WO2022156803A1 - 一种吡啶并[1,2-a]嘧啶酮类似物的应用 - Google Patents
一种吡啶并[1,2-a]嘧啶酮类似物的应用 Download PDFInfo
- Publication number
- WO2022156803A1 WO2022156803A1 PCT/CN2022/073567 CN2022073567W WO2022156803A1 WO 2022156803 A1 WO2022156803 A1 WO 2022156803A1 CN 2022073567 W CN2022073567 W CN 2022073567W WO 2022156803 A1 WO2022156803 A1 WO 2022156803A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cancer
- compound
- time
- pharmaceutically acceptable
- acceptable salt
- Prior art date
Links
- FNKRSSCRFSZXBE-UHFFFAOYSA-N pyrido[1,2-a]pyrimidin-2-one Chemical class C1=CC=CC2=NC(=O)C=CN21 FNKRSSCRFSZXBE-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 101
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 73
- 239000003814 drug Substances 0.000 claims abstract description 48
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 210000001035 gastrointestinal tract Anatomy 0.000 claims abstract description 36
- 201000010536 head and neck cancer Diseases 0.000 claims abstract description 26
- 208000014829 head and neck neoplasm Diseases 0.000 claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 11
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 10
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims abstract description 7
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 7
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims abstract description 7
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims abstract description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 6
- 201000004101 esophageal cancer Diseases 0.000 claims abstract description 6
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 6
- 201000011510 cancer Diseases 0.000 claims description 40
- 229940079593 drug Drugs 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 14
- 206010064571 Gene mutation Diseases 0.000 claims description 8
- 101150063858 Pik3ca gene Proteins 0.000 claims description 8
- 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 claims description 7
- 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 claims description 7
- 208000004333 pleomorphic adenoma Diseases 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims description 5
- 230000003211 malignant effect Effects 0.000 claims description 5
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims description 5
- 208000005450 Maxillary Sinus Neoplasms Diseases 0.000 claims description 3
- 208000002517 adenoid cystic carcinoma Diseases 0.000 claims description 3
- 201000004488 maxillary sinus cancer Diseases 0.000 claims description 3
- 208000019303 maxillary sinus carcinoma Diseases 0.000 claims description 3
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 claims description 3
- 239000006186 oral dosage form Substances 0.000 claims description 2
- 208000003200 Adenoma Diseases 0.000 claims 1
