GB2579149A - Pharmaceutical composition for preventing or treating cancer containing receptor tyrosine kinase inhibitor as active ingredient - Google Patents
Pharmaceutical composition for preventing or treating cancer containing receptor tyrosine kinase inhibitor as active ingredient Download PDFInfo
- Publication number
- GB2579149A GB2579149A GB2001368.6A GB202001368A GB2579149A GB 2579149 A GB2579149 A GB 2579149A GB 202001368 A GB202001368 A GB 202001368A GB 2579149 A GB2579149 A GB 2579149A
- Authority
- GB
- United Kingdom
- Prior art keywords
- compound
- cancer
- chemical formula
- cell
- active ingredient
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 206010028980 Neoplasm Diseases 0.000 title abstract description 23
- 201000011510 cancer Diseases 0.000 title abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 11
- 239000004480 active ingredient Substances 0.000 title description 14
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 abstract description 44
- 239000000126 substance Substances 0.000 abstract description 43
- 239000000203 mixture Substances 0.000 abstract description 24
- 230000000694 effects Effects 0.000 abstract description 23
- 230000002401 inhibitory effect Effects 0.000 abstract description 23
- 239000002246 antineoplastic agent Substances 0.000 abstract description 16
- 108091008598 receptor tyrosine kinases Proteins 0.000 abstract description 14
- 102000027426 receptor tyrosine kinases Human genes 0.000 abstract description 14
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 10
- 102000020233 phosphotransferase Human genes 0.000 abstract description 10
- 230000006907 apoptotic process Effects 0.000 abstract description 9
- 238000001959 radiotherapy Methods 0.000 abstract description 7
- 238000011394 anticancer treatment Methods 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 230000005907 cancer growth Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 44
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 39
- 229940125797 compound 12 Drugs 0.000 description 34
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 31
- 108010003374 fms-Like Tyrosine Kinase 3 Proteins 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 18
- 208000032839 leukemia Diseases 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 230000001093 anti-cancer Effects 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 10
- 229960004316 cisplatin Drugs 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- -1 bacteristats Substances 0.000 description 9
- 206010006187 Breast cancer Diseases 0.000 description 8
- 208000026310 Breast neoplasm Diseases 0.000 description 8
- 235000013402 health food Nutrition 0.000 description 8
- 201000005787 hematologic cancer Diseases 0.000 description 8
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 230000035772 mutation Effects 0.000 description 8
- 230000005855 radiation Effects 0.000 description 8
- 206010009944 Colon cancer Diseases 0.000 description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 7
- 208000029742 colonic neoplasm Diseases 0.000 description 7
- 238000012790 confirmation Methods 0.000 description 7
- 238000007796 conventional method Methods 0.000 description 7
- 201000005202 lung cancer Diseases 0.000 description 7
- 208000020816 lung neoplasm Diseases 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 6
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 230000030833 cell death Effects 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000002708 enhancing effect Effects 0.000 description 6
- 208000014829 head and neck neoplasm Diseases 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 5
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 5
- 102000001712 STAT5 Transcription Factor Human genes 0.000 description 5
- 108010029477 STAT5 Transcription Factor Proteins 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000003833 cell viability Effects 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 4
- 206010005003 Bladder cancer Diseases 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 4
- 108091008606 PDGF receptors Proteins 0.000 description 4
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 4
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 4
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 4
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 201000005112 urinary bladder cancer Diseases 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- 102000003952 Caspase 3 Human genes 0.000 description 3
- 108090000397 Caspase 3 Proteins 0.000 description 3
- 102000016736 Cyclin Human genes 0.000 description 3
- 108050006400 Cyclin Proteins 0.000 description 3
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 3
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 description 3
- 206010023825 Laryngeal cancer Diseases 0.000 description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- 208000015634 Rectal Neoplasms Diseases 0.000 description 3
- 206010038389 Renal cancer Diseases 0.000 description 3
- 208000000453 Skin Neoplasms Diseases 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 description 3
- 208000002495 Uterine Neoplasms Diseases 0.000 description 3
- 230000009702 cancer cell proliferation Effects 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 230000005754 cellular signaling Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 201000004101 esophageal cancer Diseases 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 201000010982 kidney cancer Diseases 0.000 description 3
- 206010023841 laryngeal neoplasm Diseases 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 208000026037 malignant tumor of neck Diseases 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 206010038038 rectal cancer Diseases 0.000 description 3
- 201000001275 rectum cancer Diseases 0.000 description 3
- 201000000849 skin cancer Diseases 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 201000002510 thyroid cancer Diseases 0.000 description 3
- 206010046766 uterine cancer Diseases 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- ACTKAGSPIFDCMF-UHFFFAOYSA-N 1,3-oxazol-2-amine Chemical compound NC1=NC=CO1 ACTKAGSPIFDCMF-UHFFFAOYSA-N 0.000 description 2
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 108010068192 Cyclin A Proteins 0.000 description 2
- 102100025191 Cyclin-A2 Human genes 0.000 description 2
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 2
- 108010025454 Cyclin-Dependent Kinase 5 Proteins 0.000 description 2
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 2
- 102100026805 Cyclin-dependent-like kinase 5 Human genes 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 238000000134 MTT assay Methods 0.000 description 2
- 231100000002 MTT assay Toxicity 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 102000038030 PI3Ks Human genes 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 2
