WO2024017316A1 - Pharmaceutical combination product and combination therapy - Google Patents
Pharmaceutical combination product and combination therapy Download PDFInfo
- Publication number
- WO2024017316A1 WO2024017316A1 PCT/CN2023/108288 CN2023108288W WO2024017316A1 WO 2024017316 A1 WO2024017316 A1 WO 2024017316A1 CN 2023108288 W CN2023108288 W CN 2023108288W WO 2024017316 A1 WO2024017316 A1 WO 2024017316A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- active ingredient
- pharmaceutically active
- administered
- pharmaceutical
- compound
- Prior art date
Links
- 239000013066 combination product Substances 0.000 title claims abstract description 17
- 229940127555 combination product Drugs 0.000 title claims abstract description 17
- 238000002648 combination therapy Methods 0.000 title abstract description 8
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 90
- 201000011510 cancer Diseases 0.000 claims abstract description 30
- 230000002159 abnormal effect Effects 0.000 claims abstract description 16
- 230000010261 cell growth Effects 0.000 claims abstract description 15
- 239000004480 active ingredient Substances 0.000 claims description 112
- 150000001875 compounds Chemical class 0.000 claims description 48
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 206010027476 Metastases Diseases 0.000 claims description 5
- 206010068771 Soft tissue neoplasm Diseases 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 20
- 241001465754 Metazoa Species 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 18
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 15
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 15
- 230000004614 tumor growth Effects 0.000 description 14
- 229940079593 drug Drugs 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- -1 pyrimidine compound Chemical class 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000003826 tablet Substances 0.000 description 9
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 229940095064 tartrate Drugs 0.000 description 6
- 208000031648 Body Weight Changes Diseases 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 5
- 230000004579 body weight change Effects 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000000155 isotopic effect Effects 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 238000007619 statistical method Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 229940049920 malate Drugs 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 206010027406 Mesothelioma 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
- 239000002775 capsule Substances 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- 230000002354 daily effect Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003651 drinking water Substances 0.000 description 3
- 235000020188 drinking water Nutrition 0.000 description 3
- 238000002651 drug therapy Methods 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 206010061289 metastatic neoplasm Diseases 0.000 description 3
- 208000037843 metastatic solid tumor Diseases 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 2
- ULMMVBPTWVRPSI-UHFFFAOYSA-N 2-fluoro-5-methoxy-4-[[4-[(2-methyl-3-oxo-1h-isoindol-4-yl)oxy]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-n-(1-methylpiperidin-4-yl)benzamide Chemical compound FC=1C=C(NC=2N=C(OC=3C=4C(=O)N(C)CC=4C=CC=3)C(=CN=2)C(F)(F)F)C(OC)=CC=1C(=O)NC1CCN(C)CC1 ULMMVBPTWVRPSI-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 241000269627 Amphiuma means Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000012664 BCL-2-inhibitor Substances 0.000 description 2
- 229940123711 Bcl2 inhibitor Drugs 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 229940124297 CDK 4/6 inhibitor Drugs 0.000 description 2
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- 206010014967 Ependymoma Diseases 0.000 description 2
- 229940124783 FAK inhibitor Drugs 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000003458 I kappa b kinase inhibitor Substances 0.000 description 2
- 229940121730 Janus kinase 2 inhibitor Drugs 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 208000014767 Myeloproliferative disease Diseases 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- 239000012828 PI3K inhibitor Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 108090000315 Protein Kinase C Proteins 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 229940050390 benzoate Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000012490 blank solution Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 208000030381 cutaneous melanoma Diseases 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 229940050410 gluconate Drugs 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 229940049906 glutamate Drugs 0.000 description 2
- 230000003862 health status Effects 0.000 description 2
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 2
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 229960003445 idelalisib Drugs 0.000 description 2
- YKLIKGKUANLGSB-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2[C]3N=CN=C3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 YKLIKGKUANLGSB-HNNXBMFYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229940070765 laurate Drugs 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 208000006178 malignant mesothelioma Diseases 0.000 description 2
- 201000005282 malignant pleural mesothelioma Diseases 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 2
- 206010027191 meningioma Diseases 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 210000000441 neoplastic stem cell Anatomy 0.000 description 2
- 229940049964 oleate Drugs 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 229940046159 pegylated liposomal doxorubicin Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
- 229960001860 salicylate Drugs 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000003860 storage Methods 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
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 150000003892 tartrate salts Chemical class 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- 229940070710 valerate Drugs 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- WKOLLVMJNQIZCI-UHFFFAOYSA-M vanillate Chemical compound COC1=CC(C([O-])=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-M 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- HBPXWEPKNBHKAX-NSHDSACASA-N (2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide Chemical compound S1C(C=2N=C(SC=2)C(C)(C)C)=C(C)N=C1NC(=O)N1CCC[C@H]1C(N)=O HBPXWEPKNBHKAX-NSHDSACASA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- UCJZOKGUEJUNIO-IINYFYTJSA-N (3S,4S)-8-[6-amino-5-(2-amino-3-chloropyridin-4-yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound C[C@@H]1OCC2(CCN(CC2)C2=CN=C(SC3=C(Cl)C(N)=NC=C3)C(N)=N2)[C@@H]1N UCJZOKGUEJUNIO-IINYFYTJSA-N 0.000 description 1
- DJAHKBBSJCDSOZ-AJLBTXRUSA-N (5z,9e,13e)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one;(5e,9e,13e)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C/CCC(C)=O.CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C\CCC(C)=O DJAHKBBSJCDSOZ-AJLBTXRUSA-N 0.000 description 1
- IPFOCHMOYUMURK-UHFFFAOYSA-N 1-[3-[4-[2-[4-chloro-2-hydroxy-5-(1-methylcyclopropyl)anilino]acetyl]piperazin-1-yl]azetidin-1-yl]prop-2-en-1-one Chemical compound C=1C(NCC(=O)N2CCN(CC2)C2CN(C2)C(=O)C=C)=C(O)C=C(Cl)C=1C1(C)CC1 IPFOCHMOYUMURK-UHFFFAOYSA-N 0.000 description 1
- PEMUGDMSUDYLHU-ZEQRLZLVSA-N 2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile Chemical compound ClC=1C=CC=C2C=CC=C(C=12)N1CC=2N=C(N=C(C=2CC1)N1C[C@@H](N(CC1)C(C(=C)F)=O)CC#N)OC[C@H]1N(CCC1)C PEMUGDMSUDYLHU-ZEQRLZLVSA-N 0.000 description 1
- BVAHPPKGOOJSPU-UHFFFAOYSA-N 2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(C)C=2)C(C)C)=NC=C1Cl BVAHPPKGOOJSPU-UHFFFAOYSA-N 0.000 description 1
- UYJNQQDJUOUFQJ-UHFFFAOYSA-N 2-[[5-chloro-2-[2-methoxy-4-(4-morpholinyl)anilino]-4-pyrimidinyl]amino]-N-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=NC(NC=2C(=CC(=CC=2)N2CCOCC2)OC)=NC=C1Cl UYJNQQDJUOUFQJ-UHFFFAOYSA-N 0.000 description 1
- AXRCEOKUDYDWLF-UHFFFAOYSA-N 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C(C1=CC=CC=C11)=CN1C(CC1)CCN1CC1=CC=CC=N1 AXRCEOKUDYDWLF-UHFFFAOYSA-N 0.000 description 1
- QMGUOJYZJKLOLH-UHFFFAOYSA-N 3-[1-[3-(dimethylamino)propyl]indol-3-yl]-4-(1h-indol-3-yl)pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(CCCN(C)C)C=C1C1=C(C=2C3=CC=CC=C3NC=2)C(=O)NC1=O QMGUOJYZJKLOLH-UHFFFAOYSA-N 0.000 description 1
- KIWODJBCHRADND-UHFFFAOYSA-N 3-anilino-4-[1-[3-(1-imidazolyl)propyl]-3-indolyl]pyrrole-2,5-dione Chemical compound O=C1NC(=O)C(C=2C3=CC=CC=C3N(CCCN3C=NC=C3)C=2)=C1NC1=CC=CC=C1 KIWODJBCHRADND-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- SJVQHLPISAIATJ-ZDUSSCGKSA-N 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1 SJVQHLPISAIATJ-ZDUSSCGKSA-N 0.000 description 1
- HPLNQCPCUACXLM-PGUFJCEWSA-N ABT-737 Chemical compound C([C@@H](CCN(C)C)NC=1C(=CC(=CC=1)S(=O)(=O)NC(=O)C=1C=CC(=CC=1)N1CCN(CC=2C(=CC=CC=2)C=2C=CC(Cl)=CC=2)CC1)[N+]([O-])=O)SC1=CC=CC=C1 HPLNQCPCUACXLM-PGUFJCEWSA-N 0.000 description 1
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 1
- 229960005531 AMG 319 Drugs 0.000 description 1
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 206010001197 Adenocarcinoma of the cervix Diseases 0.000 description 1
- 208000034246 Adenocarcinoma of the cervix uteri Diseases 0.000 description 1
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 1
- 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 1
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- CWHUFRVAEUJCEF-UHFFFAOYSA-N BKM120 Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=CC(N2CCOCC2)=NC(N2CCOCC2)=N1 CWHUFRVAEUJCEF-UHFFFAOYSA-N 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- 102100031658 C-X-C chemokine receptor type 5 Human genes 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 201000000274 Carcinosarcoma Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- YWPHBSHEGTZPNS-UHFFFAOYSA-N ClC=1C(=NC(=NC=1)NC1=C(C=C(C(=C1)C)C=1CCN(CC=1)C1CCOCC1)OC(C)C)NC1=C(C=CC=C1)S(=O)(=O)C(C)C Chemical compound ClC=1C(=NC(=NC=1)NC1=C(C=C(C(=C1)C)C=1CCN(CC=1)C1CCOCC1)OC(C)C)NC1=C(C=CC=C1)S(=O)(=O)C(C)C YWPHBSHEGTZPNS-UHFFFAOYSA-N 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- 239000012623 DNA damaging agent Substances 0.000 description 1
- 229940126190 DNA methyltransferase inhibitor Drugs 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 208000005431 Endometrioid Carcinoma Diseases 0.000 description 1
- 229940125830 FGFR1 inhibitor Drugs 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102100039788 GTPase NRas Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma 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
- 229920002907 Guar gum Polymers 0.000 description 1
- 206010066476 Haematological malignancy Diseases 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 101000922405 Homo sapiens C-X-C chemokine receptor type 5 Proteins 0.000 description 1
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 1
- 101000977771 Homo sapiens Interleukin-1 receptor-associated kinase 4 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102100030126 Interferon regulatory factor 4 Human genes 0.000 description 1
- 102100023533 Interleukin-1 receptor-associated kinase 4 Human genes 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- UIARLYUEJFELEN-LROUJFHJSA-N LSM-1231 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 description 1
- 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 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 229940126560 MAPK inhibitor Drugs 0.000 description 1
- 229940124647 MEK inhibitor Drugs 0.000 description 1
- 208000009018 Medullary thyroid cancer Diseases 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 208000009905 Neurofibromatoses Diseases 0.000 description 1
- 208000003019 Neurofibromatosis 1 Diseases 0.000 description 1
- 208000024834 Neurofibromatosis type 1 Diseases 0.000 description 1
- 108010085839 Neurofibromin 2 Proteins 0.000 description 1
- 102000007517 Neurofibromin 2 Human genes 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010035603 Pleural mesothelioma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 229940125999 RMC-4550 Drugs 0.000 description 1
- 229940126002 RMC-4630 Drugs 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 229940078123 Ras inhibitor Drugs 0.000 description 1
- 206010038111 Recurrent cancer Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 208000006938 Schwannomatosis Diseases 0.000 description 1
- 108010082455 Sebelipase alfa Proteins 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000034254 Squamous cell carcinoma of the cervix uteri Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- 229940125811 TNO155 Drugs 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 description 1
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 1
- 201000005969 Uveal melanoma Diseases 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- IKUYEYLZXGGCRD-ORAYPTAESA-N [3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol Chemical compound N[C@@H]1[C@@H](OCC11CCN(CC1)C=1C(=NC(=C(N=1)C)C1=C(C(=CC=C1)Cl)Cl)CO)C IKUYEYLZXGGCRD-ORAYPTAESA-N 0.000 description 1
- HISJAYUQVHMWTA-BLLLJJGKSA-N [6-(2-amino-3-chloropyridin-4-yl)sulfanyl-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl]methanol Chemical compound NC1=NC=CC(=C1Cl)SC1=C(N=C(C(=N1)CO)N1CCC2([C@@H]([C@@H](OC2)C)N)CC1)C HISJAYUQVHMWTA-BLLLJJGKSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- 229940124988 adagrasib Drugs 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 208000037844 advanced solid tumor Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960004416 alectinib hydrochloride Drugs 0.000 description 1
- GYABBVHSRIHYJR-UHFFFAOYSA-N alectinib hydrochloride Chemical group Cl.CCC1=CC=2C(=O)C(C3=CC=C(C=C3N3)C#N)=C3C(C)(C)C=2C=C1N(CC1)CCC1N1CCOCC1 GYABBVHSRIHYJR-UHFFFAOYSA-N 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 description 1
- 229960005207 auranofin Drugs 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 1
- 229960003094 belinostat Drugs 0.000 description 1
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 1
- 229960002707 bendamustine Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 206010005084 bladder transitional cell carcinoma Diseases 0.000 description 1
- 201000001528 bladder urothelial carcinoma Diseases 0.000 description 1
- 229960003008 blinatumomab Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 201000006491 bone marrow cancer Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229950003628 buparlisib Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 208000011892 carcinosarcoma of the corpus uteri Diseases 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229960001602 ceritinib Drugs 0.000 description 1
- VERWOWGGCGHDQE-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 VERWOWGGCGHDQE-UHFFFAOYSA-N 0.000 description 1
- 201000006662 cervical adenocarcinoma Diseases 0.000 description 1
- 201000006612 cervical squamous cell carcinoma Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- DREIJXJRTLTGJC-ZLBJMMTISA-N chembl3137308 Chemical compound C([C@H]1C[C@@](O)(C2)C3)C2C[C@H]3[C@H]1NC1=C2C=CNC2=NC=C1C(=O)N DREIJXJRTLTGJC-ZLBJMMTISA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 229950009221 chidamide Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- 229950006418 dactolisib Drugs 0.000 description 1
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N dactolisib Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 description 1
- 229950008937 defactinib Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000003599 detergent Substances 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
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 238000011038 discontinuous diafiltration by volume reduction Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003968 dna methyltransferase inhibitor Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 208000028730 endometrioid adenocarcinoma Diseases 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- INVTYAOGFAGBOE-UHFFFAOYSA-N entinostat Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)OCC1=CC=CN=C1 INVTYAOGFAGBOE-UHFFFAOYSA-N 0.000 description 1
- 229950005837 entinostat Drugs 0.000 description 1
- 229950002189 enzastaurin Drugs 0.000 description 1
- 230000007705 epithelial mesenchymal transition Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229950006663 filgotinib Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 108010051920 interferon regulatory factor-4 Proteins 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 206010073096 invasive lobular breast carcinoma Diseases 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229950003818 itolizumab Drugs 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 229940125399 kras g12c inhibitor Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 229950001845 lestaurtinib Drugs 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 230000005960 long-lasting response Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000004264 monolayer culture Methods 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- WXHHICFWKXDFOW-BJMVGYQFSA-N n-(2-amino-5-fluorophenyl)-4-[[[(e)-3-pyridin-3-ylprop-2-enoyl]amino]methyl]benzamide Chemical compound NC1=CC=C(F)C=C1NC(=O)C(C=C1)=CC=C1CNC(=O)\C=C\C1=CC=CN=C1 WXHHICFWKXDFOW-BJMVGYQFSA-N 0.000 description 1