- 206010001233 Adenoma benign Diseases 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 206010030155 Oesophageal carcinoma Diseases 0.000 abstract description 5
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 abstract description 2
- 208000014018 liver neoplasm Diseases 0.000 abstract description 2
- 239000008280 blood Substances 0.000 description 29
- 210000004369 blood Anatomy 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 230000000694 effects Effects 0.000 description 13
- 208000035475 disorder Diseases 0.000 description 11
- 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 10
- 239000003792 electrolyte Substances 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- 230000003907 kidney function Effects 0.000 description 10
- 150000002632 lipids Chemical class 0.000 description 10
- 230000003908 liver function Effects 0.000 description 10
- 210000002700 urine Anatomy 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 230000015271 coagulation Effects 0.000 description 8
- 238000005345 coagulation Methods 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 230000003902 lesion Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229960005167 everolimus Drugs 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- STUWGJZDJHPWGZ-LBPRGKRZSA-N (2S)-N1-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4-pyridinyl]-2-thiazolyl]pyrrolidine-1,2-dicarboxamide Chemical compound S1C(C=2C=C(N=CC=2)C(C)(C)C(F)(F)F)=C(C)N=C1NC(=O)N1CCC[C@H]1C(N)=O STUWGJZDJHPWGZ-LBPRGKRZSA-N 0.000 description 5
- 208000035473 Communicable disease Diseases 0.000 description 5
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 5
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- DWZAEMINVBZMHQ-UHFFFAOYSA-N 1-[4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl]-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea Chemical compound C1CC(N(C)C)CCN1C(=O)C(C=C1)=CC=C1NC(=O)NC1=CC=C(C=2N=C(N=C(N=2)N2CCOCC2)N2CCOCC2)C=C1 DWZAEMINVBZMHQ-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 108091007960 PI3Ks Proteins 0.000 description 4
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 4
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 4
- 229950010482 alpelisib Drugs 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000002271 resection Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 210000003718 sphenoid sinus Anatomy 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 208000010201 Exanthema Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 2
- 230000003527 anti-angiogenesis Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 208000024558 digestive system cancer Diseases 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 201000005884 exanthem Diseases 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 201000010231 gastrointestinal system cancer Diseases 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 2
