 건조 후, 감압농축하였다. 잔사를 실리카크로마토그래피로 정제하여 흰색 고체가루인 1-((9H-fluoren-9-yl)methyl) 2-benzyl 4-(tert-butyl) piperazine-1,2,4-tricarboxylate를 수득하였다.Methylene anhydride of 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, benzyl alcohol (1.02 eq) and triphenylphosphine (1.02 eq) The solution with chloride was cooled to 0°C under a stream of nitrogen. Diethyl Azodicarboxylate (DEAD) (1.02 eq) was added while maintaining below 0° C. and stirred for 1 hour. After adding water and stirring vigorously for 20 minutes, the organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica chromatography to obtain a white solid powder, 1-((9H-fluoren-9-yl)methyl) 2-benzyl 4-(tert-butyl) piperazine-1,2,4-tricarboxylate.
5) 단계 55) Step 5
[반응식 5][Scheme 5]
Figure PCTKR2019018660-appb-img-000036
Figure PCTKR2019018660-appb-img-000036
반응식 5와 같이, 실온에서 1-((9H-fluoren-9-yl)methyl) 2-benzyl 4-(tert-butyl) piperazine-1,2,4-tricarboxylate 의 메틸렌클로라이드(5.0볼륨) 용액에 트리플로로아세트산(TFA)(2.0볼륨)을 첨가하고 실온에서 30분동안 교반하였다. 소듐바이카보네이트로 중화시킨 후, 메틸렌클로라이드로 추출하고, 유기층을 brine 으로 세정하였다. 무수 마그네슘설페이트로 건조하고 농축시켜, 1-((9H-fluoren-9-yl)methyl) 2-benzyl piperazine-1,2-dicarboxylate를 수득하였다.As shown in Scheme 5, triple in methylene chloride (5.0 vol) solution of 1-((9H-fluoren-9-yl)methyl) 2-benzyl 4-(tert-butyl) piperazine-1,2,4-tricarboxylate at room temperature. Loroacetic acid (TFA) (2.0 volume) was added and stirred at room temperature for 30 minutes. After neutralizing with sodium bicarbonate, it was extracted with methylene chloride, and the organic layer was washed with brine. It was dried over anhydrous magnesium sulfate and concentrated to obtain 1-((9H-fluoren-9-yl)methyl) 2-benzyl piperazine-1,2-dicarboxylate.
6) 단계 66) Step 6
[반응식 6][Scheme 6]
Figure PCTKR2019018660-appb-img-000037
Figure PCTKR2019018660-appb-img-000037
실온에서 단계 2를 통해 수득한 2-ethylbenzofuran-3-carbaldehyde(1.0당량)와 단계 5를 통해 수득한 1-((9H-fluoren-9-yl)methyl) 2-benzyl piperazine-1,2-dicarboxylate(1.2당량)를 1,2-디클로로에탄(DCE)에 투입 후, 30분간 교반하였다. 소듐트리아세톡시보로하이드(3.0당량)를 넣고, 실온에서 철야교반하였다. 반응액에 메틸렌클로라이드와 물을 넣고, 20분간 세차게 교반하였다. 분리된 유기층을 brine으로 세정하고, 무수 마그네슘설페이트로 건조하고 농축하여 1-((9H-fluoren-9-yl)methyl) 2-benzyl 4-((2-ethylbenzofuran-3-yl)methyl)piperazine-1,2-dicarboxylate를 수득하였다.2-ethylbenzofuran-3-carbaldehyde (1.0 eq) obtained through step 2 at room temperature and 1-((9H-fluoren-9-yl)methyl) 2-benzyl piperazine-1,2-dicarboxylate obtained through step 5 (1.2 eq) was added to 1,2-dichloroethane (DCE) and stirred for 30 minutes. Sodium triacetoxyborohydride (3.0 equivalents) was added and stirred overnight at room temperature. Methylene chloride and water were added to the reaction solution, and the mixture was stirred vigorously for 20 minutes. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated to 1-((9H-fluoren-9-yl)methyl) 2-benzyl 4-((2-ethylbenzofuran-3-yl)methyl)piperazine- 1,2-dicarboxylate was obtained.
7) 단계 77) Step 7
[반응식 7][Scheme 7]
Figure PCTKR2019018660-appb-img-000038
Figure PCTKR2019018660-appb-img-000038
실온에서 1-((9H-fluoren-9-yl)methyl) 2-benzyl 4-((2-ethylbenzofuran-3-yl)methyl)piperazine-1,2-dicarboxylate(1.0당량)를 디메틸포름아미드에 용해 시킨 후, 피페리딘(10당량, 용매 중 25% 피페리딘)을 투입하고 1시간 교반하였다. 반응에 에틸아세테이트를 넣은 후, 암모늄클로라이드 수용액으로 용액내의 피페리딘을 씻어냈다. 무수 마그네슘설페이트로 건조 후, 감압농축하여 얻어진 잔사를 실리카 크로마토그래피로 정제하여 benzyl 4-((2-ethylbenzofuran-3-yl)methyl)piperazine-2-carboxylate를 수득하였다.Dissolve 1-((9H-fluoren-9-yl)methyl) 2-benzyl 4-((2-ethylbenzofuran-3-yl)methyl)piperazine-1,2-dicarboxylate (1.0 eq.) in dimethylformamide at room temperature. After the preparation, piperidine (10 equivalents, 25% piperidine in a solvent) was added and stirred for 1 hour. After adding ethyl acetate to the reaction, the piperidine in the solution was washed with an aqueous ammonium chloride solution. After drying with anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by silica chromatography to obtain benzyl 4-((2-ethylbenzofuran-3-yl)methyl)piperazine-2-carboxylate.
8) 단계 88) Step 8
[반응식 8][Scheme 8]
Figure PCTKR2019018660-appb-img-000039
Figure PCTKR2019018660-appb-img-000039
실온에서 benzyl 4-((2-ethylbenzofuran-3-yl)methyl)piperazine-2-carboxylate (1.0당량)와 N-(tert-Butoxycarbonyl)glycine(1.1당량), 그리고 (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(1.2당량)를 디메틸포름아미드로 용해 시킨 후, N,N-디이소프로필에틸아민(1.5당량)을 첨가하고 실온에서 철야교반 하였다. 암모늄클로라이드수용액과 에틸아세테이트를 사용하여 반응을 종료시켰다. 얻어진 유기층을 brine으로 세정 후, 무수 마그네슘설페이트로 건조하고 감압농축하였다. 잔사를 실리카크로마토그래피로 정제하여 benzyl 1-((tert-butoxycarbonyl)glycyl)-4-((2-ethylbenzofuran-3-yl)methyl)piperazine-2-carboxylate를 수득하였다.At room temperature, benzyl 4-((2-ethylbenzofuran-3-yl)methyl)piperazine-2-carboxylate (1.0 eq) and N-(tert-Butoxycarbonyl)glycine (1.1 eq), and (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate After dissolving (1.2 equivalents) in dimethylformamide, N,N-diisopropylethylamine (1.5 equivalents) was added and stirred overnight at room temperature. The reaction was terminated using an aqueous ammonium chloride solution and ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica chromatography to obtain benzyl 1-((tert-butoxycarbonyl)glycyl)-4-((2-ethylbenzofuran-3-yl)methyl)piperazine-2-carboxylate.
9) 단계 99) Step 9
[반응식 9][Scheme 9]
Figure PCTKR2019018660-appb-img-000040
Figure PCTKR2019018660-appb-img-000040
반응식 9와 같이, 실온에서 단계 8을 통해 수득한 benzyl 1-((tert-butoxycarbonyl)glycyl)-4-((2-ethylbenzofuran-3-yl)methyl)piperazine-2-carboxylate를 디클로로메테인(5.0볼륨)에 용해시킨 후, 트리플로로아세트산(2.0볼륨)을 첨가하여 실온에서 30분동안 교반하였다. 반응이 완료된 후, 반응액을 소듐바이카보네이트 수용액으로 중화시키고, 메틸렌클로라이드로 추출하였다. 무수 마그네슘설페이트로 건조하고 감압농축하여 benzyl 4-((2-ethylbenzofuran-3-yl)methyl)-1-glycylpiperazine-2-carboxylate를 수득하였다.As shown in Scheme 9, 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.
10) 단계 1010) Step 10
[반응식 10][Scheme 10]
Figure PCTKR2019018660-appb-img-000041
Figure PCTKR2019018660-appb-img-000041
단계 9에서 수득한 benzyl 4-((2-ethylbenzofuran-3-yl)methyl)-1-glycylpiperazine-2-carboxylate를 이소프로판올(5.0볼륨)에 용해시킨 후, 아세트산(1.5볼륨)을 넣고 가온하여 1시간 교반하였다. 반응이 완결된 후, 소듐바이카보네이트 수용액으로 중화하였다. 반응물을 메틸렌클로라이드로 추출하고, 무수 마그네슘설페이트로 건조하였다. 감압농축 후, 잔사를 실리카크로마토그래피로 정제하여 2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione(화학식 2)을 수득하였다.After dissolving benzyl 4-((2-ethylbenzofuran-3-yl)methyl)-1-glycylpiperazine-2-carboxylate obtained in step 9 in isopropanol (5.0 volume), add acetic acid (1.5 volume) and warm for 1 hour. It was stirred. After the reaction was completed, it was neutralized with an aqueous sodium bicarbonate solution. The reaction was extracted with methylene chloride and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica chromatography to obtain 2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (Formula 2). Obtained.
[화학식 2][Formula 2]
Figure PCTKR2019018660-appb-img-000042
,
Figure PCTKR2019018660-appb-img-000042
,
2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C101, L19031 또는 candidate1로 표현).2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C101, L19031 or candidate1).
1H-NMR (500 MHz, CDCl 3) δ7.58 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.24 - 7.17 (m, 2H), 4.50 (d, J = 13.0 Hz, 1H), 4.06 (d, J = 11.0 Hz, 1H), 4.00 (s, 2H), 3.64 (dd, J = 57.5, 13.0 Hz, 1H), 3.47 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.5 Hz, 1H), 2.71-2.81 (m, 3H), 2.11 (t, J = 11.5 Hz, 1H), 2.07 - 2.01 (m, 1H), 1.30 (t, J = 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.58 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.24-7.17 (m, 2H), 4.50 (d, J = 13.0 Hz, 1H), 4.06 (d, J = 11.0 Hz, 1H), 4.00 (s, 2H), 3.64 (dd, J = 57.5, 13.0 Hz, 1H), 3.47 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.5 Hz, 1H), 2.71-2.81 (m, 3H), 2.11 (t, J = 11.5 Hz, 1H), 2.07-2.01 (m, 1H), 1.30 (t, J = 7.5 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ166.32, 161.99, 158.34, 154.16, 129.60, 123.65, 122.56, 119.87, 110.94, 109.53, 57.18, 56.42, 51.84, 51.58, 44.75, 41.78, 20.18, 13.10; 13 C-NMR (126 MHz, CDCl 3 ) δ166.32, 161.99, 158.34, 154.16, 129.60, 123.65, 122.56, 119.87, 110.94, 109.53, 57.18, 56.42, 51.84, 51.58, 44.75, 41.78, 20.18, 13.10;
MS (ESI) m/z for C 18H 21N 3O 3 [M+H] + : calcd 328.1656, found 328.1655.MS (ESI) m/z for C 18 H 21 N 3 O 3 [M+H] + : calcd 328.1656, found 328.1655.
2. 제조예1-2: C101.HCl, L190012. Preparation Example 1-2: C101.HCl, L19001
제조예 1-1과 동일한 방법으로 합성하되, 전술한 제조예 1-1의 마지막에 염산을 사용하여 화학식 3의 염산염을 제조하였다.It was synthesized in the same manner as in Production Example 1-1, but using the hydrochloric acid at the end of Preparation Example 1-1 described above to prepare a hydrochloride salt of Formula 3.
[화학식 3][Formula 3]
Figure PCTKR2019018660-appb-img-000043
,
Figure PCTKR2019018660-appb-img-000043
,
2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride(C101.HCl 또는 L19001로 표현).2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride (expressed as C101.HCl or L19001).
3. 제조예2: C102, L190023. Preparation Example 2: C102, L19002
제조예 1-1과 동일한 방법으로 합성하되, 전술한 제조예 1-1의 단계 8에서 반응물질인 N-(tert-Butoxycarbonyl)glycine 대신 N-(tert-Butoxycarbonyl)-L-alanine을 사용하였고, 마지막에 염산을 사용하여 화학식 4의 염산염을 제조하였다.Synthesis in the same manner as in Production Example 1-1, N-(tert-Butoxycarbonyl)-L-alanine was used instead of N-(tert-Butoxycarbonyl)glycine as a reactant in Step 8 of Preparation Example 1-1 described above. Finally, hydrochloric acid was used to prepare hydrochloride of Formula 4.
[화학식 4][Formula 4]
Figure PCTKR2019018660-appb-img-000044
Figure PCTKR2019018660-appb-img-000044
2-((2-ethylbenzofuran-3-yl)methyl)-7-methylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride (C102 또는 L19002로 표현).2-((2-ethylbenzofuran-3-yl)methyl)-7-methylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride (expressed as C102 or L19002).
1H-NMR (500 MHz, CD 3OD) δ7.78-7.72 (m, 1H), 7.53-7.47 (m, 1H), 7.36-7.29 (m, 2H), 4.69 (dd, J = 21.3, 12.3 Hz, 1H), 4.60-4.46 (m, 3H), 4.13 (dq, J = 13.8, 6.8 Hz, 1H), 3.99 - 3.91 (m, 1H), 3.66 (s, 1H), 3.20 - 3.02 (m, 3H), 2.98 (dq, J = 7.5, 2.0 Hz, 2H), 1.46 (t, J = 7.5 Hz, 3H), 1.38 (t, J = 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CD 3 OD) δ7.78-7.72 (m, 1H), 7.53-7.47 (m, 1H), 7.36-7.29 (m, 2H), 4.69 (dd, J = 21.3, 12.3 Hz, 1H), 4.60-4.46 (m, 3H), 4.13 (dq, J = 13.8, 6.8 Hz, 1H), 3.99-3.91 (m, 1H), 3.66 (s, 1H), 3.20-3.02 (m, 3H), 2.98 (dq, J = 7.5, 2.0 Hz, 2H), 1.46 (t, J = 7.5 Hz, 3H), 1.38 (t, J = 7.5 Hz, 3H);
MS (ESI) m/z for C 19H 23N 3O 3 [M+H] +: calcd 342.1812, found 342.1813.MS (ESI) m/z for C 19 H 23 N 3 O 3 [M+H] + : calcd 342.1812, found 342.1813.
4. 제조예3: C105, L190334. Preparation Example 3: C105, L19033
제조예 1-1과 동일한 방법으로 합성하되, 전술한 제조예 1-1의 단계 8에서 반응물질인 N-(tert-Butoxycarbonyl)glycine 대신 N-(tert-Butoxycarbonyl)-L-2-cyclohexylglycine을 사용하여 화학식 5의 화합물을 수득하였다.Synthesis in the same manner as in Production Example 1-1, but instead of N-(tert-Butoxycarbonyl)glycine, a reactant, in Step 8 of Production Example 1-1, N-(tert-Butoxycarbonyl)-L-2-cyclohexylglycine was used. To obtain a compound of formula (5).
[화학식 5][Formula 5]
Figure PCTKR2019018660-appb-img-000045
,
Figure PCTKR2019018660-appb-img-000045
,
7-cyclohexyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C105 또는 L19033으로 표현).7-cyclohexyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C105 or L19033).
1H-NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.23 - 7.17 (m, 2H), 4.53 (t, J = 12.3 Hz, 1H), 4.06 (ddd, J = 20.0, 11.0, 3.0 Hz, 1H), 3.87 (d, J = 28.0 Hz, 1H), 3.70 (dd, J = 13.0, 5.5 Hz, 1H), 3.58 - 3.49 (m, 2H), 2.90 (d, J = 11.5 Hz, 1H), 2.78 (q, J = 7.5 Hz, 2H), 2.75-2.65 (m, 1H), 2.15 - 1.93 (m, 4H), 1.83-1.60 (m, 4H), 1.48 (dd, J = 32.5, 12.0 Hz, 1H), 1.34-1.26 (m 4H), 1.28-1.04 (m, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.23-7.17 (m, 2H), 4.53 (t, J = 12.3 Hz, 1H), 4.06 (ddd, J = 20.0, 11.0, 3.0 Hz, 1H), 3.87 (d, J = 28.0 Hz, 1H), 3.70 (dd, J = 13.0, 5.5 Hz, 1H), 3.58-3.49 (m, 2H), 2.90 (d, J = 11.5 Hz, 1H), 2.78 (q, J = 7.5 Hz, 2H), 2.75-2.65 (m, 1H), 2.15-1.93 (m, 4H) , 1.83-1.60 (m, 4H), 1.48 (dd, J = 32.5, 12.0 Hz, 1H), 1.34-1.26 (m 4H), 1.28-1.04 (m, 3H);
13C-NMR (126 MHz, CDCl 3) δ167.02, 166.42, 165.05, 163.54, 158.33, 158.27, 154.16, 129.62, 129.57, 128.75, 127.80, 127.19, 123.64, 123.63, 122.54, 119.90, 119.87, 110.91, 109.63, 109.57, 60.34, 59.95, 57.52, 57.09, 56.57, 56.50, 51.98, 51.89, 51.78, 51.54, 43.67, 42.11, 41.95, 41.52, 29.49, 29.30, 26.78, 26.56, 26.53, 26.39, 26.08, 25.98, 25.87, 20.16, 13.11, 13.10 ; 13 C-NMR (126 MHz, CDCl 3 ) δ167.02, 166.42, 165.05, 163.54, 158.33, 158.27, 154.16, 129.62, 129.57, 128.75, 127.80, 127.19, 123.64, 123.63, 122.54, 119.90, 119.87, 110.91 , 109.57, 60.34, 59.95, 57.52, 57.09, 56.57, 56.50, 51.98, 51.89, 51.78, 51.54, 43.67, 42.11, 41.95, 41.52, 29.49, 29.30, 26.78, 26.56, 26.53, 26.39, 26.08, 25.98, 2587. , 13.11, 13.10;
MS (ESI) m/z for C 24H 31N 3O 3 [M+H] + : calcd 410.2438 , found 410.2442.MS (ESI) m/z for C 24 H 31 N 3 O 3 [M+H] + : calcd 410.2438, found 410.2442.