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 2
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 2
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 244000299461 Theobroma cacao Species 0.000 description 2
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 2
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 2
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 230000006369 cell cycle progression Effects 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NAZDVUBIEPVUKE-UHFFFAOYSA-N 2,5-dimethoxyaniline Chemical compound COC1=CC=C(OC)C(N)=C1 NAZDVUBIEPVUKE-UHFFFAOYSA-N 0.000 description 1
- FKJSFKCZZIXQIP-UHFFFAOYSA-N 2-bromo-1-(4-bromophenyl)ethanone Chemical compound BrCC(=O)C1=CC=C(Br)C=C1 FKJSFKCZZIXQIP-UHFFFAOYSA-N 0.000 description 1
- ZJFWCELATJMDNO-UHFFFAOYSA-N 2-bromo-1-(4-fluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CBr)C=C1 ZJFWCELATJMDNO-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- XDLWNEUYUGKDTC-UHFFFAOYSA-N 5-ethylsulfonyl-2-methoxyaniline Chemical compound CCS(=O)(=O)C1=CC=C(OC)C(N)=C1 XDLWNEUYUGKDTC-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 102000004121 Annexin A5 Human genes 0.000 description 1
- 108090000672 Annexin A5 Proteins 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102000002427 Cyclin B Human genes 0.000 description 1
- 108010068150 Cyclin B Proteins 0.000 description 1
- 108010060385 Cyclin B1 Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 101150048336 Flt1 gene Proteins 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 102100032340 G2/mitotic-specific cyclin-B1 Human genes 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 101000970023 Homo sapiens NUAK family SNF1-like kinase 1 Proteins 0.000 description 1
- 101000716124 Homo sapiens T-cell surface glycoprotein CD1c Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 102100021732 NUAK family SNF1-like kinase 1 Human genes 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 101150038994 PDGFRA gene Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 102100036014 T-cell surface glycoprotein CD1c Human genes 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 229930003471 Vitamin B2 Natural products 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 235000013334 alcoholic beverage Nutrition 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 208000008585 mastocytosis Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 235000013550 pizza Nutrition 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 description 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960000342 retinol acetate Drugs 0.000 description 1
- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical compound CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 description 1
- 235000019173 retinyl acetate Nutrition 0.000 description 1
- 239000011770 retinyl acetate Substances 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019164 vitamin B2 Nutrition 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 235000019158 vitamin B6 Nutrition 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/48—Nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a receptor tyrosine kinase activity inhibiting compound represented by Chemical Formula 1 and Chemical Formula 2, wherein the compound represented by Chemical Formula 1 and Chemical Formula 2 has been confirmed to inhibit the growth of cancer cells through inhibiting kinase activity and has been confirmed to enhance cancer cell apoptosis when used in combination with existing anticancer drugs or radiation therapy. Accordingly, the compound represented by Chemical Formula 1 and Chemical Formula 2 can be provided as a pharmaceutical composition for preventing or treating cancer, or as a composition for increasing the anti-cancer treatment effect of anti-cancer treatments and radiation therapy.
Description
[DESCRIPTION]
[Invention Title]
PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING CANCER CONTAINING RECEPTOR TYROSINE KINASE INHIBITOR AS ACTIVE INGREDIENT
[Technical Field]
The present invention relates to a pharmaceutical composition for preventing or treating cancer, a composition for enhancing anticancer effect or a health food for preventing or improving cancer, comprising a receptor tyrosine kinase activity inhibiting compound as an active ingredient.
[Background Art]
Receptor tyrosine kinases (RTKs) are transmembrane proteins that penetrate the cell membrane and are one of the most important receptor groups responsible for the cellular signaling system that regulates cell proliferation, cell migration, cell cycle and cell differentiation, and human RTKs are classified into about 20. Among them, the platelet-derived growth factor receptor (PDGFR) may be activated by ligand platelet-derived growth factor (PDGF), mitogen-activated protein kinases (MAPK), phosphatidyl inositol 3-kinase (P13K) and STAT3 (signal transducer and activator of transcription 3) can activate the downstream signaling pathways. Activation of PDGFR, including mutations, is observed in gastrointestinal stromal tumors (GIST), glioblastoma multiforme, and chronic myelogenous leukemia. Internal tandem duplication (IDT) mutations in the juxtamembrane domain of the FLT3 (FMS-like tyrosine kinase 3) gene in approximately 30% of patients with acute myeloid leukemia (AML) are found in about 3% of patients with acute lymphoblastic leukemia (ALL), and as patients with this mutation are known to have a poor prognosis, FLT3 inhibition may help treat acute myeloid leukemia and acute lymphocytic leukemia A c-Kit can be activated by the ligand stem cell factor (SCF) and point mutants such as D816V or V560G can be constantly activated without ligand to have their resistance against the cell proliferation, the cell survival and the apoptosis. In particular, c-Kit activates mast cells to induce mastocytosis and increases the expression in various organs (skin, liver, gastrointestinal tract, genitals, etc.) to induce autoimmune diseases, leukemia, gastrointestinal stromal tumor (GIST), small cell lung cancer, testicular cancer, polymorphic glioblastoma and the like. About 70-80% of GISTs patients have a gain-of-function mutation of c-Kit. It has been reported that the increase of SCE by nicotine activates c-Kit of non-small cell lung cancer, thereby enabling rapid growth and metastasis of non-small cell lung cancer.
A cyclin-dependent kinase (CDK) is a serine/threonine protein kinase which is very important in the cell cycle. The complex consists of catalytic small molecule cyclin-dependent kinase (CDK) and a regulatory small molecule cyclin, and each CDK is activated by forming the complex with a specific cyclin. The progression of each cell cycle can be regulated by specific CDK/cyclin complex, in particular CDK1/cyclin B1, CDK2/cycle E and CDK2/cyclin A are important factors for cell cycle progression.