- IPNATXQRPWRHKD-UHFFFAOYSA-N n-(cyanomethyl)-4-[2-(4-morpholin-4-ium-4-ylanilino)pyrimidin-1-ium-4-yl]benzamide;dichloride Chemical compound Cl.Cl.C1=CC(C(NCC#N)=O)=CC=C1C1=CC=NC(NC=2C=CC(=CC=2)N2CCOCC2)=N1 IPNATXQRPWRHKD-UHFFFAOYSA-N 0.000 description 1
- KWRYMZHCQIOOEB-LBPRGKRZSA-N n-[(1s)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7h-purin-6-amine Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=C(F)C=C2N=C1C1=CC=CC=N1 KWRYMZHCQIOOEB-LBPRGKRZSA-N 0.000 description 1
- RDSACQWTXKSHJT-NSHDSACASA-N n-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl]-1-[(2s)-2,3-dihydroxypropyl]cyclopropane-1-sulfonamide Chemical compound C1CC1(C[C@H](O)CO)S(=O)(=O)NC=1C(OC)=CC(F)=C(F)C=1NC1=CC=C(I)C=C1F RDSACQWTXKSHJT-NSHDSACASA-N 0.000 description 1
- RIJLVEAXPNLDTC-UHFFFAOYSA-N n-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide Chemical compound C1CC1C(=O)NC(=NN12)N=C1C=CC=C2C(C=C1)=CC=C1CN1CCS(=O)(=O)CC1 RIJLVEAXPNLDTC-UHFFFAOYSA-N 0.000 description 1
- FWLMVFUGMHIOAA-UHFFFAOYSA-N n-methyl-4-[[4-[[3-[methyl(methylsulfonyl)amino]pyrazin-2-yl]methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide Chemical compound C1=CC(C(=O)NC)=CC=C1NC1=NC=C(C(F)(F)F)C(NCC=2C(=NC=CN=2)N(C)S(C)(=O)=O)=N1 FWLMVFUGMHIOAA-UHFFFAOYSA-N 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 206010061311 nervous system neoplasm Diseases 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 201000009494 neurilemmomatosis Diseases 0.000 description 1
- 201000004931 neurofibromatosis Diseases 0.000 description 1
- 208000002761 neurofibromatosis 2 Diseases 0.000 description 1
- 208000022032 neurofibromatosis type 2 Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical group N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- XVDWNSFFSMWXJJ-ASTDGNLGSA-N panobinostat lactate Chemical group CC(O)C(O)=O.CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 XVDWNSFFSMWXJJ-ASTDGNLGSA-N 0.000 description 1
- 229960003772 panobinostat lactate Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229950005157 peficitinib Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000008180 pharmaceutical surfactant Substances 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 102000016914 ras Proteins Human genes 0.000 description 1
- 108010014186 ras Proteins Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- OIRUWDYJGMHDHJ-AFXVCOSJSA-N retaspimycin hydrochloride Chemical compound Cl.N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(O)C1=CC(O)=C2NCC=C OIRUWDYJGMHDHJ-AFXVCOSJSA-N 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 229960003452 romidepsin Drugs 0.000 description 1
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- JFMWPOCYMYGEDM-XFULWGLBSA-N ruxolitinib phosphate Chemical compound OP(O)(O)=O.C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 JFMWPOCYMYGEDM-XFULWGLBSA-N 0.000 description 1
- 229960002539 ruxolitinib phosphate Drugs 0.000 description 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 1
- 210000001991 scapula Anatomy 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 229960004542 sebelipase alfa Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 201000003708 skin melanoma Diseases 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- NXQKSXLFSAEQCZ-SFHVURJKSA-N sotorasib Chemical compound FC1=CC2=C(N(C(N=C2N2[C@H](CN(CC2)C(C=C)=O)C)=O)C=2C(=NC=CC=2C)C(C)C)N=C1C1=C(C=CC=C1O)F NXQKSXLFSAEQCZ-SFHVURJKSA-N 0.000 description 1
- OAVGBZOFDPFGPJ-UHFFFAOYSA-N sotrastaurin Chemical compound C1CN(C)CCN1C1=NC(C=2C(NC(=O)C=2C=2C3=CC=CC=C3NC=2)=O)=C(C=CC=C2)C2=N1 OAVGBZOFDPFGPJ-UHFFFAOYSA-N 0.000 description 1
- 229950005814 sotrastaurin Drugs 0.000 description 1
- 230000000920 spermatogeneic effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229950006156 teprenone Drugs 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229960002410 tiagabine hydrochloride Drugs 0.000 description 1
- YUKARLAABCGMCN-PKLMIRHRSA-N tiagabine hydrochloride Chemical compound Cl.C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C YUKARLAABCGMCN-PKLMIRHRSA-N 0.000 description 1
- 229960004247 tofacitinib citrate Drugs 0.000 description 1
- SYIKUFDOYJFGBQ-YLAFAASESA-N tofacitinib citrate Chemical group OC(=O)CC(O)(C(O)=O)CC(O)=O.C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 SYIKUFDOYJFGBQ-YLAFAASESA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005290 uterine carcinosarcoma Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical group C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 1
- 229960001183 venetoclax Drugs 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Definitions
- the present invention relates to a pharmaceutical combination product comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient.
- the invention also relates to combination therapy for the treatment of abnormal cell growth, such as cancer, comprising administering to a subject a first pharmaceutically active ingredient and a second pharmaceutically active ingredient, either alone or simultaneously.
- Cancer is one of the most serious diseases threatening human life and health in contemporary times, with seven million cancer deaths worldwide every year.
- targeted drug therapy is the most promising and promising treatment for cancer, and people have been exploring effective targeted drug therapies.
- CN112585129 discloses a novel heterocyclic compound that can be used to inhibit KRASG12C mutant protein in cells.
- the patent application also discloses the combination of the heterocyclic compound with platinum-based drugs (such as cisplatin or carboplatin), SHP2 inhibitors (such as RMC-4550, RMC-4630, TNO155) and/or MEK inhibitors (such as trametidin Ni) used in combination to reduce tumor volume.
- platinum-based drugs such as cisplatin or carboplatin
- SHP2 inhibitors such as RMC-4550, RMC-4630, TNO155
- MEK inhibitors such as trametidin Ni
- WO2010058032 discloses a pyrimidine compound that can be used as a FAK inhibitor to prevent and/or treat diseases characterized by excessive or abnormal cell proliferation.
- the pyrimidine compounds include the BI853520/IN10018 compound used in clinical trials.
- WO2021155764 discloses the combination of BI853520 compounds and chemotherapy drugs, including pegylated liposomal doxorubicin (PLD), taxanes or cisplatin.
- WO2021154929 discloses combination therapies for the treatment of abnormal cell growth.
- the patent application concluded that a triple combination of a RAF/MEK inhibitor (e.g., VS-6766), a FAK inhibitor (e.g., defatinib), and a KRASG12C inhibitor (e.g., AMG-510) produced tumor regression in mice.
- a RAF/MEK inhibitor e.g., VS-6766
- FAK inhibitor e.g., defatinib
- KRASG12C inhibitor e.g., AMG-5
- Combinations of effective cancer therapeutic agents may more effectively prevent and/or treat diseases associated with abnormal cell growth (eg, cancer).
- the invention provides a pharmaceutical combination product comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient, wherein the first pharmaceutically active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof,
- said second pharmaceutically active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof
- the first pharmaceutically active ingredient is a compound of Formula (I).
- the second pharmaceutically active ingredient is a pharmaceutically acceptable salt of a compound of formula (II).
- the first pharmaceutically active ingredient is the free base of a compound of Formula (I).
- the second pharmaceutically active ingredient is a pharmaceutically acceptable salt (eg, maleate, malate, or tartrate) of a compound of formula (II).
- the weight ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is about 50:1 to about 1:50, preferably about 25:1 to about 1:25, and more preferably about 15:1 to approximately 1:15.
- first pharmaceutically active ingredient and the second pharmaceutically active ingredient may be administered separately, in no particular order. In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient may be administered simultaneously.
- the pharmaceutical combination product is in the form of a pharmaceutical composition.
- the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
- the invention provides use of a pharmaceutical combination according to the invention for the preparation of a medicament for the treatment of abnormal cell growth, such as cancer.
- the abnormal cell growth includes solid tumors, soft tissue tumors, metastases, or non-solid cancers.
- the abnormal cell growth is a KRASG12C mutation-positive locally advanced or metastatic solid tumor, such as non-small cell lung cancer, colorectal cancer, cholangiocarcinoma.
- the present invention provides a method of treating a disease associated with abnormal cell growth, comprising administering a pharmaceutical combination according to the present invention to a subject in need thereof.
- the first pharmaceutically active ingredient is administered orally. In some embodiments, the first pharmaceutically active ingredient is administered at least once per day, for example, the first pharmaceutically active ingredient is administered once per day, or the first pharmaceutically active ingredient is administered two or more times per day. In some embodiments, the first pharmaceutically active ingredient is administered in a single dose of about 1 mg to about 5000 mg.
- the second pharmaceutically active ingredient is administered orally. In some embodiments, the second pharmaceutically active ingredient is administered at least once per day, for example, the second pharmaceutically active ingredient is administered once per day, or the second pharmaceutically active ingredient is administered two or more times per day. In some embodiments, the second pharmaceutically active ingredient is administered in a single dose of about 1 mg to about 5000 mg.
- the abnormal cell growth-associated disease includes solid tumors, soft tissue Tumor, metastasis or non-solid cancer.
- the administering includes administering the first pharmaceutically active ingredient and the second pharmaceutically active ingredient separately or simultaneously.
- the first pharmaceutically active ingredient and the second pharmaceutically active ingredient according to the present invention can synergistically achieve overall tumor response and increase the median survival percentage in preclinical models.
- pharmaceutical combination products containing a first pharmaceutically active ingredient and a second pharmaceutically active ingredient can produce synergistic antitumor activity compared to a single pharmaceutically active ingredient.
- Trial data show that for KRASG12C mutation-positive locally advanced or metastatic solid tumors (such as non-small cell lung cancer, colorectal cancer, cholangiocarcinoma, etc.), the combination of the first drug active ingredient and the second drug active ingredient can achieve larger and more precise tumors. Long lasting response.
- the first and second pharmaceutically active ingredients only reduce tumor growth rate when used as single pharmaceutically active ingredients, whereas the same dose when both pharmaceutically active ingredients are combined can achieve tumor volume reduction and thus overall response Tumor growth.
- Figure 1 shows the body weight changes of mice in each administration group of the human non-small cell lung cancer cell NCI-H358 xenograft model
- Figure 2 shows the body weight change rate of mice in each administration group of the human non-small cell lung cancer cell NCI-H358 xenograft model
- Figure 3 shows the changes in tumor volume in each administration group of the human non-small cell lung cancer cell NCI-H358 xenograft model
- Figure 4 shows the tumor volume change rate in each administration group of the human non-small cell lung cancer cell NCI-H358 xenograft model.
- the present invention provides a pharmaceutical combination product containing a first pharmaceutical active ingredient.
- the first pharmaceutically active ingredient is a compound of Formula (I) or a pharmaceutically acceptable salt thereof,
- the first pharmaceutically active ingredient is a compound of Formula (I).
- the compound of formula (I) described herein is a known compound, and all its known forms and components can be used in the pharmaceutical combination products provided by the present invention.
- the preparation and identification of compounds of formula (I) have been described in PCT International Applications WO2020233592, WO2021121330 and WO2021120045.
- the first pharmaceutically active ingredient is a pharmaceutically acceptable salt of a compound of formula (I), including but not limited to hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, Sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate Acid salt, mesylate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate , succinate, gluconate, lactobiate or lauryl sulfonate, etc.
- a pharmaceutically acceptable salt of a compound of formula (I) including but not limited to hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, Sulfite, acetate, oxalate, malonate, vale
- the first pharmaceutically active ingredient can be in amorphous, crystalline forms, and combinations thereof.
- the first pharmaceutical active ingredient can also be other pharmaceutical active ingredients that have the same or similar efficacy as the compound of formula (I), such as ARS-853, ARS-1620, ARS-3248, LY3499446 and MRTX849, or pharmaceutically acceptable salts thereof.
- the present invention provides a pharmaceutical combination product containing a second pharmaceutically active ingredient.
- the second pharmaceutically active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof,
- the second pharmaceutically active ingredient is a compound of formula (II).
- the compound of formula (II) described herein is a known compound, and all its known forms and components can be used in the pharmaceutical combination products provided by the present invention. For example, the preparation and identification of compounds of formula (II) have been described in WO2010058032.
- the second pharmaceutically active ingredient is a pharmaceutically acceptable salt of the compound of formula (I), including but not limited to hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, Sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate Acid salt, mesylate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate , succinate, gluconate, lactobiate or lauryl sulfonate, etc.
- the pharmaceutically acceptable salt is a maleate, a malate or a tartrate, further preferably a tartrate.
- the pharmaceutically acceptable salts may be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid following conventional procedures for the preparation of acid addition salts from basic compounds.
- One skilled in the art will be able to identify, without undue experimentation, various synthetic methods that can be used to prepare nontoxic pharmaceutically acceptable acid addition salts.
- the second pharmaceutically active ingredient can be in amorphous, crystalline forms, and combinations thereof.
- the second pharmaceutically active ingredient can also be other pharmaceutically active ingredients that have the same or similar efficacy as the compound of formula (II), such as defactinib, TAE226, GSK2256098, PF- 03814735, BI-4464, VS-4718 and APG-2449, or pharmaceutically acceptable salts thereof.
- the pharmaceutical combination product according to the present invention contains a first pharmaceutically active ingredient and a second pharmaceutically active ingredient.
- compositions according to the invention may comprise all suitable isotopic variants of said first and/or second pharmaceutically active ingredient.
- Isotopic variants of the compounds of the invention are defined as compounds of the invention in which at least one atom is replaced by an atom of the same atomic number but with an atomic weight different from that usually or predominantly found in nature.
- isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), respectively.
- isotopic variants of the compounds of the present invention eg, those in which one or more radioactive isotopes (eg, 3 H or 14 C) are incorporated, may be used in drug and/or substrate tissue distribution studies. Tritium and carbon-14 (ie, 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
- Isotopic variants of the compounds of the invention can generally be prepared using suitable isotopic variants of suitable reagents using conventional methods known to those skilled in the art, for example, using the illustrative methods or the preparation methods described in the examples below.
- compositions according to the invention may comprise all possible stereoisomers of the first and/or second pharmaceutically active ingredient as a single stereoisomer or as any mixture of said stereoisomers in any ratio.