- 208000021010 pancreatic neuroendocrine tumor Diseases 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 230000037081 physical activity Effects 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 210000004224 pleura Anatomy 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 206010037844 rash Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 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
- 208000009999 tuberous sclerosis Diseases 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 230000001875 tumorinhibitory effect Effects 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000269627 Amphiuma means Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 206010065869 Astrocytoma, low grade Diseases 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 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
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-M L-tartrate(1-) Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000026911 Tuberous sclerosis complex Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229940042992 afinitor Drugs 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 238000004159 blood analysis Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 210000001180 ethmoid sinus Anatomy 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000011354 first-line chemotherapy Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 201000007785 kidney angiomyolipoma Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 210000001370 mediastinum Anatomy 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000001989 nasopharynx Anatomy 0.000 description 1
- 238000009099 neoadjuvant therapy Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 238000009523 phase IV clinical trial Methods 0.000 description 1
- 230000036314 physical performance Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 201000004059 subependymal giant cell astrocytoma Diseases 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Genetics & Genomics (AREA)
- Analytical Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Hospice & Palliative Care (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
一种吡啶并[1,2-a]嘧啶酮类似物的应用。具体公开了一种化合物Ⅰ或其药学上可接受的盐在制备药物中的应用,所述药物用于治疗和/或预防消化道系统癌症。所述化合物Ⅰ或其药学上可接受的盐对头颈癌、肝细胞癌、结直肠癌、食道癌、胃癌和鼻咽癌中的一种或多种均具有良好的抗肿瘤活性。
Description
本申请要求申请日为2021/1/25的中国专利申请2021100950165的优先权。本申请引用上述中国专利申请的全文。
本发明涉及生物医药技术领域,具体地,本发明涉及吡啶并[1,2-a]嘧啶酮类似物的应用。
目前,恶性肿瘤是严重威胁人类生命健康的一类疾病,其发病率和死亡率呈逐年上升的趋势,人类因癌症引起的死亡率仅次于心脑血管疾病位列第二位。癌变的本质是调控细胞生理功能的分子信号在转导过程中出现异常,导致对细胞的正常生理功能失调而无限增生。细胞信号转导与肿瘤的发生、发展、复发和转移等密切相关。传统治疗肿瘤的细胞毒类药物普遍存在着选择性低、毒副作用强及耐药性差等缺点,这促进了抗肿瘤药物向小分子靶向药物研究方向转移。
据2015中国癌症统计数据,2015年中国大约有430万的癌症新发病例,另外有280万癌症患者死亡。近年来随着抗肿瘤药物研发的推进,晚期肿瘤患者的治疗效果已得到很大的改善,但是仍有众多患者对现有的治疗手段没有应答,或者疗效欠佳,或者治疗后出现耐药,严重影响他们的生存质量,威胁其生命。因此目前仍需开发新的抗肿瘤药物,使更多患者受益。