In clinical trials, many RTK inhibitors showed an initial clinical response, which was identified as transient reactions and problems of the rapid resistance. In addition, RTK inhibitors can cause D816V mutations in KIT, D842V mutations in PDGFR, and D835V mutations in FLT3, and these mutations can hinder the binding of the RTK inhibitors to targets.
Accordingly, because RTK activation and rapid cell cycle progression in various cancer species are involved in abnormal cell regulation, there is a need for the development of inhibitors targeting CDK1/cyclin B, CD1C/cyclin A, and CDK5/p35 complex kinase activity together with the RTK activity.
[Disclosure]
[Technical Problem] The object of the present invention is to provide a composition comprising a compound capable of effectively inhibiting the activity of receptor tyrosine kinase (RTK) as an active ingredient in various cancer species as an anticancer agent, and a composition for enhancing the anticancer therapeutic effect in combination with other anticancer agents or radiation to improve the therapeutic effect.
[Technical Solution] The present invention can provide a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] in Chemical Formula 1, X may be any one selected from nitrogen and carbon.
The present invention provides a pharmaceutical composition for preventing or treating cancer comprising a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical Formula 1] In Chemical Formula 1, X may be any one selected from nitrogen and carbon.
to The present invention provides a composition for enhancing anticancer effect comprising a compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
In addition, the present invention provides a health food for preventing or improving cancer comprising a compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Advantageous Effects] According to the present invention, it was confirmed that the compound represented by the above Chemical Formula 1 inhibits the growth of the cancer cells by the inhibition of kinase activity and the combined treatment with conventional anticancer agents or radiation therapy improves the apoptosis effect of cancer cells and thus the compound represented by the above Chemical -----.../Th \ \ _ -80aet Formula 1 may be provided as a pharmaceutical composition for preventing or treating cancer or as a composition for enhancing the anticancer therapeutic effect of anticancer and radiation therapy.
[Description of Drawings]
FIG. 1 shows a result confirming that when human leukemia MV4-11 cell line was treated with 10 pM Compound 11 (Chemical Formula 1) and Compound 12 (Chemical Formula 2), the phosphorylation of STAT5 (Signal Transducer and Activator of Transcription 5) which is a sub-signaling system matrix protein of FLT3, was inhibited.
FIG. 2 is a result confirming that when human leukemia MV4-11 cell line was treated with 10pM Compound 11 (Chemical Formula 1) and Compound 12 (Chemical Formula 2), the cell death due to apoptosis occurs.
FIG. 3 is a result confirming that when human leukemia MV4-11 cell line was treated with 2pM Compound 11 (Chemical Formula 1) and Compound 12 (Chemical Formula 2) in combination with 5pM anticancer drug cisplatin, the cell proliferation was inhibited.
FIG. 4 is a result confirming that when human leukemia MV4-11 cell line was treated with 10pM Compound 11 (Chemical Formula 1) and Compound 12 (Chemical Formula 2) in combination with the radiation at 1Gy, the cell death was 20 increased [Best Mode] The present invention provides a compound represented by a following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] in Chemical Formula 1, X may be any one selected from nitrogen and carbon.
The present invention can provide a pharmaceutical composition for preventing or treating cancer comprising a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical Formula 1] in Chemical Formula 1, X may be any one selected from nitrogen and carbon.
More specifically, the compound represented by Chemical Formula 1 may inhibit receptor tyrosine kinase activity.
The cancer may be selected from the group consisting of lung cancer, tz) leukemia, breast cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, 402Et kidney cancer, blood cancer and rectal cancer, and the leukemia may be selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
According to one embodiment of the present invention, Compound 11 and Compound 12, which are compounds represented by Chemical Formula 1, exhibited the effect of inhibiting the kinase activities of 23 kinds as shown in Table 2, in particular, despite the concentration of 0.1 pM, cKit (V560G), FLT1, FLT3, FLT3 (D835Y), FLT3 (ITD), FLT4 kinases were confirmed to show a very superior inhibitory effect.
In addition, as a result of confirming the anticancer effect of Compound 11 and Compound 12 in various cancer disease cells, as shown in Table 4, both Compound 11 and Compound 12 showed excellent proliferation inhibitory effect in lung cancer, breast cancer, colon cancer and leukemia cells, since the cell viability of normal cells of CCD18-Co was not inhibited at the same concentration, selective cancer cell proliferation inhibitory effect was confirmed.
In one embodiment of the present invention, the pharmaceutical composition for preventing or treating cancer comprising the compound represented by Chemical Formula 1 or a pharmaceutically usable salt thereof as an active ingredient may be used as any one formulation selected from the group consisting of injections, granules, powders, tablets, pills, capsules, suppositories, gels, suspensions, emulsions, drops or solutions according to the conventional method.
Another embodiment of the invention may further comprise at least one additive selected from the group consisting of carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents, slip modifiers, flavors, antioxidants, buffers, bacteristats, diluents, dispersants, surfactants, binders and lubricants, which are conventionally used for the preparation of the pharmaceutical composition.
Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Solid to formulations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid formulations may contain at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin and the like in addition to the composition. Furthermore, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the to liquid formulations for oral administration include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used as simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories and the like. Examples of the non-aqueous solution and the suspension include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurinum, glycerogelatin and the like can be used.
According to one embodiment of the invention, the pharmaceutical composition may be administered intravenously, intraarterially, intraperitoneally, intramuscularly, intraarterially, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, orally, intraocularlly or intradermally to the subject in the conventional manner.
The preferred dosage of the compound represented by Chemical Formula 1 may vary depending on the condition and weight of the subject, the type and extent of the disease, the drug form, the route of administration, and the duration, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dosage may be, but is not limited to, 0.01 to 200 mg/kg, specifically 0.1 to 200 mg/kg, more specifically 0.1 to 100 mg/kg. Administration may be administered once a day or divided into several times, and the scope of the invention is not limited thereto.