- the separation of single stereoisomers, such as single enantiomers or single diastereomers, of the compounds of the invention can be achieved by any suitable state-of-the-art method, such as chromatography, in particular, for example, chiral chromatography.
- compositions according to the invention may comprise all possible tautomers of said first and/or second pharmaceutically active ingredients, either as single tautomers or in any ratio of said tautomers in the form of any mixture.
- pharmaceutical combinations according to the invention may comprise all possible crystalline forms or polymorphs of said first and/or second pharmaceutically active ingredient, either as a single polymorph or as more than one polymorph. A mixture of polymorphs in any proportion.
- the pharmaceutical combination product according to the present invention also contains an optional third pharmaceutical active ingredient selected from the group consisting of HDAC inhibitors, CDK4/6 inhibitors, ALK inhibitors, JAK2 inhibitors, Bcl-2 inhibitors , Hsp90 inhibitors, glucocorticoids, vinca alkaloids, antimetabolites, DNA damaging agents, lenalidomide, rituximab, PKC interferogens, Lyn/Fyn inhibitors, Syk inhibitors, PI3K inhibitors , PKC ⁇ inhibitor, IKK inhibitor, 20s proteasome, IRF-4, IRAK4 antibody, CXCR4 antibody, CXCR5 antibody, GLS antibody, PLK antibody, CD20 antibody, TopoII inhibitor, DNA methyltransferase inhibitor, Ras/MAPK inhibitor or FGFR1 inhibitor;
- the HDAC inhibitor is preferably panobinostat lactate, belinostat, chidamide, romidepsin, vorinostat, bexenostat or entino
- pharmaceutical combinations according to the invention further comprise one or more pharmaceutically acceptable excipients, diluents or carriers.
- a pharmaceutical composition product according to the present invention may comprise a first pharmaceutically active ingredient alone and a second pharmaceutically active ingredient alone.
- pharmaceutical combination products according to the present invention may include tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection liquids, sterile powders for injection and concentrates for injection), respectively. solution), suppository, inhaler or spray first pharmaceutically active ingredient and second pharmaceutically active ingredient.
- the pharmaceutical composition product according to the present invention may be a pharmaceutical composition comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient.
- the first pharmaceutically active ingredient and the second pharmaceutically active ingredient are formulated together into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and Concentrated solution for injection), suppository, inhalation or spray.
- the first and/or second pharmaceutically active ingredient according to the invention may be tabletted using conventional tablet bases such as lactose, sucrose and cornstarch in combination with a binder such as gum arabic, cornstarch or gelatin, after administration
- Disintegrants that aid tablet disintegration and dissolution such as potato starch, alginic acid, corn starch and guar gum, tragacanth, and acacia gum are used to improve tablet particle flow and prevent tablet materials from interacting with tablet molds and punches.
- Lubricants adhered to the head surface such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate, dyes, colorants used to enhance the aesthetic qualities of the tablets and make them more acceptable to patients and flavorings such as peppermint, oil of wintergreen, or cherry essence.
- Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (such as ethanol, benzyl alcohol and polyvinyl alcohols), with or without the addition of a pharmaceutically acceptable surfactant. , suspending agent or emulsifier.
- Various other materials may be present as coatings or otherwise modify the physical form of the dosage unit.
- tablets, pills, or capsules may be coated with shellac, sugar, or both.
- Dispersible powders and granules are suitable for the preparation of aqueous suspensions. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as those mentioned above for sweetening, flavoring and coloring agents, may also be present.
- the pharmaceutical combination product according to the invention also includes a commercial package comprising instructions for simultaneous, separate or sequential administration of the pharmaceutically active ingredients according to the invention to a patient in need thereof.
- the dosage regimen of the first pharmaceutically active ingredient and the second pharmaceutically active ingredient in the pharmaceutical combination product according to the present invention can be adjusted to provide an optimal desired response, e.g., maximum therapeutic response and/or minimum adverse effects. effect.
- the single dosage of the first pharmaceutically active ingredient may range from 1 to 5000mg.
- the administration frequency of the first pharmaceutically active ingredient may be 5 times a day, 4 times a day, 3 times a day, 2 times a day, once a day, once every 2 days, etc.
- the single dose of the second pharmaceutically active ingredient may range from 1 to 5000 mg.
- the administration frequency of the second pharmaceutically active ingredient may be 5 times a day, 4 times a day, 3 times a day, 2 times a day, once a day, once every 2 days, etc.
- the weight ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient in the pharmaceutical combination product according to the present invention may be from about 50:1 to about 1:50, preferably from about 25:1 to about 1: 25, and more preferably about 15:1 to about 1:15. In some embodiments, the weight ratio may be from about 14:1 to about 1:14, from about 13:1 to about 1:13, from about 12:1 to about 1:12, from about 11:1 to about 1:1. 11. About 10:1 to about 1:10, about 9:1 to about 1:9, about 8:1 to about 1:8, about 7:1 to about 1:7, about 6:1 to about 1: 6.
- the weight ratio is about 14:1, about 12:1, about 10:1, about 8:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:4, or about 1:5.
- the dosage is within the level of one of ordinary skill in the art, and the single dose or daily dose of the drug can be determined according to various factors such as the degree of disease, time of disease, age, health status and complications of the subject to be administered. And change.
- the pharmaceutical combination products according to the invention may be administered, alone or in combination, by oral administration.
- the pharmaceutical combination products according to the invention may be administered, alone or in combination, parenterally, i.e. subcutaneously, intravenously, intraocularly, Intrasynovial, intramuscular, or interperitoneal administration, as an injectable dose of the compound, preferably in a physiologically acceptable diluent and a pharmaceutical carrier, which may be a sterile liquid or mixture of liquids, such as water, saline , aqueous dextrose solutions and related sugar solutions, alcohols such as ethanol, isopropyl alcohol or cetyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,1- Dioxolane-4-carbinol, ethers such as poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters or fatty acid glycerides or acetylated
- an oral dosage form may be presented in a package or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms of the active ingredient.
- a package or dispenser device such as an FDA-approved kit, which may contain one or more unit dosage forms of the active ingredient.
- the packaging may include metal or plastic foil, such as a blister pack.
- Packaging or dispenser devices may accompany administration instructions.
- the present invention provides a combination therapy for the treatment of abnormal cell growth, comprising administering to a subject in need thereof a pharmaceutical combination according to the present invention.
- the pharmaceutical composition product of the present invention includes a therapeutically effective amount of a first pharmaceutically active ingredient and a therapeutically effective amount of a second pharmaceutically active ingredient; in some embodiments, the pharmaceutical composition product of the present invention may include a therapeutically effective amount of a second pharmaceutically active ingredient.
- the abnormal cell growth such as cancer
- the cancer includes, but is not limited to, solid tumors, soft tissue tumors, metastases, or non-solid cancers.
- the cancer is a solid tumor.
- the solid tumor is a malignant tumor of an organ (e.g., lung, breast, lymphatic, gastrointestinal tract (e.g., colon), and genitourinary (e.g., kidney, urothelial or testicular tumors), pharynx, prostate, and ovary) (eg sarcomas, adenocarcinomas and carcinomas).
- the cancer is mesothelioma; neurofibromatosis; e.g., neurofibromatosis type 2, neurofibromatosis type 1; kidney cancer; lung cancer, non-small cell lung cancer; liver cancer; thyroid cancer; Ovarian cancer; breast cancer; nervous system tumors; schwannoma; meningioma; schwannomatosis; acoustic neuroma; adenoid cystic carcinoma; ependymoma; or ependymoma.
- neurofibromatosis e.g., neurofibromatosis type 2, neurofibromatosis type 1
- kidney cancer lung cancer, non-small cell lung cancer
- liver cancer thyroid cancer
- Ovarian cancer breast cancer
- breast cancer nervous system tumors
- schwannoma meningioma
- schwannomatosis acoustic neuroma
- adenoid cystic carcinoma ependymoma
- the cancer is mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma), breast cancer (e.g., triple negative breast cancer), ovarian cancer (e.g., , advanced ovarian cancer), lung cancer (eg, non-small cell lung cancer (NSCLC), eg, KRAS-mutated NSCLC)), or non-hematologic malignancies.
- the cancer is non-small cell lung cancer (NSCLC), e.g., KRAS-mutated NSCLC).
- the cancer is melanoma (e.g., N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma), colorectal cancer (e.g., metastatic colorectal cancer), leukemia (e.g., acute myeloid leukemia), adenocarcinoma (eg, pancreatic adenocarcinoma), or solid tumor (eg, locally advanced solid tumor, metastatic solid tumor, hepatocellular carcinoma).
- melanoma e.g., N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma
- colorectal cancer e.g., metastatic colorectal cancer
- leukemia e.g., acute myeloid leukemia
- adenocarcinoma eg, pancreatic adenocarcinoma
- solid tumor eg, locally advanced solid tumor, metastatic solid tumor, hepatocellular carcinoma
- the cancer may include cancer characterized by comprising cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells.
- Cancers may include cancers that have been characterized as enriched in cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells (eg, tumors or metastatic tumors enriched in cells undergoing epithelial-mesenchymal transition).
- the tumor can be a primary tumor, which is located at the anatomic site where the tumor growth begins.
- the cancer can also be metastatic, meaning it appears in at least a second anatomical location other than the one where the tumor grew.
- This cancer may be a relapsing cancer, which is a cancer that comes back after treatment and after a period of time when the cancer is undetectable.
- Recurrent cancer can be anatomically localized to the primary tumor, e.g., anatomically close to the primary tumor; in an area of the primary tumor, such as a lymph node located near the primary tumor; or distant from the original tumor, e.g., anatomically close to the primary tumor An area that is scientifically distant from the original tumor.
- Cancers may also include lung adenocarcinoma, colorectal cancer (CRC), endometrioid carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, cervical adenocarcinoma, hepatocellular carcinoma , pancreatic cancer, biphasic pleural mesothelioma, renal clear cell carcinoma, renal clear cell carcinoma, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine carcinosarcoma or uterine malignant mixed Mullerian tumor, or other cancers.
- lung adenocarcinoma colorectal cancer (CRC), endometrioid carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, cervical adenocarcinoma, hepatocellular carcinoma , pancreatic cancer, biphasic ple
- cancers include, but are not limited to, uveal melanoma, brain, abdomen, esophagus, gastrointestinal tract, glioma, liver, tongue, neuroblastoma, osteosarcoma, ovary, retinoblastoma, Wilms tumor, multiple myeloid neoplasms, skin, lymphomas, blood and bone marrow cancers (e.g., advanced hematologic malignancies, leukemias, such as acute myeloid leukemia (e.g., primary or secondary)), acute lymphoblastic leukemia, acute lymphoblastic leukemia, T-cell Leukemia, hematologic malignancies, advanced myeloproliferative disorders, myelodysplastic syndromes, relapsed or refractory multiple myeloma, advanced myeloproliferative disorders), retina, bladder, cervix, kidney, endometrium, meningioma , lymphoma, skin, uterus,
- the term "about” modifying a quantity relevant to the present invention refers to variations in numerical quantities that may occur, such as through routine testing and handling; through inadvertent errors in such testing and handling; through the manufacture of the ingredients used in the present invention. , differences in origin or purity, etc.
- "about” a particular value also includes that particular value, for example, about 10% includes 10%. Whether or not modified by the term “about,” the claims include equivalents of the recited quantities. In one embodiment, the term “about” means within 20%, within 10%, or within 5% of the reported value.
- treating refers to the elimination, reduction, or alleviation of a disease or disorder and/or symptoms associated therewith.
- treatment may include “preventive treatment,” which refers to the reduction of disease or disease in a subject who is not affected by the disease but is at risk or susceptible to developing the disease or condition or relapsing the disease or condition. Possibility of redevelopment of the condition or recurrence of previously controlled disease.
- treatment and synonyms are understood to mean the administration of a therapeutically effective amount of a pharmaceutical composition according to the invention to a subject in need of such treatment.
- the term “therapeutically effective amount” refers to an amount of an active compound or agent that elicits a biological or pharmaceutical response in a tissue system, animal, or human being sought by a researcher, veterinarian, MD, or other clinician, including Reduction or reversal of symptoms of the disease or condition being treated.
- the term “therapeutically effective amount” may be based on a single pharmaceutically active ingredient or a combination of two pharmaceutically active ingredients.
- the first active pharmaceutical ingredient (API) is a compound of formula (I), which is prepared according to the method disclosed in patent applications WO2020233592, WO2021121330 or WO2021120045, with a purity of greater than 99%, and is stored at room temperature in the dark.
- the second active pharmaceutical ingredient (API) is a tartrate salt of a compound of formula (II) prepared according to the method disclosed in patent application WO2010058032.
- the tartrate salt of a compound of formula (II) is prepared according to acid addition from a basic compound.
- the salt is prepared by conventional operations.
- the tartrate of the compound of formula (II) has a purity of greater than 97% and is stored in the dark at 4°C.
- the animal information card for each cage indicates the number of animals in the cage, gender, strain, date of receipt, dosage regimen, experiment number, group and experiment start date. All cages, bedding and drinking water are sterilized before use. Cages, feed and drinking water were changed twice a week.
- the feeding environment and lighting conditions are as follows:
- Cage Made of polycarbonate, volume 300mmx180mmx150mm.
- the bedding material is corn cobs and is changed twice a week.
- Experimental animals can eat freely during the entire experimental period (irradiation sterilization, dry granular form food).
- Drinking water Experimental animals can drink sterilized water freely.
- mice were divided into 4 groups, with 8 mice in each group, and were administered according to the administration method in Table A.
- Table a Animal groupings and dosing regimens for in vivo drug efficacy tests
- Human non-small cell lung cancer cell NCI-H358 ( CRL-5807TM) in vitro monolayer culture, the culture conditions are basal medium RPMI-1640 added with 10% fetal bovine serum, 100 units per ml of penicillin and 100 ⁇ g per ml of streptomycin, in a 5% CO 2 cell culture incubator at 37 degrees Celsius nourish. Passage was performed twice a week with routine digestion treatment with trypsin digestion. When cells are full When the concentration is 80%-90% and the number reaches the required number, cells are collected, counted, and inoculated.
- Routine examinations include observing tumor growth and the effects of drug treatment on the daily behavioral performance of the animals, such as behavioral activities, food and water intake (visual inspection only), and weight changes (measure body weight twice a week). Appearance signs or other abnormalities. The number of animal deaths and side effects within the group were recorded based on the number of animals in each group.
- the experimental indicator is to examine whether tumor growth is inhibited, delayed or cured.
- Tumor diameter was measured twice weekly using vernier calipers.
- TGI The antitumor efficacy of the compounds was evaluated by TGI (%).
- TGI (%) reflects the tumor growth inhibition rate.
- TGI (%) [1-(Average tumor volume at the end of administration in a certain treatment group-Average tumor volume at the beginning of administration in this treatment group)/(Average tumor volume at the end of treatment in the solvent control group- Average tumor volume in the solvent control group at the beginning of treatment)] ⁇ 100%.