5. 제조예4: C107, L190035. Preparation Example 4: C107, L19003
제조예 1-1과 동일한 방법으로 합성하되, 전술한 제조예 1-1의 단계 8에서 반응물질인 N-(tert-Butoxycarbonyl)glycine 대신 N-(tert-Butoxycarbonyl)-L-methionine을 사용하였고, 마지막에 염산을 사용하여 화학식 6의 염산염을 제조하였다.Synthesis in the same manner as in Production Example 1-1, N-(tert-Butoxycarbonyl)-L-methionine was used instead of N-(tert-Butoxycarbonyl)glycine as a reactant in Step 8 of Production Example 1-1 described above. Finally, hydrochloric acid was used to prepare hydrochloride of Formula 6.
[화학식 6][Formula 6]
Figure PCTKR2019018660-appb-img-000046
,
Figure PCTKR2019018660-appb-img-000046
,
2-((2-ethylbenzofuran-3-yl)methyl)-7-(2-(methylthio)ethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride (C107 또는 L19003으로 표현).2-((2-ethylbenzofuran-3-yl)methyl)-7-(2-(methylthio)ethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride (as C107 or L19003 expression).
1H-NMR (500 MHz, CD 3OD) δ7.80-7.76 (m, 1H), 7.50-7.47 (m, 1H), 7.34-7.30 (m, 2H), 4.72-4.57 (m, 4H), 4.25-4.21 (m, 1H), 4.00 (t, J = 9.8 Hz, 1H), 3.70 (s, 1H), 3.41 - 3.32 (m, 1H), 3.24 - 3.07 (m, 2H), 3.00 (dq, J = 11.0, 3.9 Hz, 2H), 2.64 - 2.50 (m, 2H), 2.28 - 2.18 (m, 1H), 2.14-2.06 (m, 1H), 2.00 (d, J = 22.5 Hz, 3H), 1.38 (dt, J = 7.5, 3.5 Hz, 3H) ; 1 H-NMR (500 MHz, CD 3 OD) δ7.80-7.76 (m, 1H), 7.50-7.47 (m, 1H), 7.34-7.30 (m, 2H), 4.72-4.57 (m, 4H), 4.25-4.21 (m, 1H), 4.00 (t, J = 9.8 Hz, 1H), 3.70 (s, 1H), 3.41-3.32 (m, 1H), 3.24-3.07 (m, 2H), 3.00 (dq, J = 11.0, 3.9 Hz, 2H), 2.64-2.50 (m, 2H), 2.28-2.18 (m, 1H), 2.14-2.06 (m, 1H), 2.00 (d, J = 22.5 Hz, 3H), 1.38 (dt, J = 7.5, 3.5 Hz, 3H);
MS (ESI) m/z for C 21H 27N 3O 3S [M+H] + : calcd 402.1846, found 402.1843.MS (ESI) m/z for C 21 H 27 N 3 O 3 S [M+H] + : calcd 402.1846, found 402.1843.
6. 제조예5: C108, L190046. Preparation Example 5: C108, L19004
제조예 1-1과 동일한 방법으로 합성하되, 전술한 제조예 1-1의 단계 8에서 반응물질인 N-(tert-Butoxycarbonyl)glycine 대신 N-(tert-Butoxycarbonyl)-S-benzyl-L-cysteine을 사용하였고, 마지막에 염산을 사용하여 화학식 7의 염산염을 제조하였다.Synthesized in the same manner as in Preparation Example 1-1, but instead of N-(tert-Butoxycarbonyl)glycine, a reactant in Step 8 of Preparation Example 1-1, N-(tert-Butoxycarbonyl)-S-benzyl-L-cysteine Was used, and at the end, hydrochloric acid was used to prepare hydrochloride of Formula 7.
[화학식 7][Formula 7]
Figure PCTKR2019018660-appb-img-000047
,
Figure PCTKR2019018660-appb-img-000047
,
7-((benzylthio)methyl)-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride (C108 또는 L19004로 표현).7-((benzylthio)methyl)-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride (expressed as C108 or L19004) .
1H-NMR (500 MHz, CD 3OD) δ7.78 - 7.69 (m, 1H), 7.49-7.46 (m, 1H), 7.29 - 7.26 (m, 7H), 4.70 - 4.64 (m, 1H), 4.59 (s, 1H), 4.53-4.39 (m, 2H), 4.36 - 4.32 (m, 1H), 3.94 (d, J = 10.5 Hz, 1H), 3.71 (d, J = 2.5 Hz, 1H), 3.51 (dd, J = 42.0, 13.2 Hz, 2H), 3.09 (dd, J = 14.5, 4.0 Hz, 2H), 3.03 (dd, J = 14.5, 3.5 Hz, 1H), 2.99 - 2.88 (m, 2H), 2.80 (ddd, J = 35.5, 14.5, 3.8 Hz, 2H), 1.36 (dt, J = 12.0, 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CD 3 OD) δ7.78-7.69 (m, 1H), 7.49-7.46 (m, 1H), 7.29-7.26 (m, 7H), 4.70-4.64 (m, 1H), 4.59 (s, 1H), 4.53-4.39 (m, 2H), 4.36-4.32 (m, 1H), 3.94 (d, J = 10.5 Hz, 1H), 3.71 (d, J = 2.5 Hz, 1H), 3.51 (dd, J = 42.0, 13.2 Hz, 2H), 3.09 (dd, J = 14.5, 4.0 Hz, 2H), 3.03 (dd, J = 14.5, 3.5 Hz, 1H), 2.99-2.88 (m, 2H), 2.80 (ddd, J = 35.5, 14.5, 3.8 Hz, 2H), 1.36 (dt, J = 12.0, 7.5 Hz, 3H);
MS (ESI) m/z for C 26H 29N 3O 3S [M+H] + : calcd 464.2002, found 464.2001.MS (ESI) m/z for C 26 H 29 N 3 O 3 S [M+H] + : calcd 464.2002, found 464.2001.
7. 제조예6: C109, L190357. Preparation Example 6: C109, L19035
제조예 1-1과 동일한 방법으로 합성하되, 전술한 제조예 1-1의 단계 8에서 반응물질인 N-(tert-Butoxycarbonyl)glycine 대신 N-(tert-Butoxycarbonyl)-L-proline을 사용하여 화학식 8의 화합물을 수득하였다.Synthesis in the same manner as in Preparation Example 1-1, but using N-(tert-Butoxycarbonyl)-L-proline instead of the reactant N-(tert-Butoxycarbonyl)glycine in Step 8 of Preparation Example 1-1 described above The compound of 8 was obtained.
[화학식 8][Formula 8]
Figure PCTKR2019018660-appb-img-000048
,
Figure PCTKR2019018660-appb-img-000048
,
2-((2-ethylbenzofuran-3-yl)methyl)octahydro-6H-pyrazino[1,2-a]pyrrolo[1,2-d]pyrazine-6,11(2H)-dione (C109 또는 L19035로 표현).2-((2-ethylbenzofuran-3-yl)methyl)octahydro-6H-pyrazino[1,2-a]pyrrolo[1,2-d]pyrazine-6,11(2H)-dione (expressed as C109 or L19035 ).
1H-NMR (500 MHz, CDCl 3) δ7.58 (dd, J = 13.0, 7.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.24 - 7.15 (m, 2H), 4.45 (dd, J = 59.0, 13.0 Hz, 1H), 4.13 - 3.98 (m, 2H), 3.81 - 3.66 (m, 2H), 3.62-3.37 (m, 3H), 2.96 - 2.71 (m, 4H), 2.48 - 2.40 (m, 1H), 2.15 - 1.82 (m, 5H), 1.30 (dt, J = 16.0, 8.0 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.58 (dd, J = 13.0, 7.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.24-7.15 (m, 2H), 4.45 ( dd, J = 59.0, 13.0 Hz, 1H), 4.13-3.98 (m, 2H), 3.81-3.66 (m, 2H), 3.62-3.37 (m, 3H), 2.96-2.71 (m, 4H), 2.48- 2.40 (m, 1H), 2.15-1.82 (m, 5H), 1.30 (dt, J = 16.0, 8.0 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ167.19, 164.43, 163.30, 162.81, 158.31, 158.30, 154.16, 154.13, 129.66, 129.62, 123.63, 123.56, 122.58, 122.48, 119.97, 119.85, 110.90, 110.87, 109.75, 109.49, 61.16, 59.10, 58.76, 57.14, 56.28, 55.82, 52.01, 51.91, 51.67, 51.43, 45.51, 45.42, 42.04, 41.75, 31.82, 30.15, 29.96, 22.89, 22.07, 21.92, 20.19, 20.17, 14.37, 13.10 ; 13 C-NMR (126 MHz, CDCl 3 ) δ167.19, 164.43, 163.30, 162.81, 158.31, 158.30, 154.16, 154.13, 129.66, 129.62, 123.63, 123.56, 122.58, 122.48, 119.97, 119.85, 110.90, 110.87, 110.87 , 109.49, 61.16, 59.10, 58.76, 57.14, 56.28, 55.82, 52.01, 51.91, 51.67, 51.43, 45.51, 45.42, 42.04, 41.75, 31.82, 30.15, 29.96, 22.89, 22.07, 21.92, 20.19, 20.17, 14.37 ;
MS (ESI) m/z for C 21H 25N 3O 3 [M+H] + : calcd 368.1969, found 368.1974.MS (ESI) m/z for C 21 H 25 N 3 O 3 [M+H] + : calcd 368.1969, found 368.1974.
8. 제조예7-1: C111, L190378. Production Example 7-1: C111, L19037
제조예 1-1과 동일한 방법으로 합성하되, 전술한 제조예 1-1의 단계 8에서 반응물질인 N-(tert-Butoxycarbonyl)glycine 대신 N-(tert-Butoxycarbonyl)-L-phenylalanine을 사용하여, 화학식 9의 화합물을 제조하였다.Synthesis in the same manner as in Production Example 1-1, using N-(tert-Butoxycarbonyl)-L-phenylalanine instead of N-(tert-Butoxycarbonyl)glycine as a reactant in Step 8 of Preparation Example 1-1, A compound of Formula 9 was prepared.
[화학식 9][Formula 9]
Figure PCTKR2019018660-appb-img-000049
Figure PCTKR2019018660-appb-img-000049
7-benzyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C111 또는 L19037로 표현).7-benzyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C111 or L19037).
1H-NMR (500 MHz, CDCl 3) δ7.49 (dd, J = 12.5, 7.5 Hz, 1H), 7.40 (dd, J = 8.0, 5.0 Hz, 1H), 7.34-7.16 (m, 7H), 4.46 (dd, J = 39.5, 13.0 Hz, 1H), 4.34(d, J = 26.5 Hz, 1H), 3.83(dd, J = 10.5, 2.5 Hz, 0.5H), 3.55(dd, J = 62.5, 13.5 Hz, 1H), 3.39 (s, 1H), 3.35(dd, J = 13.5, 4.0 Hz, 0.5H), 3.30-3.21(m, 1H), 3.04(dd, J = 13.5, 4.0 Hz, 0.5H), 2.97(dd, J = 13.5, 4.0 Hz, 1H), 2.86-2.79(m, 1H), 2.76-2.69(m, 3H), 2.59(dd, J = 12.5, 3.0 Hz, 0.5H), 2.44(dd, J = 12.5, 3.5 Hz, 0.5H), 1.97-1.90(m, 1H), 1.69(dd, J = 12.0, 3.0 Hz, 0.5H), 1.28(dt, J = 7.5, 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.49 (dd, J = 12.5, 7.5 Hz, 1H), 7.40 (dd, J = 8.0, 5.0 Hz, 1H), 7.34-7.16 (m, 7H), 4.46 (dd, J = 39.5, 13.0 Hz, 1H), 4.34 (d, J = 26.5 Hz, 1H), 3.83 (dd, J = 10.5, 2.5 Hz, 0.5H), 3.55 (dd, J = 62.5, 13.5 Hz, 1H), 3.39 (s, 1H), 3.35 (dd, J = 13.5, 4.0 Hz, 0.5H), 3.30-3.21 (m, 1H), 3.04 (dd, J = 13.5, 4.0 Hz, 0.5H) , 2.97 (dd, J = 13.5, 4.0 Hz, 1H), 2.86-2.79 (m, 1H), 2.76-2.69 (m, 3H), 2.59 (dd, J = 12.5, 3.0 Hz, 0.5H), 2.44 ( dd, J = 12.5, 3.5 Hz, 0.5H), 1.97-1.90 (m, 1H), 1.69 (dd, J = 12.0, 3.0 Hz, 0.5H), 1.28 (dt, J = 7.5, 7.5 Hz, 3H) ;
13C-NMR (126 MHz, CDCl 3) δ167.02, 166.39, 164.80, 162.84, 158.28, 158.19, 154.13, 135.21, 135.03, 131.16, 130.32, 129.69, 129.63, 128.89, 128.79, 127.89, 127.52, 123.63, 123.59, 122.53, 122.48, 119.88, 119.82, 110.90, 110.88, 109.58, 109.43, 57.62, 56.35, 56.12, 55.96, 55.91, 55.32, 51.77, 51.40, 51.34, 51.30, 41.08, 41.4, 40.73, 20.16, 20.10, 13.10, 13.07 ; 13 C-NMR (126 MHz, CDCl 3 ) δ167.02, 166.39, 164.80, 162.84, 158.28, 158.19, 154.13, 135.21, 135.03, 131.16, 130.32, 129.69, 129.63, 128.89, 128.79, 127.89, 127.52, 1235963, 123.63 , 122.53, 122.48, 119.88, 119.82, 110.90, 110.88, 109.58, 109.43, 57.62, 56.35, 56.12, 55.96, 55.91, 55.32, 51.77, 51.40, 51.34, 51.30, 41.08, 41.4, 40.73, 20.16, 20.10, 13.10 ;
MS (ESI) m/z for C 25H 27N 3O 3 [M+H] + : calcd 418.2125, found 418.2129.MS (ESI) m/z for C 25 H 27 N 3 O 3 [M+H] + : calcd 418.2125, found 418.2129.
9. 제조예7-2: C111.HCl, L190059. Preparation Example 7-2: C111.HCl, L19005
제조예 7-1과 동일한 방법으로 합성하되, 전술한 제조예 7-1의 마지막에 염산을 사용하여 화학식 10의 염산염을 제조하였다.It was synthesized in the same manner as in Production Example 7-1, and hydrochloric acid of Formula 10 was prepared at the end of Production Example 7-1 described above.
[화학식 10][Formula 10]
Figure PCTKR2019018660-appb-img-000050
,
Figure PCTKR2019018660-appb-img-000050
,
7-benzyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride(C111.HCl 또는 L19005로 표현).7-benzyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride (expressed as C111.HCl or L19005).
10. 제조예8: C121, L1900610. Preparation Example 8: C121, L19006
제조예 1-1과 동일한 방법으로 합성하되, 전술한 제조예 1-1의 단계 8에서 반응물질인 N-(tert-Butoxycarbonyl)glycine 대신 N-(tert-Butoxycarbonyl)-3-(1-naphthyl)-D-alanine을 사용하였고, 마지막에 염산을 사용하여 화학식 11의 염산염을 제조하였다.Synthesis in the same manner as in Production Example 1-1, but instead of N-(tert-Butoxycarbonyl)glycine, the reactant in Step 8 of Production Example 1-1, N-(tert-Butoxycarbonyl)-3-(1-naphthyl) -D-alanine was used, and hydrochloric acid was used to prepare hydrochloride of the formula (11).
[화학식 11][Formula 11]
Figure PCTKR2019018660-appb-img-000051
,
Figure PCTKR2019018660-appb-img-000051
,
2-((2-ethylbenzofuran-3-yl)methyl)-7-(naphthalen-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride (C121 또는 L19006으로 표현).2-((2-ethylbenzofuran-3-yl)methyl)-7-(naphthalen-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride (expressed as C121 or L19006 ).
1H-NMR (500 MHz, CD 3OD) δ8.07 (dd, J = 18.8, 8.5 Hz, 1H), 7.84 (dd, J = 12.8, 8.0 Hz, 1H), 7.64 - 7.21 (m, 9H), 4.59 (s, 1H), 4.50-4.43 (m, 1H), 4.40 (d, J = 14.0 Hz, 0.5H), 4.23 (bs, 1H), 4.18 (d, J = 14 Hz, 0.5H), 4.02 (d, J = 11.5 Hz, 0.5H), 3.90 (dd, J = 14.0, 3.0 Hz, 0.5H), 3.81 (bs, 1H), 3.74 (dd, J = 14.0, 4.0 Hz, 0.5H), 3.54-3.49 (m, 1H), 3.36-3.20 (m, 1H), 3.09 (dd, J = 29.0, 11.5 Hz, 1H), 2.86-2.70 (m, 3.5H), 2.57 (d, J = 11.0 Hz, 0.5H), 2.17-2.08 (m, 0.5H), 1.31 (dt, J = 17.5, 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CD 3 OD) δ8.07 (dd, J = 18.8, 8.5 Hz, 1H), 7.84 (dd, J = 12.8, 8.0 Hz, 1H), 7.64-7.21 (m, 9H) , 4.59 (s, 1H), 4.50-4.43 (m, 1H), 4.40 (d, J = 14.0 Hz, 0.5H), 4.23 (bs, 1H), 4.18 (d, J = 14 Hz, 0.5H), 4.02 (d, J = 11.5 Hz, 0.5H), 3.90 (dd, J = 14.0, 3.0 Hz, 0.5H), 3.81 (bs, 1H), 3.74 (dd, J = 14.0, 4.0 Hz, 0.5H), 3.54-3.49 (m, 1H), 3.36-3.20 (m, 1H), 3.09 (dd, J = 29.0, 11.5 Hz, 1H), 2.86-2.70 (m, 3.5H), 2.57 (d, J = 11.0 Hz , 0.5H), 2.17-2.08 (m, 0.5H), 1.31 (dt, J = 17.5, 7.5 Hz, 3H);
MS (ESI) m/z for C 29H 29N 3O 3 [M+H] + : calcd 468.2282, found 468.2284.MS (ESI) m/z for C 29 H 29 N 3 O 3 [M+H] + : calcd 468.2282, found 468.2284.
11. 제조예9: C122, L1900711.Production Example 9: C122, L19007
제조예 1-1과 동일한 방법으로 합성하되, 전술한 제조예 1-1의 단계 8에서 반응물질인 N-(tert-Butoxycarbonyl)glycine 대신 N-(tert-Butoxycarbonyl)-3-(2-naphthyl)-D-alanine을 사용하였고, 마지막에 염산을 사용하여 화학식 12의 염산염을 제조하였다.Synthesis in the same manner as in Production Example 1-1, but instead of N-(tert-Butoxycarbonyl)glycine, the reactant in Step 8 of Production Example 1-1, N-(tert-Butoxycarbonyl)-3-(2-naphthyl) -D-alanine was used, and hydrochloric acid was used to prepare hydrochloride of the formula (12).
