CN107334767B - A kind of application of pyridazinone compound in oncotherapy - Google Patents
A kind of application of pyridazinone compound in oncotherapy Download PDFInfo
- Publication number
- CN107334767B CN107334767B CN201710429186.6A CN201710429186A CN107334767B CN 107334767 B CN107334767 B CN 107334767B CN 201710429186 A CN201710429186 A CN 201710429186A CN 107334767 B CN107334767 B CN 107334767B
- Authority
- CN
- China
- Prior art keywords
- compound
- pyridazinone compound
- tumor
- pyridazinone
- imb5036
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- -1 pyridazinone compound Chemical class 0.000 title claims abstract description 27
- 201000007270 liver cancer Diseases 0.000 claims abstract description 8
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 9
- 239000002775 capsule Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 229940100688 oral solution Drugs 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 24
- 230000000694 effects Effects 0.000 abstract description 11
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 238000002474 experimental method Methods 0.000 abstract description 4
- 230000005909 tumor killing Effects 0.000 abstract description 3
- 230000005778 DNA damage Effects 0.000 abstract description 2
- 231100000277 DNA damage Toxicity 0.000 abstract description 2
- 230000006378 damage Effects 0.000 abstract description 2
- 230000035755 proliferation Effects 0.000 abstract description 2
- 230000005782 double-strand break Effects 0.000 abstract 1
- 238000000338 in vitro Methods 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 230000010534 mechanism of action Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 8
- 230000000259 anti-tumor effect Effects 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 4
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 230000001665 lethal effect Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 210000004940 nucleus Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 235000020985 whole grains Nutrition 0.000 description 3
- 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
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 230000000118 anti-neoplastic effect 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
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000000314 lubricant Substances 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
- 238000000034 method Methods 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- VPXGOSNPXCNGAI-UHFFFAOYSA-N (4-methylsulfanylphenyl)methyl 2-morpholin-4-yl-5-nitrobenzoate Chemical compound C1=CC(SC)=CC=C1COC(=O)C1=CC([N+]([O-])=O)=CC=C1N1CCOCC1 VPXGOSNPXCNGAI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- XNYLGZGSUSLBKD-UHFFFAOYSA-N 3-[3-(trifluoromethyl)phenyl]-1h-pyridazin-6-one Chemical compound FC(F)(F)C1=CC=CC(C2=NNC(=O)C=C2)=C1 XNYLGZGSUSLBKD-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
- 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
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 229940122434 Calcium sensitizer Drugs 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 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
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 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
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 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
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-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
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- 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
- 238000002835 absorbance Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 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
- 201000011510 cancer Diseases 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 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
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 230000017260 vegetative to reproductive phase transition of meristem Effects 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of application of pyridazinone compound in oncotherapy, pyridazinone compound of the present invention, its mechanism of action is by causing DNA damage to DNA of tumor cell double-strand break, experiment in vitro shows stronger inhibited proliferation to kinds of tumor cells, it is tested in vivo for treating mouse bearing liver cancer, moderate tumor killing effect can be obtained.Pyridazinone compound of the invention, structural formula are as follows:The compound is a kind of brand new compound by causing DNA of tumor cell double-strand damage, is the prospect of anti-tumor drug with good development.
Description
Technical field:
The invention belongs to pharmaceutical technology fields.More particularly it relates to which a kind of pyridazinone compound is controlled in tumour
Application in treatment.
Background technique:
Malignant tumour is to seriously threaten the common disease of human health and life.The poison of the anti-tumor drug of clinical application at present
Property be puzzlement chemotherapy of tumors the problem of, find new anti-tumor drug be anti-tumor drug research a big task.The present invention relates to
And compound be pyridazinone compound.Pyridazinone compound is that one kind has the active heterocyclic compound of good biological,
It is occupied an important position in the research fields such as pesticide medicine.Pyridazinone compound can be used as calcium sensitizer for treating heart function
Can obstacle and heart failure cardiotonic drug, in addition platelet aggregation-against, decompression and anti-inflammatory, Hemorrhagic shock, in terms of
There is certain curative effect.Certain Pyridazinones Derivatives also have good activity in antitumor action, such as:
Chinese patent 200880017969.2 discloses a kind of pyridazinone derivative, has anti-tumor activity.
Chinese patent 200910127196.X discloses a kind of 6- (3- (trifluoromethyl) phenyl) pyridazine -3 (2H) -one
Parent nucleus has the purposes of pyridazinone compound in the preparation of antitumor drugs shown in following structural formula I, especially anti-liver
Purposes in cancer drug.