In the present invention, the 'subject' may be a mammal including a human, but it is not limited thereto.
The present invention can provide a composition for enhancing anticancer effect comprising a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1] In Chemical Formula 1, X may be any one selected from nitrogen and carbon.
The composition for enhancing anticancer effect may be treated in combination with an anticancer agent or radiation.
The anticancer agent may be any one or more selected from the group consisting of cisplatin, 5-fluorouracil, paclitaxel, doxorubicin, daunorubicin, vinblastine, vincristine, actinomycin D, teniposide, etoposide, cyclophosphamide, epirubicin, adriamycin, daunomycin and mitomycin-C.
The composition may include 1 to 99 parts by weight of the anticancer agent and 1 to 99 parts by weight of the compound represented by Chemical Formula 1 based on 100 parts by weight of the total composition.
The composition may enhance the anticancer effect against any one cancer selected from the group consisting of lung cancer, leukemia, breast cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, blood cancer and rectal cancer.
The leukemia may be selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic 402Et lymphocytic leukemia.
According to another embodiment of the present invention, MV4-11 leukemia cells were co-treated with 2 pM of Compound 11 and 12 and 5 pM of cisplatin (5 pM), a known anticancer agent for 48 hours, and subjected to MTT assay for the analysis of the cell viability and as shown in FIG. 3, the cell proliferation inhibitory effect of the experimental group in which cisplatin and Compound 11 were co-administered was 40% or more higher than that of the control group treated with cisplatin as an anticancer agent alone, and the experimental group in which cisplatin and Compound 12 were administered in lo combination was confirmed to increase at least 60%.
In addition, the cultured human blood cancer cell MV4-11 cell line was treated with 10 pM Compound 11 and Compound 12 and irradiation at 1Gy of radiation and then cultured for 48 hours and analyzed by using FACSort flow cytometer (Becton dickinson, USA) for apoptosis-induced cells and the cell death by the apoptosis in the MV4-11 human blood cancer cell line was induced at least 2.1-fold and 1.8-fold, respectively, as compared with the radiation alone group as shown in FIG. 4.
From the above results, it was confirmed that Compound 11 and Compound 12 of the present invention can be treated in combination with the conventional anticancer treatment or radiation therapy to increase anticancer effect.
In addition, the present invention can provide a health food for preventing or improving cancer comprising a compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1]
N r \\ so:Et
-\ 0 N I-1 \ J1 x --
In Chemical Formula 1, X may be any one selected from nitrogen and carbon.
The cancer may be any one selected from the group consisting of lung cancer, leukemia, breast cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, breast cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer and rectal cancer.
The leukemia may be selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
The health food may be used with other foods or food additives in addition to the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and may be appropriately used according to the conventional method. The mixed amount of the active ingredient may be appropriately determined depending on the purpose of use thereof, for example, prophylactic, health or therapeutic treatment.
The effective dose of the compound contained in the health food 20 composition may be used in accordance with the effective dose of the therapeutic agent, but in the case of prolonged intake for the purpose of health and hygiene or health control, it may be less than the above range and since the active ingredient has no problem in terms of safety, it is evident that the active ingredient may be used in an amount above the above range.
There is no particular limitation on the kind of the health food, for example, meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic drinks, vitamin complexes, etc. Hereinafter, the present invention will be described in detail with reference to the following examples. The examples are only for describing the present invention in more detail and it is obvious to those skilled in the art that that the scope of the present invention is not limited by these examples embodiments in accordance with the gist of the present invention.
<Reference Example> Materials and instruments The melting point of the synthesized compound was determined using a Kruess M5000 Melting Point apparatus, and the value was not corrected. Proton NMR spectra were recorded on Avance-300 (Bruker) at 300 MHz. Chemical shifts were recorded in ppm and Me4Si was used as the reference standard.
Mass spectra were recorded in JEOL, JMS-600W VG Trio-2 GC-MS.
The reaction product was purified by clean column chromatography using silica gel 60 (230-400 mesh, Merck) and was subjected to trace observation by thin layer chromatography using pre-coated silica gel 60 F254 (E. Merch, Mumbai, India). Spots were stained using phosphomolybdic acid (PMA) or Hanesian's solution and visualized under UV light (254 nm).
<Example 1> Compound synthesis Compounds shown in Table 1 were synthesized in the same manner as in Reaction Scheme 1 below.
[Reaction Scheme 1] P.1.-Dv(w r Iryt.rkr-rrtkk 2a4 At, Hekk HR2.
Ii tr-WH ar.
R 31t4 C fr c Sr -B.2 L'H'RR.R'R/RRR-0 H000H,,Arrr H r; RS0HtE a ar, R2. keE;
EWt * as,HH H: H xt, R H NICL," 4411441 fat:NrcHkrkkkr 3.6144 1. Azide synthesis 4'-Bromophenacyl bromide (1.0 eq) or 2-bromo-4'-fluoroacetophenone was dissolved in 0.2 M acetone and sodium azide (3.0 eq) was added. After reacting for 16 hours at room temperature with stirring, the mixture was filtered and concentrated under vacuum to obtain an azide compound (la-b) (93% yield).
2. Isothiocyanate synthesis Aniline, p-anisidine, 2,5-dimethoxyaniline, 1-naphthylamine or 3-amino-4-methoxyphenyl ethyl sulfone of 1.0 eq, as an amine solution was dissolved in dichloromethane (DCM), respectively and treated with thiophosgene of 1.2 eq and stirred for 4 hours. After the reaction was completed, the mixture was diluted with saturated K2CO3 solution and extracted with DCM in each time.