PI3K-AKT-mTOR是细胞周期调控的一个重要通路,对细胞生长、分裂、生存和繁殖等至关重要,其过渡活化参与多种肿瘤的发生、发展、存活和迁移。PI3K(磷脂酰肌醇3-激酶,phosphatidylinositol 3-kinase)、AKT和mTOR(mammalian target of rapamycin)是此通路的关键分子,因此成为抗肿瘤治 疗的靶标,已有PI3K或mTOR特异性的抑制剂上市,而此两个分子的双重抑制剂理论上可以有更好的抗肿瘤疗效。
PF-05212384(PKI-587)是辉瑞公司开发的PI3K和mTOR双靶点抑制剂,目前处于二期临床实验阶段。依维莫司(依维莫司)是诺华公司开发的口服mTOR单靶点抑制剂,商品名Afinitor,于2009年3月由FDA批准上市。国际上依维莫司被批准用于多种适应症:晚期肾细胞癌(RCC)、结节性硬化症相关室管膜下巨细胞星型细胞瘤(TSC-SEGA)及肾血管平滑肌脂肪瘤(TSC-AML)、晚期胰腺神经内分泌肿瘤(pNET)、绝经后雌激素受体阳性/HER-2阴性的晚期乳腺癌(BC)等肿瘤。
发明内容
本发明提供了吡啶并[1,2-a]嘧啶酮类似物的新应用,该类化合物或其药学上可接受的盐对消化道系统癌症具有良好的抗肿瘤活性,例如对头颈癌、肝细胞癌、结直肠癌、食道癌、胃癌和鼻咽癌中的一种或多种具有良好的抗肿瘤活性。
本发明提供了化合物Ⅰ或其药学上可接受的盐在制备药物中的应用,所述化合物Ⅰ的结构如下所示:
所述药物用于治疗和/或预防消化道系统癌症。
其中,所述消化道系统癌症可为野生型或PIK3CA突变的消化道系统癌症。
所述消化道系统癌症可为头颈癌。较佳地,所述头颈癌可为PIK3CA野 生型头颈癌或PIK3CA突变的头颈癌。
较佳地,所述头颈癌可为多形性腺瘤,例如恶性多形性腺瘤,再例如右颌下恶性多形性腺瘤。
较佳地,所述头颈癌可为上颌窦癌。
较佳地,所述头颈癌可为腺样囊性癌。
所述消化道系统癌症可为肝细胞癌。
所述消化道系统癌症可为结直肠癌。
所述消化道系统癌症可为食道癌。
所述消化道系统癌症可为胃癌。
所述消化道系统癌症可为鼻咽癌。
本发明中,所述药物以口服剂型呈现。
本发明中,所述药物以片剂呈现。
本发明还提供了用于治疗和/或预防消化道系统癌症的化合物Ⅰ或其药学上可接受的盐,所述化合物Ⅰ的结构如下所示:
其中,所述消化道系统癌症如前任一方案所述。
本发明提供了治疗和/或预防消化道系统癌症的方法,其通过向患者施用治疗有效量的所述化合物Ⅰ或其药学上可接受的盐。所述消化道系统癌症如前任一方案所述。
所述化合物Ⅰ或其药学上可接受的盐在制备药物中的应用或所述治疗和/或预防消化道系统癌症的方法中,所述化合物Ⅰ或其药学上可接受的盐的剂量可以根据受试者/患者的体重来施用,较佳地,所述化合物Ⅰ或其药学上可 接受的盐的施用剂量为0.1-2.0mg/次,例如:0.1mg/次、0.2mg/次、0.3mg/次、0.4mg/次、0.5mg/次、0.6mg/次、0.7mg/次、0.8mg/次、0.9mg/次、1.0mg/次、1.1mg/次、1.2mg/次、1.3mg/次、1.4mg/次、1.5mg/次、1.6mg/次、1.7mg/次、1.8mg/次、1.9mg/次或2.0mg/次。
所述应用或所述治疗和/或预防消化道系统癌症的方法中,所述化合物Ⅰ或其药学上可接受的盐的施用频率可为1次/日或2次/日。
所述应用或所述治疗和/或预防消化道系统癌症的方法中,所述化合物Ⅰ或其药学上可接受的盐可经口服施用。
较佳地,所述应用或所述治疗和/或预防癌症的方法中,所述化合物Ⅰ或其药学上可接受的盐经口服施用,施用剂量为0.1-2.0mg/次,例如0.1mg/次、0.4mg/次、0.5mg/次、0.6mg/次、0.7mg/次、0.9mg/次或1.1mg/次,施用频率为1次/日。
所述应用或所述治疗和/或预防消化道系统癌症的方法中,可包括检测患者是否携带PIK3CA基因突变的步骤。
本发明还提供了一种组合药盒,其包括药盒A和药盒B;
其中所述药盒A包括检测PIK3CA基因突变的试剂;所述药盒B包括化合物Ⅰ或其药学上可接受的盐。
较佳地,所述药盒A与药盒B的施用时间不分先后或者所述药盒中先施用所述药盒A。
较佳地,所述药盒A中,所述检测PIK3CA基因突变的试剂用于检测消化道系统癌症(例如头颈癌)患者是否携带PIK3CA基因突变。
较佳地,所述药盒B中,所述化合物Ⅰ或其药学上可接受的盐的含量为治疗有效量。
较佳地,所述药盒B还包括药学上可接受的辅料。
较佳地,所述药盒B中,所述化合物Ⅰ或其药学上可接受的盐的剂量和施用频率如前任一方案所述。
较佳地,所述组合药盒用于治疗和/或预防消化道系统癌症,所述消化道系统癌症如前任一方案所述。
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于:锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸,所述无机酸包括但不限于:盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸,所述有机酸包括但不限于:乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时,可以 被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“治疗”指治疗性疗法。涉及具体病症时,治疗指:(1)缓解疾病或者病症的一种或多种生物学表现,(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现,(3)改善与病症相关的一种或多种症状、影响或副作用,或者与病症或其治疗相关的一种或多种症状、影响或副作用,或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“治疗有效量”是指在给予患者时足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化,但可由本领域技术人员根据需要进行调整。
术语“药学上可接受的辅料”是指生产药品和调配处方时使用的赋形剂和附加剂,是除活性成分以外,包含在药物制剂中的所有物质。可参见中华人民共和国药典(2020年版)四部或Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009 Sixth Edition)。
术语“患者”是指根据本发明的实施例,即将或已经接受了该化合物给药的任何动物,哺乳动物为优,人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等,以人类为最优。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:化合物Ⅰ对头颈癌、肝细胞癌、结直肠癌、食道癌、胃癌和鼻咽癌中的一种或多种均具有良好的抗肿瘤活性。