Chinese patent 201410018618.0 discloses a series of Pyridazinones Derivatives and its antineoplastic action.
Chinese patent 201310306863.7 discloses pyridazinone compound as tyrosine kinase inhibitor, especially
Purposes in c-Met inhibitor.
Compound IMB5036 and IMB5043 are the compound of the known structure in existing compound library, can be from the market
It is commercially available, can also synthesize to obtain according to corresponding chemical synthesis process, two compounds of the invention are bought from ENAMINE
Ltd company.Its anti-tumor activity so far and there are no any report.Although two compounds belong to pyridazinone compound,
But in structure and the prior art has significant difference, and the present inventor is found surprisingly that during antitumor medicine screening
Both compounds have lethal effect to kinds of tumors.
Summary of the invention:
The present invention provides a kind of pyridazinone compound, structural formula is as follows:
Wherein, R1, R2 are simultaneously halogen, are preferably simultaneously Cl, or are simultaneously Br;R3 is O, and R4 is selected from such as flowering structure:
It is preferred that following two pyridazinone compound:
Compound I is named as IMB5036, and No. CAS is 1090393-42-2.
Compound ii is named as IMB5043, and No. CAS is 1089995-96-9.
Present inventors studied the pharmaceutical activity of both compounds, it is found that it is good IMB5036 and IMB5043 has
Anti-tumor activity, it is especially best to liver cancer treatment effect.Being further discovered that can be by causing DNA double chain fracture that DNA is caused to damage
Wound is to play antitumor action.
For this purpose, it includes IMB5036 and IMB5043 anti-swollen in preparation that the present invention, which provides a kind of above-mentioned pyridazinone compound,
Application in tumor medicine.
Tumour of the present invention is selected from: liver cancer, colorectal cancer, cancer of pancreas, the cancer of the esophagus, lung cancer, oophoroma, breast cancer,
The tumour that fibrosarcoma and other treatments are resisted or be resistant to.
The present invention further provides the pharmaceutical composition containing pyridazinone compound, the pyridazinone compound structure
As described above.
Illustrate beneficial effects of the present invention below by way of experimental data.
Test example 1: cytotoxicity of the compound to culture cell.
MTT (Methyl thiazoly tetrazolium assay salt) method detection compound IMB5036 and IMB5043 makees the cell toxicant of culture cell
With.Cell is used containing 10% fetal calf serum (Giboco BRL Inc.), 2mM glutamine, 100 μ g/ml streptomysins and 100U/mL
The RPMI-1640 culture medium (Giboco BRL Inc.) of penicillin contains 5%CO at 37 DEG C2Incubator in cultivate.
The tumor cell line used is usual cell strain, this room saves, also commercially such as ATCC cell bank
(Rockville, MD, USA), National Laboratory cellular resources shared platform etc. are bought.The cell dissociation of logarithmic growth phase counts,
96 orifice plates are laid on by 4000 cells/wells, after culture 24 hours, the drug of various concentration are added, each drug concentration sets 3 and puts down
Row hole.After continuing culture 48 hours, every hole is added with the 20 μ L of MTT (Amresco, Ohio, USA) of the PBS 5mg/mL dissolved,
It after 37 DEG C are continued culture 4 hours, inhales and abandons supernatant, 150 μ L dimethyl sulfoxides are added, shaking table shakes 15 minutes at room temperature, microplate reader
The absorbance value A of 570nm is measured on (Thermo Labsystems, Multiskan MK3).Experiment is all provided with no medicine control every time
Hole and each 3 hole of cell-free blank well.By formula: inhibiting rate %=(A control group-A administration group)/(A control group-A blank group) ×
100% calculates drug to the proliferation inhibition rate and calculation of half inhibitory concentration (IC of cell50).The results are shown in Table 1, two kinds of chemical combination
Object has preferable lethal effect to the tumour cell of separate sources, and IMB5036 makees the killing of human liver cancer cells Hep G2
With most strong, IC50It is 1.85 μM;IMB5043 is also most strong to the lethal effect of SMMC-7721, IC50It is 3.56 μM.And Human embryo
Liver cell L02 is then insensitive to two compounds.
Cytotoxic activity of the table 1.IMB5036 and IMB5043 to tumour cell and normal cell L02
Test example 2: indirect immunofluorescence detects influence of the IMB5036 and IMB5043 to DNA damage.