[화학식 12][Formula 12]
Figure PCTKR2019018660-appb-img-000052
,
Figure PCTKR2019018660-appb-img-000052
,
2-((2-ethylbenzofuran-3-yl)methyl)-7-(naphthalen-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride (C122 또는 L19007로 표현).2-((2-ethylbenzofuran-3-yl)methyl)-7-(naphthalen-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride (expressed as C122 or L19007 ).
1H-NMR (500 MHz, CD 3OD) δ8.00 - 7.15 (m, 11H), 4.64 (d, J = 15.0 Hz, 1H), 4.59 (s, 1H), 4.52 - 4.45 (m, 1H), 4.42 (s, 1H), 4.19 (d, J = 10.5 Hz, 0.5H), 3.65-3.33 (m, 3.5H), 3.27 (d, J = 11 Hz, 0.5H), 3.19-3.06 (m, 2H), 2.96-2.82 (m, 2H), 2.64-2.52 (m, 1.5H), 2.14 (dt, J = 12.5, 3.0 Hz, 0.5H), 2.14 (dt, J = 12.5, 3.0 Hz, 0.5H) 1.27 (dt, J = 27.0, 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CD 3 OD) δ8.00-7.15 (m, 11H), 4.64 (d, J = 15.0 Hz, 1H), 4.59 (s, 1H), 4.52-4.45 (m, 1H) , 4.42 (s, 1H), 4.19 (d, J = 10.5 Hz, 0.5H), 3.65-3.33 (m, 3.5H), 3.27 (d, J = 11 Hz, 0.5H), 3.19-3.06 (m, 2H), 2.96-2.82 (m, 2H), 2.64-2.52 (m, 1.5H), 2.14 (dt, J = 12.5, 3.0 Hz, 0.5H), 2.14 (dt, J = 12.5, 3.0 Hz, 0.5H ) 1.27 (dt, J = 27.0, 7.5 Hz, 3H);
MS (ESI) m/z for C 29H 29N 3O 3 [M+H] + : calcd 468.2282, found 468.2283.MS (ESI) m/z for C 29 H 29 N 3 O 3 [M+H] + : calcd 468.2282, found 468.2283.
12. 제조예10: C201, L1900812. Preparation Example 10: C201, L19008
제조예 1-1에서 수득한 화합물(화학식 2)을 출발물질로 사용하여 아래 반응식 11의 단계를 추가적으로 더 진행하여 화학식 13의 화합물을 수득하였다.Using the compound obtained in Preparation Example 1-1 (Chemical Formula 2) as a starting material, a further step of Reaction Scheme 11 below was further performed to obtain a compound of Chemical Formula 13.
[반응식 11][Scheme 11]
Figure PCTKR2019018660-appb-img-000053
Figure PCTKR2019018660-appb-img-000053
상온에서 2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione과 소듐하이드라이드(2.0당량), 디메틸포르마이드를 첨가하고 1시간 교반 후, 메틸아이오다이드를 넣고 실온에서 철야교반하였다. TLC로 반응을 확인한 후, 암모늄클로라이드 수용액과 에틸아세테이트로 반응을 종결하였다. 유기층을 수용액으로 세정 후, 무수 마그네슘설페이트로 건조하고 감압농축하였다. 잔사를 실리카크로마토그래피로 정제하여 2-((2-ethylbenzofuran-3-yl)methyl)-8-methylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione 을 수득하였다.2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione, sodium hydride (2.0 eq.) and dimethylformamide were added at room temperature. After stirring for 1 hour, methyl iodide was added and stirred overnight at room temperature. After confirming the reaction by TLC, the reaction was terminated with an aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with an aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica chromatography to obtain 2-((2-ethylbenzofuran-3-yl)methyl)-8-methylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione.
[화학식 13][Formula 13]
Figure PCTKR2019018660-appb-img-000054
,
Figure PCTKR2019018660-appb-img-000054
,
2-((2-ethylbenzofuran-3-yl)methyl)-8-methylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C201 또는 L19008로 표현).2-((2-ethylbenzofuran-3-yl)methyl)-8-methylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C201 or L19008).
1H-NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.25 - 7.16 (m, 2H), 4.49 (d, J = 13.0 Hz, 1H), 4.09 - 4.03 (m, 1H), 3.97-3.96 (m, 2H), 3.78 - 3.50 (m, 3H), 2.95 (s, 3H), 2.89 (d, J = 11.5 Hz, 1H), 2.80-2.70 (m, 3H), 2.11 - 1.99 (m, 2H), 1.30 (t, J = 7.5 Hz, 3H) ; 13C-NMR (126 MHz, CDCl 3) δ163.73, 161.65, 158.36, 154.15, 129.62, 123.62, 122.56, 119.88, 110.91, 109.49, 57.45, 56.85, 51.76, 51.43, 51.40, 41.56, 33.62, 20.18, 13.08 ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.25-7.16 (m, 2H), 4.49 (d, J = 13.0 Hz, 1H), 4.09-4.03 (m, 1H), 3.97-3.96 (m, 2H), 3.78-3.50 (m, 3H), 2.95 (s, 3H), 2.89 (d, J = 11.5 Hz , 1H), 2.80-2.70 (m, 3H), 2.11-1.99 (m, 2H), 1.30 (t, J = 7.5 Hz, 3H); 13 C-NMR (126 MHz, CDCl 3 ) δ163.73, 161.65, 158.36, 154.15, 129.62, 123.62, 122.56, 119.88, 110.91, 109.49, 57.45, 56.85, 51.76, 51.43, 51.40, 41.56, 33.62, 20.18, 13.08 ;
MS (ESI) m/z for C 19H 23N 3O 3 [M+H] + : calcd 342.1812, found 342.1802.MS (ESI) m/z for C 19 H 23 N 3 O 3 [M+H] + : calcd 342.1812, found 342.1802.
13. 제조예11: C202, L1900913. Preparation Example 11: C202, L19009
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 에틸아이오다이드를 사용하여 화학식 14의 화합물을 수득하였다.It was synthesized in the same manner as in Preparation Example 10, but using ethyl iodide instead of methyl iodide as a reactant, a compound of Formula 14 was obtained.
[화학식 14][Formula 14]
Figure PCTKR2019018660-appb-img-000055
,
Figure PCTKR2019018660-appb-img-000055
,
8-ethyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C202 또는 L19009로 표현).8-ethyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C202 or L19009).
1H-NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.23 - 7.16 (m, 2H), 4.48 (d, J = 13.0 Hz, 1H), 4.07 - 4.03 (m, 1H), 4.01 - 3.91 (m, 2H), 3.72 (d, J = 13.5 Hz, 1H), 3.59-3.52 (m 2H), 3.50 - 3.35 (m, 2H), 2.88 (d, J = 11.5 Hz, 1H), 2.81-2.70 (m, 3H), 2.08 (t, J = 11.5 Hz, 1H), 2.02 (dt, J = 11.5, 3.0 Hz, 1H), 1.30 (t, J = 7.5 Hz, 3H), 1.15 (t, J = 7.3 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.23-7.16 (m, 2H), 4.48 (d, J = 13.0 Hz, 1H), 4.07-4.03 (m, 1H), 4.01-3.91 (m, 2H), 3.72 (d, J = 13.5 Hz, 1H), 3.59-3.52 (m 2H), 3.50-3.35 ( m, 2H), 2.88 (d, J = 11.5 Hz, 1H), 2.81-2.70 (m, 3H), 2.08 (t, J = 11.5 Hz, 1H), 2.02 (dt, J = 11.5, 3.0 Hz, 1H ), 1.30 (t, J = 7.5 Hz, 3H), 1.15 (t, J = 7.3 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ163.20, 162.05, 158.29, 154.15, 129.63, 123.60, 122.53, 119.90, 110.89, 109.60, 57.54, 56.89, 51.81, 51.39, 48.81, 41.59, 41.12, 20.18, 13.08, 11.83 ; 13 C-NMR (126 MHz, CDCl 3 ) δ163.20, 162.05, 158.29, 154.15, 129.63, 123.60, 122.53, 119.90, 110.89, 109.60, 57.54, 56.89, 51.81, 51.39, 48.81, 41.59, 41.12, 20.18, 13.08 , 11.83;
MS (ESI) m/z for C 20H 25N 3O 3 [M+H] + : calcd 356.1969, found 356.1955.MS (ESI) m/z for C 20 H 25 N 3 O 3 [M+H] + : calcd 356.1969, found 356.1955.
14. 제조예12: C203, L1901014. Preparation Example 12: C203, L19010
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 부틸브로마이드를 사용하여 화학식 15의 화합물을 수득하였다.Synthesis in the same manner as in Preparation Example 10, but using a butyl bromide instead of the reactant methyl iodide to obtain a compound of Formula 15.
[화학식 15][Formula 15]
Figure PCTKR2019018660-appb-img-000056
,
Figure PCTKR2019018660-appb-img-000056
,
8-butyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C203 또는 L19010으로 표현).8-butyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C203 or L19010).
1H-NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.24 - 7.16 (m, 2H), 4.48 (d, J = 13.0 Hz, 1H), 4.06 (d, J = 11.0 Hz, 1H), 3.95 (d, J = 4.5 Hz, 2H), 3.72 (d, J = 13.0 Hz, 1H), 3.60-3.52 (m, 2H), 3.37 (t, J = 7.5 Hz, 2H), 2.88 (d, J = 11.5 Hz, 1H), 2.80 - 2.69 (m, 3H), 2.07 (t, J = 11.5 Hz, 1H), 2.02 (dt, J = 11.5, 3.3 Hz, 1H), 1.57 - 1.49 (m, 2H), 1.36 - 1.28 (m, 5H), 0.93 (t, J = 7.3 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.24-7.16 (m, 2H), 4.48 (d, J = 13.0 Hz, 1H), 4.06 (d, J = 11.0 Hz, 1H), 3.95 (d, J = 4.5 Hz, 2H), 3.72 (d, J = 13.0 Hz, 1H), 3.60-3.52 (m, 2H), 3.37 (t, J = 7.5 Hz, 2H), 2.88 (d, J = 11.5 Hz, 1H), 2.80-2.69 (m, 3H), 2.07 (t, J = 11.5 Hz, 1H), 2.02 ( dt, J = 11.5, 3.3 Hz, 1H), 1.57-1.49 (m, 2H), 1.36-1.28 (m, 5H), 0.93 (t, J = 7.3 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ163.43, 162.09, 158.28, 154.15, 129.63, 123.59, 122.52, 119.90, 110.88, 109.59, 57.52, 56.94, 51.80, 51.38, 49.34, 45.97, 41.59, 28.63, 20.17, 20.12, 13.95, 13.07 ; 13 C-NMR (126 MHz, CDCl 3 ) δ163.43, 162.09, 158.28, 154.15, 129.63, 123.59, 122.52, 119.90, 110.88, 109.59, 57.52, 56.94, 51.80, 51.38, 49.34, 45.97, 41.59, 28.63, 20.17 , 20.12, 13.95, 13.07;
MS (ESI) m/z for C 22H 29N 3O 3 [M+H] + : calcd 384.2282, found 384.2260.MS (ESI) m/z for C 22 H 29 N 3 O 3 [M+H] + : calcd 384.2282, found 384.2260.
15. 제조예13: C204, L1901115. Preparation Example 13: C204, L19011
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 헥실브로마이드를 사용하여 화학식 16의 화합물을 수득하였다.Synthesis in the same manner as in Production Example 10, using a hexyl bromide instead of the reactant methyl iodide to obtain a compound of formula (16).
[화학식 16][Formula 16]
Figure PCTKR2019018660-appb-img-000057
,
Figure PCTKR2019018660-appb-img-000057
,
2-((2-ethylbenzofuran-3-yl)methyl)-8-hexylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C204 또는 L19011로 표현).2-((2-ethylbenzofuran-3-yl)methyl)-8-hexylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C204 or L19011).
1H-NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.24 - 7.16 (m, 2H), 4.48 (d, J = 13.0 Hz, 1H), 4.06 (d, J = 11.0 Hz, 1H), 3.96 (d, J = 5.0 Hz, 2H), 3.72 (d, J = 13.5 Hz, 1H), 3.59-3.52 (m, 2H), 3.37 (dd, J = 8.8, 6.8 Hz, 2H), 2.88 (d, J = 11.0 Hz, 1H), 2.81-2.70 (m, 3H), 2.07 (t, J = 11.0 Hz, 1H), 2.02 (dd, J = 3.5, 11.5, Hz, 1H), 1.57 - 1.50 (m, 2H), 1.32-1.26 (t, J = 6.1 Hz, 9H), 0.88 (t, J = 7.0 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.24-7.16 (m, 2H), 4.48 (d, J = 13.0 Hz, 1H), 4.06 (d, J = 11.0 Hz, 1H), 3.96 (d, J = 5.0 Hz, 2H), 3.72 (d, J = 13.5 Hz, 1H), 3.59-3.52 (m, 2H), 3.37 (dd, J = 8.8, 6.8 Hz, 2H), 2.88 (d, J = 11.0 Hz, 1H), 2.81-2.70 (m, 3H), 2.07 (t, J = 11.0 Hz, 1H), 2.02 (dd, J = 3.5, 11.5, Hz, 1H), 1.57-1.50 (m, 2H), 1.32-1.26 (t, J = 6.1 Hz, 9H), 0.88 (t, J = 7.0 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ163.41, 162.11, 158.30, 154.16, 129.63, 123.60, 122.53, 119.89, 110.89, 109.58, 57.53, 56.95, 51.81, 51.38, 49.36, 46.25, 41.60, 31.63, 26.55, 26.52, 22.73, 20.17, 14.22, 13.07 ; 13 C-NMR (126 MHz, CDCl 3 ) δ163.41, 162.11, 158.30, 154.16, 129.63, 123.60, 122.53, 119.89, 110.89, 109.58, 57.53, 56.95, 51.81, 51.38, 49.36, 46.25, 41.60, 31.63, 26.55 , 26.52, 22.73, 20.17, 14.22, 13.07;
MS (ESI) m/z for C 24H 33N 3O 3 [M+H] + : calcd 412.2595, found 412.2566.MS (ESI) m/z for C 24 H 33 N 3 O 3 [M+H] + : calcd 412.2595, found 412.2566.
16. 제조예14: C206, L1901216. Preparation Example 14: C206, L19012
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 벤질 브로마이드를 사용하여 화학식 17의 화합물을 수득하였다.It was synthesized in the same manner as in Preparation Example 10, but a compound of Formula 17 was obtained using benzyl bromide instead of methyl iodide as a reactant.
[화학식 17][Formula 17]
Figure PCTKR2019018660-appb-img-000058
,
Figure PCTKR2019018660-appb-img-000058
,
8-benzyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C206 또는 L19012로 표현).8-benzyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C206 or L19012).
1H-NMR (500 MHz, CDCl 3) δ7.60 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.36 - 7.29 (m, 3H), 7.26 - 7.17 (m, 4H), 4.57 (q, J = 14.5 Hz, 2H), 4.46 (d, J = 13.0 Hz, 1H), 4.13 (d, J = 11.0 Hz, 1H), 3.85 (s, 2H), 3.73 (d, J = 13.5 Hz, 1H), 3.62-3.56 (m, 2H), 2.89 - 2.85 (m, 1H), 2.78 (q, J = 7.5 Hz, 2H), 2.73 (dd, J = 12.5, 3.5 Hz, 1H), 2.12 (t, J = 11.0 Hz, 1H), 2.02 (dd, J = 11.5, 3.5 Hz, 1H), 1.30 (t, J = 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.60 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.36-7.29 (m, 3H), 7.26-7.17 ( m, 4H), 4.57 (q, J = 14.5 Hz, 2H), 4.46 (d, J = 13.0 Hz, 1H), 4.13 (d, J = 11.0 Hz, 1H), 3.85 (s, 2H), 3.73 ( d, J = 13.5 Hz, 1H), 3.62-3.56 (m, 2H), 2.89-2.85 (m, 1H), 2.78 (q, J = 7.5 Hz, 2H), 2.73 (dd, J = 12.5, 3.5 Hz , 1H), 2.12 (t, J = 11.0 Hz, 1H), 2.02 (dd, J = 11.5, 3.5 Hz, 1H), 1.30 (t, J = 7.5 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ163.69, 161.91, 158.31, 154.18, 135.15, 129.63, 129.18, 128.72, 128.44, 123.63, 122.55, 119.90, 110.93, 109.59, 57.61, 56.97, 51.82, 51.37, 49.55, 48.77, 41.61, 20.20, 13.10 ; 13 C-NMR (126 MHz, CDCl 3 ) δ163.69, 161.91, 158.31, 154.18, 135.15, 129.63, 129.18, 128.72, 128.44, 123.63, 122.55, 119.90, 110.93, 109.59, 57.61, 56.97, 51.82, 51.37, 49.55 , 48.77, 41.61, 20.20, 13.10;
MS (ESI) m/z for C 25H 27N 3O 3 [M+H] + : calcd 418.2153, found 418.2093.MS (ESI) m/z for C 25 H 27 N 3 O 3 [M+H] + : calcd 418.2153, found 418.2093.
17. 제조예15: C207, L1901317. Preparation Example 15: C207, L19013
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 4-메틸벤질 브로마이드를 사용하여 화학식 18의 화합물을 수득하였다.Synthesis in the same manner as in Preparation Example 10, using 4-methylbenzyl bromide instead of the reactant methyl iodide to obtain a compound of Formula 18.
[화학식 18][Formula 18]
Figure PCTKR2019018660-appb-img-000059
,
Figure PCTKR2019018660-appb-img-000059
,
2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-methylbenzyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C207 또는 L19013으로 표현).2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-methylbenzyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C207 or L19013).
1H-NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.26 - 7.17 (m, 2H), 7.14 (s, 4H), 4.52 (dd, J = 32.5, 14.0 Hz, 2H), 4.45 (d, J = 13.5 Hz, 1H), 4.12 (dd, J = 10.5, 2.5 Hz, 1H), 3.84 (s, 2H), 3.73 (d, J = 13.5 Hz, 1H), 3.61-3.56 (m, 2H), 2.89 - 2.85 (m, 1H), 2.78 (q, J = 7.5 Hz, 2H), 2.72 (dt, J = 12.5, 3.0 Hz, 1H), 2.33 (s, 3H), 2.20 (d, J = 11.5 Hz, 1H), 2.01 (dt, J = 11.5, 3.0 Hz, 1H), 1.30 (t, J = 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.26-7.17 (m, 2H), 7.14 (s, 4H), 4.52 (dd, J = 32.5, 14.0 Hz, 2H), 4.45 (d, J = 13.5 Hz, 1H), 4.12 (dd, J = 10.5, 2.5 Hz, 1H), 3.84 (s, 2H), 3.73 (d, J = 13.5 Hz, 1H), 3.61-3.56 (m, 2H), 2.89-2.85 (m, 1H), 2.78 (q, J = 7.5 Hz, 2H), 2.72 (dt, J = 12.5, 3.0 Hz, 1H), 2.33 (s, 3H), 2.20 (d, J = 11.5 Hz, 1H), 2.01 (dt, J = 11.5, 3.0 Hz, 1H), 1.30 (t, J = 7.5 Hz, 3H) ;
13C-NMR (126 MHz, CDCl 3) δ163.60, 161.97, 158.30, 154.18, 138.24, 132.11, 129.83, 129.64, 128.77, 123.63, 122.55, 119.90, 110.92, 109.60, 57.62, 56.97, 51.82, 51.37, 49.28, 48.66, 41.59, 21.36, 20.19, 13.10 ; 13 C-NMR (126 MHz, CDCl 3 ) δ163.60, 161.97, 158.30, 154.18, 138.24, 132.11, 129.83, 129.64, 128.77, 123.63, 122.55, 119.90, 110.92, 109.60, 57.62, 56.97, 51.82, 51.37, 49. , 48.66, 41.59, 21.36, 20.19, 13.10;
MS (ESI) m/z for C 26H 29N 3O 3S [M+H] + : calcd 432.2282, found 432.2240.MS (ESI) m/z for C 26 H 29 N 3 O 3 S [M+H] + : calcd 432.2282, found 432.2240.