- TGI values have the following meanings:
- the body weight changes and change rates of tumor-bearing mice in different groups are shown in Figures 1 and 2.
- the relative body weight change is calculated based on the animal body weight at the beginning of dosing. Data points represent the mean weight percent change within the group. Error bars represent standard error (SEM).
- the tumor growth volumes of animals in different groups at various time periods are shown in Table 2.
- TGI% tumor growth inhibition rate
- the p value is calculated based on the relative tumor volume of each mouse in different groups.
- the One-way ANOVA method is used to obtain the P value by comparing the control group and each administration group.
- P ⁇ 0.01 statistical analysis represents a significant difference between each group and the control group.
- P>0.05 statistical analysis means there is no significant difference between each group and the control group.
- c.P value is the P value obtained by comparing the first API and second API combined dose group with the single drug group using the One-wayANOVA method. P ⁇ 0.01 statistical analysis represents significant differences between each group and the control group.
- QD is once a day.
- the tumor weights of animals in different groups are shown in Table 4.
- the P value is obtained by comparing the control group and each administration group using the T-test method. P ⁇ 0.01 statistical analysis represents a significant difference between each group and the control group.
- the P value is obtained by comparing the (first API + second API) combination group and the two single-drug groups using the T-test method. P ⁇ 0.01 statistical analysis represents a significant difference between each single-drug group and the combination group.
- QD is once a day.
- the first API and the second API of the test drug were evaluated individually and in combination. Efficacy of the combination in subcutaneous xenografts of human non-small cell lung cancer cells NCI-H358. After administration, the body weight changes of the animals in each group at different time points are shown in Figures 1 and 2.
- the changes in tumor volume and weight in each group at different time points are shown in Table 2, Table 3, Table 4 and Figure 3 and Figure 4.
- the tumor volume in the white group reached 1255.3 cubic millimeters.
- the tumor growth inhibition rates TGI (%) of the first API and the second API were 84.95% and 60.05%, respectively.
- the tumor growth inhibition rate TGI (%) of the combined treatment group of the first API compound and the second API compound reached 118.85%.
- the TGI value showed that the efficacy of the combination of the first API compound and the second API compound was significantly better than that of each single dose group (p ⁇ 0.01), achieving overall tumor remission.
Abstract
A pharmaceutical combination product and a combination therapy thereof are provided. Specifically, a pharmaceutical combination product comprising a first active pharmaceutical ingredient and a second active pharmaceutical ingredient is provided. Further provided is a combination therapy for treating abnormal cell growth (e.g. cancer) which comprises the administration of the pharmaceutical combination product to a subject in need.
Description
相关申请的交叉引用Cross-references to related applications
本申请要求2022年07月20日提交的中国专利申请号CN202210872332.3的优先权,其内容通过引用整体并入本文。This application claims the priority of Chinese patent application number CN202210872332.3 submitted on July 20, 2022, the content of which is incorporated herein by reference in its entirety.
本发明涉及药物组合产品,其包含第一药物活性成分和第二药物活性成分。本发明还涉及治疗异常细胞生长(例如癌症)的组合疗法,其包括向受试者单独或同时施用第一药物活性成分和第二药物活性成分。The present invention relates to a pharmaceutical combination product comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient. The invention also relates to combination therapy for the treatment of abnormal cell growth, such as cancer, comprising administering to a subject a first pharmaceutically active ingredient and a second pharmaceutically active ingredient, either alone or simultaneously.
癌症是当代最严重的威胁人类生命和健康的疾病之一,在世界范围内,每年癌症死亡人数达七百万。目前,癌症的治疗主要采用四种方法:手术治疗、药物治疗、放射治疗及免疫治疗;此外,还有辅助疗法。在当前的各种治疗方法中,靶向药物疗法是最有前景和最有希望治疗癌症的一种疗法,人们一直探索有效的靶向药物疗法。Cancer is one of the most serious diseases threatening human life and health in contemporary times, with seven million cancer deaths worldwide every year. Currently, there are four main methods used in cancer treatment: surgery, drug therapy, radiotherapy and immunotherapy; in addition, there are adjuvant therapies. Among the various current treatment methods, targeted drug therapy is the most promising and promising treatment for cancer, and people have been exploring effective targeted drug therapies.
CN112585129公开了一种新型的杂环化合物,其可以用于抑制细胞中的KRASG12C突变蛋白。该专利申请还公开了所述杂环化合物与铂基药物(例如顺铂或卡铂)、SHP2抑制剂(例如RMC-4550、RMC-4630、TNO155)和/或MEK抑制剂(例如曲美替尼)组合使用,用于减少肿瘤体积。CN112585129 discloses a novel heterocyclic compound that can be used to inhibit KRASG12C mutant protein in cells. The patent application also discloses the combination of the heterocyclic compound with platinum-based drugs (such as cisplatin or carboplatin), SHP2 inhibitors (such as RMC-4550, RMC-4630, TNO155) and/or MEK inhibitors (such as trametidin Ni) used in combination to reduce tumor volume.
WO2010058032公开了一种嘧啶类化合物,其可以作为FAK抑制剂用于预防和/或治疗以过度或异常细胞增殖为特征的疾病。该嘧啶类化合物包括用于临床试验的BI853520/IN10018化合物。WO2010058032 discloses a pyrimidine compound that can be used as a FAK inhibitor to prevent and/or treat diseases characterized by excessive or abnormal cell proliferation. The pyrimidine compounds include the BI853520/IN10018 compound used in clinical trials.
WO2021155764公开了BI853520化合物与化疗药物的联用,该化疗药物包括聚乙二醇化脂质体阿霉素(PLD)、紫杉烷或顺铂。WO2021155764 discloses the combination of BI853520 compounds and chemotherapy drugs, including pegylated liposomal doxorubicin (PLD), taxanes or cisplatin.
WO2021154929公开了治疗异常细胞生长的联合疗法。该专利申请
的结论表明,RAF/MEK抑制剂(例如VS-6766)、FAK抑制剂(例如地法替尼)和KRASG12C抑制剂(例如AMG-510)的三重组合在小鼠中产生肿瘤消退。WO2021154929 discloses combination therapies for the treatment of abnormal cell growth. The patent application concluded that a triple combination of a RAF/MEK inhibitor (e.g., VS-6766), a FAK inhibitor (e.g., defatinib), and a KRASG12C inhibitor (e.g., AMG-510) produced tumor regression in mice.
尽管癌症患者有许多治疗选择,但仍需要有效和安全的治疗剂,并且需要可以用于有效的长期癌症治疗的新组合疗法。有效的癌症治疗剂的组合可以更有效地预防和/或治疗异常细胞生长相关疾病(例如癌症)。Although there are many treatment options for cancer patients, there is a need for effective and safe therapeutic agents, and there is a need for new combination therapies that can be used for effective long-term cancer treatment. Combinations of effective cancer therapeutic agents may more effectively prevent and/or treat diseases associated with abnormal cell growth (eg, cancer).
发明内容Contents of the invention
在一个方面,本发明提供一种包含第一药物活性成分和第二药物活性成分的药物组合产品,其中所述第一药物活性成分是式(I)的化合物或其药学上可接受的盐,
In one aspect, the invention provides a pharmaceutical combination product comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient, wherein the first pharmaceutically active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof,
In one aspect, the invention provides a pharmaceutical combination product comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient, wherein the first pharmaceutically active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof,
和其中所述第二药物活性成分是式(II)的化合物或其药学上可接受的盐,
and wherein said second pharmaceutically active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof,
and wherein said second pharmaceutically active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof,
在一些实施方案中,所述第一药物活性成分是式(I)的化合物。在一些实施方案中,所述第二药物活性成分是式(II)化合物的药学上可接受的盐。In some embodiments, the first pharmaceutically active ingredient is a compound of Formula (I). In some embodiments, the second pharmaceutically active ingredient is a pharmaceutically acceptable salt of a compound of formula (II).
在一些实施方案中,所述第一药物活性成分是式(I)的化合物的游离碱。
在一些实施方案中,所述第二药物活性成分是式(II)化合物的药学上可接受的盐(例如,马来酸盐、苹果酸盐或酒石酸盐)。In some embodiments, the first pharmaceutically active ingredient is the free base of a compound of Formula (I). In some embodiments, the second pharmaceutically active ingredient is a pharmaceutically acceptable salt (eg, maleate, malate, or tartrate) of a compound of formula (II).
在一些实施方案中,所述第一药物活性成分与所述第二药物活性成分的重量比为约50:1至约1:50,优选约25:1至约1:25,和更优选约15:1至约1:15。In some embodiments, the weight ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is about 50:1 to about 1:50, preferably about 25:1 to about 1:25, and more preferably about 15:1 to approximately 1:15.
在一些实施方案中,所述第一药物活性成分与所述第二药物活性成分可以单独给药,不分先后。在一些实施方案中,所述第一药物活性成分与所述第二药物活性成分可以同时给药。In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient may be administered separately, in no particular order. In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient may be administered simultaneously.
在一些实施方案中,所述药物组合产品呈药物组合物的形式。在一些实施方案中,其中所述药物组合物还包含一种或多种可药用的赋形剂。In some embodiments, the pharmaceutical combination product is in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
在另一个方面,本发明提供一种根据本发明所述的药物组合产品在制备用于治疗异常细胞生长(例如癌症)的药物中的用途。In another aspect, the invention provides use of a pharmaceutical combination according to the invention for the preparation of a medicament for the treatment of abnormal cell growth, such as cancer.
在一些实施方案中,所述异常细胞生长包括实体瘤、软组织肿瘤、转移或非实体癌。在一些实施方案中,所述异常细胞生长是KRASG12C突变阳性的局部晚期或转移性实体肿瘤,例如非小细胞肺癌、结直肠癌、胆管癌。In some embodiments, the abnormal cell growth includes solid tumors, soft tissue tumors, metastases, or non-solid cancers. In some embodiments, the abnormal cell growth is a KRASG12C mutation-positive locally advanced or metastatic solid tumor, such as non-small cell lung cancer, colorectal cancer, cholangiocarcinoma.
在又一个方面,本发明提供一种治疗异常细胞生长相关疾病的方法,其包括向有需要的受试者施用根据本发明所述的药物组合产品。In yet another aspect, the present invention provides a method of treating a disease associated with abnormal cell growth, comprising administering a pharmaceutical combination according to the present invention to a subject in need thereof.
在一些实施方案中,所述第一药物活性成分通过口服施用。在一些实施方案中,所述第一药物活性成分每天至少施用一次,例如,所述第一药物活性成分每天施用一次,或,所述第一药物活性成分每天施用两次或多次。在一些实施方案中,所述第一药物活性成分以约1mg至约5000mg的单剂量施用。In some embodiments, the first pharmaceutically active ingredient is administered orally. In some embodiments, the first pharmaceutically active ingredient is administered at least once per day, for example, the first pharmaceutically active ingredient is administered once per day, or the first pharmaceutically active ingredient is administered two or more times per day. In some embodiments, the first pharmaceutically active ingredient is administered in a single dose of about 1 mg to about 5000 mg.
在一些实施方案中,所述第二药物活性成分通过口服施用。在一些实施方案中,所述第二药物活性成分每天至少施用一次,例如,所述第二药物活性成分每天施用一次,或,所述第二药物活性成分每天施用两次或多次。在一些实施方案中,所述第二药物活性成分以约1mg至约5000mg的单剂量施用。In some embodiments, the second pharmaceutically active ingredient is administered orally. In some embodiments, the second pharmaceutically active ingredient is administered at least once per day, for example, the second pharmaceutically active ingredient is administered once per day, or the second pharmaceutically active ingredient is administered two or more times per day. In some embodiments, the second pharmaceutically active ingredient is administered in a single dose of about 1 mg to about 5000 mg.
在一些实施方案中,所述异常细胞生长相关疾病包括实体瘤、软组织
肿瘤、转移或非实体癌。在一些实施方案中,所述施用包括将第一药物活性成分与第二药物活性成分单独给药或同时给药。In some embodiments, the abnormal cell growth-associated disease includes solid tumors, soft tissue Tumor, metastasis or non-solid cancer. In some embodiments, the administering includes administering the first pharmaceutically active ingredient and the second pharmaceutically active ingredient separately or simultaneously.
令人惊奇地发现,根据本发明的第一药物活性成分和第二药物活性成分可以协同地实现肿瘤总体缓解,并增加临床前模型中的中值存活百分比。Surprisingly, it was found that the first pharmaceutically active ingredient and the second pharmaceutically active ingredient according to the present invention can synergistically achieve overall tumor response and increase the median survival percentage in preclinical models.
在衍生自患者的肿瘤异种移植中,与单一药物活性成分相比,包含第一药物活性成分和第二药物活性成分的药物组合产品可以产生协同的抗肿瘤活性。试验数据表明,对于KRASG12C突变阳性的局部晚期或转移性实体肿瘤(例如非小细胞肺癌、结直肠癌、胆管癌等),第一药物活性成分和第二药物活性成分的组合可以实现更大和更持久的应答。重要的是,第一药物活性成分和第二药物活性成分用作单一药物活性成分时仅能降低肿瘤生长速率,而相同剂量在两种药物活性成分组合时可以实现肿瘤体积减小,从而总体缓解肿瘤生长。In patient-derived tumor xenografts, pharmaceutical combination products containing a first pharmaceutically active ingredient and a second pharmaceutically active ingredient can produce synergistic antitumor activity compared to a single pharmaceutically active ingredient. Trial data show that for KRASG12C mutation-positive locally advanced or metastatic solid tumors (such as non-small cell lung cancer, colorectal cancer, cholangiocarcinoma, etc.), the combination of the first drug active ingredient and the second drug active ingredient can achieve larger and more precise tumors. Long lasting response. Importantly, the first and second pharmaceutically active ingredients only reduce tumor growth rate when used as single pharmaceutically active ingredients, whereas the same dose when both pharmaceutically active ingredients are combined can achieve tumor volume reduction and thus overall response Tumor growth.
图1显示了人非小细胞肺癌细胞NCI-H358异种移植模型各给药组的小鼠体重变化;Figure 1 shows the body weight changes of mice in each administration group of the human non-small cell lung cancer cell NCI-H358 xenograft model;
图2显示了人非小细胞肺癌细胞NCI-H358异种移植模型各给药组的小鼠体重变化率;Figure 2 shows the body weight change rate of mice in each administration group of the human non-small cell lung cancer cell NCI-H358 xenograft model;
图3显示了人非小细胞肺癌细胞NCI-H358异种移植模型各给药组的肿瘤体积变化;Figure 3 shows the changes in tumor volume in each administration group of the human non-small cell lung cancer cell NCI-H358 xenograft model;
图4显示了人非小细胞肺癌细胞NCI-H358异种移植模型各给药组的肿瘤体积变化率。Figure 4 shows the tumor volume change rate in each administration group of the human non-small cell lung cancer cell NCI-H358 xenograft model.