The SMMC-7721 cell inoculation of logarithmic growth phase adds after 24 hours respectively in six orifice plates for being covered with coverslip
Enter 1 μM of IMB5036 and 2 μM of IMB5046, while control wells are set, after drug-treated 24 hours, takes out coverslip and successively use
PBS is washed 3 times, fixes 15 minutes with 4% paraformaldehyde, the penetrating processing of 0.1%TritonX-100 15 minutes, 1%BSA room temperature
Closing 30 minutes;AF488 label γ-H2AX antibody (EMD Millipore) is added to be incubated for 1 hour at 37 DEG C of temperature, fluorescence
It observes and takes pictures under microscope (Olympus IX81).As the result is shown IMB5036 and with IMB5043 processing neoplastic cell nuclei with it is right
It is compared according to group, the pH2AX foci of formation significantly increases (Fig. 1).
The animal experiment therapeutic scheme of test example 3:IMB5036 and IMB5043.
With the interior curative effect of human liver cancer SMMC-7721 xenograft tumor models evaluation compound.Take SMMC-7721 thin
Born of the same parents press 1 × 107It is subcutaneous that/0.2mL/ is only inoculated in NIH nu/nu mouse armpit, takes tumor mass to cut into physiological saline after two weeks
2mm3Fritter, it is subcutaneous that tumor mass is transplanted to nude mice armpit with trochar.7th day by nude mice press tumor mass size packets, every group 7
Only, make the tumor mass size average value of every group of animal close.Compound is dissolved in dimethyl sulfoxide (Sigma)/polyoxyethylene caster
In oily (Cremophor EL) (Sigma)/physiological saline (1:2:17) mixed liquor, intraperitoneal administration, dosage be 12.5 or
25mg/kg, 5 times/week, 0.2mL/, successive administration two weeks.Every 2-3 days tumour major diameter a of measurement and therewith during experiment
Vertical minor axis b, and record the weight of animals.With formula V=1/2ab2Calculate knurl product and inhibiting rate (control group knurl product-examination
Test a group knurl product)/control group knurl product × 100%.When knurl product reaches 1000mm3When de- neck put to death animal.
The experimental results showed that IMB5036 can significantly inhibit the growth of tumour, the IMB5036 of 12.5 and 25mg/kg passes through
Intraperitoneal administration, the 28th day tumour inhibiting rate is respectively 30.6% and 66.2% (Fig. 2) after administration, and the animal of all processing groups does not have
Apparent weight loss or the exception (Fig. 3) of behavior, illustrate that mouse can preferably be resistant to the drug of this dose.IMB5043 is aobvious
Moderate tumor killing effect is shown, the IMB5043 of 12.5 and 25mg/kg is by intraperitoneal administration, the 28th day tumor suppression after administration
Rate is respectively 28.6% and 58.8% (Fig. 4), and the animal of all processing groups does not have apparent weight loss or the exception of behavior (figure
5), illustrate that mouse can preferably be resistant to the drug of this dose.
The present invention further comprises the compounds of this invention or its pharmaceutically acceptable salt, the pharmaceutically acceptable salt
Selected from inorganic acid or organic acid formation salt, such as with hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or acetic acid, trifluoroacetic acid, lemon
The salt that acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid are formed,
Their alkali metal salt, alkali salt, silver salt, barium salt etc. can be prepared according to a conventional method.
The present invention also provides the pharmaceutical compositions containing compounds of the invention or their medicinal salts.Pharmaceutical composition is to be suitble to medicine
Dosage form exists.Medicinal preparation is selected from tablet, capsule, granule, oral solution, injection etc..
Pharmaceutical composition of the invention, as dosage form, the effective quantity of the invention compound contained in every dose is 0.1~
1000mg, described every dose refers to each preparation unit, such as every of tablet, every of capsule, also can refer to each taking agent
Amount, such as each taking 100mg.
Solid can be used when being prepared into the solid pharmaceutical preparation of tablet, Capsule form in pharmaceutical composition of the invention
Carrier.Workable solid carrier is preferably selected from diluent, flavoring agent, solubilizer, lubricant, suspending agent, adhesive, expansion
One of agent etc. or many kinds of substance, or can be encapsulating substance.Suitable solid carrier includes magnesium carbonate, magnesium stearate, talcum
Powder, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, cocoa butter etc..Due to them
It is easy to be administered, tablet and the best oral solid formulation of Capsules representative.