The combined organic layers were dried under anhydrous MgSO4, filtered and concentrated under vacuum to obtain isothiocyanate compound (2a-l).
3. lsooxazole synthesis Triphenylphosphine (PPhs; 1.0 eq) was added into a solution in which 1.0 eq of azide compound (1 a-b) synthesized by the above method and isothiocyanate compound (2a-l; 1.0 eq) dissolved in 0.2 M dioxane were mixed and stirred.
The mixture was stirred for 4 hours while heating to 90 °C and after the reaction was completed, the temperature was cooled to room temperature and the solvent was removed under pressure.
After removal of solvent, the residue was purified by clean column chromatography on silica gel using ethyl acetate (Et0Ac)/hexane (1:10) as mobile phase to obtain as eluent (3a-j, 32% yield).
4. Cross coupling Pd(dppf)C12 (0.5 mol%) was added into a solution in which the synthesized 3e compound, 3-pyridinylboronic acid (1.5 eq) or phenylboronic acid (1.5 eq) and K2COs dissolved in 0.2M DMF were mixed, the mixed solution was stirred at 90 °C for 10 hours and then extracted with ethyl acetate and water at each time.
The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under vacuum. The residue was purified by clean column chromatography on silica gel using Et0Ac/hexane (1:5) as mobile phase to obtain the following Compounds 11(3k) and Compound 12 (31) as eluents (3k and 31, 35% yield, respectively).
[Compound 11] El la N-(5-(ethylsulfonyI)-2-methoxypheny1)-5-(4-(pyridin-3-yl)phenyl) oxazol-2-amine (Compound (3k)) White solid, mp = 183-185 °C, 1H NMR (300 MHz, DMSO-c16)5 10.52 (s, 1H), 9.86 (br s, 1H), 8.68-9.02 (m, 1H), 7.41-7.88 (m, 9H), 7.08-7.38 (m, 1H), 3.83-4.20 (m, 3H), 3.24 (br d, J=7.70 Hz, 2H), 1.15 (br t, J=7.34 Hz, 3H); MS (FAB) m/z 436 (MN) [Compound 12] 5-(bipheny1-4-y1)-N-(5-(ethylsulfony1)-2-methoxyphenyl)oxazol-2-amine (Compound (31)) Yellow solid, mp = 203.0-203.2 °C, 1H NMR (300 MHz, DMSO-c16)5 10.52 (s, 1H), 9.81 (s, 1H), 8.70-8.84 (m, 1H), 7.18-7.85 (m, 11H), 3.90-4.06 (m, 3H), 3.14-3.28 (m, 2H), 1.05-1.18 (m, 3H); MS (FAB) m/z 435 (MH+).
<Example 2> Confirmation of kinase activity inhibitory effect The RTK kinase activity inhibitory effect of Compound 11 and Compound 12 synthesized as in Example 1 was confirmed.
The kinase profiling services of Eurofins (England) and Reaction Biology (USA) were used to measure the inhibition effects of various kinase activities of Compounds 11 and Compound 12 at concentrations of 0.1 pM and shown in Table 2 below.
[Table 2]
Kinase Compound 11(0.1 pM) Compound 12 activity % (0.1 pM) activity % Abl 68 72 ARK5 73 71 CDK1/cyclinB 78 77 CDK5/p35 75 72 cKit(h) 74 78 cKit(D816H)(h) 64 88 cKit(V560G)(h) 41 57 Flt1(h) 18 28 F1t3(D835Y)(h) 6 11 F1t3(1TD)(h) 8 15 F1t3(h) 8 20 F1t4(h) 2 1 PDGFRa(h) 78 77 PDGFRp(h) 79 84 As shown in the Table 2, Compound 11 and Compound 12 showed the effect of inhibiting kinase activity of 23 kinds, in particular, despite the concentration of 0.1 pM cKit (V560G), FLT1, FLT3, FLT3 (D835Y), FLT3 (ITD), FLT4 kinases showed a very excellent inhibitory effect.
In addition, with respect to the kinase exhibited a significant inhibitory effect, the half maximal inhibitory concentration (IC5o) of the Compound 11 and Compound 12 was confirmed, as shown in Table 3.
[Table 3]
IC50 Compound 11 (pM) Compound 12 (pM) FLT3 0.025 0.008 FLT3(D835Y) 0.009 0.007 FLT3(ITD) 0.004 0.016 As shown in the above Table 3, Compound 11 and Compound 12 showed an excellent inhibitory effect of 50% inhibitory concentration as nM level for FLT3 and D835Y in FLT3 genes, ITD mutant FLT3 kinase.
<Example 3> Confirmation of effects on various human cancer cell lines With respect to the cell proliferation rate of various cancer cell lines, the cancer cell proliferation inhibitory effect of Compound 11 and Compound 12 synthesized in Example 1 was confirmed.
First, human lung cancer cell line H1299, human breast cancer cell line 20 MDA-MB231, human colon cancer cell line HCT116, human acute leukemia cell line MV4-11, human normal colon cell line CCD18-Co purchased from the American Type Culture Collection (ATCC) were incubated in DMEM (Dulbecco's modified Eagle's medium, WELGENE), RPM! (WELGENE) or MEM (MV4-11; WELGENE) medium containing 10% fetal bovine serum (FBS, WELGENE, Korea), 100 pg/ml streptomycin and 100 unit/mIpenicillin (GIBCO, UK) under 5% CO2 and 37 °C, respectively, and used for the experiment.
1. Confirmation of STAT5 phosphorylation inhibitory effect After treatment with Compound 11 and Compound 12 in cultured MV4-11 leukemia cells, it was confirmed by Western blot whether the phosphorylation of STAT5, a sub-signaling system of FLT3, was inhibited.