第一药物活性成分First pharmaceutical active ingredient
本发明提供了一种包含第一药物活性成分的药物组合产品。在一些实施方案中,所述第一药物活性成分是式(I)的化合物或其药学上可接受的盐,
The present invention provides a pharmaceutical combination product containing a first pharmaceutical active ingredient. In some embodiments, the first pharmaceutically active ingredient is a compound of Formula (I) or a pharmaceutically acceptable salt thereof,
The present invention provides a pharmaceutical combination product containing a first pharmaceutical active ingredient. In some embodiments, the first pharmaceutically active ingredient is a compound of Formula (I) or a pharmaceutically acceptable salt thereof,
在一些实施方案中,所述第一药物活性成分是式(I)的化合物。本文所述式(I)的化合物是已知化合物,其所有已知形式和成分,都可以用于本发明所提供的药物组合产品中。例如,式(I)化合物的制备和确认已经描述在PCT国际申请WO2020233592、WO2021121330和WO2021120045中。In some embodiments, the first pharmaceutically active ingredient is a compound of Formula (I). The compound of formula (I) described herein is a known compound, and all its known forms and components can be used in the pharmaceutical combination products provided by the present invention. For example, the preparation and identification of compounds of formula (I) have been described in PCT International Applications WO2020233592, WO2021121330 and WO2021120045.
在一些实施方案中,所述第一药物活性成分是式(I)化合物的药学上可接受的盐,其包括但不限于盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐等。In some embodiments, the first pharmaceutically active ingredient is a pharmaceutically acceptable salt of a compound of formula (I), including but not limited to hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, Sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate Acid salt, mesylate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate , succinate, gluconate, lactobiate or lauryl sulfonate, etc.
在一些实施方案中,所述第一药物活性成分可以是无定形、结晶形式及其组合。In some embodiments, the first pharmaceutically active ingredient can be in amorphous, crystalline forms, and combinations thereof.
在另一些实施方案中,所述第一药物活性成分还可以是与式(I)化合物药效相同或相似的其他药物活性成分,例如现有技术中已知的ARS-853、ARS-1620、ARS-3248、LY3499446和MRTX849,或其药学上可接受的盐。In other embodiments, the first pharmaceutical active ingredient can also be other pharmaceutical active ingredients that have the same or similar efficacy as the compound of formula (I), such as ARS-853, ARS-1620, ARS-3248, LY3499446 and MRTX849, or pharmaceutically acceptable salts thereof.
第二药物活性成分Second pharmaceutical active ingredient
本发明提供了一种包含第二药物活性成分的药物组合产品。在一些实
施方案中,所述第二药物活性成分是式(II)的化合物或其药学上可接受的盐,
The present invention provides a pharmaceutical combination product containing a second pharmaceutically active ingredient. In some practical In embodiments, the second pharmaceutically active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof,
The present invention provides a pharmaceutical combination product containing a second pharmaceutically active ingredient. In some practical In embodiments, the second pharmaceutically active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof,
在一些实施方案中,所述第二药物活性成分是式(II)的化合物。本文所述式(II)的化合物是已知化合物,其所有已知形式和成分,都可以用于本发明所提供的药物组合产品中。例如,式(II)化合物的制备和确认已经描述在WO2010058032中。In some embodiments, the second pharmaceutically active ingredient is a compound of formula (II). The compound of formula (II) described herein is a known compound, and all its known forms and components can be used in the pharmaceutical combination products provided by the present invention. For example, the preparation and identification of compounds of formula (II) have been described in WO2010058032.
在一些实施方案中,所述第二药物活性成分是式(I)化合物的药学上可接受的盐,其包括但不限于盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐等。在一些实施方案中,所述药学上可接受的盐为马来酸盐、苹果酸盐或酒石酸盐,进一步,优选为酒石酸盐。In some embodiments, the second pharmaceutically active ingredient is a pharmaceutically acceptable salt of the compound of formula (I), including but not limited to hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, Sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate Acid salt, mesylate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate , succinate, gluconate, lactobiate or lauryl sulfonate, etc. In some embodiments, the pharmaceutically acceptable salt is a maleate, a malate or a tartrate, further preferably a tartrate.
所述药学上可接受的盐可以按照由碱性化合物制备酸加成盐的常规操作通过将游离碱溶于合适的溶剂并且用酸处理该溶液来得到。本领域技术人员无需过多实验即可确定各种可用来制备无毒的药学上可接受的酸加成盐的合成方法。The pharmaceutically acceptable salts may be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid following conventional procedures for the preparation of acid addition salts from basic compounds. One skilled in the art will be able to identify, without undue experimentation, various synthetic methods that can be used to prepare nontoxic pharmaceutically acceptable acid addition salts.
在一些实施方案中,所述第二药物活性成分可以是无定形、结晶形式及其组合。In some embodiments, the second pharmaceutically active ingredient can be in amorphous, crystalline forms, and combinations thereof.
在另一些实施方案中,所述第二药物活性成分还可以是与式(II)化合物药效相同或相似的其他药物活性成分,例如现有技术中已知的defactinib、TAE226、GSK2256098、PF-03814735、BI-4464、VS-4718和APG-2449,或其药学上可接受的盐。
In other embodiments, the second pharmaceutically active ingredient can also be other pharmaceutically active ingredients that have the same or similar efficacy as the compound of formula (II), such as defactinib, TAE226, GSK2256098, PF- 03814735, BI-4464, VS-4718 and APG-2449, or pharmaceutically acceptable salts thereof.
药物组合产品drug combination products
根据本发明的药物组合产品包含第一药物活性成分和第二药物活性成分。The pharmaceutical combination product according to the present invention contains a first pharmaceutically active ingredient and a second pharmaceutically active ingredient.
根据本发明的药物组合产品可以包括所述第一和/或第二药物活性成分的所有合适的同位素变体。本发明化合物的同位素变体定义为:其中至少一个原子被原子序数相同但原子量不同于自然界中通常或主要发现的原子量的原子替代的本发明的化合物。可以掺入本发明的化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的同位素,例如分别为2H(氘)、3H(氚)、11C、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I和131I。本发明化合物的某些同位素变体,例如,其中引入一个或多个放射性同位素(例如,3H或14C)的那些变体可用于药物和/或底物组织分布研究。尤其优选氚和碳-14(即,14C)同位素,这是由于它们的容易制备和可检测性。进一步,用同位素诸如氘取代可以提供由更好的代谢稳定性导致的确定的治疗优点,例如增加的体内半衰期或减小的剂量需求,并且因此在一些情况下可以是优选的。通常可以利用本领域技术人员已知的常规方法,例如,利用说明性方法或下文实施例所描述的制备方法,使用合适试剂的合适的同位素变体来制备本发明化合物的同位素变体。Pharmaceutical combinations according to the invention may comprise all suitable isotopic variants of said first and/or second pharmaceutically active ingredient. Isotopic variants of the compounds of the invention are defined as compounds of the invention in which at least one atom is replaced by an atom of the same atomic number but with an atomic weight different from that usually or predominantly found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), respectively. 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S , 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I , 129I and 131I . Certain isotopic variants of the compounds of the present invention, eg, those in which one or more radioactive isotopes (eg, 3 H or 14 C) are incorporated, may be used in drug and/or substrate tissue distribution studies. Tritium and carbon-14 (ie, 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may provide certain therapeutic advantages resulting from better metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. Isotopic variants of the compounds of the invention can generally be prepared using suitable isotopic variants of suitable reagents using conventional methods known to those skilled in the art, for example, using the illustrative methods or the preparation methods described in the examples below.
根据本发明的药物组合产品可以包括作为单一立体异构体或呈任何比率的所述立体异构体的任何混合物的所述第一和/或第二药物活性成分的所有可能的立体异构体。可通过任意适合的现有技术方法例如色谱法,特别是例如手性色谱法实现本发明化合物的单一立体异构体例如单一对映体或单一非对映体的分离。Pharmaceutical combinations according to the invention may comprise all possible stereoisomers of the first and/or second pharmaceutically active ingredient as a single stereoisomer or as any mixture of said stereoisomers in any ratio. . The separation of single stereoisomers, such as single enantiomers or single diastereomers, of the compounds of the invention can be achieved by any suitable state-of-the-art method, such as chromatography, in particular, for example, chiral chromatography.
根据本发明的药物组合产品可以包括所述第一和/或第二药物活性成分的所有可能的互变异构体,其是单一互变异构体或所述互变异构体的任意比例的任意混合物的形式。Pharmaceutical combinations according to the invention may comprise all possible tautomers of said first and/or second pharmaceutically active ingredients, either as single tautomers or in any ratio of said tautomers in the form of any mixture.
另外,根据本发明的药物组合产品可以包括所述第一和/或第二药物活性成分的所有可能的结晶形式或多晶型物,其作为单一多晶型物或多于
一种多晶型物的任意比例的混合物。Additionally, pharmaceutical combinations according to the invention may comprise all possible crystalline forms or polymorphs of said first and/or second pharmaceutically active ingredient, either as a single polymorph or as more than one polymorph. A mixture of polymorphs in any proportion.
在一些实施方案中,根据本发明的药物组合产品还包含任选的第三药物活性成分,其选自HDAC抑制剂、CDK4/6抑制剂、ALK抑制剂、JAK2抑制剂、Bcl-2抑制剂、Hsp90抑制剂、糖皮质激素、长春花生物碱、抗代谢物、DNA损伤剂、来那度胺、利妥昔单抗、PKC干扰原、Lyn/Fyn抑制剂、Syk抑制剂、PI3K抑制剂、PKCβ抑制剂、IKK抑制剂、20s蛋白酶体、IRF-4、IRAK4抗体、CXCR4抗体、CXCR5抗体、GLS抗体、PLK抗体、CD20抗体、TopoII抑制剂、DNA甲基转移酶抑制剂、Ras/MAPK抑制剂或FGFR1抑制剂;所述HDAC抑制剂,优选帕比司他乳酸、贝利司他、西达本胺、罗米地辛、伏立诺他、倍赛诺他或恩替诺特,所述CDK4/6抑制剂,优选Palbociclib、Blinatumomab、Tiagabine Hydrochloride或Itolizumab,所述Bcl-2抑制剂,优选Venetoclax、安普利森钠、ABT-737或HA14-1,所述Hsp90抑制剂,优选Sebelipase alfa或RetaspimycinHydrochloride,所述JAK2抑制剂,优选枸橼酸托法替尼、RuxolitinibPhosphate、Lestaurtinib、Momelotinib Dihydrochloride、Peficitinib或Filgotinib,所述PKC干扰原,优选替普瑞酮、Truheal、HO/03/03、Sotrastaurin、恩扎妥林或GF109203X,所述ALK抑制剂,优选AlectinibHydrochloride、色瑞替尼、克唑替尼、苯达莫司汀、卡莫司汀、洛莫司汀、盐酸氮芥或NVP-TAE684,所述PI3K抑制剂,优选GS-1101、IPI-145、BKM120、BEZ235、GDC-0941、AMG319、CAL-101或A66,所述IKK抑制剂,优选金诺芬、BAY86-9766或RDEA-119。In some embodiments, the pharmaceutical combination product according to the present invention also contains an optional third pharmaceutical active ingredient selected from the group consisting of HDAC inhibitors, CDK4/6 inhibitors, ALK inhibitors, JAK2 inhibitors, Bcl-2 inhibitors , Hsp90 inhibitors, glucocorticoids, vinca alkaloids, antimetabolites, DNA damaging agents, lenalidomide, rituximab, PKC interferogens, Lyn/Fyn inhibitors, Syk inhibitors, PI3K inhibitors , PKCβ inhibitor, IKK inhibitor, 20s proteasome, IRF-4, IRAK4 antibody, CXCR4 antibody, CXCR5 antibody, GLS antibody, PLK antibody, CD20 antibody, TopoII inhibitor, DNA methyltransferase inhibitor, Ras/MAPK inhibitor or FGFR1 inhibitor; the HDAC inhibitor is preferably panobinostat lactate, belinostat, chidamide, romidepsin, vorinostat, bexenostat or entinostat, The CDK4/6 inhibitor is preferably Palbociclib, Blinatumomab, Tiagabine Hydrochloride or Itolizumab, the Bcl-2 inhibitor is preferably Venetoclax, Amplesen sodium, ABT-737 or HA14-1, and the Hsp90 inhibitor is preferably Sebelipase alfa or RetaspimycinHydrochloride, the JAK2 inhibitor is preferably tofacitinib citrate, RuxolitinibPhosphate, Lestaurtinib, Momelotinib Dihydrochloride, Peficitinib or Filgotinib, the PKC interference source is preferably teprenone, Truheal, HO/03/03 , Sotrastaurin, enzastaurin or GF109203X, the ALK inhibitor is preferably AlectinibHydrochloride, ceritinib, crizotinib, bendamustine, carmustine, lomustine, nitrogen mustard or NVP -TAE684, the PI3K inhibitor, preferably GS-1101, IPI-145, BKM120, BEZ235, GDC-0941, AMG319, CAL-101 or A66, the IKK inhibitor, preferably auranofin, BAY86-9766 or RDEA -119.
在一些实施方案中,根据本发明的药物组合产品还包含一种或多种可药用的赋形剂、稀释剂或载体。In some embodiments, pharmaceutical combinations according to the invention further comprise one or more pharmaceutically acceptable excipients, diluents or carriers.
在一些实施方案中,根据本发明的药物组合物产品可以包含单独的第一药物活性成分和单独的第二药物活性成分。例如,根据本发明的药物组合产品可以包含分别配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂的第一药物活性成分和第二药物活性成分。替代地,
根据本发明的药物组合物产品可以是包含第一药物活性成分和第二药物活性成分的药物组合物。例如,将第一药物活性成分和第二药物活性成分一起配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。In some embodiments, a pharmaceutical composition product according to the present invention may comprise a first pharmaceutically active ingredient alone and a second pharmaceutically active ingredient alone. For example, pharmaceutical combination products according to the present invention may include tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection liquids, sterile powders for injection and concentrates for injection), respectively. solution), suppository, inhaler or spray first pharmaceutically active ingredient and second pharmaceutically active ingredient. alternatively, The pharmaceutical composition product according to the present invention may be a pharmaceutical composition comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient. For example, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient are formulated together into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and Concentrated solution for injection), suppository, inhalation or spray.