图1为化合物Ⅰ对人源结直肠癌CO-04-0032裸鼠皮下异种移植肿瘤模型的体内药效结果。
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1用CTG方法测试化合物Ⅰ在头颈癌和/或肝细胞癌细胞系中的IC
50
1、实验材料
(1)细胞系
表1头颈癌和/或肝细胞癌细胞系
表2食道癌细胞系
备注:1).细胞培养条件为:37℃,5%CO
2和95%湿度。
2).IC
50值:达到50%抑制效果时抑制剂的浓度。
3).CAL-27和RPMI 2650:头颈癌癌细胞模型;HepG2:肝细胞癌细胞。CAL-27、RPMI 2650和HepG2细胞购买于ATCC,其中,
No分别为CRL-2095
TM、CCL-30
TM、HB-8065
TM。
4).KYSE-150和TE-1均为食道癌细胞模型,KYSE-150细胞系购买于DSMZ(德国微生物和细胞培养物保藏中心),DSMZ No为ACC375;TE-1细胞系购买于中国科学院典型培养物保藏委员会细胞库,目录号为:TCHu89。
5).RPMI 1640/F12培养基为RPMI 1640培养基与F12培养基1:1混合。
6).表1、表2中10%FBS中的百分数为体积百分数。
(2)试剂
1).FBS(胎牛血清)(购于ExCell,产品号:FND500);
2).MEM培养基(购于Hyclone,产品号:SH30024.01);
3).DMEM培养基(购于Gibco,产品号:C11995500BT);
4).MEM NEAA(购于Gibco,产品号:11140-050);
5).RPMI1640培养基(购于Gibco,产品号:11875-119);
6).F12培养基(购于Gibco,产品号:11765-054);
(3)供试品和阳性对照品
供试品:化合物Ⅰ;
阳性对照品:Cisplatin,分子量:300.05;溶剂:PBS(磷酸盐缓冲液);储存条件:2-8℃;供应商:齐鲁制药。
阳性对照品:Alpelisib,分子量:441.47;溶剂:DMSO;供应商:上海陶素生化科技有限公司,CAS号:1217486-61-7。
2.CTG方法测定化合物细胞增殖IC
50
步骤1:收集处于指数生长期的细胞并用Vi-Cell XR细胞计数仪进行活细胞计数。用培养基将细胞悬液调整到适当浓度。每孔加90μL细胞悬液于96-孔细胞培养板,最终细胞浓度为1500~6000细胞/孔。
步骤2:化合物Ⅰ给药起始浓度为3μM,对照药物Alpelisib与Cisplatin给药起始浓度为10μM,三倍连续稀释,一共9个浓度梯度和一个DMSO的对照,每孔DMSO终浓度为0.1%,置于37℃,5%CO
2孵箱中培养72小时。
步骤3:药物处理72小时后,按照CTG操作说明,每孔加入50μL(1/2培养体积)预先融化并平衡到室温的CTG溶液,用微孔板震荡器混匀2分钟,于室温放置10分钟后用Envision2104读板仪测定荧光信号值。
3.数据分析
细胞存活率用公式:V
sample/V
vehicle control×100%计算。其中V
sample为药物处理组的读数,V
vehicle control为溶剂对照组的平均值。应用GraphPad Prism 5.0软件,使用非线性回归模型绘制S型剂量-存活率曲线并计算IC
50值。
4.实验结果
表3化合物Ⅰ和Cisplatin在检测的各细胞系上的IC
50数值
结论,从表3的实验结果可以看出,化合物Ⅰ对RPMI2650、CAL-27和HepG2肿瘤细胞达到50%抑制效果时抑制剂的浓度都低于1μM。
表4化合物Ⅰ和Alpelisib在检测的各细胞系上的IC
50数值
结论,从表4的实验结果可以看出,化合物Ⅰ对KYSE-150、TE-1的肿瘤细胞达到50%抑制效果时抑制剂的浓度都低于1μM,与对照阳性化合物Alpelisib(半数抑制浓度>2μM)相比有着显著的疗效。
实施例2研究受试药对人源结直肠癌CO-04-0032裸鼠皮下异种移植肿瘤模型的体内药效学研究
实验目的:研究受试药对人源结直肠癌CO-04-0032裸鼠皮下异种移植肿瘤模型具有体内药效。
实验设计:
(1)动物:BALB/c裸小鼠,雌性,6周龄,体重16-18克。由上海西普尔-必凯实验动物有限公司提供。
(2)对照品
PF05212384和依维莫司都购于上海陶素生化科技有限公司。
(3)肿瘤接种:将体积约30mm
3CO-04-0032肿瘤块皮下接种于每只小鼠的右后背,肿瘤平均体积达到182mm
3时开始分组给药。CO-04-0032是药明康德新药开发有限公司自主开发的人源结肠癌PDX模型。实验分组和给药方案见下表5。
表5
备注:溶媒为1%甲基纤维素,所述百分数为体积百分数。
(3)体内药效结果:见图1和表6所示
表6化合物Ⅰ对CO-04-0032异种移植瘤模型的抑瘤药效评价
(基于给药后28天数据得出)
注:
a.平均值±SEM。
b.肿瘤生长抑制由T/C和TGI(TGI(%)=[1-(T
28-T
0)/(V
28-V
0)]×100)计 算。
实验结果:化合物Ⅰ在人源结直肠癌CO-04-0032异种移植瘤模型中的体内药效。给药28天时,与溶媒2组相比,化合物Ⅰ在0.1mg/kg、0.2mg/kg、0.4mg/kg和0.6mg/kg的剂量下,T/C分别为:52%,39%,30%和19%,TGI分别为58%,64%,76%和90%,且在剂量较高的3个剂量组与对照组相比p值均小于0.05。由此结果可知在人源结直肠癌CO-04-0032异种移植瘤模型中,化合物Ⅰ在0.2mg/kg、0.4mg/kg和0.6mg/kg的剂量具有显著抗肿瘤作用,且呈剂量依赖性。参照药PF05212384在20mg/kg组(T/C=68%,TGI=44%,p=0.860)。依维莫司在5mg/kg组(T/C=42%,TGI=60%,p=0.027)。
实验结论:化合物Ⅰ在0.6mg/kg剂量的抑瘤作用显著强于20mg/kg剂量下的PF05212384(p=0.041);化合物Ⅰ在0.6mg/kg剂量的抑瘤作用显著强于5mg/kg剂量下的依维莫司(p=0.008)。
实施例3头颈癌临床实验1