18. 제조예16: C208, L1901418. Preparation Example 16: C208, L19014
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 4-클로로벤질 브로마이드를 사용하여 화학식 19의 화합물을 수득하였다.It was synthesized in the same manner as in Preparation Example 10, but 4-chlorobenzyl bromide was used instead of methyl iodide as a reactant to obtain a compound of Formula 19.
[화학식 19][Formula 19]
Figure PCTKR2019018660-appb-img-000060
,
Figure PCTKR2019018660-appb-img-000060
,
8-(4-chlorobenzyl)-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C208 또는 L19014로 표현).8-(4-chlorobenzyl)-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C208 or L19014).
1H-NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.25 - 7.17 (m, 4H), 4.52 (dd, J = 23.5, 14.5 Hz, 2H), 4.46 (d, J = 13.0 Hz, 1H), 4.12 (dd, J = 11.0, 3.0 Hz, 1H), 3.84 (d, J = 2.0 Hz, 2H), 3.73 (d, J = 13.5 Hz, 1H), 3.61-3.56 (m, 2H), 2.88 (d, J = 11.5 Hz, 1H), 2.81-2.70 (m, 3H), 2.10 (t, J = 11.0 Hz, 1H), 2.02 (td, J = 11.5, 3.5 Hz, 1H), 1.31 (t, J = 8.0 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.25 -7.17 (m, 4H), 4.52 (dd, J = 23.5, 14.5 Hz, 2H), 4.46 (d, J = 13.0 Hz, 1H), 4.12 (dd, J = 11.0, 3.0 Hz, 1H), 3.84 ( d, J = 2.0 Hz, 2H), 3.73 (d, J = 13.5 Hz, 1H), 3.61-3.56 (m, 2H), 2.88 (d, J = 11.5 Hz, 1H), 2.81-2.70 (m, 3H ), 2.10 (t, J = 11.0 Hz, 1H), 2.02 (td, J = 11.5, 3.5 Hz, 1H), 1.31 (t, J = 8.0 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ163.78, 161.69, 158.32, 154.18, 134.41, 133.73, 130.09, 129.61, 129.37, 123.65, 122.55, 119.88, 110.94, 109.54, 57.56, 56.89, 51.81, 51.35, 48.96, 48.82, 41.64, 20.19, 13.10 ; 13 C-NMR (126 MHz, CDCl 3 ) δ163.78, 161.69, 158.32, 154.18, 134.41, 133.73, 130.09, 129.61, 129.37, 123.65, 122.55, 119.88, 110.94, 109.54, 57.56, 56.89, 51.81, 51.35, 48.96 , 48.82, 41.64, 20.19, 13.10;
MS (ESI) m/z for C 25H 26ClN 3O 3 [M+H] + : calcd 452.1736, found 452.1688.MS (ESI) m/z for C 25 H 26 ClN 3 O 3 [M+H] + : calcd 452.1736, found 452.1688.
19. 제조예17: C209, L1901519. Preparation Example 17: C209, L19015
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 4-브로모벤질 브로마이드를 사용하여 화학식 20의 화합물을 수득하였다.It was synthesized in the same manner as in Preparation Example 10, but 4-bromobenzyl bromide was used instead of methyl iodide as a reactant to obtain a compound of Formula 20.
[화학식 20][Formula 20]
Figure PCTKR2019018660-appb-img-000061
,
Figure PCTKR2019018660-appb-img-000061
,
8-(4-bromobenzyl)-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C209 또는 L19015로 표현).8-(4-bromobenzyl)-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C209 or L19015).
1H-NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.25 - 7.17 (m, 2H), 7.13 (d, J = 8.5 Hz, 2H), 4.55-4.43 (m, 3H), 4.12 (d, J = 10.0 Hz, 1H), 3.84 (s, 2H), 3.73 (d, J = 13.0 Hz, 1H), 3.61 - 3.55 (m, 2H), 2.88 (d, J = 10.5 Hz, 1H), 2.81-2.69 (m, 3H), 2.10 (t, J = 11.0 Hz, 1H), 2.02 (dt, J = 11.5, 3.0 Hz 1H), 1.31 (t, J = 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.25 -7.17 (m, 2H), 7.13 (d, J = 8.5 Hz, 2H), 4.55-4.43 (m, 3H), 4.12 (d, J = 10.0 Hz, 1H), 3.84 (s, 2H), 3.73 ( d, J = 13.0 Hz, 1H), 3.61-3.55 (m, 2H), 2.88 (d, J = 10.5 Hz, 1H), 2.81-2.69 (m, 3H), 2.10 (t, J = 11.0 Hz, 1H) ), 2.02 (dt, J = 11.5, 3.0 Hz 1H), 1.31 (t, J = 7.5 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ163.79, 161.67, 158.32, 154.18, 134.24, 132.33, 130.41, 129.61, 123.65, 122.55, 122.52, 119.88, 110.94, 109.54, 57.55, 56.89, 51.81, 51.35, 49.03, 48.84, 41.64, 20.19, 13.10 ; 13 C-NMR (126 MHz, CDCl 3 ) δ163.79, 161.67, 158.32, 154.18, 134.24, 132.33, 130.41, 129.61, 123.65, 122.55, 122.52, 119.88, 110.94, 109.54, 57.55, 56.89, 51.81, 51.35, 49.03 , 48.84, 41.64, 20.19, 13.10;
MS (ESI) m/z for C 25H 26BrN 3O 3 [M+H] + : calcd 496.1230, found 496.1192.MS (ESI) m/z for C 25 H 26 BrN 3 O 3 [M+H] + : calcd 496.1230, found 496.1192.
20. 제조예18: C210, L1901620. Preparation Example 18: C210, L19016
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 4-플루오로벤질 브로마이드를 사용하여 화학식 21의 화합물을 수득하였다.It was synthesized in the same manner as in Preparation Example 10, using 4-fluorobenzyl bromide instead of the reactant methyl iodide to obtain a compound of Formula 21.
[화학식 21][Formula 21]
Figure PCTKR2019018660-appb-img-000062
,
Figure PCTKR2019018660-appb-img-000062
,
2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-fluorobenzyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C210 또는 L19016으로 표현).2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-fluorobenzyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C210 or L19016).
1H-NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.25 - 7.17 (m, 4H), 7.02 (t, J = 8.5 Hz, 2H), 4.53 (dd, J = 32.5, 14.5 Hz, 2H), 4.46 (d, J = 13.0 Hz, 1H), 4.12 (dd, J = 11.0, 3.0 Hz, 1H), 3.85 (s, 2H), 3.73 (d, J = 13.5 Hz, 1H), 3.59 (m, 2H), 2.88 (d, J = 11.5 Hz, 1H), 2.81-2.70 (m, 3H), 2.11 (t, J = 11.5 Hz, 1H), 2.02 (dt, J = 11.5, 3.5 Hz, 1H), 1.30 (t, J = 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.25-7.17 (m, 4H), 7.02 (t, J = 8.5 Hz, 2H), 4.53 (dd, J = 32.5, 14.5 Hz, 2H), 4.46 (d, J = 13.0 Hz, 1H), 4.12 (dd, J = 11.0, 3.0 Hz, 1H), 3.85 ( s, 2H), 3.73 (d, J = 13.5 Hz, 1H), 3.59 (m, 2H), 2.88 (d, J = 11.5 Hz, 1H), 2.81-2.70 (m, 3H), 2.11 (t, J = 11.5 Hz, 1H), 2.02 (dt, J = 11.5, 3.5 Hz, 1H), 1.30 (t, J = 7.5 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ163.72, 161.75, 158.31, 154.18, 131.07, 131.04, 130.56, 130.50, 129.62, 123.64, 122.55, 119.89, 116.20, 116.03, 110.93, 109.56, 57.58, 56.91, 51.82, 51.36, 48.87, 48.74, 41.62, 20.19, 13.10 ; 13 C-NMR (126 MHz, CDCl 3 ) δ163.72, 161.75, 158.31, 154.18, 131.07, 131.04, 130.56, 130.50, 129.62, 123.64, 122.55, 119.89, 116.20, 116.03, 110.93, 109.56, 57.58, 56.91, 51.82 , 51.36, 48.87, 48.74, 41.62, 20.19, 13.10;
MS (ESI) m/z for C 25H 26FN 3O 3 [M+H] + : calcd 436.2031, found 436.1994.MS (ESI) m/z for C 25 H 26 FN 3 O 3 [M+H] + : calcd 436.2031, found 436.1994.
21. 제조예19: C211, L1901721. Preparation Example 19: C211, L19017
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 4-트리플루오로메틸벤질 브로마이드를 사용하여 화학식 22의 화합물을 수득하였다.It was synthesized in the same manner as in Preparation Example 10, but 4-trifluoromethylbenzyl bromide was used instead of methyl iodide as a reactant to obtain a compound of Formula 22.
[화학식 22][Formula 22]
Figure PCTKR2019018660-appb-img-000063
,
Figure PCTKR2019018660-appb-img-000063
,
2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-(trifluoromethyl)benzyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C211 또는 L19017로 표현).2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-(trifluoromethyl)benzyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C211 or L19017 ).
1H-NMR (500 MHz, CDCl 3) δ7.62-7.58 (m, 3H), 7.41 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.26-7.19 (m, 2H), 4.62 (s, 2H), 4.47 (d, J = 13.5 Hz, 1H), 4.15 (dd, J = 11.0, 3.0 Hz, 1H), 3.87 (d, J = 4.0 Hz, 2H), 3.73 (d, J = 13.0 Hz, 1H), 3.62-3.57 (m, 2H), 2.90 (d, J = 11.5 Hz, 1H), 2.82-2.71 (m, 3H), 2.12 (t, J = 11.0 Hz, 1H), 2.03 (dt, J = 11.5, 3.5 Hz, 1H), 1.31 (t, J = 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.62-7.58 (m, 3H), 7.41 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.26-7.19 ( m, 2H), 4.62 (s, 2H), 4.47 (d, J = 13.5 Hz, 1H), 4.15 (dd, J = 11.0, 3.0 Hz, 1H), 3.87 (d, J = 4.0 Hz, 2H), 3.73 (d, J = 13.0 Hz, 1H), 3.62-3.57 (m, 2H), 2.90 (d, J = 11.5 Hz, 1H), 2.82-2.71 (m, 3H), 2.12 (t, J = 11.0 Hz , 1H), 2.03 (dt, J = 11.5, 3.5 Hz, 1H), 1.31 (t, J = 7.5 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ163.93, 161.55, 158.34, 154.18, 139.28, 129.60, 128.92, 126.21, 126.18, 126.15, 126.12, 123.66, 122.56, 119.87, 110.95, 109.52, 57.55, 56.88, 51.81, 51.35, 49.20, 49.03, 41.67, 20.19, 13.08 ; 13 C-NMR (126 MHz, CDCl 3 ) δ163.93, 161.55, 158.34, 154.18, 139.28, 129.60, 128.92, 126.21, 126.18, 126.15, 126.12, 123.66, 122.56, 119.87, 110.95, 109.52, 57.55, 56.88 , 51.35, 49.20, 49.03, 41.67, 20.19, 13.08;
MS (ESI) m/z for C 26H 26F 3N 3O 3 [M+H] + : calcd 486.1999, found 486.1958.MS (ESI) m/z for C 26 H 26 F 3 N 3 O 3 [M+H] + : calcd 486.1999, found 486.1958.
22. 제조예20: C212, L1901822. Preparation Example 20: C212, L19018
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 4-시아노벤질 브로마이드를 사용하여 화학식 23의 화합물을 수득하였다.It was synthesized in the same manner as in Preparation Example 10, using 4-cyanobenzyl bromide instead of the reactant methyl iodide to obtain a compound of Formula 23.
[화학식 23][Formula 23]
Figure PCTKR2019018660-appb-img-000064
,
Figure PCTKR2019018660-appb-img-000064
,
4-((8-((2-ethylbenzofuran-3-yl)methyl)-1,4-dioxooctahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)benzonitrile (C212 또는 L19018로 표현).4-((8-((2-ethylbenzofuran-3-yl)methyl)-1,4-dioxooctahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)benzonitrile (expressed as C212 or L19018 ).
1H-NMR (500 MHz, CDCl 3) δ7.64 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.5 Hz, 2H), 7.30 (dt, J = 8.0, 1.5 Hz, 1H), 7.19 (dt, J = 7.5, 1.5 Hz, 1H), 4.61 (s, 2H), 4.47 (d, J = 13.5 Hz, 1H), 4.15 (dd, J = 11.0, 3.0 Hz, 1H), 3.88 (d, J = 5.5 Hz, 2H), 3.73 (d, J = 13.5 Hz, 1H), 3.63-3.56 (m, 2H), 2.90 (d, J = 12.0 Hz, 1H), 2.81-2.72 (m, 3H), 2.12 (t, J = 11.5 Hz, 1H), 2.04 (dt, J = 12.0, 3.5 Hz, 1H), 1.31 (t, J = 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.64 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.5 Hz, 2H), 7.30 (dt, J = 8.0, 1.5 Hz, 1H), 7.19 (dt, J = 7.5, 1.5 Hz, 1H), 4.61 (s, 2H), 4.47 (d, J = 13.5 Hz, 1H), 4.15 (dd, J = 11.0, 3.0 Hz, 1H), 3.88 (d, J = 5.5 Hz, 2H), 3.73 (d, J = 13.5 Hz, 1H), 3.63-3.56 ( m, 2H), 2.90 (d, J = 12.0 Hz, 1H), 2.81-2.72 (m, 3H), 2.12 (t, J = 11.5 Hz, 1H), 2.04 (dt, J = 12.0, 3.5 Hz, 1H ), 1.31 (t, J = 7.5 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ164.05, 161.42, 158.33, 154.17, 140.63, 132.98, 129.59, 129.16, 123.66, 122.55, 119.85, 118.57, 112.43, 110.95, 109.48, 57.50, 56.81, 51.80, 51.34, 49.33, 49.20, 41.70, 20.19, 13.09 ; 13 C-NMR (126 MHz, CDCl 3 ) δ164.05, 161.42, 158.33, 154.17, 140.63, 132.98, 129.59, 129.16, 123.66, 122.55, 119.85, 118.57, 112.43, 110.95, 109.48, 57.50, 56.81, 51.80, 51.34 , 49.33, 49.20, 41.70, 20.19, 13.09;
MS (ESI) m/z for C 26H 26N 4O 3 [M+H] + : calcd 443.2078, found 443.2043.MS (ESI) m/z for C 26 H 26 N 4 O 3 [M+H] + : calcd 443.2078, found 443.2043.
23. 제조예21: C213, L1901923. Preparation Example 21: C213, L19019
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 4-니트로벤질 브로마이드를 사용하여 화학식 24의 화합물을 수득하였다.It was synthesized in the same manner as in Preparation Example 10, but 4-nitrobenzyl bromide was used instead of methyl iodide as a reactant to obtain a compound of Formula 24.
[화학식 24][Formula 24]
Figure PCTKR2019018660-appb-img-000065
,
Figure PCTKR2019018660-appb-img-000065
,
2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-nitrobenzyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C213 또는 L19019로 표현).2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-nitrobenzyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C213 or L19019).
1H-NMR (500 MHz, CDCl 3) δ8.20 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 7.5 Hz, 1H), 7.26-7.17 (m, 2H), 4.67 (s, 2H), 4.47 (d, J = 13.0 Hz, 1H), 4.17 (dd, J = 11.0, 3.0 Hz, 1H), 3.90 (d, J = 5.5 Hz, 2H), 3.74 (d, J = 13.0 Hz, 1H), 3.63 - 3.56 (m, 2H), 2.91 (d, J = 11.5 Hz, 1H), 2.82-2.73 (m, 3H), 2.13 (t, J = 11.0 Hz, 1H), 2.04 (dd, J = 11.5, 3.0 Hz, 1H), 1.31 (t, J = 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ8.20 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 7.5 Hz, 1H), 7.26-7.17 (m, 2H), 4.67 (s, 2H), 4.47 (d, J = 13.0 Hz, 1H), 4.17 (dd, J = 11.0, 3.0 Hz, 1H), 3.90 (d, J = 5.5 Hz, 2H), 3.74 (d, J = 13.0 Hz, 1H), 3.63-3.56 (m, 2H), 2.91 (d, J = 11.5 Hz, 1H), 2.82- 2.73 (m, 3H), 2.13 (t, J = 11.0 Hz, 1H), 2.04 (dd, J = 11.5, 3.0 Hz, 1H), 1.31 (t, J = 7.5 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ164.10, 161.37, 158.35, 154.18, 148.02, 142.61, 129.59, 129.30, 124.40, 123.67, 122.56, 119.85, 110.96, 109.47, 57.50, 56.81, 51.80, 51.34, 49.26, 49.11, 41.71, 20.19, 13.09 ; 13 C-NMR (126 MHz, CDCl 3 ) δ164.10, 161.37, 158.35, 154.18, 148.02, 142.61, 129.59, 129.30, 124.40, 123.67, 122.56, 119.85, 110.96, 109.47, 57.50, 56.81, 51.80, 51.34, 49 , 49.11, 41.71, 20.19, 13.09;
MS (ESI) m/z for C 25H 26N 4O 5 [M+H] + : calcd 463.1976, found 463.1939.MS (ESI) m/z for C 25 H 26 N 4 O 5 [M+H] + : calcd 463.1976, found 463.1939.
23. 제조예22: C214, L1902023. Preparation Example 22: C214, L19020
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 4-페닐벤질 브로마이드를 사용하여 화학식 25의 화합물을 수득하였다.It was synthesized in the same manner as in Preparation Example 10, but 4-phenylbenzyl bromide was used instead of methyl iodide as a reactant to obtain a compound of Formula 25.