The weight ratio of the compounds of this invention that described pharmaceutical composition contains in the composition is 0.1~99.9%, drug
The weight ratio of acceptable carrier in the composition is 0.1~99.9%.
It is uniform for ease of administration and dosage, said medicine preparation is configured to dosage unit form and is particularly advantageous.
The dosage unit form of preparation refers to the physical separation unit for being suitable for single dose, and each unit, which contains, generates desired control
The active constituent for the predetermined amount of therapeutic effect calculated.This dosage unit form can be packaged form, such as tablet, capsule.
Although the amount of contained active constituent can change in dosage unit form, generally according to selected active constituent
Effect is adjusted within the scope of 1~800mg.
Those skilled in the art can determine the preferred dose suitable for certain situation according to a conventional method.Generally, start treatment
Amount is lower than the optimal dose of active constituent, dosage is then gradually increased, until reaching optimum therapeuticing effect.It rises for convenience
See, total daily dose can be divided into several parts, be administered in several times.
The present invention is compared with pyridazinone compound in the prior art, and anti-tumor activity is higher, and toxic side effect is smaller, this
Invention pyridazinone compound LD50 numerical value is much higher than the pyridazinone compound of the prior art, is suitable as oral antineoplastic
Object uses.
Detailed description of the invention:
Fig. 1 IMB5036 and IMB5043 can cause human liver cancer cells Hep G2 nucleus γ-H2AX foci shape
At increasing (Fig. 1).
Fig. 2 IMB5036 can significantly inhibit the growth of tumour, and the IMB5036 of 12.5 and 25mg/kg passes through intraperitoneal administration,
The 28th day tumour inhibiting rate is respectively 30.6% and 66.2% (Fig. 2) after administration.
The animal of all IMB5036 processing groups of Fig. 3 does not have apparent weight loss or the exception of behavior (Fig. 3).
The tumor killing effect that Fig. 4 IMB5043 is shown, the IMB5043 of 12.5 and 25mg/kg is by intraperitoneal administration, after administration
28th day tumour inhibiting rate is respectively 28.6% and 58.8% (Fig. 4).
The animal of all IMB5043 processing groups of Fig. 5 does not have apparent weight loss or the exception of behavior (Fig. 5).
Specific embodiment
The present invention is further illustrated by the following examples, but not as limitation of the present invention.
Embodiment 1
The preparation of tablet
Any one compound of IMB5036 and IMB5043 0.5g, starch 4.5g, Icing Sugar 0.9g and distilled water 1ml are taken, on
State component after mixing, pelletize, whole grain is dry, be added a small amount of lubricant tabletting packing to get.
Embodiment 2
The preparation of capsule
Any one compound of IMB5036 and IMB5043 0.5g, starch 4.5g, Icing Sugar 0.9g and distilled water 1ml are taken, on
State component after mixing, pelletize, whole grain is dry, dispense capsule to get.
Embodiment 3
The preparation of granule
Any one compound of IMB5036 and IMB5043 0.5g, starch 4.5g, Icing Sugar 0.9g and distilled water 1ml are taken, on
State component after mixing, pelletize, whole grain is dry, packing to get.
Claims (3)
1. a kind of pyridazinone compound application in preparation of anti-tumor drugs, the pyridazinone compound structure is as follows:
Wherein the tumour is selected from: liver cancer, colorectal cancer, cancer of pancreas.
2. application according to claim 1, wherein the drug is selected from tablet, capsule, granule, oral solution, injection
Agent.