根据本发明的第一和/或第二药物活性成分可以用常规片剂基质诸如乳糖、蔗糖和玉米淀粉与如下组分的组合压片:粘合剂诸如***胶、玉米淀粉或明胶,施用后帮助片剂崩解和溶出的崩解剂诸如马铃薯淀粉、藻酸、玉米淀粉和瓜尔胶、黄蓍胶、***胶,用于改善片剂颗粒流动和防止片剂材料与片剂模具和冲头表面粘附的润滑剂例如滑石、硬脂酸或硬脂酸镁、硬脂酸钙或硬脂酸锌,用于增强片剂的美学品质和使它们更容易被患者接受的染料、着色剂和矫味剂诸如薄荷、冬青油或樱桃香精。用于口服液体剂型中的合适的赋形剂包括磷酸二钙和稀释剂,例如水和醇(例如乙醇、苯甲醇和聚乙烯醇类),其添加或不添加药学上可接受的表面活性剂、助悬剂或乳化剂。各种其它材料可以以包衣的方式存在或者以其它方式改变剂量单位的物理形式。例如,可以用虫胶、糖或二者将片剂、丸剂或胶囊剂进行包衣。可分散的粉剂和颗粒剂适合用于制备水性混悬剂。它们以与分散剂或润湿剂、助悬剂以及一种或多种防腐剂混合的方式提供活性成分。合适的分散或润湿剂和悬浮剂通过上述已提及的那些例示。也可存在额外的赋形剂,例如上述那些甜味剂、矫味剂和着色剂。The first and/or second pharmaceutically active ingredient according to the invention may be tabletted using conventional tablet bases such as lactose, sucrose and cornstarch in combination with a binder such as gum arabic, cornstarch or gelatin, after administration Disintegrants that aid tablet disintegration and dissolution such as potato starch, alginic acid, corn starch and guar gum, tragacanth, and acacia gum are used to improve tablet particle flow and prevent tablet materials from interacting with tablet molds and punches. Lubricants adhered to the head surface such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate, dyes, colorants used to enhance the aesthetic qualities of the tablets and make them more acceptable to patients and flavorings such as peppermint, oil of wintergreen, or cherry essence. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (such as ethanol, benzyl alcohol and polyvinyl alcohols), with or without the addition of a pharmaceutically acceptable surfactant. , suspending agent or emulsifier. Various other materials may be present as coatings or otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both. Dispersible powders and granules are suitable for the preparation of aqueous suspensions. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as those mentioned above for sweetening, flavoring and coloring agents, may also be present.
根据本发明的药物组合产品还包括商业包装物,该商业包装物包括用于向有需要的患者同时、分开或顺序施用根据本发明的药物活性成分的说明书。The pharmaceutical combination product according to the invention also includes a commercial package comprising instructions for simultaneous, separate or sequential administration of the pharmaceutically active ingredients according to the invention to a patient in need thereof.
组合疗法combination therapy
在一些实施方案中,可以通过调节在根据本发明的药物组合产品中的第一药物活性成分和第二药物活性成分的剂量方案以提供最适期望应答,例如,最大治疗应答和/或最小不良作用。In some embodiments, the dosage regimen of the first pharmaceutically active ingredient and the second pharmaceutically active ingredient in the pharmaceutical combination product according to the present invention can be adjusted to provide an optimal desired response, e.g., maximum therapeutic response and/or minimum adverse effects. effect.
在一些实施方案中,所述第一药物活性成分的单剂量范围可以为1至
5000mg。在一些实施方案中,所述第一药物活性成分的给药频次可以为每天5次、每天4次、每天3次、每天2次、每天1次、每2天1次、等。In some embodiments, the single dosage of the first pharmaceutically active ingredient may range from 1 to 5000mg. In some embodiments, the administration frequency of the first pharmaceutically active ingredient may be 5 times a day, 4 times a day, 3 times a day, 2 times a day, once a day, once every 2 days, etc.
在一些实施方案中,所述第二药物活性成分的单剂量范围可以为1至5000mg。在一些实施方案中,所述第二药物活性成分的给药频次可以为每天5次、每天4次、每天3次、每天2次、每天1次、每2天1次、等。In some embodiments, the single dose of the second pharmaceutically active ingredient may range from 1 to 5000 mg. In some embodiments, the administration frequency of the second pharmaceutically active ingredient may be 5 times a day, 4 times a day, 3 times a day, 2 times a day, once a day, once every 2 days, etc.
在一些实施方案中,根据本发明的药物组合产品中的第一药物活性成分与第二药物活性成分的重量比可以为约50:1至约1:50,优选约25:1至约1:25,和更优选约15:1至约1:15。在一些实施方案中,所述重量比可以为约14:1至约1:14、约13:1至约1:13、约12:1至约1:12、约11:1至约1:11、约10:1至约1:10、约9:1至约1:9、约8:1至约1:8、约7:1至约1:7、约6:1至约1:6、约5:1至约1:5、约4:1至约1:4、约3:1至约1:3、约2:1至约1:2或约1:1,例如,所述重量比约为14∶1、约12∶1、约10∶1、约8∶1、约6∶1、约5∶1、约4∶1、约3∶1、约2∶1、约1∶1、约1∶1.2、约1∶1.5、约1∶2、约1∶2.5、约1∶3、约1∶4、或约1∶5。In some embodiments, the weight ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient in the pharmaceutical combination product according to the present invention may be from about 50:1 to about 1:50, preferably from about 25:1 to about 1: 25, and more preferably about 15:1 to about 1:15. In some embodiments, the weight ratio may be from about 14:1 to about 1:14, from about 13:1 to about 1:13, from about 12:1 to about 1:12, from about 11:1 to about 1:1. 11. About 10:1 to about 1:10, about 9:1 to about 1:9, about 8:1 to about 1:8, about 7:1 to about 1:7, about 6:1 to about 1: 6. About 5:1 to about 1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, about 2:1 to about 1:2 or about 1:1, for example, so The weight ratio is about 14:1, about 12:1, about 10:1, about 8:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:4, or about 1:5.
所述给药剂量在本领域普通技术人员的水平内,并且药物的单剂量或日剂量可以根据待施用的受试者的发病程度、发病时间、年龄、健康状况和并发症等的各种因素而变化。The dosage is within the level of one of ordinary skill in the art, and the single dose or daily dose of the drug can be determined according to various factors such as the degree of disease, time of disease, age, health status and complications of the subject to be administered. And change.
根据本发明的药物组合产品可以,单独地或组合地,通过口服施用,替代地,根据本发明的药物组合产品可以,单独地或组合地,肠胃外施用,即皮下、静脉内、眼内、滑膜内、肌内或腹膜间,作为优选在生理学上可接受的稀释剂与药物载体中的化合物的可注射剂量施用,所述药物载体可以是无菌液体或液体的混合物,诸如水、盐水、右旋糖水溶液和相关糖溶液,醇诸如乙醇、异丙醇或十六醇,二醇类诸如丙二醇或聚乙二醇,甘油缩酮类诸如2,2-二甲基-1,1-二氧杂环戊烷-4-甲醇,醚类诸如聚(乙二醇)400、油、脂肪酸、脂肪酸酯或脂肪酸甘油酯或乙酰化脂肪酸甘油酯,加入或不加入药学上可接受的表面活性剂诸如皂或洗涤剂,助悬剂诸如果
胶、卡波姆、甲基纤维素、羟丙基甲基纤维素或羧甲基纤维素,或乳化剂和其它药物助剂。The pharmaceutical combination products according to the invention may be administered, alone or in combination, by oral administration. Alternatively, the pharmaceutical combination products according to the invention may be administered, alone or in combination, parenterally, i.e. subcutaneously, intravenously, intraocularly, Intrasynovial, intramuscular, or interperitoneal administration, as an injectable dose of the compound, preferably in a physiologically acceptable diluent and a pharmaceutical carrier, which may be a sterile liquid or mixture of liquids, such as water, saline , aqueous dextrose solutions and related sugar solutions, alcohols such as ethanol, isopropyl alcohol or cetyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,1- Dioxolane-4-carbinol, ethers such as poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters or fatty acid glycerides or acetylated fatty acid glycerides, with or without the addition of a pharmaceutically acceptable surface Active agents such as soap or detergent, suspending agents such as Glue, carbomer, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or emulsifiers and other pharmaceutical auxiliaries.
在每日一次给予式(I)所示化合物和式(II)所示化合物的情况下,这可以通过给予含有式(I)所示化合物和式(II)所示化合物的组合的固定剂量组合来完成。In the case of once-daily administration of a compound represented by formula (I) and a compound represented by formula (II), this may be achieved by administering a fixed dose combination containing a combination of a compound represented by formula (I) and a compound represented by formula (II) To be done.
如果需要口服剂型可以在包装或分配器装置中呈现,例如FDA认可的试剂盒,其可含有有活性成分的一种或多种单位剂型。例如,包装可以包括金属或塑料箔,例如泡罩包装。包装或分配器装置可以伴随着给药指令。If an oral dosage form is desired, it may be presented in a package or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms of the active ingredient. For example, the packaging may include metal or plastic foil, such as a blister pack. Packaging or dispenser devices may accompany administration instructions.
治疗用途therapeutic use
本发明提供了治疗异常细胞生长的组合疗法,其包括向有需求的受试者施用根据本发明的药物组合产品。The present invention provides a combination therapy for the treatment of abnormal cell growth, comprising administering to a subject in need thereof a pharmaceutical combination according to the present invention.
在一些实施方案中,本发明的药物组合物产品包含治疗有效量的第一药物活性成分和治疗有效量的第二药物活性成分;在一些实施方案中,本发明的药物组合物产品可以包含治疗有效量的单独的第一药物活性成分和治疗有效量的单独的第二药物活性成分。In some embodiments, the pharmaceutical composition product of the present invention includes a therapeutically effective amount of a first pharmaceutically active ingredient and a therapeutically effective amount of a second pharmaceutically active ingredient; in some embodiments, the pharmaceutical composition product of the present invention may include a therapeutically effective amount of a second pharmaceutically active ingredient. An effective amount of a first pharmaceutically active ingredient alone and a therapeutically effective amount of a second pharmaceutically active ingredient alone.
在一些实施方案中,所述异常细胞生长,例如癌症,非限制性的包括实体瘤、软组织肿瘤、转移或非实体癌。在一些实施方案中,癌症是实体瘤。在一些实施方案中,实体瘤是器官(例如肺、乳腺、淋巴、胃肠道(例如结肠)和泌尿生殖器(例如肾、泌尿道上皮或睾丸的肿瘤)、咽、***和卵巢)的恶性肿瘤(例如肉瘤、腺癌和癌)。在一些实施方案中,所述癌症为间皮瘤;神经纤维瘤病;例如,2型神经纤维瘤病、1型神经纤维瘤病;肾癌;肺癌、非小细胞肺癌;肝癌;甲状腺癌;卵巢癌;乳腺癌;神经***肿瘤;神经鞘瘤;脑膜瘤;神经鞘瘤病(schwannomatosis);听神经瘤;腺样囊性癌;室管膜瘤;或室管膜肿瘤。在一些实施方案中,所述癌症为间皮瘤(例如,恶性胸膜间皮瘤,例如,手术可切除的恶性胸膜间皮瘤)、乳腺癌(例如,三阴性乳腺癌)、卵巢癌(例如,晚期卵巢癌)、肺癌(例如,非小细胞肺癌(NSCLC),例如,KRAS突变的NSCLC))或非血液恶性肿瘤。
在一些实施方案中,所述癌症为非小细胞肺癌(NSCLC),例如,KRAS突变的NSCLC)。在一些实施方案中,所述癌症为黑素瘤(例如,N-Ras突变的局部晚期或转移恶性的皮肤黑素瘤)、结肠直肠癌(例如,转移性结肠直肠癌)、白血病(例如,急性骨髓性白血病)、腺癌(例如,胰腺腺癌)或实体瘤(例如,局部晚期的实体瘤、转移性实体瘤、肝细胞癌)。In some embodiments, the abnormal cell growth, such as cancer, includes, but is not limited to, solid tumors, soft tissue tumors, metastases, or non-solid cancers. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is a malignant tumor of an organ (e.g., lung, breast, lymphatic, gastrointestinal tract (e.g., colon), and genitourinary (e.g., kidney, urothelial or testicular tumors), pharynx, prostate, and ovary) (eg sarcomas, adenocarcinomas and carcinomas). In some embodiments, the cancer is mesothelioma; neurofibromatosis; e.g., neurofibromatosis type 2, neurofibromatosis type 1; kidney cancer; lung cancer, non-small cell lung cancer; liver cancer; thyroid cancer; Ovarian cancer; breast cancer; nervous system tumors; schwannoma; meningioma; schwannomatosis; acoustic neuroma; adenoid cystic carcinoma; ependymoma; or ependymoma. In some embodiments, the cancer is mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma), breast cancer (e.g., triple negative breast cancer), ovarian cancer (e.g., , advanced ovarian cancer), lung cancer (eg, non-small cell lung cancer (NSCLC), eg, KRAS-mutated NSCLC)), or non-hematologic malignancies. In some embodiments, the cancer is non-small cell lung cancer (NSCLC), e.g., KRAS-mutated NSCLC). In some embodiments, the cancer is melanoma (e.g., N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma), colorectal cancer (e.g., metastatic colorectal cancer), leukemia (e.g., acute myeloid leukemia), adenocarcinoma (eg, pancreatic adenocarcinoma), or solid tumor (eg, locally advanced solid tumor, metastatic solid tumor, hepatocellular carcinoma).
所述癌症可包括特征为包含癌症干细胞、癌症相关间充质细胞或肿瘤起始癌细胞的癌症。癌症可包括已被表征为富含癌症干细胞、癌症相关间充质细胞或肿瘤起始癌细胞的癌症(例如,富含经历上皮-间充质转化的细胞的肿瘤或转移性肿瘤)。The cancer may include cancer characterized by comprising cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells. Cancers may include cancers that have been characterized as enriched in cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells (eg, tumors or metastatic tumors enriched in cells undergoing epithelial-mesenchymal transition).
肿瘤可以是原发性肿瘤,即位于肿瘤生长起始的解剖部位。该癌症也可以是转移性的,即至少出现除肿瘤生长起始的解剖部位之外的第二解剖部位。这种癌症可能是一种复发性癌症,即在治疗后以及在一段时间内无法检测到癌症后复发的癌症。复发癌可以在解剖学上定位于原发肿瘤的局部,例如,在解剖学上靠近原发肿瘤;在原发肿瘤区域,例如位于原发肿瘤附近的***;或远离原始肿瘤,例如,在解剖学上远离原始肿瘤的区域。The tumor can be a primary tumor, which is located at the anatomic site where the tumor growth begins. The cancer can also be metastatic, meaning it appears in at least a second anatomical location other than the one where the tumor grew. This cancer may be a relapsing cancer, which is a cancer that comes back after treatment and after a period of time when the cancer is undetectable. Recurrent cancer can be anatomically localized to the primary tumor, e.g., anatomically close to the primary tumor; in an area of the primary tumor, such as a lymph node located near the primary tumor; or distant from the original tumor, e.g., anatomically close to the primary tumor An area that is scientifically distant from the original tumor.
癌症还可包括肺腺癌、结直肠癌(CRC)、子宫内膜样癌、膀胱尿路上皮癌、乳腺浸润性小叶癌、宫颈鳞状细胞癌、皮肤黑色素瘤、***、肝细胞癌、胰腺癌、双相型胸膜间皮瘤、肾透明细胞癌、肾透明细胞癌、胃腺癌、管状胃腺癌、子宫癌肉瘤或子宫恶性混合苗勒管瘤、或其他癌症。Cancers may also include lung adenocarcinoma, colorectal cancer (CRC), endometrioid carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, cervical adenocarcinoma, hepatocellular carcinoma , pancreatic cancer, biphasic pleural mesothelioma, renal clear cell carcinoma, renal clear cell carcinoma, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine carcinosarcoma or uterine malignant mixed Mullerian tumor, or other cancers.