[화학식 25][Formula 25]
Figure PCTKR2019018660-appb-img-000066
,
Figure PCTKR2019018660-appb-img-000066
,
8-([1,1'-biphenyl]-4-ylmethyl)-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C214 또는 L19020으로 표현).8-([1,1'-biphenyl]-4-ylmethyl)-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (Expressed as C214 or L19020).
1H-NMR (500 MHz, CDCl 3) δ7.61 - 7.54 (m, 5H), 7.46 - 7.39 (m, 3H), 7.37-7.31 (m, 3H), 7.24 - 7.17 (m, 2H), 4.60 (q, J = 14.5 Hz, 2H), 4.46 (d, J = 13.0 Hz, 1H), 4.14 (, J = 11.0 Hz, 1H), 3.90 (s, 2H), 3.73 (d, J = 13.5 Hz, 1H), 3.63-3.57 (m, 2H), 2.88 (d, J = 12.0 Hz, 1H), 2.81-2.70 (m, 3H), 2.14 (t, J = 11.0 Hz, 1H), 2.02 (dt, J = 12.0, 3.5 Hz, 1H), 1.31 (t, J = 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.61-7.54 (m, 5H), 7.46-7.39 (m, 3H), 7.37-7.31 (m, 3H), 7.24-7.17 (m, 2H), 4.60 (q, J = 14.5 Hz, 2H), 4.46 (d, J = 13.0 Hz, 1H), 4.14 (, J = 11.0 Hz, 1H), 3.90 (s, 2H), 3.73 (d, J = 13.5 Hz, 1H), 3.63-3.57 (m, 2H), 2.88 (d, J = 12.0 Hz, 1H), 2.81-2.70 (m, 3H), 2.14 (t, J = 11.0 Hz, 1H), 2.02 (dt, J = 12.0, 3.5 Hz, 1H), 1.31 (t, J = 7.5 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ163.73, 161.91, 158.33, 154.19, 141.46, 140.70, 134.13, 129.65, 129.23, 129.08, 127.93, 127.76, 127.33, 123.65, 122.57, 119.92, 110.94, 109.59, 57.63, 56.97, 51.84, 51.38, 49.29, 48.84, 41.63, 20.21, 13.13 ; 13 C-NMR (126 MHz, CDCl 3 ) δ163.73, 161.91, 158.33, 154.19, 141.46, 140.70, 134.13, 129.65, 129.23, 129.08, 127.93, 127.76, 127.33, 123.65, 122.57, 119.92, 110.94, 109 , 56.97, 51.84, 51.38, 49.29, 48.84, 41.63, 20.21, 13.13;
MS (ESI) m/z for C 31H 31N 3O 3 [M+H] + : calcd 494.2438, found 494.2394.MS (ESI) m/z for C 31 H 31 N 3 O 3 [M+H] + : calcd 494.2438, found 494.2394.
24. 제조예23: C215, L1902124. Preparation Example 23: C215, L19021
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 페닐에틸 브로마이드를 사용하여 화학식 26의 화합물을 수득하였다.It was synthesized in the same manner as in Preparation Example 10, but a compound of Formula 26 was obtained using phenylethyl bromide instead of the reactant methyl iodide.
[화학식 26][Formula 26]
Figure PCTKR2019018660-appb-img-000067
,
Figure PCTKR2019018660-appb-img-000067
,
2-((2-ethylbenzofuran-3-yl)methyl)-8-phenethylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C215 또는 L19021로 표현).2-((2-ethylbenzofuran-3-yl)methyl)-8-phenethylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C215 or L19021).
1H-NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.31-7.16 (m, 7H), 4.44 (d, J = 13.0 Hz, 1H), 4.02 (dd, J = 11.0, 3.5 Hz, 1H), 3.78 (d, J = 7.0 Hz, 2H), 3.70 (d, J = 13.5 Hz, 1H), 3.65-3.54 (m, 3H), 3.51 (d, J = 11.0 Hz, 1H), 2.91 - 2.85 (m, 3H), 2.78 (q, J = 7.5 Hz, 2H), 2.71 (dt, J = 12.5, 3.0 Hz, 1H), 2.03 - 1.95 (m, 2H), 1.30 (t, J = 7.5 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.31-7.16 (m, 7H), 4.44 (d, J = 13.0 Hz, 1H), 4.02 (dd, J = 11.0, 3.5 Hz, 1H), 3.78 (d, J = 7.0 Hz, 2H), 3.70 (d, J = 13.5 Hz, 1H), 3.65-3.54 ( m, 3H), 3.51 (d, J = 11.0 Hz, 1H), 2.91-2.85 (m, 3H), 2.78 (q, J = 7.5 Hz, 2H), 2.71 (dt, J = 12.5, 3.0 Hz, 1H ), 2.03-1.95 (m, 2H), 1.30 (t, J = 7.5 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ163.53, 161.89, 158.30, 154.17, 138.14, 129.64, 128.97, 128.94, 127.06, 123.63, 122.55, 119.91, 110.92, 109.59, 57.48, 56.86, 51.82, 51.41, 50.13, 48.14, 41.60, 33.08, 20.19, 13.12 ; 13 C-NMR (126 MHz, CDCl 3 ) δ163.53, 161.89, 158.30, 154.17, 138.14, 129.64, 128.97, 128.94, 127.06, 123.63, 122.55, 119.91, 110.92, 109.59, 57.48, 56.86, 51.82, 51.41, 50. , 48.14, 41.60, 33.08, 20.19, 13.12;
MS (ESI) m/z for C 26H 29N 3O 3 [M+H] + : calcd 432.2282, found 432.2239.MS (ESI) m/z for C 26 H 29 N 3 O 3 [M+H] + : calcd 432.2282, found 432.2239.
25. 제조예24: C216, L1902225. Preparation Example 24: C216, L19022
제조예 10과 동일한 방법으로 합성하되, 반응물질인 메틸아이오다이드 대신 4-플루오로페네틸 브로마이드(4-fluorophenethyl bromide)를 사용하여 화학식 27의 화합물을 수득하였다.It was synthesized in the same manner as in Preparation Example 10, but 4-fluorophenethyl bromide was used instead of methyl iodide as a reactant to obtain a compound of Formula 27.
[화학식 27][Formula 27]
Figure PCTKR2019018660-appb-img-000068
,
Figure PCTKR2019018660-appb-img-000068
,
2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-fluorophenethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C216 또는 L19022로 표현).2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-fluorophenethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C216 or L19022).
1H-NMR (500 MHz, CDCl 3) δ7.58 (d, J = 7.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.23 - 7.17 (m, 2H), 7.17 - 7.12 (m, 2H), 6.97 (t, J = 8.5 Hz, 2H), 4.44 (d, J = 13.0 Hz, 1H), 4.01 (dd, J = 11.0, 3.0 Hz, 1H), 3.82 (d, J = 6.0, 2H), 3.69 (d, J = 13.5 Hz, 1H), 3.63 - 3.47 (m, 4H), 2.88 - 2.83 (m, 3H), 2.79 - 2.70 (m, 3H), 2.01 - 1.95 (m, 2H), 1.29 (t, J = 7.8 Hz, 3H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.58 (d, J = 7.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.23-7.17 (m, 2H), 7.17-7.12 ( m, 2H), 6.97 (t, J = 8.5 Hz, 2H), 4.44 (d, J = 13.0 Hz, 1H), 4.01 (dd, J = 11.0, 3.0 Hz, 1H), 3.82 (d, J = 6.0 , 2H), 3.69 (d, J = 13.5 Hz, 1H), 3.63-3.47 (m, 4H), 2.88-2.83 (m, 3H), 2.79-2.70 (m, 3H), 2.01-1.95 (m, 2H) ), 1.29 (t, J = 7.8 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ163.57, 161.78, 158.32, 154.16, 133.74, 133.72, 130.41, 130.34, 129.62, 123.63, 122.54, 119.89, 115.88, 115.71, 110.92, 109.55, 57.45, 56.82, 51.80, 51.41, 50.00, 47.95, 41.61, 32.20, 20.18, 13.10 ; 13 C-NMR (126 MHz, CDCl 3 ) δ163.57, 161.78, 158.32, 154.16, 133.74, 133.72, 130.41, 130.34, 129.62, 123.63, 122.54, 119.89, 115.88, 115.71, 110.92, 109.55, 57.45, 56.82, 51.80 , 51.41, 50.00, 47.95, 41.61, 32.20, 20.18, 13.10;
MS (ESI) m/z for C 26H 28FN 3O 3 [M+H] + : calcd 450.2188, found 450.2155.MS (ESI) m/z for C 26 H 28 FN 3 O 3 [M+H] + : calcd 450.2188, found 450.2155.
26. 제조예25: C302, L1902326. Preparation Example 25: C302, L19023
제조예 1-1과 동일한 방법으로 합성하되, 단계 1(반응식1)에서 반응물질인 에틸아이오다이드 대신 메틸아이오다이드를 사용하여 화학식 28의 화합물을 수득하였다.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.
[화학식 28][Formula 28]
Figure PCTKR2019018660-appb-img-000069
,
Figure PCTKR2019018660-appb-img-000069
,
2-((2-methylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C302 또는 L19023으로 표현).2-((2-methylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C302 or L19023).
1H-NMR (500 MHz, CDCl 3) δ7.57 (d, J = 7.0 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.24 - 7.17 (m, 2H), 4.50 (d, J = 13.5Hz, 1H), 4.06 (d, J = 11.0 Hz, 1H), 4.00 (s, 2H), 3.64 (dd, J = 52.0, 13.5 Hz, 2H), 3.46 (d, J = 11.5 Hz, 1H), 2.90 (d, J = 11.5 Hz, 1H), 2.75 (td, J = 12.5, 3.0 Hz, 1H), 2.42 (s, 3H), 2.12 (t, J = 11.5 Hz, 1H), 2.06 - 2.02 (td, J = 11.5, 3.0 Hz, 1H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.57 (d, J = 7.0 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.24-7.17 (m, 2H), 4.50 (d, J = 13.5Hz, 1H), 4.06 (d, J = 11.0 Hz, 1H), 4.00 (s, 2H), 3.64 (dd, J = 52.0, 13.5 Hz, 2H), 3.46 (d, J = 11.5 Hz, 1H), 2.90 (d, J = 11.5 Hz, 1H), 2.75 (td, J = 12.5, 3.0 Hz, 1H), 2.42 (s, 3H), 2.12 (t, J = 11.5 Hz, 1H), 2.06- 2.02 (td, J = 11.5, 3.0 Hz, 1H);
13C-NMR (126 MHz, CDCl 3) δ166.24, 161.97, 154.13, 153.42, 129.60, 123.64, 122.61, 119.68, 110.83, 110.45, 57.17, 56.34, 51.95, 51.60, 44.76, 41.75, 12.48 ; 13 C-NMR (126 MHz, CDCl 3 ) δ166.24, 161.97, 154.13, 153.42, 129.60, 123.64, 122.61, 119.68, 110.83, 110.45, 57.17, 56.34, 51.95, 51.60, 44.76, 41.75, 12.48;
MS (ESI) m/z for C 17H 19N 3O 3 [M+H] + : calcd 314.1499, found 314.1508.MS (ESI) m/z for C 17 H 19 N 3 0 3 [M+H] + : calcd 314.1499, found 314.1508.
27. 제조예26: C303, L1902427. Preparation Example 26: C303, L19024
제조예 1-1과 동일한 방법으로 합성하되, 단계 1(반응식1)에서 생성된 2-에틸 벤조퓨란 대신 2-부틸 벤조퓨란을 구매하여 반응시키고, 화학식 29의 화합물을 수득하였다.It was synthesized in the same manner as in Production Example 1-1, but instead of 2-ethyl benzofuran produced in Step 1 (Scheme 1), 2-butyl benzofuran was purchased for reaction, and a compound of Formula 29 was obtained.
[화학식 29][Formula 29]
Figure PCTKR2019018660-appb-img-000070
,
Figure PCTKR2019018660-appb-img-000070
,
2-((2-butylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C303 또는 L19024로 표현).2-((2-butylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C303 or L19024).
1H NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.24-7.16 (m, 2H), 4.50 (d, J = 13.0 Hz, 1H), 4.07 (d, J = 11.0 Hz, 1H), 4.00 (s, 2H), 3.65 (dd, J = 66.0, 13.5 Hz, 2H), 3.47 (d, J = 11.5 Hz, 1H), 2.89 (d, J = 11.5 Hz, 1H), 2.77 - 2.71 (m, 3H), 2.12 (t, J = 11.0 Hz, 1H), 2.03 (td, J = 11.5, 3.0 Hz, 1H), 1.74 - 1.67 (m, 2H), 1.42 - 1.33 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H) ; 1 H NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.24-7.16 (m, 2H), 4.50 (d, J = 13.0 Hz, 1H), 4.07 (d, J = 11.0 Hz, 1H), 4.00 (s, 2H), 3.65 (dd, J = 66.0, 13.5 Hz, 2H), 3.47 (d, J = 11.5 Hz, 1H ), 2.89 (d, J = 11.5 Hz, 1H), 2.77-2.71 (m, 3H), 2.12 (t, J = 11.0 Hz, 1H), 2.03 (td, J = 11.5, 3.0 Hz, 1H), 1.74 -1.67 (m, 2H), 1.42-1.33 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ166.35, 161.98, 157.33, 154.18, 129.57, 123.61, 122.52, 119.88, 110.92, 110.24, 57.20, 56.51, 51.96, 51.56, 44.76, 41.79, 30.60, 26.44, 22.63, 14.10 ; 13 C-NMR (126 MHz, CDCl 3 ) δ166.35, 161.98, 157.33, 154.18, 129.57, 123.61, 122.52, 119.88, 110.92, 110.24, 57.20, 56.51, 51.96, 51.56, 44.76, 41.79, 30.60, 26.44, 22.63 , 14.10;
MS (ESI) m/z for C 20H 25N 3O 3 [M+H] + : calcd 356.1969, found 356.1979.MS (ESI) m/z for C 20 H 25 N 3 O 3 [M+H] + : calcd 356.1969, found 356.1979.
28. 제조예27: C304, L1902528. Preparation Example 27: C304, L19025
제조예 1-1과 동일한 방법으로 합성하되, 단계 1(반응식1)에서 반응물질인 에틸아이오다이드 대신 헥실브로마이드를 사용하여 화학식 30의 화합물을 수득하였다.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.
[화학식 30][Formula 30]
Figure PCTKR2019018660-appb-img-000071
,
Figure PCTKR2019018660-appb-img-000071
,
2-((2-hexylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C304 또는 L19025로 표현).2-((2-hexylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C304 or L19025).
1H NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.24-7.16 (m, 2H), 4.65 (s, 1H), 4.47 (d, J = 13.5 Hz, 1H), 4.04 (d, J = 11.0 Hz, 1H), 3.96 (s, 2H), 3.64 (dd, J = 70.0, 13.0 Hz, 2H), 3.46 (d, J = 11.5 Hz, 1H), 2.88 (d, J = 11.5 Hz, 1H), 2.76 - 2.72 (m, 3H), 2.10 (d, J = 11.0 Hz, 1H), 2.01 (td, J = 11.5, 3.0 Hz, 1H), 1.75 - 1.66 (m, 2H), 1.37 - 1.28 (m, 5H), 0.88 (t, J = 7.0 Hz, 3H) ; 1 H NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.24-7.16 (m, 2H), 4.65 (s, 1H ), 4.47 (d, J = 13.5 Hz, 1H), 4.04 (d, J = 11.0 Hz, 1H), 3.96 (s, 2H), 3.64 (dd, J = 70.0, 13.0 Hz, 2H), 3.46 (d , J = 11.5 Hz, 1H), 2.88 (d, J = 11.5 Hz, 1H), 2.76-2.72 (m, 3H), 2.10 (d, J = 11.0 Hz, 1H), 2.01 (td, J = 11.5, 3.0 Hz, 1H), 1.75-1.66 (m, 2H), 1.37-1.28 (m, 5H), 0.88 (t, J = 7.0 Hz, 3H);
13C-NMR (126 MHz, CDCl 3) δ166.27, 162.03, 157.39, 154.18, 129.59, 123.62, 122.53, 119.88, 110.93, 110.20, 57.18, 56.51, 51.94, 51.52, 44.72, 41.78, 31.79, 29.23, 28.48, 26.75, 22.79, 14.32 ; 13 C-NMR (126 MHz, CDCl 3 ) δ166.27, 162.03, 157.39, 154.18, 129.59, 123.62, 122.53, 119.88, 110.93, 110.20, 57.18, 56.51, 51.94, 51.52, 44.72, 41.78, 31.79, 29.23, 28.48 , 26.75, 22.79, 14.32;
MS (ESI) m/z for C 22H 29N 3O 3 [M+H] + : calcd 384.2282, found 384.2292.MS (ESI) m/z for C 22 H 29 N 3 O 3 [M+H] + : calcd 384.2282, found 384.2292.
29. 제조예28: C306, L1902629. Preparation Example 28: C306, L19026
제조예 1-1과 동일한 방법으로 합성하되, 단계 1(반응식1)에서 반응물질인 에틸아이오다이드 대신 벤질브로마이드를 사용하여 화학식 31의 화합물을 수득하였다.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.
[화학식 31][Formula 31]
Figure PCTKR2019018660-appb-img-000072
,
Figure PCTKR2019018660-appb-img-000072
,
2-((2-benzylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C306 또는 L19026으로 표현).2-((2-benzylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C306 or L19026).
1H-NMR (500 MHz, CDCl 3) δ7.64 (d, J = 7.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.31 - 7.19 (m, 6H), 4.47 (d, J = 13.0 Hz, 1H), 4.14 (s, 2H), 4.05 (d, J = 11.0 Hz, 1H), 4.01 (s, 2H), 3.69 (dd, J = 73.0, 13.5 Hz, 2H), 3.49 (d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.5 Hz, 1H), 2.70 (dt, J = 12.5, 3.0 Hz, 1H), 2.13 (t, J = 11.5 Hz, 1H), 2.00 (dt, J = 11.5, 3.0 Hz, 1H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.64 (d, J = 7.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.31-7.19 (m, 6H), 4.47 (d, J = 13.0 Hz, 1H), 4.14 (s, 2H), 4.05 (d, J = 11.0 Hz, 1H), 4.01 (s, 2H), 3.69 (dd, J = 73.0, 13.5 Hz, 2H), 3.49 ( d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.5 Hz, 1H), 2.70 (dt, J = 12.5, 3.0 Hz, 1H), 2.13 (t, J = 11.5 Hz, 1H), 2.00 ( dt, J = 11.5, 3.0 Hz, 1H);
13C-NMR (126 MHz, CDCl 3) δ166.27, 162.01, 154.96, 154.40, 137.71, 129.45, 128.86, 128.79, 126.93, 124.06, 122.73, 120.07, 111.55, 111.23, 57.16, 56.58, 51.92, 51.58, 44.77, 41.73, 33.09 ; 13 C-NMR (126 MHz, CDCl 3 ) δ166.27, 162.01, 154.96, 154.40, 137.71, 129.45, 128.86, 128.79, 126.93, 124.06, 122.73, 120.07, 111.55, 111.23, 57.16, 56.58, 51.92, 51.58, 44.77 , 41.73, 33.09;
MS (ESI) m/z for C 23H 23N 3O 3 [M+H] + : calcd 390.1812, found 390.1820.MS (ESI) m/z for C 23 H 23 N 3 O 3 [M+H] + : calcd 390.1812, found 390.1820.