病例资料:受试者1,男,40岁,于2020-04-30签署知情同意书,基线期进行生命体征、体格检查、ECOG体力评分、感染性疾病标志物、血常规、尿常规、凝血功能、肝功能、肾功能、电解质、空腹血糖、血脂、12导联心电图等检查,其中患有右颌下恶性多形性腺瘤,受试者肿瘤携带PIK3CA突变,病灶位置右肺纵隔旁,一线化疗失败,基线直径26mm。2020年5月12日开始服用含化合物Ⅰ的片剂,剂量为1.1mg,单次给药,每日一次,其中,1.1mg剂量含化合物Ⅰ为0.5mg规格的片剂两片和含化合物Ⅰ为0.1mg规格的片剂一片,确认受试者安全后,一周后于2020年5月18日起至2021年11月26日期间病人开始服用含化合物Ⅰ的片剂,剂量为1.1mg,每日一次,1.1mg剂量含化合物Ⅰ为0.5mg规格的片剂两片和含化合物Ⅰ为0.1mg规格的片剂一片,进行生命体征、体格检查、血常规检查、尿常规检查、肝功能、肾功能、 电解质、空腹血糖、血脂、12导联心电图等检查,临床意义判定正常;无任何严重副作用;ECOG体力评分,能够自由走动及从事轻体力活动,包括一般家务或办公室工作;受试者于2020年7月6日因皮疹停药,经口服和外用多种抗皮疹药物治疗,痊愈后,于2020年8月25日恢复用药,开始服用含化合物Ⅰ的片剂,剂量为0.7mg,每日一次,0.7mg剂量含化合物Ⅰ为0.5mg规格的片剂一片和含化合物Ⅰ为0.1mg规格的片剂两片,于2021年11月28日进行第20个月的肿瘤评估,C20D28肿瘤直径16.8mm,与基线相比,肿瘤体积缩小38%,判定为PR。
实施例4头颈癌临床实验2
病例资料:受试者2,女,51岁,于2019-11-26签署知情同意书,基线期进行生命体征、体格检查、ECOG体力评分、感染性疾病标志物、血常规、尿常规、凝血功能、肝功能、肾功能、电解质、空腹血糖、血脂、12导联心电图等检查,其肿瘤诊断为头颈癌(上颌窦癌),受试者携带PIK3CA突变,病灶位置左侧筛窦肿块(基线直径30mm),蝶窦肿块(基线直径43mm)及蝶窦多发结节,经术后放化疗、复发后免疫治疗无效。2019年12月03日开始服用含化合物Ⅰ的片剂,剂量为0.7mg,单次给药,一日一次,0.7mg剂量含化合物Ⅰ为0.5mg规格的片剂一片和含化合物Ⅰ为0.1mg规格的片剂两片,确认受试者安全后,一周后于2019年12月09日开始服用含化合物Ⅰ的片剂,剂量为0.7mg,单次给药,一日一次,0.7mg剂量含化合物Ⅰ为0.5mg规格的片剂一片和含化合物Ⅰ为0.1mg规格的片剂两片,进行生命体征、体格检查、血常规、尿常规、凝血功能、肝功能、肾功能、电解质、空腹血糖、血脂、12导联心电图等检查,临床意义判定正常;2019年12月10日开始每日连续服用含化合物Ⅰ为0.7mg的片剂,至2020年7月20日进行C8D28肿瘤评估,肿瘤缩小达到PR,蝶蝶窦肿块消失,受试者疼痛明显减轻并恢复视力。受试者继续每日服用0.7mg的化合物Ⅰ片剂直至2021年12月6日进行第26 个月的肿瘤评估仍为PR,无进展生存已超过26个月。
实施例5头颈癌临床实验3
病例资料:受试者3,男,60岁,受试者于2010年发现患有头颈癌(腺样囊性癌)IV期并实施左上颌骨切除术进行手术切除。2019年复发后实施化疗,抗血管生成抑制剂等疗法新辅助治疗,并于2020-06-09实施左上颌骨扩大切除术切除。术后实施多次放疗但仍疾病进展。受试者于2020-12-09签署知情同意书,基线期进行生命体征、体格检查、ECOG体力评分、感染性疾病标志物、血常规、尿常规、凝血功能、肝功能、肾功能、电解质、空腹血糖、血脂、12导联心电图等检查符合入组条件。既往基因检测结果显示,受试者肿瘤的PIK3CA为野生型(未突变)。2020-12-10日入组前筛查,靶病灶位置与大小为(1)右中肺近胸膜,直径为13.3mm,(2)左肺上叶结节,直径为12.8mm;总直径为26.1mm。受试者于2020年12月17日开始服用含化合物Ⅰ的片剂,剂量为1.1mg,单次给药,一日一次,1.1mg剂量含化合物Ⅰ为0.5mg规格的片剂两片和含化合物Ⅰ为0.1mg规格的片剂一片,确认受试者安全后,一周后于2020年12月24日起至2021年02月18日期间病人开始服用含化合物Ⅰ的片剂,剂量为1.1mg,每日一次,1.1mg剂量含化合物Ⅰ为0.5mg规格的片剂两片和含化合物Ⅰ为0.1mg规格的片剂一片,并于每周(服药后第一个月内)或每两周(服药后第一个月以后)进行生命体征、体格检查、血常规检查、尿常规检查、肝功能、肾功能、电解质、空腹血糖、血脂、12导联心电图等检查,无任何严重副作用;ECOG体力评分,能够自由走动及从事轻体力活动,包括一般家务或办公室工作;2021年02月18日影像学肿瘤评估,靶病灶位置与大小为(1)右中肺近胸膜,直径为8.5mm,(2)左肺上叶结节,直径为12mm;总直径为20.5mm,与基线比较,肿瘤体积缩小21.5%。
实施例6胃癌临床实验
病例资料:受试者4,男,53岁,于2019-11-05签署知情同意书,基线期进行生命体征、体格检查、ECOG体力评分、感染性疾病标志物、血常规、尿常规、凝血功能、肝功能、肾功能、电解质、空腹血糖、血脂、12导联心电图等检查,其肿瘤诊断为胃癌Ⅳ期,病灶位置肝右叶、肝后右叶,基线直径36.4mm、33.1mm。受试者4在用药前接受两次手术方案、5次包括化疗、抗血管生成抑制剂联合化疗以及免疫治疗方案均耐药;受试者4于2019年11月14日开始服用含化合物Ⅰ的片剂,剂量为0.7mg,单次给药,一日一次,0.7mg剂量中含化合物Ⅰ为0.5mg规格的片剂一片和含化合物Ⅰ为0.1mg规格的片剂两片,确认受试者安全后,一周后于2019年11月20日开始每日连续服用含化合物Ⅰ为0.7mg的片剂,单次给药,一日一次,0.7mg剂量中含化合物Ⅰ为0.5mg规格的片剂一片和含化合物Ⅰ为0.1mg规格的片剂两片。第一个周期后降低剂量至0.4mg,单次给药,一日一次,0.4mg剂量中含化合物Ⅰ为0.1mg规格的片剂四片,直至2020年4月9日。期间进行生命体征、体格检查、血常规、尿常规、凝血功能、肝功能、肾功能、电解质、空腹血糖、血脂、12导联心电图等检查,除一次3级以上高血糖之外无其它严重副作用;治疗后第二个月访视(C2D28)靶病灶肿瘤缩小(-9%),肿瘤评估为SD(与基线瘤体积相比>-30%但<20%),无进展生存期为5个月。
实施例7鼻咽癌Ⅳ期临床实验
病例资料:受试者5,女,50岁,于2019-08-19签署知情同意书,基线期进行生命体征、体格检查、ECOG体力评分、感染性疾病标志物、血常规、尿常规、凝血功能、肝功能、肾功能、电解质、空腹血糖、血脂、12导联心电图等检查,其肿瘤诊断为有鼻咽癌Ⅳ期,病灶位置鼻咽左后,基线直径23.1mm。受试者5在用药前接受两次手术方案、2次放疗、9次不同的化疗方案以及免疫治疗方案均耐药;2019年08月28日开始服用含化合物Ⅰ的片 剂,剂量为0.4mg,单次给药,一日一次,0.4mg剂量含化合物Ⅰ为0.1mg规格的片剂四片,确认受试者安全后,一周后于2019年09月03日开始每日连续服用含化合物Ⅰ的片剂,剂量为0.4mg,单次给药,一日一次,0.4mg剂量含化合物Ⅰ为0.1mg规格的片剂四片。期间进行生命体征、体格检查、血常规、尿常规、凝血功能、肝功能、肾功能、电解质、空腹血糖、血脂、12导联心电图等检查,无严重副作用;受试者4每两个月进行一次靶病灶肿瘤评估,结果均为SD(与基线瘤体积相比>-30%但<20%);无进展生存(PFS)为10个月。