其他癌症包括但不限于葡萄膜黑色素瘤、脑、腹部、食道、胃肠道、胶质瘤、肝、舌、神经母细胞瘤、骨肉瘤、卵巢、视网膜母细胞瘤、Wilms瘤、多发性骨髓瘤、皮肤、淋巴瘤、血液和骨髓癌(如晚期血液***恶性肿瘤、白血病,如急性髓系白血病(如原发性或继发性)),急性淋巴细胞白血病、急性淋巴细胞白血病、T细胞白血病、血液***恶性肿瘤、晚期骨髓增生性疾病、骨髓增生异常综合征、复发或难治性多发性骨髓瘤、晚期骨髓增生性疾病)、视网膜、膀胱、宫颈、肾脏、子宫内膜、脑膜瘤、淋巴瘤、皮肤、子宫、肺、非小细胞肺、鼻咽癌、神经母细胞瘤、实体瘤、血液***恶性肿瘤、鳞状细胞癌、睾丸、甲状腺、间皮瘤、脑外阴、肉瘤、
肠、口腔、内分泌、唾液、***细胞***瘤、散发性髓样甲状腺癌、非增殖性睾丸细胞、与恶性肥大细胞相关的癌症、非霍奇金淋巴瘤和弥漫性大B细胞淋巴瘤。Other cancers include, but are not limited to, uveal melanoma, brain, abdomen, esophagus, gastrointestinal tract, glioma, liver, tongue, neuroblastoma, osteosarcoma, ovary, retinoblastoma, Wilms tumor, multiple myeloid neoplasms, skin, lymphomas, blood and bone marrow cancers (e.g., advanced hematologic malignancies, leukemias, such as acute myeloid leukemia (e.g., primary or secondary)), acute lymphoblastic leukemia, acute lymphoblastic leukemia, T-cell Leukemia, hematologic malignancies, advanced myeloproliferative disorders, myelodysplastic syndromes, relapsed or refractory multiple myeloma, advanced myeloproliferative disorders), retina, bladder, cervix, kidney, endometrium, meningioma , lymphoma, skin, uterus, lung, non-small cell lung, nasopharyngeal carcinoma, neuroblastoma, solid tumor, hematological malignancy, squamous cell carcinoma, testis, thyroid, mesothelioma, cerebral vulva, sarcoma, Intestinal, oral, endocrine, salivary, spermatogenic seminomas, sporadic medullary thyroid cancer, nonproliferative testicular cells, malignant mast cell-related cancers, non-Hodgkin lymphoma, and diffuse large B-cell lymphoma tumor.
定义definition
如本文所用,修饰与本发明有关的量的术语“约”是指可能发生的数值数量变化,例如通过常规测试和处理;通过此类测试和处理中的无意错误;通过本发明所用成分的制造、来源或纯度上的差异等。如本文所使用的,“约”特定值还包括该特定值,例如,约10%包括10%。不论是否被术语“约”修饰,权利要求均包括所列举数量的等同形式。在一个实施方案中,术语“约”是指在所报告的数值的20%以内、10%以内或5%以内。As used herein, the term "about" modifying a quantity relevant to the present invention refers to variations in numerical quantities that may occur, such as through routine testing and handling; through inadvertent errors in such testing and handling; through the manufacture of the ingredients used in the present invention. , differences in origin or purity, etc. As used herein, "about" a particular value also includes that particular value, for example, about 10% includes 10%. Whether or not modified by the term "about," the claims include equivalents of the recited quantities. In one embodiment, the term "about" means within 20%, within 10%, or within 5% of the reported value.
如本文所用,术语“治疗”是指消除、减轻或缓解疾病或病症和/或与之相关的症状。尽管没有排除,但是治疗疾病或病症并不需要完全消除所述疾病、病症或与其相关的症状。如本文所用,术语“治疗”可以包括“预防性治疗”,其是指,对没有患病,但有风险或易于再发展疾病或病症或者复发疾病或病症的受试者而言,降低疾病或病症的再发展或先前控制的复发的可能性。术语“治疗”和同义词理解为向需要这种治疗的受试者施用治疗有效量的根据本发明的药物组合物。As used herein, the term "treating" or "treating" refers to the elimination, reduction, or alleviation of a disease or disorder and/or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition or symptoms associated therewith. As used herein, the term "treatment" may include "preventive treatment," which refers to the reduction of disease or disease in a subject who is not affected by the disease but is at risk or susceptible to developing the disease or condition or relapsing the disease or condition. Possibility of redevelopment of the condition or recurrence of previously controlled disease. The term "treatment" and synonyms are understood to mean the administration of a therapeutically effective amount of a pharmaceutical composition according to the invention to a subject in need of such treatment.
如本文所用,术语“治疗有效量”是指在研究人员、兽医、医学博士或其他临床医生正在寻求的组织***、动物或人类中引发生物或药物反应的活性化合物或药剂的量,该反应包括所治疗的疾病或病症的症状的减轻或逆转。本文中,术语“治疗有效量”可以基于单个药物活性成分,也可以基于两个药物活性成分的组合。As used herein, the term "therapeutically effective amount" refers to an amount of an active compound or agent that elicits a biological or pharmaceutical response in a tissue system, animal, or human being sought by a researcher, veterinarian, MD, or other clinician, including Reduction or reversal of symptoms of the disease or condition being treated. As used herein, the term "therapeutically effective amount" may be based on a single pharmaceutically active ingredient or a combination of two pharmaceutically active ingredients.
实施例Example
化合物原料来源及储藏Sources and storage of compound raw materials
下列实施例中未注明具体条件的实验方法均可以按照这类反应的常规条件进行或者按照制造厂商所建议的条件进行。
Experimental methods without specifying specific conditions in the following examples can be carried out according to the conventional conditions for this type of reaction or according to the conditions recommended by the manufacturer.
如果没有特别说明,以下实施例中所使用的实验材料和试剂均可从市售渠道获得。Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources.
第一药物活性成分(API)是式(I)的化合物,其按照专利申请WO2020233592、WO2021121330或WO2021120045中公开的方法制备,纯度为大于99%,在室温下避光保存。The first active pharmaceutical ingredient (API) is a compound of formula (I), which is prepared according to the method disclosed in patent applications WO2020233592, WO2021121330 or WO2021120045, with a purity of greater than 99%, and is stored at room temperature in the dark.
第二药物活性成分(API)是式(II)化合物的酒石酸盐,式(II)化合物按照专利申请WO2010058032中公开的方法制备,式(II)化合物的酒石酸盐按照由碱性化合物制备酸加成盐的常规操作制得,所述式(II)化合物的酒石酸盐的纯度为大于97%,在4℃下避光保存。The second active pharmaceutical ingredient (API) is a tartrate salt of a compound of formula (II) prepared according to the method disclosed in patent application WO2010058032. The tartrate salt of a compound of formula (II) is prepared according to acid addition from a basic compound. The salt is prepared by conventional operations. The tartrate of the compound of formula (II) has a purity of greater than 97% and is stored in the dark at 4°C.
实验动物
experimental animals
experimental animals
实施例1Example 1
1、动物饲养1. Animal feeding
动物到达后在实验环境饲养3-7天后方开始实验。动物在SPF级动物房以独立送风***(IVC)笼具饲养(每笼5只)。每笼动物信息卡注明笼内动物数目,性别,品系,接收日期,给药方案,实验编号,组别以及实验开始日期。所有笼具、垫料及饮水在使用前均灭菌。笼具、饲料及饮水每周更换两次。饲养环境及光照情况如下:After the animals arrived, they were raised in the experimental environment for 3-7 days before starting the experiment. Animals were kept in SPF-grade animal rooms in independent ventilation system (IVC) cages (5 animals per cage). The animal information card for each cage indicates the number of animals in the cage, gender, strain, date of receipt, dosage regimen, experiment number, group and experiment start date. All cages, bedding and drinking water are sterilized before use. Cages, feed and drinking water were changed twice a week. The feeding environment and lighting conditions are as follows:
温度:20-26摄氏度。Temperature: 20-26 degrees Celsius.
湿度:32-70%。Humidity: 32-70%.
笼具:以聚碳酸酯制成,体积300mmx180mmx150mm。垫料为玉米芯,每周更换两次。Cage: Made of polycarbonate, volume 300mmx180mmx150mm. The bedding material is corn cobs and is changed twice a week.
食物:实验动物在整个实验阶段中可自由进食(照射灭菌,干颗粒状
食物)。Food: Experimental animals can eat freely during the entire experimental period (irradiation sterilization, dry granular form food).
饮水:实验动物可自由饮用灭菌水。Drinking water: Experimental animals can drink sterilized water freely.
2、动物分组和给药2. Animal grouping and drug administration
将小鼠分成4组,每组8只,分别按照表a中的给药方法进行给药。The mice were divided into 4 groups, with 8 mice in each group, and were administered according to the administration method in Table A.
表a:体内药效试验动物分组以及给药方案
Table a: Animal groupings and dosing regimens for in vivo drug efficacy tests
Table a: Animal groupings and dosing regimens for in vivo drug efficacy tests
3、空白溶液和化合物溶液配置3. Blank solution and compound solution configuration
按表1所述的方法和配方配置空白对照组,并将第一API和第二API分别按照下述方法和配方,配置成溶液。Configure the blank control group according to the method and formula described in Table 1, and prepare the first API and the second API into solutions according to the following method and formula respectively.
表1:空白溶液和化合物溶液配置及贮存条件
Table 1: Configuration and storage conditions of blank solution and compound solution
Table 1: Configuration and storage conditions of blank solution and compound solution
4、细胞培养4. Cell culture
人非小细胞肺癌细胞NCI-H358(CRL-5807TM)体外单层培养,培养条件为基础培养基RPMI-1640中加入10%胎牛血清,100单位每毫升青霉素和100微克每毫升链霉素,37摄氏度5%CO2细胞培养箱中培养。一周两次用胰蛋白消化酶进行常规消化处理传代。当细胞饱
和度为80%-90%,数量到达要求时,收取细胞,计数,接种。Human non-small cell lung cancer cell NCI-H358 ( CRL-5807TM) in vitro monolayer culture, the culture conditions are basal medium RPMI-1640 added with 10% fetal bovine serum, 100 units per ml of penicillin and 100 μg per ml of streptomycin, in a 5% CO 2 cell culture incubator at 37 degrees Celsius nourish. Passage was performed twice a week with routine digestion treatment with trypsin digestion. When cells are full When the concentration is 80%-90% and the number reaches the required number, cells are collected, counted, and inoculated.
5、肿瘤细胞接种5. Tumor cell inoculation
将含有1×107个NCI-H358细胞的100μLPBS皮下接种于每只小鼠的右前肢肩胛皮下,在细胞接种后第28天,开始分组给药,每组平均肿瘤体积为246.38mm3。100 μL PBS containing 1 × 10 7 NCI-H358 cells was inoculated subcutaneously into the right forelimb scapula of each mouse. On the 28th day after cell inoculation, group administration began. The average tumor volume of each group was 246.38 mm 3 .
6、实验动物日常观察6. Daily observation of experimental animals
每天监测动物的健康状况及死亡情况,例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响如行为活动,摄食摄水量(仅目测),体重变化(每周测量两次体重),外观体征或其它不正常情况。基于各组动物数量记录了组内动物死亡数和副作用。Monitor the health status and death of the animals every day. Routine examinations include observing tumor growth and the effects of drug treatment on the daily behavioral performance of the animals, such as behavioral activities, food and water intake (visual inspection only), and weight changes (measure body weight twice a week). Appearance signs or other abnormalities. The number of animal deaths and side effects within the group were recorded based on the number of animals in each group.
7、肿瘤测量和实验指标7. Tumor measurement and experimental indicators
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。The experimental indicator is to examine whether tumor growth is inhibited, delayed or cured.
每周两次用游标卡尺测量肿瘤直径。Tumor diameter was measured twice weekly using vernier calipers.
肿瘤体积的计算公式为:V=0.5a×b2,a和b分别表示肿瘤的长径和短径。The calculation formula of tumor volume is: V=0.5a×b 2 , where a and b represent the long and short diameters of the tumor respectively.
化合物的抑瘤疗效用TGI(%)评价。TGI(%),反映肿瘤生长抑制率。The antitumor efficacy of the compounds was evaluated by TGI (%). TGI (%) reflects the tumor growth inhibition rate.
TGI(%)的计算:TGI(%)=[1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100%。Calculation of TGI (%): TGI (%) = [1-(Average tumor volume at the end of administration in a certain treatment group-Average tumor volume at the beginning of administration in this treatment group)/(Average tumor volume at the end of treatment in the solvent control group- Average tumor volume in the solvent control group at the beginning of treatment)] × 100%.
TGI值具有以下含义:TGI values have the following meanings:
a)TGI>100%,表明肿瘤总体缓解;a) TGI>100%, indicating overall tumor response;
b)TGI=100%,表明肿瘤生长停滞;b) TGI=100%, indicating tumor growth arrest;
c)100%>TGI,表明肿瘤生长速度降低。c) 100%>TGI, indicating reduced tumor growth rate.
8、实验结果8. Experimental results
8.1体重8.1 Weight
不同组荷瘤鼠体重变化以及变化率情况如图1和图2所示。图中,相对体重变化为基于开始给药时动物体重计算得出。数据点代表组内平均体重变化百分比。误差线代表标准误(SEM)。The body weight changes and change rates of tumor-bearing mice in different groups are shown in Figures 1 and 2. In the figure, the relative body weight change is calculated based on the animal body weight at the beginning of dosing. Data points represent the mean weight percent change within the group. Error bars represent standard error (SEM).
8.2肿瘤生长体积
8.2 Tumor growth volume
不同组动物在各个时间段的肿瘤生长体积如表2所示。The tumor growth volumes of animals in different groups at various time periods are shown in Table 2.
表2.各组不同时间段肿瘤体积
Table 2. Tumor volume in each group at different time periods
Table 2. Tumor volume in each group at different time periods
8.3肿瘤生长抑制率8.3 Tumor growth inhibition rate
在给药期间动物可以耐受受试药物,因此以最后一天(第二十八天)的数据计算肿瘤生长抑制率(TGI%)和p值,见表3。The animals could tolerate the test drug during the administration period, so the tumor growth inhibition rate (TGI%) and p value were calculated based on the data on the last day (day 28), as shown in Table 3.
表3:肿瘤大小抑制评价
Table 3: Tumor size inhibition evaluation
Table 3: Tumor size inhibition evaluation
备注:Remark:
a.平均值±标准差a.Mean ± standard deviation
b.p值根据不同组中各老鼠的相对肿瘤体积计算,运用One-way ANOVA方法通过对比对照组和各给药组得出P值,P<0.01统计学分析代表各组与对照组存在显著差异,P>0.05统计学分析代表各组于对照组之间不存在显著差异。b. The p value is calculated based on the relative tumor volume of each mouse in different groups. The One-way ANOVA method is used to obtain the P value by comparing the control group and each administration group. P<0.01 statistical analysis represents a significant difference between each group and the control group. P>0.05 statistical analysis means there is no significant difference between each group and the control group.
c.P值运用One-wayANOVA方法通过对比第一API和第二API联合剂量组与单药组得出的P值。P<0.01统计学分析代表各组与对照组存在显著差异。c.P value is the P value obtained by comparing the first API and second API combined dose group with the single drug group using the One-wayANOVA method. P<0.01 statistical analysis represents significant differences between each group and the control group.