30. 제조예29: C308, L1902730. Preparation Example 29: C308, L19027
제조예 1-1과 동일한 방법으로 합성하되, 단계 1(반응식1)에서 반응물질인 에틸아이오다이드 대신 4-클로로벤질브로마이드를 사용하여 화학식 32의 화합물을 수득하였다.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.
[화학식 32][Formula 32]
Figure PCTKR2019018660-appb-img-000073
,
Figure PCTKR2019018660-appb-img-000073
,
2-((2-(4-chlorobenzyl)benzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C308 또는 L19027로 표현).2-((2-(4-chlorobenzyl)benzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C308 or L19027).
1H-NMR (500 MHz, CDCl 3) δ7.62 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.26 - 7.15 (m, 6H), 4.48 (d, J = 13.0 Hz, 1H), 4.09 (s, 2H), 4.05 - 4.00 (m, 3H), 3.69 (dd, J = 58.0, 13.5 Hz, 2H), 3.46 (d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.5 Hz, 1H), 2.70 (dt, J = 12.5, 3.0 Hz, 1H), 2.09 (t, J = 11.0 Hz, 1H), 2.02 (dt, J = 11.5, 3.0 Hz, 1H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.62 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.26-7.15 (m, 6H), 4.48 (d, J = 13.0 Hz, 1H), 4.09 (s, 2H), 4.05-4.00 (m, 3H), 3.69 (dd, J = 58.0, 13.5 Hz, 2H), 3.46 (d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.5 Hz, 1H), 2.70 (dt, J = 12.5, 3.0 Hz, 1H), 2.09 (t, J = 11.0 Hz, 1H), 2.02 (dt, J = 11.5, 3.0 Hz, 1H) );
13C-NMR (126 MHz, CDCl 3) δ166.01, 161.93, 154.40, 154.29, 136.14, 132.75, 130.12, 129.30, 128.96, 124.23, 122.83, 120.07, 111.75, 111.24, 57.12, 56.48, 51.88, 51.69, 44.80, 41.73, 32.43 ; 13 C-NMR (126 MHz, CDCl 3 ) δ166.01, 161.93, 154.40, 154.29, 136.14, 132.75, 130.12, 129.30, 128.96, 124.23, 122.83, 120.07, 111.75, 111.24, 57.12, 56.48, 51.88, 51.69, 44.80 , 41.73, 32.43;
MS (ESI) m/z for C 23H 22ClN 3O 3 [M+H] + : calcd 424.1423, found 424.1423.MS (ESI) m/z for C 23 H 22 ClN 3 O 3 [M+H] + : calcd 424.1423, found 424.1423.
31. 제조예30: C310, L1902831. Preparation Example 30: C310, L19028
제조예 1-1과 동일한 방법으로 합성하되, 단계 1(반응식1)에서 반응물질인 에틸아이오다이드 대신 4-플루오로벤질브로마이드를 사용하여 화학식 33의 화합물을 수득하였다.It was synthesized in the same manner as in Production Example 1-1, but using 4-fluorobenzyl bromide instead of ethyl iodide as a reactant in Step 1 (Scheme 1) to obtain a compound of Formula 33.
[화학식 33][Formula 33]
Figure PCTKR2019018660-appb-img-000074
,
Figure PCTKR2019018660-appb-img-000074
,
2-((2-(4-fluorobenzyl)benzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C310 또는 L19028로 표현).2-((2-(4-fluorobenzyl)benzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C310 or L19028).
1H-NMR (500 MHz, CDCl 3) δ7.65-7.61 (m, 2H), 7.38 (d, J = 7.5 Hz, 1H), 7.25-7.18 (m, 3H), 6.97 (t, J = 8.5 Hz, 2H), 4.47 (d, J = 13.0 Hz, 1H), 4.10 (s, 2H), 4.02 (d, J = 11.0 Hz, 1H) 3.97 (s, 2H), 3.69 (dd, J = 50.5, 13.5 Hz, 2H), 3.47 (d, J = 10.5 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 2.74-2.67 (m, 1H), 2.10 (t, J = 11.5 Hz, 1H), 2.032.06-2.00 (m, 1H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.65-7.61 (m, 2H), 7.38 (d, J = 7.5 Hz, 1H), 7.25-7.18 (m, 3H), 6.97 (t, J = 8.5 Hz, 2H), 4.47 (d, J = 13.0 Hz, 1H), 4.10 (s, 2H), 4.02 (d, J = 11.0 Hz, 1H) 3.97 (s, 2H), 3.69 (dd, J = 50.5, 13.5 Hz, 2H), 3.47 (d, J = 10.5 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 2.74-2.67 (m, 1H), 2.10 (t, J = 11.5 Hz, 1H) , 2.032.06-2.00 (m, 1H);
13C-NMR (126 MHz, CDCl 3) δ165.41, 162.72, 162.33, 160.77, 154.50, 154.25, 133.36, 133.34, 130.22, 130.15, 129.28, 124.01, 122.68, 120.06, 115.59, 115.43, 111.60, 111.03, 57.08, 56.42, 51.79, 51.68, 44.65, 41.55, 32.13 ; 13 C-NMR (126 MHz, CDCl 3 ) δ165.41, 162.72, 162.33, 160.77, 154.50, 154.25, 133.36, 133.34, 130.22, 130.15, 129.28, 124.01, 122.68, 120.06, 115.59, 115.43, 111.60, 111.03, 57.08 , 56.42, 51.79, 51.68, 44.65, 41.55, 32.13;
MS (ESI) m/z for C 23H 22FN 3O 3 [M+H] + : calcd4 08.1718, found 408.1723.MS (ESI) m/z for C 23 H 22 FN 3 O 3 [M+H] + : calcd4 08.1718, found 408.1723.
32. 제조예31: C315, L1903032. Preparation Example 31: C315, L19030
제조예 1-1과 동일한 방법으로 합성하되, 단계 1(반응식1)에서 반응물질인 에틸아이오다이드 대신 페닐에틸브로마이드를 사용하여 화학식 34의 화합물을 수득하였다.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.
[화학식 34][Formula 34]
Figure PCTKR2019018660-appb-img-000075
,
Figure PCTKR2019018660-appb-img-000075
,
2-((2-phenethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (C315 또는 L19030으로 표현).2-((2-phenethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (expressed as C315 or L19030).
1H-NMR (500 MHz, CDCl 3) δ7.59 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.28-7.24 (m, 3H), 7.23 - 7.18 (m, 2H), 7.15 (d, J = 7.0 Hz, 2H), 4.41 (d, J = 11.5 Hz, 1H), 4.04 (d, J = 11.0 Hz, 1H), 4.00 (s, 2H), 3.45 (dd, J = 84.0, 13.5 Hz, 2H), 3.42 (d, J = 11.0 Hz, 1H), 3.03-3.09 (m, 4H), 2.69 - 2.63 (m, 2H), 2.04 (t, J = 11.0 Hz, 1H), 1.87 - 1.80 (m, 1H) ; 1 H-NMR (500 MHz, CDCl 3 ) δ7.59 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.28-7.24 (m, 3H), 7.23-7.18 ( m, 2H), 7.15 (d, J = 7.0 Hz, 2H), 4.41 (d, J = 11.5 Hz, 1H), 4.04 (d, J = 11.0 Hz, 1H), 4.00 (s, 2H), 3.45 ( dd, J = 84.0, 13.5 Hz, 2H), 3.42 (d, J = 11.0 Hz, 1H), 3.03-3.09 (m, 4H), 2.69-2.63 (m, 2H), 2.04 (t, J = 11.0 Hz , 1H), 1.87-1.80 (m, 1H);
13C-NMR (126 MHz, CDCl 3) δ166.24, 161.90, 155.71, 154.27, 141.08, 129.43, 128.72, 128.70, 126.49, 123.84, 122.62, 120.06, 111.15, 110.98, 57.17, 56.49, 51.75, 51.27, 44.77, 41.74, 34.57, 29.10 ; 13 C-NMR (126 MHz, CDCl 3 ) δ166.24, 161.90, 155.71, 154.27, 141.08, 129.43, 128.72, 128.70, 126.49, 123.84, 122.62, 120.06, 111.15, 110.98, 57.17, 56.49, 51.75, 51.27, 44.77 , 41.74, 34.57, 29.10;
MS (ESI) m/z for C 24H 25N 3O 3 [M+H] + : calcd 404.1969, found 404.1972.MS (ESI) m/z for C 24 H 25 N 3 O 3 [M+H] + : calcd 404.1969, found 404.1972.
전술한 제조예들에 의해 합성된 화학식 2 내지 화학식 34의 화합물 구조를 하기 표 2에 나타내었다.The compound structures of Formulas 2 to 34 synthesized by the above-described preparation examples are shown in Table 2 below.
화학식Chemical formula 화학구조Chemical structure 화학식Chemical formula 화학구조Chemical structure
22
Figure PCTKR2019018660-appb-img-000076
Figure PCTKR2019018660-appb-img-000076
 		33
Figure PCTKR2019018660-appb-img-000077
Figure PCTKR2019018660-appb-img-000077
44
Figure PCTKR2019018660-appb-img-000078
Figure PCTKR2019018660-appb-img-000078
 		55
Figure PCTKR2019018660-appb-img-000079
Figure PCTKR2019018660-appb-img-000079
66
Figure PCTKR2019018660-appb-img-000080
Figure PCTKR2019018660-appb-img-000080
 		77
Figure PCTKR2019018660-appb-img-000081
Figure PCTKR2019018660-appb-img-000081
88
Figure PCTKR2019018660-appb-img-000082
Figure PCTKR2019018660-appb-img-000082
 		99
Figure PCTKR2019018660-appb-img-000083
Figure PCTKR2019018660-appb-img-000083
1010
Figure PCTKR2019018660-appb-img-000084
Figure PCTKR2019018660-appb-img-000084
 		1111
Figure PCTKR2019018660-appb-img-000085
Figure PCTKR2019018660-appb-img-000085
1212
Figure PCTKR2019018660-appb-img-000086
Figure PCTKR2019018660-appb-img-000086
 		1313
Figure PCTKR2019018660-appb-img-000087
Figure PCTKR2019018660-appb-img-000087
1414
Figure PCTKR2019018660-appb-img-000088
Figure PCTKR2019018660-appb-img-000088
 		1515
Figure PCTKR2019018660-appb-img-000089
Figure PCTKR2019018660-appb-img-000089
1616
Figure PCTKR2019018660-appb-img-000090
Figure PCTKR2019018660-appb-img-000090
 		1717
Figure PCTKR2019018660-appb-img-000091
Figure PCTKR2019018660-appb-img-000091
1818
Figure PCTKR2019018660-appb-img-000092
Figure PCTKR2019018660-appb-img-000092
 		1919
Figure PCTKR2019018660-appb-img-000093
Figure PCTKR2019018660-appb-img-000093
2020
Figure PCTKR2019018660-appb-img-000094
Figure PCTKR2019018660-appb-img-000094
 		2121
Figure PCTKR2019018660-appb-img-000095
Figure PCTKR2019018660-appb-img-000095
2222
Figure PCTKR2019018660-appb-img-000096
Figure PCTKR2019018660-appb-img-000096
 		2323
Figure PCTKR2019018660-appb-img-000097
Figure PCTKR2019018660-appb-img-000097
2424
Figure PCTKR2019018660-appb-img-000098
Figure PCTKR2019018660-appb-img-000098
 		2525
Figure PCTKR2019018660-appb-img-000099
Figure PCTKR2019018660-appb-img-000099
2626
Figure PCTKR2019018660-appb-img-000100
Figure PCTKR2019018660-appb-img-000100
 		2727
Figure PCTKR2019018660-appb-img-000101
Figure PCTKR2019018660-appb-img-000101
2828
Figure PCTKR2019018660-appb-img-000102
Figure PCTKR2019018660-appb-img-000102
 		2929
Figure PCTKR2019018660-appb-img-000103
Figure PCTKR2019018660-appb-img-000103
3030
Figure PCTKR2019018660-appb-img-000104
Figure PCTKR2019018660-appb-img-000104
 		3131
Figure PCTKR2019018660-appb-img-000105
Figure PCTKR2019018660-appb-img-000105
3232
Figure PCTKR2019018660-appb-img-000106
Figure PCTKR2019018660-appb-img-000106
 		3333
Figure PCTKR2019018660-appb-img-000107
Figure PCTKR2019018660-appb-img-000107
3434
Figure PCTKR2019018660-appb-img-000108
Figure PCTKR2019018660-appb-img-000108
 		-- --
실험예Experimental Example
1. 제조예 1-1의 화합물의 항암 치료 활성 증진 효과1. The effect of enhancing the anticancer therapeutic activity of the compound of Preparation Example 1-1
1-1. 파클리탁셀 활성 증진 효과1-1. Paclitaxel activity enhancing effect
1-1-1. 암 세포에 대한 활성 증진 효과1-1-1. Effect of promoting activity on cancer cells
파클리탁셀의 복용 후 재발 및 전이된 환자 유래 암 줄기세포성 갑상선 암 세포(ATC)에 대하여 제조예 1-1의 화합물(150 nM) 단독; 파클리탁셀(12 nM) 단독; 또는 파클리탁셀(5 nM)과 제조예 1-1의 화합물(70 nM)의 조합을 처리한 뒤 처리 시간에 따른 세포 수의 변화를 확인하였다. 또한, 파클리탁셀, 제조예 1-1의 화합물 및 파클리탁셀과 제조예 1-1의 화합물 조합의 처리 농도에 따른 세포 생존율의 변화를 도 1에 나타내었다. 또한, 상기 파클리탁셀, 제조예 1-1의 화합물 및 이들의 조합의 처리 농도에 따른 세포 생존율의 변화를 측정하여 그 결과를 도 2에 나타내었다.A compound (150 nM) of Preparation Example 1-1 for cancer stem cell thyroid cancer cells (ATC) derived from patients who relapsed and metastasized after taking paclitaxel; Paclitaxel (12 nM) alone; Or after treating the combination of paclitaxel (5 nM) and the compound of Preparation Example 1-1 (70 nM), the change in cell number according to the treatment time was confirmed. In addition, 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. In addition, 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.
도 1 및 도 2에서 보는 바와 같이, 항암제 내성 갑상선 암 세포에 파클리탁셀을 단독으로 처리한 경우 음성 대조군에 비하여 암세포 수 및 암 세포의 생존율에 변화가 없었지만, 제조예 1-1의 화합물을 파클리탁셀과 함께 처리한 경우 줄기세포성 갑상선 암세포의 세포수와 세포 생존율이 현저히 감소하는 것을 확인할 수 있었다.1 and 2, when paclitaxel alone was treated with anti-cancer drug-resistant thyroid cancer cells, the number of cancer cells and the survival rate of cancer cells did not change compared to the negative control group, but the compound of Preparation Example 1-1 was combined with paclitaxel. When treated, it was confirmed that the cell number and cell viability of stem cell thyroid cancer cells were significantly reduced.
1-1-2. 암 세포 이식 마우스의 종양 크기 변화 분석1-1-2. Analysis of tumor size change in cancer cell transplanted mice
파클리탁셀의 복용 후 재발 및 전이된 환자 유래 암 줄기세포성 갑상선 암 세포를 인-비트로에서 배양한 뒤, BALB/c 누드 암컷 마우스의 왼쪽 위 옆구리의 피하에 배양한 세포를 2.0 X 10 7 cell/마우스가 되도록 주입하였다. 7 일 후, 10 마리씩 그룹화한 뒤, 각 그룹별로 제조예 1-1의 화합물(60 mg/kg) 단독을 경구 투여; 파클리탁셀(25 mg/kg) 단독을 복강 내 주사; 또는 제조예 1-1의 화합물(27 mg/kg)을 경구 투여하고 파클리탁셀(11 mg/kg)을 복강 내 주사한 뒤, 마우스를 안락사 시키고 60 일 간 캘리퍼스를 이용하여 매일 종양의 부피 변화를 측정하여 그 결과를 도 3에 나타내었다. 종양의 부피는 하기 수학식 1을 이용하여 평가하였다.After taking paclitaxel, 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. 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.
[수학식 1][Equation 1]
종양의 부피 = L × S 2/2Tumor volume = L × S 2 /2
(단, L은 가장 긴 직경, S는 가장 짧은 직경을 의미한다.)(However, L means the longest diameter and S means the shortest diameter.)
도 3과 같이 항암제 내성 갑상선 암 세포를 이종 이식한 마우스 모델에 파클리탁셀을 단독으로 투여한 경우 음성 대조군에 비하여 종양 부피 변화가 없었으나, 제조예 1-1의 화합물을 파클리탁셀과 함께 처리한 경우 종양의 부피가 현저히 감소하는 것을 확인할 수 있었다.As shown in FIG. 3, when paclitaxel alone was administered to a mouse model transplanted with xenograft-resistant thyroid cancer cells, tumor volume did not change compared to the negative control group, but when the compound of Preparation Example 1-1 was treated with paclitaxel, the tumor It was confirmed that the volume was significantly reduced.
1-2. 이리노테칸 활성 증진 효과1-2. Irinotecan activity enhancing effect
1-2-1. 암 세포에 대한 활성 증진 효과1-2-1. Effect of promoting activity on cancer cells
이리노테칸의 복용 후 재발 및 전이된 환자 유래 암 줄기세포성 위암 세포에 대하여 제조예 1-1의 화합물(170 nM) 단독; 이리노테칸(8.9 μM) 단독; 또는 이리노테칸(4.5 μM)과 제조예 1-1의 화합물(75 nM)의 조합을 처리한 뒤 처리 시간에 따른 세포 수의 변화를 측정하여 그 결과를 도 4에 나타내었다.A compound (170 nM) of Preparation Example 1-1 for cancer stem cell gastric cancer cells derived from a patient who has relapsed and metastasized after taking irinotecan; Irinotecan (8.9 μM) alone; Or after treating the combination of irinotecan (4.5 μM) and the compound of Preparation Example 1-1 (75 nM), the change in cell number according to the treatment time was measured, and the results are shown in FIG. 4.