After treatment with Compound 11 or Compound 12 at 0.1, 1, 2, 5 or 10 pM concentrations for 1 hour, cells were obtained and cell lysates were obtained by methods commonly used in the art. The cell lysates were separated by electrophoresis using 9% gradient SDS-PAGE and transferred to nitrocellulose membranes (BioRad, Hercules, CA, USA). The membrane was blocked with 5% skim milk, followed by reacting anti-phospho-STAT5 antibody (Santa Cruz Biotechnology, USA) as the primary antibody and anti-13-actin (Santa Cruz Biotechnology) as a control for 1 hour. Thereafter, horseradish peroxidase conjugated anti-mouse IgG antibody (Santa Cruz Biotechnology) was incubated and visualized using an ECL system (GE, USA).
As a result, as shown in FIG. 1, it was confirmed that phosphorylation of STAT5, which is a substrate protein of FLT3 kinase, was suppressed from 1 hour in MV4-11 leukemia cells treated with Compound 11 or Compound 12.
2. Confirmation of survival inhibition effect of cancer cell line Various cell lines cultured by the above method were incubated for 24 hours after dispensing in 96-well plates with the number of 3 x 103, respectively, and then treated with Compounds 11 and Compound 12 synthesized as in Example 1 at 10 pM concentrations, respectively, and incubated for 48 hours. Then 0.5 mg/m L MTT (3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide solution was added to each well and further incubated for 3 hours at 37°C. After incubation, the supernatant was removed, and the formed formazan crystals were dissolved in DMSO and measured at 590 nm using a spectrometer (Labsystems, USA) and the control group was treated with DMSO.
The results were shown in Table 4 below as relative proliferation in respect of 100% survival rate.
[Table 4]
Experimental group DMSO (Control) Compound 11 Compound 12 MV4-11 100 ± 10.78 15.15 ± 0.26 14.69 ± 0.82 Blood cancer cells DLD-1 100 ± 2.31 45.15 ± 0.26 44.69 ± 0.82 Colon cancer cells H460 100 ± 5.25 76.40 ± 2.21 58.61 ± 3.42 Lung cancer cells MDA-M B231 100 ± 4.70 72.53 ± 3.84 45.91 ± 4.22 Breast cancer cells CCD18-Co 100 ± 1.25 98.20 ± 4.85 95.52 ± 1.22 Colon normal cells As shown in the Table 4, Compound 11 and Compound 12 according to is the present invention showed an excellent proliferation inhibitory effect in lung cancer, breast cancer, colon cancer and leukemia cells, and because cell survival rate of CCD18-Co normal cells was not inhibited at the same concentration, it was confirmed that the selective cancer cell proliferation inhibitory effect occurred.
In addition, acute leukemia cells MV4-11 were treated with the compounds synthesized in Example 1, i.e. Derivative 2 to Derivative 12 synthesized in Example 1 and the inhibitory effect on the cell survival was confirmed.
Cells were dispensed in 96-well plates with the number of 3 x 103, incubated for 24 hours, and then treated with 10 pM Compound 2 to Compound 12 synthesized in Example 1, respectively, and incubated for 48 hours. Then 0.5 mg/mL of MIT solution was added to each well and further incubated at 37 °C.
for 3 hours. After incubation, the supernatant was removed and the formed formazan crystals were dissolved in DMSO and measured at 590 nm using a spectrometer.
The control group was treated with DMSO, and the cell viability was expressed as a relative value for 100% survival rate as shown in Table 5 below.
[Table 5]
Experimental group Cell viability (%) DMSO 100 ± 4.34 Compound 2 32.43 ± 1.77 Compound 3 59.25 ± 2.09 Compound 4 44.16 ± 1.49 Compound 5 29.30 ± 1.34 Compound 6 30.89 ± 1.00 Compound 7 34.30 ± 0.80 Compound 8 34.58 ± 1.19 Compound 9 65.75 ± 2.11 Compound 10 79.53 ±4.04 Compound 11 29.39 ± 0.53 Compound 12 34.11 ± 1.19 On the other hand, caspase-3 involved in cell death and the cleavage of PARP (poly-ADP ribose polymerase) involved in DNA repair was confirmed by Western blotting. At this time, the protein and cleaved PARP protein were detected with caspase-3 antibody (Cell signaling technology, Inc. USA) and PARP-1 antibody (PARP-1, Cell signaling technology, Inc. USA).
As a result, as shown in FIG. 2, the caspase-3 expression and the cleavage of PARP (poly-ADP ribose polymerase), which are genes related to the cell death due to apoptosis were confirmed to be increased in MV4-11 leukemia cells treated with Compound 11 and Compound 12.
<Example 4> Confirmation of anticancer effect by combined treatment 1. Confirmation of anticancer effect by combination treatment with anticancer agent As in Example 3, the cultured MV4-11 leukemia cells were co-treated with 15 2 pM of Compound 11 or Compound 12 and 5 pM of cisplatin (5 pM), a known anticancer agent for 48 hours, and subjected to MTT assay for the analysis of the cell viability.
As a result, as shown in FIG. 3, the cell proliferation inhibitory effect of the experimental group in which cisplatin and Compound 1 were co-administered was 40% or more higher than that of the control group treated with cisplatin as an anticancer agent alone, and the experimental group in which cisplatin and Compound 2 were administered in combination was confirmed to increase at least 60%.
From the above results, it was confirmed that Compound 11 and Compound 12 according to the present invention can be used as an anticancer agent adjuvant that can enhance the therapeutic effect of anticancer agent.