QD为每天一次。QD is once a day.
8.4肿瘤重量8.4 Tumor weight
不同组动物肿瘤重量如表4所示。The tumor weights of animals in different groups are shown in Table 4.
表4:肿瘤重量抑制评价
Table 4: Tumor weight inhibition evaluation
Table 4: Tumor weight inhibition evaluation
备注:Remark:
a.平均值±标准差a.Mean ± standard deviation
b.P值运用T-test方法通过对比对照组和各给药组得出,P<0.01统计学分析代表各组与对照组存在显著差异。b. The P value is obtained by comparing the control group and each administration group using the T-test method. P<0.01 statistical analysis represents a significant difference between each group and the control group.
c.P值运用T-test方法通过对比(第一API+第二API)联合用药组和两个单药组得出,P<0.01统计学分析代表各单药组与联合用药组存在显著差异。c. The P value is obtained by comparing the (first API + second API) combination group and the two single-drug groups using the T-test method. P<0.01 statistical analysis represents a significant difference between each single-drug group and the combination group.
QD为每天一次。QD is once a day.
在本实施例中,评价了受试药物的第一API和第二API的单药以及联
合用药在人非小细胞肺癌细胞NCI-H358皮下异种移植型中的药效。给药后,各组在不同时间点动物体重变化情况如图1和图2所示。In this example, the first API and the second API of the test drug were evaluated individually and in combination. Efficacy of the combination in subcutaneous xenografts of human non-small cell lung cancer cells NCI-H358. After administration, the body weight changes of the animals in each group at different time points are shown in Figures 1 and 2.
给药后,各组在不同时间点肿瘤体积和重量变化如表2、表3、表4以及图3、图4所示。给药后第二十七天空白组肿瘤体积达到1255.3立方毫米。在单药治疗组中,第一API和第二API的肿瘤生长抑制率TGI(%)分别为84.95%和60.05%。相比之下,第一API化合物和第二API化合物的联合用药组的肿瘤生长抑制率TGI(%)达到118.85%。TGI数值表明,第一API化合物和第二API化合物的联合用药组的药效显著优于各单药剂量组(p<0.01),实现了肿瘤总体缓解作用。After administration, the changes in tumor volume and weight in each group at different time points are shown in Table 2, Table 3, Table 4 and Figure 3 and Figure 4. On the 27th day after administration, the tumor volume in the white group reached 1255.3 cubic millimeters. In the monotherapy group, the tumor growth inhibition rates TGI (%) of the first API and the second API were 84.95% and 60.05%, respectively. In comparison, the tumor growth inhibition rate TGI (%) of the combined treatment group of the first API compound and the second API compound reached 118.85%. The TGI value showed that the efficacy of the combination of the first API compound and the second API compound was significantly better than that of each single dose group (p<0.01), achieving overall tumor remission.
应当理解,上述说明可以阐述本发明的一个或多个、但不是全部的示例性实施方案,本发明的范围不应受到任何上述示例性实施方案的限制。It should be understood that the above description may illustrate one or more, but not all, exemplary embodiments of the invention, and that the scope of the invention should not be limited by any of the above exemplary embodiments.
如果本发明的各方面被描述为“包括”或“包含”特征,则还可以想到“由…组成”或“基本上由…组成”的实施方案。If aspects of the invention are described as "comprising" or "comprising" features, embodiments "consisting of" or "consisting essentially of" are also contemplated.
本文描述的所有各种方面、实施方案、选项和数值范围可以以任何和所有变型进行组合。All of the various aspects, embodiments, options and numerical ranges described herein can be combined in any and all variations.
前面对特定实施方案的描述将如此充分地揭示本发明的一般性质,从而使得在不脱离本发明的一般概念的情况下,其他人可以通过应用本领域技术知识容易地修改和/或适应诸如这些特定实施方案的各种应用,而无需过度实验。因此,基于本文提出的教导和指导,这样的适应和修改也包含在所公开的实施方案的等同形式的含义和范围内。应当理解,本文中的措词或术语是出于描述而非限制的目的,因此本说明书的术语或措辞将由技术人员根据教导和指导来解释。
The foregoing description of specific embodiments will disclose the general nature of the invention so fully that others, by applying knowledge in the art, may readily modify and/or adapt the invention without departing from the general concept thereof, such as Various applications of these specific embodiments without undue experimentation. Therefore, such adaptations and modifications are intended to be included within the meaning and scope of equivalents of the disclosed embodiments based on the teachings and guidance presented herein. It is to be understood that the words or phrases used herein are for the purpose of description and not of limitation and are therefore to be interpreted by the skilled person in accordance with the teaching and guidance of the skilled person.
Claims (10)
- 一种包含第一药物活性成分和第二药物活性成分的药物组合产品,其中所述第一药物活性成分是式(I)的化合物或其药学上可接受的盐,
A pharmaceutical combination product comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient, wherein the first pharmaceutically active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof,
和其中所述第二药物活性成分是式(II)的化合物或其药学上可接受的盐,
and wherein said second pharmaceutically active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof,
- 根据权利要求1所述的药物组合产品,其中所述第一药物活性成分是式(I)的化合物,和其中所述第二药物活性成分是式(II)化合物的药学上可接受的盐。The pharmaceutical combination of claim 1, wherein the first pharmaceutically active ingredient is a compound of formula (I), and wherein the second pharmaceutically active ingredient is a pharmaceutically acceptable salt of a compound of formula (II).
- 根据前述权利要求中任一项所述的药物组合产品,其中所述第一药物活性成分与所述第二药物活性成分的重量比为约50∶1至约1∶50,优选约25∶1至约1∶25,和更优选约15∶1至约1∶15。The pharmaceutical combination product according to any one of the preceding claims, wherein the weight ratio of the first pharmaceutical active ingredient to the second pharmaceutical active ingredient is about 50:1 to about 1:50, preferably about 25:1 to about 1:25, and more preferably from about 15:1 to about 1:15.
- 根据前述权利要求中任一项所述的药物组合产品,其中所述第一药物活性成分与所述第二药物活性成分单独给药或同时给药。A pharmaceutical combination according to any one of the preceding claims, wherein the first pharmaceutically active ingredient and the second pharmaceutically active ingredient are administered separately or simultaneously.
- 根据前述权利要求中任一项所述的药物组合产品,其中所述药物组合产品呈药物组合物的形式,其中所述药物组合物还包含一种或多种可药用的赋形剂。 The pharmaceutical combination according to any one of the preceding claims, wherein the pharmaceutical combination is in the form of a pharmaceutical composition, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
- 一种根据前述权利要求中任一项所述的药物组合产品在制备用于治疗异常细胞生长(例如癌症)的药物中的用途。Use of a pharmaceutical combination according to any one of the preceding claims for the manufacture of a medicament for the treatment of abnormal cell growth, such as cancer.
- 根据前述权利要求所述的用途,其中所述异常细胞生长包括实体瘤、软组织肿瘤、转移或非实体癌。Use according to the preceding claims, wherein the abnormal cell growth comprises solid tumors, soft tissue tumors, metastases or non-solid cancers.
- 一种治疗异常细胞生长相关疾病的方法,其包括向有需要的受试者施用治疗有效量的根据权利要求1至5中任一项所述的药物组合产品。A method of treating diseases related to abnormal cell growth, comprising administering a therapeutically effective amount of the pharmaceutical combination product according to any one of claims 1 to 5 to a subject in need.
- 根据权利要求8所述的方法,其中所述第一药物活性成分通过口服施用;优选地,其中所述第一药物活性成分每天至少施用一次,例如,所述第一药物活性成分每天施用一次,或,所述第一药物活性成分每天施用两次或多次;优选地,其中所述第一药物活性成分以约1mg至约5000mg的单剂量施用;The method of claim 8, wherein the first pharmaceutically active ingredient is administered orally; preferably, wherein the first pharmaceutically active ingredient is administered at least once a day, for example, the first pharmaceutically active ingredient is administered once a day, Or, the first pharmaceutically active ingredient is administered two or more times per day; preferably, wherein the first pharmaceutically active ingredient is administered in a single dose of about 1 mg to about 5000 mg;和/或and / or其中所述第二药物活性成分通过口服施用;优选地,其中所述第二药物活性成分每天至少施用一次,例如,所述第二药物活性成分每天施用一次,或,所述第二药物活性成分每天施用两次或多次;优选地,其中所述第二药物活性成分以约1mg至约5000mg的单剂量施用。wherein the second pharmaceutically active ingredient is administered orally; preferably, wherein the second pharmaceutically active ingredient is administered at least once a day, for example, the second pharmaceutically active ingredient is administered once a day, or, the second pharmaceutically active ingredient Administration is two or more times per day; preferably, wherein the second pharmaceutically active ingredient is administered in a single dose of about 1 mg to about 5000 mg.
- 根据权利要求8所述的方法,其中所述异常细胞生长相关疾病包括实体瘤、软组织肿瘤、转移或非实体癌,其中所述施用包括将第一药物活性成分与第二药物活性成分单独给药或同时给药。 The method of claim 8, wherein the abnormal cell growth-related disease includes solid tumors, soft tissue tumors, metastases or non-solid cancers, wherein the administering comprises administering the first pharmaceutically active ingredient separately from the second pharmaceutically active ingredient. or administered simultaneously.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210872332.3A CN117462553A (en) | 2022-07-20 | 2022-07-20 | Pharmaceutical combination and combination therapy |
CN202210872332.3 | 2022-07-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024017316A1 true WO2024017316A1 (en) | 2024-01-25 |
Family
ID=89617179
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2023/108288 WO2024017316A1 (en) | 2022-07-20 | 2023-07-20 | Pharmaceutical combination product and combination therapy |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN117462553A (en) |
WO (1) | WO2024017316A1 (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102292322A (en) * | 2008-11-24 | 2011-12-21 | 贝林格尔.英格海姆国际有限公司 | Substituted pyrimidines for the treatment of diseases such as cancer |
AR101982A1 (en) * | 2014-09-18 | 2017-01-25 | Araxes Pharma Llc | COMBINED THERAPIES FOR THE TREATMENT OF CANCER AND COMPOSITIONS |
CN112585129A (en) * | 2019-05-21 | 2021-03-30 | 益方生物科技(上海)股份有限公司 | Heterocyclic compounds, their preparation and use |
WO2021120045A1 (en) * | 2019-12-18 | 2021-06-24 | InventisBio Co., Ltd. | Heterocyclic compounds, preparation methods and uses thereof |
-
2022
- 2022-07-20 CN CN202210872332.3A patent/CN117462553A/en active Pending
-
2023
- 2023-07-20 WO PCT/CN2023/108288 patent/WO2024017316A1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102292322A (en) * | 2008-11-24 | 2011-12-21 | 贝林格尔.英格海姆国际有限公司 | Substituted pyrimidines for the treatment of diseases such as cancer |
AR101982A1 (en) * | 2014-09-18 | 2017-01-25 | Araxes Pharma Llc | COMBINED THERAPIES FOR THE TREATMENT OF CANCER AND COMPOSITIONS |
CN112585129A (en) * | 2019-05-21 | 2021-03-30 | 益方生物科技(上海)股份有限公司 | Heterocyclic compounds, their preparation and use |
WO2021120045A1 (en) * | 2019-12-18 | 2021-06-24 | InventisBio Co., Ltd. | Heterocyclic compounds, preparation methods and uses thereof |
WO2021121330A1 (en) * | 2019-12-18 | 2021-06-24 | InventisBio Co., Ltd. | Heterocyclic compounds, preparation methods and uses thereof |
Non-Patent Citations (1)
Title |
---|
GANDARA D, MARRONE K; GOVINDAN R; SKOULIDIS F; DURM G; CLARKE J; FRANK R; KRAUSS J; SNYDER W; DAI T; MATHER O; CIFUENTES P; HINDOY: "Abstract P05-02: A phase 1b study evaluating the combination of sotorasib, a KRASG12C inhibitor, and afatinib, a pan-ErbB tyrosine kinase inhibitor, in advanced KRAS p.G12C mutated non-small cell lung cancer (NSCLC) | Molecular Cancer Therapeutics | American Association for Cancer Research", MOL CANCER THER (2021) 20 (12_SUPPLEMENT), 31 December 2021 (2021-12-31), XP093004836, Retrieved from the Internet <URL:https://aacrjournals.org/mct/article/20/12_Supplement/P05-02/675859/Abstract-P05-02-A-phase-1b-study-evaluating-the> [retrieved on 20221205], DOI: 10.1158/1535-7163.TARG-21-P05-02 * |
Also Published As
Publication number | Publication date |
---|---|
CN117462553A (en) | 2024-01-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6911047B2 (en) | Combination therapy of Notch and CDK4 / 6 inhibitors for the treatment of cancer | |
US20230398119A1 (en) | Combination therapy involving diaryl macrocyclic compounds | |
CN112641787A (en) | Combination therapy comprising a B-Raf inhibitor and a second inhibitor | |
AU2015360095A1 (en) | Quinoline derivative against non-small cell lung cancer | |
CN105338980A (en) | Pharmaceutical combinations | |
JP2019511529A (en) | Combination therapy with a Notch inhibitor and a PI3K / mTOR inhibitor for use in the treatment of cancer | |
EP4119557A1 (en) | Pharmaceutical combination comprising pyridino[1,2-a]pyrimidinone compound | |
EP4358965A1 (en) | Erk1/2 and shp2 inhibitors combination therapy | |
EP4358964A1 (en) | Erk1/2 and kras g12c inhibitors combination therapy | |
TW202207933A (en) | Pharmaceutical combination comprising tno155 and nazartinib | |
WO2024017316A1 (en) | Pharmaceutical combination product and combination therapy | |
TW202110454A (en) | Use of cdk4/6 inhibitor combined with vegfr inhibitor in preparing medicine of tumor treatment | |
CN113329749A (en) | Combination therapy for the treatment of uveal melanoma | |
CN111617081B (en) | Pharmaceutical composition combining substituted butenamide and mTOR inhibitor and application of pharmaceutical composition | |
CN117177752A (en) | Compounds and compositions for the treatment of MPNST | |
CN111195250A (en) | Application of combination of cydapamide and DICE and combined medicine | |
CN106999485B (en) | Anti-squamous cell lung carcinoma quinoline derivatives | |
WO2023011415A1 (en) | Pharmaceutical composition of egfr inhibitor and use thereof | |
US20180228795A1 (en) | Combination therapy for cancer | |
WO2022199656A1 (en) | Pharmaceutical combination, kit containing same, and use thereof | |
WO2023246869A1 (en) | Pharmaceutical combination for treating tumors and use thereof | |
CA3170021A1 (en) | Use of pyrido[1,2-a]pyrimidinone compound in treating lymphoma | |
CA3198190A1 (en) | Use of sodium trans-[tetrachloridobis(1h-indazole)ruthenate(iii)] for treating cancers | |
WO2023111810A1 (en) | Combination therapies and uses for treating cancer | |
TW202333675A (en) | Use of combination therapy for treating cancer |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23842378 Country of ref document: EP Kind code of ref document: A1 |