도 4와 같이 항암제 내성 위암 세포에 이리노테칸을 단독으로 처리한 경우 음성 대조군에 비하여 암 세포 수에 아무런 변화가 없었지만, 제조예 1-1의 화합물을 이리노테칸과 함께 처리한 경우 암 세포의 수가 현저히 감소하는 것을 확인할 수 있었다.As shown in FIG. 4, when irinotecan was treated with anti-cancer drug-resistant gastric cancer cells alone, there was no change in the number of cancer cells compared to the negative control group, but when the compound of Preparation Example 1-1 was treated with irinotecan, the number of cancer cells was significantly reduced. I could confirm that.
1-2-2. 암 세포 이식 마우스의 종양 크기 변화 분석1-2-2. Analysis of tumor size change in cancer cell transplanted mice
이리노테칸의 복용 후 재발 및 전이된 환자 유래 암 줄기세포성 위암 세포를 인-비트로에서 배양한 뒤, BALB/c 누드 암컷 마우스의 왼쪽 위 옆구리의 피하에 배양한 세포를 2.0 X 10 7 cell/마우스가 되도록 주입하였다. 7 일 후, 10 마리씩 그룹화한 뒤, 각 그룹별로 제조예 1-1의 화합물(70 mg/kg) 단독을 경구 투여; 이리노테칸(75 mg/kg) 단독을 경구 투여; 또는 제조예 1-1의 화합물(32 mg/kg)과 이리노테칸(55 mg/kg)을 경구 투여한 뒤, 마우스를 안락사 시키고 40 일 간 캘리퍼스를 이용하여 매일 종양의 부피 변화를 측정하여 도 5에 나타내었다. 종양의 부피는 전술한 수학식 1에 의해 계산되었다. 또한, 40 일 경과 후 종양의 무게를 측정하여 그 결과를 도 6에 나타내었고, 41 일간 마우스의 몸무게를 측정하여 그 결과를 도 7에 나타내었다.After infusion of irinotecan, cancer stem cell gastric cancer cells from patients relapsed and metastasized were cultured in vitro, and cells cultured under the left upper flank of BALB/c nude female mice were 2.0 X 10 7 cells/mouse. Inject as much as possible. After 7 days, after grouping 10 animals, each group was administered orally with the compound of Preparation Example 1-1 (70 mg/kg) alone; Oral administration of irinotecan (75 mg/kg) alone; Alternatively, after orally administering the compound of Preparation Example 1-1 (32 mg/kg) and irinotecan (55 mg/kg), the mice were euthanized and the volume change of the tumor was measured daily using a caliper for 40 days, to FIG. 5. Shown. The tumor volume was calculated by Equation 1 above. In addition, after 40 days, the weight of the tumor was measured, and the result is shown in FIG. 6, and the weight of the mouse was measured for 41 days, and the result is shown in FIG. 7.
도 5 및 도 6과 같이, 항암제 내성 위암 세포를 이종 이식한 마우스 모델에 이리노테칸을 단독으로 투여한 경우 음성 대조군에 비해 종양 부피나 무게의 변화가 없었으나, 이리노테칸과 함께 제조예 1-1의 화합물을 함께 처리한 경우 종양의 부피 및 무게가 현저히 감소하는 것을 확인할 수 있었다.5 and 6, when the irinotecan alone was administered to a mouse model in which a cancer-resistant gastric cancer cell was transplanted xenograft, there was no change in tumor volume or weight compared to the negative control, but the compound of Preparation Example 1-1 together with irinotecan When treated together, it was confirmed that the volume and weight of the tumor was significantly reduced.
또한, 도 7과 같이 마우스 모델에 제조예 1-1의 화합물을 단독으로 투여하거나 이리노테칸과 함께 병용 투여한 경우에 음성 대조군과 비교하여 마우스의 몸무게에 변화가 없는 것을 볼 수 있는 바, 독성 문제는 없는 것으로 확인할 수 있었다.In addition, when the compound of Preparation Example 1-1 was administered alone or in combination with irinotecan to the mouse model as shown in FIG. 7, it was seen that there was no change in the weight of the mouse compared to the negative control. It was confirmed that there was no.
1-3. 방사선 치료 활성 증진 효과1-3. Effect of promoting radiotherapy activity
1-3-1. 암 세포에 대한 활성 증진 효과1-3-1. Effect of promoting activity on cancer cells
방사선 조사 치료 후 재발 및 전이된 환자 유래 암 줄기세포성 대장암 세포에 대하여 제조예 1-1의 화합물(150 nM) 단독으로 처리; Faxitron X-레이(Faxitro Bioptics, AZ, USA)를 5 Gy의 세기로 조사(RT); 또는 제조예 1-1의 화합물 (75 nM)을 처리하고 상기 X-레이를 5 Gy의 세기로 조사한 뒤 처리 시간에 따른 암 세포 수의 변화를 측정하였고, 그 결과를 도 8에 나타내었다.Treatment with a compound (150 nM) of Preparation Example 1-1 for cancer stem cell colorectal cancer cells derived from patients who have relapsed and metastasized after irradiation treatment; Faxitron X-ray (Faxitro Bioptics, AZ, USA) investigated at a intensity of 5 Gy (RT); Alternatively, after treating the compound of Preparation Example 1-1 (75 nM) and irradiating the X-ray with an intensity of 5 Gy, changes in the number of cancer cells according to the treatment time were measured, and the results are shown in FIG. 8.
도 8과 같이, 방사선 내성 대장암 세포에 방사선만을 조사한 경우에는 음성 대조군에 비하여 암 세포 수에 변화가 없었지만, 방사선 조사와 함께 제조예 1-1의 화합물을 처리한 경우 암 세포의 수가 현저히 감소하는 것을 확인할 수 있었다.As shown in FIG. 8, when only radiation-resistant colorectal cancer cells were irradiated, there was no change in the number of cancer cells compared to the negative control group, but when the compound of Preparation Example 1-1 was treated with radiation, the number of cancer cells was significantly reduced. I could confirm that.
1-3-2. 마우스 종양 크기 변화 분석1-3-2. Mouse tumor size change analysis
방사선 조사 치료 후 재발 및 전이된 환자 유래 암 줄기세포성 대장암 세포를 인-비트로에서 배양한 뒤, BALB/c 누드 암컷 마우스의 왼쪽 위 옆구리의 피하에 배양한 세포를 2.0 X 10 7 cell/마우스가 되도록 주입하였다. 7 일 후, 10 마리씩 그룹화한 뒤, 각 그룹별로 제조예 1-1의 화합물(60 mg/kg)을 경구 투여; Faxitron X-레이(Faxitro Bioptics, AZ, USA)를 5 Gy의 세기로 조사; 또는 제조예 1-1의 화합물(27 mg/kg)을 경구 투여하고 상기 X-레이를 5 Gy의 세기로 조사한 뒤, 마우스를 안락사 시키고 40 일 간 캘리퍼스를 이용하여 매일 종양의 부피 변화를 측정하였고, 그 결과를 도 9에 나타내었다. 종양의 부피는 전술한 수학식 1에 의해 계산되었다. 또한, 40 일 경과 후 종양의 무게를 측정하여 그 결과를 도 10에 나타내었고, 41 일간 마우스의 몸무게를 측정하여 그 결과를 도 11에 나타내었다.After irradiation treatment, 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. After 7 days, after grouping 10 animals, 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; Alternatively, 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. In addition, after 40 days, 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.
도 9 및 도 10과 같이, 방사선 내성 대장암 세포를 이종 이식한 마우스 모델에 방사선만을 단독으로 조사한 경우는 음성 대조군에 비해 종양 부피나 무게의 변화가 없었으나, 방사선 조사와 함께 제조예 1-1의 화합물을 함께 투여한 경우 종양의 부피와 무게가 현저히 감소한 것을 확인할 수 있었다.9 and 10, when the radiation-resistant colorectal cancer cells were irradiated with xenograft alone, only the radiation alone did not change the tumor volume or weight compared to the negative control group, but with irradiation, Preparation Example 1-1 When the compound was administered together, it was confirmed that the tumor volume and weight were significantly reduced.
또한, 도 11과 같이 마우스 모델에 제조예 1-1의 화합물을 단독으로 투여하거나 방사선 조사와 함께 투여한 경우에 음성 대조군과 비교하여 마우스의 몸무게에 변화가 없는 것을 볼 수 있는 바, 독성 문제는 없는 것으로 확인할 수 있었다.In addition, as shown in FIG. 11, when the compound of Preparation Example 1-1 was administered to a mouse model alone or administered with irradiation, it can be seen that there is no change in the body weight of the mouse compared to the negative control. It was confirmed that there was no.
2. 제조예 화합물들의 항암 치료 활성 증진 효과2. The effect of enhancing the anticancer therapeutic activity of the preparation compounds
2-1. 실험 방법2-1. Experimental method
제조예 화합물들의 항암 치료 활성 증진 효과를 확인하기 위해, 제조예 1-1 내지 31에 의해 제조된 화합물 또는 염(이하, 제조예 화합물)을 이용하였고, 상피성 난소암 세포주인 SKOV3 및 이로부터 유래하여 파클리탁셀 항암제에 저항성을 갖는 내성 세포주로 제작된 SKOV3-TR를 대상으로 세포 실험을 진행하였다.In order to confirm the effect of enhancing the anticancer therapeutic activity of the compounds of Preparation Example, 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.
12-well에서 자라고 있는 두 세포주에 각 제조예의 화합물 2μM 단독; 파클리탁셀(SKOV3의 경우 0.2μM, SKOV3-TR의 경우 5μM) 단독; 또는 파클리탁셀과 각 제조예의 화합물의 조합을 처리한 뒤 72시간 후에 살아있는 세포수를 측정하였다. 파클리탁셀과 제조예의 화합물들의 병용처리는 우선 제조예의 화합물들 각각을 2μM씩 4 시간 전처리(pretreatment)한 후 파클리탁셀을 SKOV3-TR 세포주에는 5μM, SKOV3 세포주에는 0.2μM 처리하였다.2 μM of compound of each preparation alone in two cell lines growing in 12-well; Paclitaxel (0.2 μM for SKOV3, 5 μM for SKOV3-TR) alone; Alternatively, the number of living cells was measured 72 hours after the combination of paclitaxel and the compound of each preparation was treated. For the combination treatment of paclitaxel and the compounds of the preparation example, each of the compounds of the preparation example was pretreated for 4 hours at 2 μM, followed by treatment of paclitaxel with 5 μM in the SKOV3-TR cell line and 0.2 μM in the SKOV3 cell line.
세포의 형태학적 분석을 위해 파클리탁셀을 처리하고 24시간, 48시간, 72시간 후에 'None(아무것도 처리하지 않은 샘플)', 'DMSO(파클리탁셀의 용매)', '에탄올(제조예의 화합물들의 용매)', '파클리탁셀', '파클리탁셀+에탄올', '파클리탁셀+제조예1-2의 화합물(L19001)'을 처리한 세포들의 이미지를 얻었다.24 hours, 48 hours, 72 hours after paclitaxel treatment for cell morphological analysis,'None (sample without treatment)','DMSO (solvent of paclitaxel)','ethanol (solvent of compounds of the preparation examples)' ,'Paclitaxel','Paclitaxel+ethanol','Paclitaxel+Compound (L19001) of Preparation Example 1-2' images were obtained.
또한, 세포 생존율 분석을 위해 파클리탁셀 혹은 제조예 화합물들을 단독 처리하거나 파클리탁셀과 제조예 화합물들 각각을 병용처리하고 72시간 후에 Image J 분석을 통해 살아있는 세포수를 측정하였다.In addition, for cell viability analysis, 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.
2-2. 세포 형태학적 분석2-2. Cell morphological analysis
세포의 형태학적 분석 결과, DMSO 및 에탄올을 단독 처리한 군의 경우 아무것도 처리하지 않은 군(None)과 비교하여 특별한 차이를 보이지 않는 것으로 보아 본 실험에 사용된 용매의 양은 세포에 영향을 주지 않음을 알 수 있었다. 또한 제조예의 화합물들 각각은 단독 처리시 SKOV3-TR 및 SKOV3에서 별다른 형태학적 변화를 야기하지는 않았다. 도 12는 None, 에탄올, 제조예 1-2의 화합물(L19001, 2μM)을 처리한 후 24시간, 48시간, 72시간 후의 이미지를 캡쳐한 것이다.As a result of the morphological analysis of the cells, the DMSO and ethanol-treated groups showed no particular difference compared to the non-treated group (None), so the amount of solvent used in this experiment did not affect the cells. Could know. In addition, each of the compounds of the preparation example did not cause any morphological changes in SKOV3-TR and SKOV3 when treated alone. 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 μM).
또한, 제조예 화합물들이 파클리탁셀에 의한 항암효능을 증진시킬 수 있는지 확인하기 위해, 파클리탁셀을 처리하기 4시간 전에 제조예들의 화합물을 전처리한 후 파클리탁셀에 의한 암세포사멸에 미치는 영향을 평가하였다. 파클리탁셀 처리 시 SKOV3-TR 및 SKOV3에서 세포사멸 유발 및 세포성장 억제 현상 등으로 인해 살아있는 세포수가 감소한 것을 확인하였다. In addition, in order to confirm whether the preparation compounds can enhance the anticancer efficacy by paclitaxel, the effects of paclitaxel on cancer cell death were evaluated after pretreatment of the compounds of the preparations 4 hours before treatment with paclitaxel. When 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.
구체적으로, 내성 암 세포주인 SKOV3-TR에서는 제조예들의 화합물의 처리에 의해 이러한 현상이 예외 없이 더 두드러졌는데 반해, 일반 암 세포주인 SKOV3에서는 제조예 화합물들의 처리에 의한 파클리탁셀 암세포사멸 상승효과가 SKOV3-TR 만큼 뚜렷하지는 않았다. 도 13 및 도 14는 2 종류의 세포주에 파클리탁셀 단독 혹은 파클리탁셀+제조예 1-2의 화합물(L19001)을 처리하고 72시간 후의 이미지를 나타낸다.Specifically, in the resistant cancer cell line SKOV3-TR, this phenomenon was more prominent without exception by treatment of the compounds of the preparations, whereas in the general cancer cell line SKOV3, the synergistic effect of paclitaxel cancer cell death by treatment of the preparation compounds was SKOV3- It wasn't as clear as TR. 13 and 14 show images after 72 hours of treatment with paclitaxel alone or paclitaxel + compound 1-2 of Production Example 1-2 (L19001) in two types of cell lines.
2-3. 세포 생존율 분석2-3. Cell viability analysis
Image J 프로그램을 활용하여 살아있는 세포수를 측정함으로써 2 종류 암세포주의 세포생존율을 분석하였다.Cell viability was analyzed by measuring the number of living cells using the Image J program.
도 15 내지 도 18에서와 같이, DMSO 및 에탄올을 단독 처리한 군의 경우 아무것도 처리하지 않은 군(None)과 비교하여 세포 생존율에 있어 특별한 차이를 보이지 않는 것으로 보아, 본 실험에 사용된 용매의 양은 세포 생존율에 영향을 주지 않음을 알 수 있었다.15 to 18, in the case of DMSO and ethanol alone, the amount of the solvent used in this experiment was shown to show no particular difference in cell viability compared to the group not treated with anything (None). It was found that it did not affect the cell viability.
제조예 화합물이 세포 생존율에 영향을 미치는지 확인하기 위해, SKOV3-TR 및 SKOV3 세포주에 제조예의 화합물들 각각을 2μM씩 처리한 후 72시간 후 세포수를 측정하였다. 그 결과, 제조예의 화합물들 각각을 단독 처리한 경우 SKOV3-TR 및 SKOV3에서 세포 생존율에 크게 영향을 미치지 않았다. 도 15 및 도 16은 SKOV3-TR 및 SKOV3 세포주에서 None, 에탄올 및 제조예의 화합물들 각각을 처리한 후 72시간 후 세포수를 나타낸다.In order to confirm that the preparation compound affects cell viability, 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 μM. As a result, when each of the compounds of the preparation example was treated alone, 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.
또한, 제조예 화합물들이 파클리탁셀에 의한 항암효능을 증진시킬 수 있는지 살펴보기 위해, 파클리탁셀을 처리하기 4시간 전에 제조예 화합물들을 2μM씩 전처리한 후 파클리탁셀에 의한 암세포사멸에 미치는 영향을 평가하였다. 그 결과 파클리탁셀을 단독처리 하는 경우에 비해, 제조예 화합물들을 전처리한 후 파클리탁셀 처리 시 SKOV3-TR 및 SKOV3에서 세포사멸 유발 및 세포성장 억제 현상 등으로 인해 세포수가 감소하는 것을 확인하였다. 특히, 일반 암 세포주인 SKOV3에 비해 내성암 세포주인 SKOV3-TR에서는 제조예 화합물들의 전처리에 의해 세포수가 감소하는 현상이 예외 없이 더 두드러진 것을 확인하였다. 도 17 및 도 18은 SKOV3-TR 및 SKOV3 세포주에서 None, DMSO, 에탄올, 파클리탁셀 단독처리 및 제조예의 화합물들 각각을 전처리한 후 파클리탁셀 처리 72시간 후의 세포수를 나타낸다.In addition, in order to examine whether the preparation compounds can enhance the anti-cancer effect by paclitaxel, the effect of paclitaxel on cancer cell death was evaluated after pretreatment with 2 μM of the preparation compounds 4 hours before treatment with paclitaxel. As a result, compared to the case where paclitaxel was treated alone, it was confirmed that 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. In particular, compared to the general cancer cell line SKOV3, in the resistant cancer cell line SKOV3-TR, it was confirmed that 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.

Claims (29)

  1. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염:A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2019018660-appb-img-000109
    Figure PCTKR2019018660-appb-img-000109
    상기 화학식 1에서, In Chemical Formula 1,
    n은 0 내지 4의 정수이고;n is an integer from 0 to 4;
    R 1은 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이고;R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl;
    R 3은 C1 내지 C6의 알킬이고, 상기 R 3이 복수 개인 경우 이들은 서로 동일하거나 상이하며;R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
    L 1은 직접결합이거나 C1 내지 C6의 알킬렌이고;L 1 is a direct bond or C1 to C6 alkylene;
    R 2는 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이며, R 4는 수소, C1 내지 C4의 알킬, C3 내지 C8의 사이클로알킬 또는 아릴(C1 내지 C4)알킬이거나,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 2와 R 4가 4 내지 7원환을 이루며 서로 연결되고;R 2 and R 4 form a 4 to 7-membered ring and are connected to each other;
    상기 R 1 내지 R 4의 알킬과, 상기 R 1, R 2 및 R 4의 아릴알킬, 상기 R 4의 사이클로알킬, 상기 L 1의 알킬렌은 각각 독립적으로 C1 내지 C6의 알킬기, 할로기, 아릴기, 할로알킬기, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환되고, 복수 개의 치환기로 치환되는 경우, 이들은 서로 동일하거나 상이함.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.