2. Confirmation of anticancer effect by combined treatment with radiation pM of Compound 11 and Compound 12 were treated in combination of irradiation at 1Gy radiation in cultured human blood cancer cell MV4-11 cell line and cultured for 48 hours and double-stained with annexin V and propidium iodide (P1) and analyzed using a FACSort flow cytometer (Becton dickinson, USA) to determine total apoptosis by summing early and late apoptotic cells.
As a result, it was confirmed that the cell death by the apoptosis in the MV4-1 1 human blood cancer cell line was induced at least 2.1-fold and 1.8-fold, respectively, as compared with the radiation alone group as shown in FIG. 4. From the above results, it was confirmed that Compound 11 and Compound 12 of the present invention can be used as a radiotherapy aid that can enhance the therapeutic effect of radiotherapy.
The following describes an example of the preparation of a composition comprising Compound 11 or Compound 12 according to the present invention, but the present invention is not intended to be limited thereto but merely to be described in detail.
<Prescription Example 1> Prescription example of pharmaceutical composition 1. Preparation of powder A powder was prepared by mixing 20 mg of compound, 100 mg of lactose and 10 mg of talc and filling into an airtight bag.
2. Preparation of tablet A tablet was prepared by mixing 20 mg of compound, 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate, followed by tablet compression according to a conventional method of preparing the tablets.
3. Preparation of capsule A capsule was prepared by mixing 10 mg of compound, 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate and filling into gelatin capsules according to a conventional method of preparing the capsules.
4. Preparation of Injection An injection was prepared by mixing 10 mg of compound, appropriate amount of sterile distilled water for injection and appropriate amount of a pH adjusting agent and preparing in the above-described content of ingredients per ampoule (2 ml) according to a conventional method of preparing the injections.
5. Preparation of ointment An ointment was prepared by mixing 10 mg of compound, 250 mg of PEG-4000, 650 mg of PEG-400, 10 mg of white petrolatum, 1.44 mg of paraoxybenzoic acid methyl, 0.18 mg of paraoxybenzoic acid propyl and the remaining amount of purified water according to the conventional method of preparing the ointments.
<Prescription Example 2> Health functional food 1. Preparation of health food A health food was preparing by mixing 1 mg of compound, appropriate amount of vitamin mixture (70 pg of vitamin A acetate, 1.0 mg of vitamin E, 0.13 mg of vitamin B, 0.15 mg of vitamin B2, 0.5 mg of vitamin B6, 0.2 pg of vitamin B12, 10 mg of vitamin C, 10 pg of biotin, 1.7 mg of nicotinic acid amide, 50 pg of folic acid, 0.5 mg of calcium pantothenate) and appropriate amount of mineral mixture (1.75 mg ferrous sulfate, 0.82 mg of zinc oxide, 25.3 mg of magnesium carbonate, 15 mg of potassium monophosphate, 55 mg of dicalcium phosphate, 90 mg of potassium citrate, 100 mg of calcium carbonate, 24.8 mg of magnesium chloride), and preparing granules according to a conventional method.
2. Preparation of health drinks 1 mg of compound, 1000 mg of citric acid, 100 g of oligosaccharide, 2 g of plum concentrate, 1 g of taurine, and purified water were added to make 900 ml in total and after mixing the above components according to a conventional health drinks manufacturing method, and then the mixture was stirred and heated at 85 °C for about 1 hour, the resulting solution was filtered to obtain in a sterilized 2 L container, and followed by sealed sterilization and storing in refrigerated.
While the present invention has been particularly described with reference to specific embodiments thereof, it is apparent that this specific description is only a preferred embodiment and that the scope of the present invention is not limited thereby to those skilled in the art. That is, the practical scope of the present invention is defined by the appended claims and their equivalents.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020170098524A KR101948555B1 (en) | 2017-08-03 | 2017-08-03 | Pharmaceutical composition for preventing or treating cancer comprising receptor tyrosine kinases inhibitor |
PCT/KR2018/002500 WO2019027117A1 (en) | 2017-08-03 | 2018-02-28 | Pharmaceutical composition for preventing or treating cancer containing receptor tyrosine kinase inhibitor as active ingredient |
Publications (3)
Publication Number | Publication Date |
---|---|
GB202001368D0 GB202001368D0 (en) | 2020-03-18 |
GB2579149A true GB2579149A (en) | 2020-06-10 |
GB2579149B GB2579149B (en) | 2022-05-11 |
Family
ID=65233921
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB2001368.6A Active GB2579149B (en) | 2017-08-03 | 2018-02-28 | Pharmaceutical composition for preventing or treating cancer containing receptor tyrosine kinase inhibitor as active ingredient |
Country Status (4)
Country | Link |
---|---|
KR (1) | KR101948555B1 (en) |
DE (1) | DE112018003936T5 (en) |
GB (1) | GB2579149B (en) |
WO (1) | WO2019027117A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114533885B (en) * | 2022-03-25 | 2023-08-01 | 南京中医药大学 | Compound pharmaceutical composition with isoliensinine and chemotherapeutic drugs as active ingredients |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004032882A2 (en) * | 2002-10-10 | 2004-04-22 | Smithkline Beecham Corporation | Chemical compounds |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060135483A1 (en) | 2004-07-09 | 2006-06-22 | Cheruvallath Zacharia S | Oxygen/nitrogen heterocycle inhibitors of tyrosine phosphatases |