Claims (16)
- 如权利要求1所述的化合物Ⅰ或其药学上可接受的盐在制备药物中的应用,其特征在于,所述消化道系统癌症为野生型或PIK3CA突变的消化道系统癌症。
- 如权利要求1所述的化合物Ⅰ或其药学上可接受的盐在制备药物中的应用,其特征在于,所述消化道系统癌症为头颈癌。
- 如权利要求3所述的化合物Ⅰ或其药学上可接受的盐在制备药物中的应用,其特征在于,所述头颈癌为PIK3CA野生型头颈癌或PIK3CA突变的头颈癌。
- 如权利要求3所述的化合物Ⅰ或其药学上可接受的盐在制备药物中的应用,其特征在于,所述头颈癌为多形性腺瘤,例如恶性多形性腺瘤,再例如右颌下恶性多形性腺瘤。
- 如权利要求3所述的化合物Ⅰ或其药学上可接受的盐在制备药物中的应用,其特征在于,所述头颈癌为上颌窦癌或腺样囊性癌。
- 如权利要求1所述的化合物Ⅰ或其药学上可接受的盐在制备药物中的应用,其特征在于,所述消化道系统癌症为肝细胞癌。
- 如权利要求1所述的化合物Ⅰ或其药学上可接受的盐在制备药物中的 应用,其特征在于,所述消化道系统癌症为结直肠癌。
- 如权利要求1所述的化合物Ⅰ或其药学上可接受的盐在制备药物中的应用,其特征在于,所述消化道系统癌症为食道癌。
- 如权利要求1所述的化合物Ⅰ或其药学上可接受的盐在制备药物中的应用,其特征在于,所述消化道系统癌症为胃癌。
- 如权利要求1所述的化合物Ⅰ或其药学上可接受的盐在制备药物中的应用,其特征在于,所述消化道系统癌症为鼻咽癌。
- 如权利要求1-11至少一项所述的化合物Ⅰ或其药学上可接受的盐在制备药物中的应用,其特征在于,其满足以下条件中的一种或多种:(1)所述药物以口服剂型呈现;(2)所述药物以片剂呈现;(3)所述化合物Ⅰ或其药学上可接受的盐的施用剂量为0.1-2.0mg/次,例如:0.1mg/次、0.2mg/次、0.3mg/次、0.4mg/次、0.5mg/次、0.6mg/次、0.7mg/次、0.8mg/次、0.9mg/次、1.0mg/次、1.1mg/次、1.2mg/次、1.3mg/次、1.4mg/次、1.5mg/次、1.6mg/次、1.7mg/次、1.8mg/次、1.9mg/次或2.0mg/次;(4)所述化合物Ⅰ或其药学上可接受的盐的施用频率为1次/日或2次/日。
- 一种组合药盒,其包括药盒A和药盒B;其中所述药盒A包括检测PIK3CA基因突变的试剂;所述药盒B包括化合物Ⅰ或其药学上可接受的盐;较佳地,所述组合药盒满足以下条件中的一种或多种:(1)所述药盒A与药盒B的施用时间不分先后或者所述药盒中先施用所述药盒A;(2)所述药盒A中,所述检测PIK3CA基因突变的试剂用于检测消化道系统癌症(例如头颈癌)患者是否携带PIK3CA基因突变;所述消化道系 统癌症如权利要求1-11至少一项所述;(3)所述药盒B中,所述化合物Ⅰ或其药学上可接受的盐的含量为治疗有效量;(4)所述药盒B还包括药学上可接受的辅料;(5)所述药盒B中,所述化合物Ⅰ或其药学上可接受的盐的剂量和施用频率如权利要求12所述;(6)所述组合药盒用于治疗和/或预防消化道系统癌症,所述消化道系统癌症如权利要求1-11至少一项所述。
- 如权利要求15所述的治疗和/或预防消化道系统癌症的方法,其特征在于,所述方法还包括检测患者是否携带PIK3CA基因突变的步骤。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP22742280.5A EP4282866A1 (en) | 2021-01-25 | 2022-01-24 | Use of pyrido[1,2-a]pyrimidone analogue |
US18/261,832 US20240091229A1 (en) | 2021-01-25 | 2022-01-24 | Use of pyrido[1,2-a]pyrimidone analogue |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110095016.5 | 2021-01-25 | ||
CN202110095016 | 2021-01-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022156803A1 true WO2022156803A1 (zh) | 2022-07-28 |
Family
ID=82460318
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/073567 WO2022156803A1 (zh) | 2021-01-25 | 2022-01-24 | 一种吡啶并[1,2-a]嘧啶酮类似物的应用 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20240091229A1 (zh) |
EP (1) | EP4282866A1 (zh) |
CN (1) | CN114788829B (zh) |
TW (1) | TW202228703A (zh) |
WO (1) | WO2022156803A1 (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105461712A (zh) * | 2014-06-17 | 2016-04-06 | 南京明德新药研发股份有限公司 | 作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物 |
WO2017101829A1 (zh) * | 2015-12-16 | 2017-06-22 | 辰欣药业股份有限公司 | 吡啶并[1,2-a]嘧啶酮类似物的晶型及其制备方法和中间体 |
WO2021219101A1 (zh) * | 2020-04-30 | 2021-11-04 | 广州嘉越医药科技有限公司 | 一种含杂环的化合物的应用 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2658912C1 (ru) * | 2014-06-17 | 2018-06-26 | Шанхай Цзя Тань Фарматек Ко. Лтд. | АНАЛОГ ПИРИДИНО[1,2-А]ПИРИМИДОНА, ИСПОЛЬЗУЕМЫЙ В КАЧЕСТВЕ ИНГИБИТОРА mTOR/PI3K |