  2. 청구항 1에 있어서, 상기 n은 0 내지 2의 정수이고;The method according to claim 1, wherein n is an integer from 0 to 2;
    상기 R 1은 C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이며;R 1 is C 1 to C 6 alkyl or aryl (C 1 to C 2) alkyl;
    상기 L 1은 C1 내지 C4의 알킬렌이고;L 1 is C1 to C4 alkylene;
    상기 R 2는 수소, C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이고, 상기 R 4는 수소, C1 내지 C4의 알킬, C3 내지 C6의 사이클로알킬 또는 아릴(C1 내지 C2)알킬이거나,R 2 is hydrogen, C1 to C6 alkyl or aryl (C1 to C2)alkyl, and R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl (C1 to C2)alkyl,
    상기 R 2와 상기 R 4가 4 내지 6원환을 이루며 서로 연결되는, 화합물 또는 이의 약학적으로 허용 가능한 염.The compound or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 form a 4 to 6-membered ring and are linked to each other.
  3. 청구항 1에 있어서, 상기 n은 0 내지 1의 정수이고;The method according to claim 1, wherein n is an integer from 0 to 1;
    상기 R 1은 C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이며;R 1 is C1 to C6 alkyl, phenylmethyl or phenylethyl;
    상기 L 1은 C1 내지 C2의 알킬렌이고;L 1 is C1 to C2 alkylene;
    상기 R 2는 수소, C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이고, 상기 R 4는 수소, C1 내지 C2의 알킬, C5 내지 C6의 사이클로알킬, 페닐메틸 또는 나프틸메틸이거나,R 2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl, and R 4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl,
    상기 R 2와 상기 R 4가 5 내지 6원환을 이루며 서로 연결되는, 화합물 또는 이의 약학적으로 허용 가능한 염.The compound or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 form a 5 to 6 membered ring and are linked to each other.
  4. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 항암 활성 증진용 약학 조성물:A pharmaceutical composition for enhancing anti-cancer activity comprising a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2019018660-appb-img-000110
    Figure PCTKR2019018660-appb-img-000110
    상기 화학식 1에서, In Chemical Formula 1,
    n은 0 내지 4의 정수이고;n is an integer from 0 to 4;
    R 1은 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이고;R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl;
    R 3은 C1 내지 C6의 알킬이고, 상기 R 3이 복수 개인 경우 이들은 서로 동일하거나 상이하며;R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
    L 1은 직접결합이거나 C1 내지 C6의 알킬렌이고;L 1 is a direct bond or C1 to C6 alkylene;
    R 2는 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이며, R 4는 수소, C1 내지 C4의 알킬, C3 내지 C8의 사이클로알킬 또는 아릴(C1 내지 C4)알킬이거나,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 2와 R 4가 4 내지 7원환을 이루며 서로 연결되고;R 2 and R 4 form a 4 to 7-membered ring and are connected to each other;
    상기 R 1 내지 R 4의 알킬과, 상기 R 1, R 2 및 R 4의 아릴알킬, 상기 R 4의 사이클로알킬, 상기 L 1의 알킬렌은 각각 독립적으로 C1 내지 C6의 알킬기, 할로기, 아릴기, 할로알킬기, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환되고, 복수 개의 치환기로 치환되는 경우, 이들은 서로 동일하거나 상이함.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.
  5. 청구항 4에 있어서, 상기 n은 0 내지 2의 정수이고;The method according to claim 4, wherein n is an integer from 0 to 2;
    상기 R 1은 C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이며;R 1 is C 1 to C 6 alkyl or aryl (C 1 to C 2) alkyl;
    상기 L 1은 C1 내지 C4의 알킬렌이고;L 1 is C1 to C4 alkylene;
    상기 R 2는 수소, C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이고, 상기 R 4는 수소, C1 내지 C4의 알킬, C3 내지 C6의 사이클로알킬 또는 아릴(C1 내지 C2)알킬이거나,R 2 is hydrogen, C1 to C6 alkyl or aryl (C1 to C2)alkyl, and R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl (C1 to C2)alkyl,
    상기 R 2와 상기 R 4가 4 내지 6원환을 이루며 서로 연결되는, 약학 조성물.The R 2 and R 4 form a 4 to 6 membered ring and are connected to each other, a pharmaceutical composition.
  6. 청구항 4에 있어서, 상기 n은 0 내지 1의 정수이고;The method according to claim 4, wherein n is an integer from 0 to 1;
    상기 R 1은 C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이며;R 1 is C1 to C6 alkyl, phenylmethyl or phenylethyl;
    상기 L 1은 C1 내지 C2의 알킬렌이고;L 1 is C1 to C2 alkylene;
    상기 R 2는 수소, C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이고, 상기 R 4는 수소, C1 내지 C2의 알킬, C5 내지 C6의 사이클로알킬, 페닐메틸 또는 나프틸메틸이거나,R 2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl, and R 4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl,
    상기 R 2와 상기 R 4가 5 내지 6원환을 이루며 서로 연결되는, 약학 조성물.The R 2 and R 4 form a 5 to 6 membered ring and are connected to each other, a pharmaceutical composition.
  7. 청구항 4에 있어서, 상기 항암 활성 증진은 항암제 또는 방사선의 항암 활성 증진인, 약학 조성물.The pharmaceutical composition according to claim 4, wherein the anti-cancer activity enhancement is an anti-cancer agent or radiation anti-cancer activity enhancement.
  8. 청구항 7에 있어서, 상기 항암제는 탁센 계열 항암제 및 캄프토테신 계열 항암제 중 적어도 하나인, 약학 조성물.The pharmaceutical composition of claim 7, wherein the anticancer agent is at least one of a taxane-based anticancer agent and a camptothecin-based anticancer agent.
  9. 청구항 8에 있어서, 상기 탁센 계열 항암제는 파클리탁셀, 도세탁셀 및 카바지탁셀로 이루어진 군에서 선택된 적어도 하나인, 약학 조성물.The pharmaceutical composition of claim 8, wherein the taxane-based anticancer agent is at least one selected from the group consisting of paclitaxel, docetaxel and cabazitaxel.
  10. 청구항 8에 있어서, 상기 캄프토테신 계열 항암제는 이리노테칸, 토포테칸 및 벨로테칸으로 이루어진 군에서 선택된 적어도 하나인, 약학 조성물.The pharmaceutical composition of claim 8, wherein the camptothecin-based anticancer agent is at least one selected from the group consisting of irinotecan, topotecan and belotecane.
  11. 청구항 4에 있어서, 내성암에 대한 항암 활성 증진용인 약학 조성물.The method according to claim 4, Pharmaceutical composition for enhancing anticancer activity against resistant cancer.
  12. 청구항 11에 있어서, 상기 내성암은 탁센 계열 항암제 및 캄프토테신 계열 항암제 중 적어도 하나에 대한 내성암인, 약학 조성물.The pharmaceutical composition of claim 11, wherein the resistant cancer is resistant to at least one of taxane-based anti-cancer agents and camptothecin-based anti-cancer agents.
  13. 청구항 11에 있어서, 상기 내성암은 방사선에 대한 내성암인, 약학 조성물.The pharmaceutical composition of claim 11, wherein the resistant cancer is radiation resistant cancer.
  14. 청구항 11에 있어서, 상기 내성암은 갑성선암, 위암, 대장암, 난소암, 유방암, 폐암, 카포시 육종, 자궁경부암, 췌장암, 두경부암, 직장암, 결장암, 식도암 및 전립선암으로 이루어진 군에서 선택된 적어도 하나인, 약학 조성물.The method of claim 11, wherein 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.
  15. 청구항 4에 있어서, 항암제를 더 포함하는 약학 조성물.The pharmaceutical composition of claim 4, further comprising an anti-cancer agent.
  16. 청구항 15에 있어서, 상기 항암제는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 마시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 파조파닙, 토세라닙, 닌테다닙, 레고라페닙, 세막사닙, 티보자닙, 포나티닙, 카보잔티닙 카보플라틴, 소라페닙, 렌바티닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 5-플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 케페시타빈, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 올라파립, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴, 보리노스텟, 엔티노스텟 및 카르무스틴으로 이루어진 군에서 선택된 적어도 하나를 포함하는, 약학 조성물.The method according to claim 15, wherein the anti-cancer agent is 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, hydroxycarbamide, dasatinib, estramustine , Gemtuzumab ozogamycin, britumomab tucetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium chitosan, gemcitabine, doxyfluridine , Pemetrexed, tegapur, capecitabine, gimeracin, oteracyl, azacitidine, methotrexate, uracil, cytarabine, 5-fluorouracil, fludagabine, enositabine, flutamide, ke Pecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmophor, raltitrexed, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, Teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus, Temozolomide, busulfan, iphosphamide, cyclophosphamide, melphalan, altretmine, dacarbazine, chiotepa, nimustine, chlorambucil, mitoractol, leucovorin, tretonin, exmestan, Aminoglutethimide, anagrelide, olaparib, navelvin, padrazol, tamoxifen, toremifene, testolactone, anastrozole, letrozole, borozol, bicalutamide, lomustine, vorinostat, A pharmaceutical composition comprising at least one selected from the group consisting of entinosted and carmustine.
  17. 청구항 15에 있어서, 상기 항암제는 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염과 1:0.001 내지 1:1000의 몰 농도비로 포함되는, 약학 조성물.The method according to claim 15, wherein the anticancer agent is a pharmaceutical composition comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in a molar concentration ratio of 1:0.001 to 1:1000.
  18. 내성암이 있는 대상에게 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 치료적 유효량을 투여하는 단계를 포함하는 암 치료 방법: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:
    [화학식 1][Formula 1]
    Figure PCTKR2019018660-appb-img-000111
    Figure PCTKR2019018660-appb-img-000111
    상기 화학식 1에서, In Chemical Formula 1,
    n은 0 내지 4의 정수이고;n is an integer from 0 to 4;
    R 1은 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이고;R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl;
    R 3은 C1 내지 C6의 알킬이고, 상기 R 3이 복수 개인 경우 이들은 서로 동일하거나 상이하며;R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
    L 1은 직접결합이거나 C1 내지 C6의 알킬렌이고;L 1 is a direct bond or C1 to C6 alkylene;
    R 2는 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이며, R 4는 수소, C1 내지 C4의 알킬, C3 내지 C8의 사이클로알킬 또는 아릴(C1 내지 C4)알킬이거나,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 2와 R 4가 4 내지 7원환을 이루며 서로 연결되고;R 2 and R 4 form a 4 to 7-membered ring and are connected to each other;
    상기 R 1 내지 R 4의 알킬과, 상기 R 1, R 2 및 R 4의 아릴알킬, 상기 R 4의 사이클로알킬, 상기 L 1의 알킬렌은 각각 독립적으로 C1 내지 C6의 알킬기, 할로기, 아릴기, 할로알킬기, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환되고, 복수 개의 치환기로 치환되는 경우, 이들은 서로 동일하거나 상이함.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.
  19. 청구항 18에 있어서, 상기 n은 0 내지 2의 정수이고;The method according to claim 18, wherein n is an integer from 0 to 2;
    상기 n은 0 내지 2의 정수이고;N is an integer from 0 to 2;
    상기 R 1은 C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이며;R 1 is C 1 to C 6 alkyl or aryl (C 1 to C 2) alkyl;
    상기 L 1은 C1 내지 C4의 알킬렌이고;L 1 is C1 to C4 alkylene;
    상기 R 2는 수소, C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이고, 상기 R 4는 수소, C1 내지 C4의 알킬, C3 내지 C6의 사이클로알킬 또는 아릴(C1 내지 C2)알킬이거나,R 2 is hydrogen, C1 to C6 alkyl or aryl (C1 to C2)alkyl, and R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl (C1 to C2)alkyl,
    상기 R 2와 상기 R 4가 4 내지 6원환을 이루며 서로 연결되는, 암 치료 방법.The R 2 and R 4 form a 4-6 membered ring and are linked to each other, a method for treating cancer.
  20. 청구항 18에 있어서, 상기 n은 0 내지 1의 정수이고; The method according to claim 18, wherein n is an integer from 0 to 1;
    상기 R 1은 C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이며;R 1 is C1 to C6 alkyl, phenylmethyl or phenylethyl;
    상기 L 1은 C1 내지 C2의 알킬렌이고;L 1 is C1 to C2 alkylene;
    상기 R 2는 수소, C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이고, 상기 R 4는 수소, C1 내지 C2의 알킬, C5 내지 C6의 사이클로알킬, 페닐메틸 또는 나프틸메틸이거나,R 2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl, and R 4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl,
    상기 R 2와 상기 R 4가 5 내지 6원환을 이루며 서로 연결되는, 암 치료 방법.The R 2 and R 4 form a 5 to 6 membered ring and are linked to each other, a method for treating cancer.
  21. 청구항 18에 있어서, 상기 내성암은 탁산 계열 항암제 및 캄토테신 계열 항암제 중 적어도 하나에 대한 내성암인, 암 치료 방법.The method of claim 18, wherein the resistant cancer is resistant to at least one of taxane-based anti-cancer agents and camptothecin-based anti-cancer agents.
  22. 청구항 18에 있어서, 상기 내성암은 방사선에 대한 내성암인, 암 치료 방법.The method of claim 18, wherein the resistant cancer is radiation resistant cancer.
  23. 청구항 18에 있어서, 상기 내성암은 갑성선암, 위암, 대장암, 난소암, 유방암, 폐암, 카포시 육종, 자궁경부암, 췌장암, 두경부암, 직장암, 결장암, 식도암 및 전립선암으로 이루어진 군에서 선택된 적어도 하나인, 암 치료 방법.The method according to claim 18, wherein the resistant cancer is 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. Phosphorus, how to treat cancer.
  24. 내성암 치료에 사용하기 위한 하기 화학식 1로 표시되는 화합물의 용도:Use of a compound represented by Formula 1 for use in the treatment of resistant cancer:
    [화학식 1][Formula 1]
    Figure PCTKR2019018660-appb-img-000112
    Figure PCTKR2019018660-appb-img-000112
    상기 화학식 1에서, In Chemical Formula 1,
    n은 0 내지 4의 정수이고;n is an integer from 0 to 4;
    R 1은 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이고;R 1 is hydrogen, C1 to C10 alkyl or aryl(C1 to C4)alkyl;
    R 3은 C1 내지 C6의 알킬이고, 상기 R 3이 복수 개인 경우 이들은 서로 동일하거나 상이하며;R 3 is C1 to C6 alkyl, and when R 3 is plural, they are the same or different from each other;
    L 1은 직접결합이거나 C1 내지 C6의 알킬렌이고;L 1 is a direct bond or C1 to C6 alkylene;
    R 2는 수소, C1 내지 C10의 알킬 또는 아릴(C1 내지 C4)알킬이며, R 4는 수소, C1 내지 C4의 알킬, C3 내지 C8의 사이클로알킬 또는 아릴(C1 내지 C4)알킬이거나,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 2와 R 4가 4 내지 7원환을 이루며 서로 연결되고;R 2 and R 4 form a 4 to 7-membered ring and are connected to each other;
    상기 R 1 내지 R 4의 알킬과, 상기 R 1, R 2 및 R 4의 아릴알킬, 상기 R 4의 사이클로알킬, 상기 L 1의 알킬렌은 각각 독립적으로 C1 내지 C6의 알킬기, 할로기, 아릴기, 할로알킬기, 나이트로기, 시아노기, 알킬싸이오기 또는 아릴알킬싸이오기의 치환기로 치환되거나 비치환되고, 복수 개의 치환기로 치환되는 경우, 이들은 서로 동일하거나 상이함.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.
  25. 청구항 24에 있어서, 상기 n은 0 내지 2의 정수이고;25. The method of claim 24, wherein n is an integer from 0 to 2;
    상기 R 1은 C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이며;R 1 is C 1 to C 6 alkyl or aryl (C 1 to C 2) alkyl;
    상기 L 1은 C1 내지 C4의 알킬렌이고;L 1 is C1 to C4 alkylene;
    상기 R 2는 수소, C1 내지 C6의 알킬 또는 아릴(C1 내지 C2)알킬이고, 상기 R 4는 수소, C1 내지 C4의 알킬, C3 내지 C6의 사이클로알킬 또는 아릴(C1 내지 C2)알킬이거나,R 2 is hydrogen, C1 to C6 alkyl or aryl (C1 to C2)alkyl, and R 4 is hydrogen, C1 to C4 alkyl, C3 to C6 cycloalkyl or aryl (C1 to C2)alkyl,
    상기 R 2와 상기 R 4가 4 내지 6원환을 이루며 서로 연결되는, 용도.The R 2 and the R 4 form a 4-6 membered ring and are connected to each other.
  26. 청구항 24에 있어서, 상기 n은 0 내지 1의 정수이고;25. The method of claim 24, wherein n is an integer from 0 to 1;
    상기 R1은 C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이며;R1 is C1 to C6 alkyl, phenylmethyl or phenylethyl;
    상기 L1은 C1 내지 C2의 알킬렌이고;L1 is C1 to C2 alkylene;
    상기 R2는 수소, C1 내지 C6의 알킬, 페닐메틸 또는 페닐에틸이고, 상기 R4는 수소, C1 내지 C2의 알킬, C5 내지 C6의 사이클로알킬, 페닐메틸 또는 나프틸메틸이거나,R2 is hydrogen, C1 to C6 alkyl, phenylmethyl or phenylethyl, and R4 is hydrogen, C1 to C2 alkyl, C5 to C6 cycloalkyl, phenylmethyl or naphthylmethyl,
    상기 R2와 상기 R4가 5 내지 6원환을 이루며 서로 연결되는, 용도.The R2 and R4 form a 5 to 6-membered ring and are connected to each other.
  27. 청구항 24에 있어서, 상기 내성암은 탁산 계열 항암제 및 캄토테신 계열 항암제 중 적어도 하나에 대한 내성암인, 용도.The use according to claim 24, wherein the resistant cancer is resistant to at least one of taxane-based anti-cancer agents and camptothecin-based anti-cancer agents.
  28. 청구항 24에 있어서, 상기 내성암은 방사선에 대한 내성암인, 용도.25. The use according to claim 24, wherein the resistant cancer is radiation resistant cancer.
  29. 청구항 24에 있어서, 상기 내성암은 갑성선암, 위암, 대장암, 난소암, 유방암, 폐암, 카포시 육종, 자궁경부암, 췌장암, 두경부암, 직장암, 결장암, 식도암 및 전립선암으로 이루어진 군에서 선택된 적어도 하나인, 용도.The method according to claim 24, wherein the resistant cancer is 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. Phosphorus, uses.
PCT/KR2019/018660 2018-12-27 2019-12-27 Novel compound and pharmaceutical composition comprising same for enhancing anticancer activity WO2020139044A1 (en)

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