-
2017
- 2017-08-03 KR KR1020170098524A patent/KR101948555B1/en active IP Right Grant
-
2018
- 2018-02-28 GB GB2001368.6A patent/GB2579149B/en active Active
- 2018-02-28 DE DE112018003936.6T patent/DE112018003936T5/en active Pending
- 2018-02-28 WO PCT/KR2018/002500 patent/WO2019027117A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004032882A2 (en) * | 2002-10-10 | 2004-04-22 | Smithkline Beecham Corporation | Chemical compounds |
Non-Patent Citations (6)
Title |
---|
HARRIS, P. A. et al., "Discovery and Evaluation of 2-anilino-5-aryloxazoles as a Novel Class of VEGFR2 Kinase Inhibitors", Journal of Medicinal Chemistry, (20050000), vol. 48, pages 1610 - 1619, See abstract; compound 39; and tables 3-7. * * |
LINTNEROVA, L. et al., "A Development of Chimeric VEGFR2 TK Inhibitor Based on Two Ligand Conformers fromPDB: 1Y6A Complex-Medicinal Chemistry Consequences of a TKs Analysis", European Journal of Medicinal Chemistry, (20140000), vol. 72, pages 146 - 159, See abstract; and figure 1 * |
MURAR, M. et al., "Novel CLK1 Inhibitors Based on N-aryloxazol-2-amine Skeleton - A Possible Way to Dual VEGFR2 TK/CLK Ligands", European Journal of Medicinal Chemistry, (20161118), vol. 126, pages 754 - 761, * See page 756; and formulas 1-4. * * |
RAGNO, R. et al., "Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Inhibitors: Development and Validation of Predictive 3-D QSAR Models through Extensive Ligand- and Structure-based Approaches", Journal of Computer-Aided Molecular Design, 2015, vol. 29, pp 757 - 776, See pp 757,758;& table 2 * |
SHARMA, B. K. et al., "Modeling of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Kinase Inhibitory Activity of 2-anilino-5-aryloxazoles Using Chemometric Tools", Journal of Enzyme Inhibition and Medicinal Chemistry, (2009), vol. 24, no. 1, pages 86-93, See abstract; fig 1; & table I * |
VOJTICKOVA, M. et al., "Ynamide Click Chemistry in Development of Triazole VEGFR2 TK Modulators", European Journal of Medicinal Chemistry, (2015), vol. 103, pages 105 - 122, See abstract; and figures 1, 7. * |
Also Published As
Publication number | Publication date |
---|---|
WO2019027117A1 (en) | 2019-02-07 |
GB202001368D0 (en) | 2020-03-18 |
KR101948555B1 (en) | 2019-02-15 |
DE112018003936T5 (en) | 2020-04-30 |
KR20190014715A (en) | 2019-02-13 |
GB2579149B (en) | 2022-05-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5974124B2 (en) | Compositions of kinase inhibitors and their use for the treatment of cancer and other diseases associated with kinases | |
CN102816175B (en) | A kind of heterocycle pyridine compounds, its intermediate, preparation method and purposes | |
KR101789430B1 (en) | Novel compound having SMO-inhibitory activity and composition for preventing or treating cancer comprising the same as an active ingredient | |
CN110831926A (en) | Novel tetralinyl urea derivatives | |
CN104768962B (en) | Leaving group is the platinum-like compounds of the malonate derivative containing amino or alkylamino | |
TW201915004A (en) | Thienopyridine compound, and preparing method, pharmaceutical composition and application thereof for preparing a medicament capable of preventing or treating tumor growth and metastasis | |
KR101924801B1 (en) | Composition for preventing or treating cancer comprising triazolopyridine derivatives | |
WO2013041014A1 (en) | Platinum compound having amino- or alkylamino-containing succinic acid derivatives as leaving group, preparation method therefor, and use thereof | |
KR20190115017A (en) | N1- (4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) cyclohexane-1, as a CK1 and / or IRAK1 inhibitor for treating cancer, 4-diamine derivatives and related compounds | |
WO2013007172A1 (en) | Platinum compounds for treating cell proliferative disease, preparation methods and uses thereof | |
KR101948555B1 (en) | Pharmaceutical composition for preventing or treating cancer comprising receptor tyrosine kinases inhibitor | |
JP2020502167A (en) | Pharmaceutical composition for preventing or treating DYRK-related diseases, comprising a pyridine compound as an active ingredient | |
US11629121B2 (en) | Benzylideneacetone derivative and use thereof | |
KR101713027B1 (en) | Composition for preventing or treating cancer comprising phenyloxazol derivatives | |
KR101325783B1 (en) | Anticancer composition containig the naphthalenylphenyldihydropyrazole | |
KR101767602B1 (en) | Novel N-phenylpyrimidin-2-amine derivatives compound, Manufacturing method thereof, Pharmaceutical composition for preventing and treating cancer containing the same and Methods for preventing and treating cancer using the same | |
CN114539129B (en) | Allylamine bifunctional compound and application thereof | |
KR102100729B1 (en) | Anthraquinone-based compounds and composition for preventing or treating cancer diseases comprising the same | |
KR20190012556A (en) | Novel benzylideneacetone derivatives and uses thereof | |
CN108186630B (en) | Application of isatin analogue in preparation of antitumor drugs | |
KR101283004B1 (en) | Anticancer composition containig the benzochalcone | |
KR101290579B1 (en) | Anticancer composition containig the benzochalcone | |
KR20220089327A (en) | Novel quinazoline compounds and medical use thereof | |
KR101514285B1 (en) | Pharmaceutical composition for prevention or treatment of cancer disease containing aminodihydroquinolin compound or pharmaceutically acceptable salt thereof | |
CN102688232A (en) | Synthesis and application of isoindole-1, 3-dione derivative as RSK2 inhibitor |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
789A | Request for publication of translation (sect. 89(a)/1977) |
Ref document number: 2019027117 Country of ref document: WO |