CN117679421A (zh) * | 2021-01-18 | 2024-03-12 | 广州嘉越医药科技有限公司 | 一种吡啶并[1,2-a]嘧啶酮化合物的应用 |
-
2022
- 2022-01-11 CN CN202210028243.0A patent/CN114788829B/zh active Active
- 2022-01-24 WO PCT/CN2022/073567 patent/WO2022156803A1/zh active Application Filing
- 2022-01-24 TW TW111102822A patent/TW202228703A/zh unknown
- 2022-01-24 EP EP22742280.5A patent/EP4282866A1/en active Pending
- 2022-01-24 US US18/261,832 patent/US20240091229A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105461712A (zh) * | 2014-06-17 | 2016-04-06 | 南京明德新药研发股份有限公司 | 作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物 |
WO2017101829A1 (zh) * | 2015-12-16 | 2017-06-22 | 辰欣药业股份有限公司 | 吡啶并[1,2-a]嘧啶酮类似物的晶型及其制备方法和中间体 |
WO2021219101A1 (zh) * | 2020-04-30 | 2021-11-04 | 广州嘉越医药科技有限公司 | 一种含杂环的化合物的应用 |
Non-Patent Citations (4)
Title |
---|
"Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH |
"Volume Four or Handbook of Pharmaceutical Excipients", article "Pharmacopoeia of the People's Republic of China" |
BERGE ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104 |
CAS, no. 1217486- 61-7 |
Also Published As
Publication number | Publication date |
---|---|
CN114788829B (zh) | 2023-06-20 |
TW202228703A (zh) | 2022-08-01 |
EP4282866A1 (en) | 2023-11-29 |
US20240091229A1 (en) | 2024-03-21 |
CN114788829A (zh) | 2022-07-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6429292B2 (ja) | Her2増幅性癌の処置のための方法 | |
TWI798199B (zh) | 癌症治療 | |
KR101475167B1 (ko) | 복합 항암 요법 | |
CN111053768A (zh) | 用于治疗黑素瘤的药物组合 | |
CN106659716A (zh) | 阿吡莫德组合物及其使用方法 | |
EP2750675A1 (en) | Synergistic combinations of pi3k- and mek-inhibitors | |
CN110652514A (zh) | 第三代egfr抑制剂的制药用途 | |
WO2020211860A1 (zh) | 用于治疗尤因肉瘤的喹啉类化合物或其药学上可接受的盐 | |
JP2022508183A (ja) | 神経芽細胞腫の治療における使用のためのオーロラaキナーゼ阻害剤 | |
WO2022152296A1 (zh) | 一种吡啶并[1,2-a]嘧啶酮类似物的应用 | |
TW202045173A (zh) | 癌症治療 | |
US20220184055A1 (en) | Chiauranib for treatment of small cell lung cancer | |
CN110198716A (zh) | 癌症治疗 | |
WO2022156803A1 (zh) | 一种吡啶并[1,2-a]嘧啶酮类似物的应用 | |
TWI835050B (zh) | 一種吡啶并[1,2-a]嘧啶酮類似物的應用 | |
CN114728003A (zh) | 治疗b细胞恶性肿瘤的阿卡替尼和卡帕塞替尼的治疗组合 | |
WO2021089005A1 (zh) | 一种fgfr抑制剂的用途 | |
CN113893351A (zh) | 组合物及其在制备治疗癌症的药物中的应用 | |
KR20150003786A (ko) | Pi3k 저해제 및 mek 저해제를 이용한 암 치료 방법 | |
WO2023016321A1 (zh) | 恩沙替尼或其盐在治疗携带met 14外显子跳跃突变的疾病中的用途 | |
US20230165862A1 (en) | Cancer therapy using 3,5-disubstituted benzene alkynyl compound and mek inhibitor | |
US20240010622A1 (en) | Mitochondrial atp inhibitors targeting the gamma subunit prevent metastasis | |
WO2024088275A1 (zh) | 一种萘酰胺化合物治疗耐药性肿瘤的用途 | |
TW202345848A (zh) | 使用突變idh抑制劑之組合療法 | |
WO2024088273A1 (zh) | 一种萘酰胺化合物治疗kras突变相关疾病的用途 |
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: 22742280 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 18261832 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2022742280 Country of ref document: EP Effective date: 20230825 |