3. a kind of with inhibition liver cancer, colorectal cancer, the pharmaceutical composition of cancer of pancreas, which is characterized in that the pharmaceutical composition contains
There is pyridazinone compound, the pyridazinone compound structure is as follows:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710429186.6A CN107334767B (en) | 2017-06-08 | 2017-06-08 | A kind of application of pyridazinone compound in oncotherapy |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710429186.6A CN107334767B (en) | 2017-06-08 | 2017-06-08 | A kind of application of pyridazinone compound in oncotherapy |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107334767A CN107334767A (en) | 2017-11-10 |
CN107334767B true CN107334767B (en) | 2019-03-05 |
Family
ID=60220582
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710429186.6A Expired - Fee Related CN107334767B (en) | 2017-06-08 | 2017-06-08 | A kind of application of pyridazinone compound in oncotherapy |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107334767B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022258992A1 (en) * | 2021-06-10 | 2022-12-15 | Universitetet I Oslo | Pyridazinones for the treatment or prevention of hypertension |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109620829B (en) * | 2018-12-29 | 2021-04-06 | 温州医科大学附属第一医院 | Pharmaceutical composition for treating acute respiratory distress syndrome and preparation method thereof |
CN111297870B (en) * | 2020-03-20 | 2021-03-26 | 中国医学科学院医药生物技术研究所 | Application of nitrobenzoic acid compounds in preparation of drugs for treating tumors |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1277605A (en) * | 1997-08-22 | 2000-12-20 | 艾博特公司 | Arylpyridazinones as prostaglandin endoperoxide H synthase biosynthesis inhibitors |
CN1342149A (en) * | 1998-10-27 | 2002-03-27 | 艾博特公司 | Prostaglandin endoperoxide H synthase biosynthesis inhibitors |
CN1583727A (en) * | 2003-12-30 | 2005-02-23 | 浙江工业大学 | Synthesis of fluoropyridazinone |
WO2005111019A1 (en) * | 2004-05-18 | 2005-11-24 | Aventis Pharma S.A. | Novel pyridazinone derivatives as inhibitors of cdk2 |
CN101326167A (en) * | 2005-12-05 | 2008-12-17 | 默克专利有限公司 | Pyridiazinone derivatives for tumour treatment |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101538245B (en) * | 2008-03-18 | 2011-02-16 | 中国科学院上海药物研究所 | One-class pyridazinone compounds and preparation method and application thereof |
CN103893178B (en) * | 2014-03-19 | 2016-06-01 | 中山大学 | Benzene-sulfamide compound is in the application prepared in anti-HIV-1 virus drugs |
CN106467495A (en) * | 2015-08-19 | 2017-03-01 | 中国科学院上海药物研究所 | Pyridazinone compound, its preparation method, pharmaceutical composition and purposes |
CN107964007B (en) * | 2016-10-20 | 2021-02-12 | 沈阳中化农药化工研发有限公司 | Pyridazinone compound and application thereof |
-
2017
- 2017-06-08 CN CN201710429186.6A patent/CN107334767B/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1277605A (en) * | 1997-08-22 | 2000-12-20 | 艾博特公司 | Arylpyridazinones as prostaglandin endoperoxide H synthase biosynthesis inhibitors |
CN1342149A (en) * | 1998-10-27 | 2002-03-27 | 艾博特公司 | Prostaglandin endoperoxide H synthase biosynthesis inhibitors |
CN1583727A (en) * | 2003-12-30 | 2005-02-23 | 浙江工业大学 | Synthesis of fluoropyridazinone |
WO2005111019A1 (en) * | 2004-05-18 | 2005-11-24 | Aventis Pharma S.A. | Novel pyridazinone derivatives as inhibitors of cdk2 |
CN101326167A (en) * | 2005-12-05 | 2008-12-17 | 默克专利有限公司 | Pyridiazinone derivatives for tumour treatment |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022258992A1 (en) * | 2021-06-10 | 2022-12-15 | Universitetet I Oslo | Pyridazinones for the treatment or prevention of hypertension |
Also Published As
Publication number | Publication date |
---|---|
CN107334767A (en) | 2017-11-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105377299B (en) | For treat prostate cancer comprising dihydro pyrazine simultaneously-combination treatments of pyrazine compound and androgen receptor antagonists | |
HUE026654T2 (en) | New pharmaceutical compositions comprising 4-(4-(3-(4-chloro-3-trifluoromethyl-phenyl)-ureido)-3-fluoro-phenoxy)-pyridine-2-carboxylic acid for the treatment of hyper-proliferative disorders | |
CN107334767B (en) | A kind of application of pyridazinone compound in oncotherapy | |
Takagi et al. | In vivo antitumor activity of a novel sulfonamide, HMN-214, against human tumor xenografts in mice and the spectrum of cytotoxicity of its active metabolite, HMN-176 | |
CN104662022A (en) | Means and method for treating solid tumours | |
CN106146372B (en) | For preventing and treating the organic selenium compounds of cancer | |
CN109843868A (en) | The active inhibition of OLIG2 | |
CN106349228B (en) | Substituted quianzolinones and its preparation method and application | |
CN101801461A (en) | [1, the 10]-phenanthroline derivant that is used for the treatment of nervous tissue's degeneration or blood disease | |
CN105367582B (en) | Bilobalide B derivates and its application in drug | |
CN110302386A (en) | Combination product comprising limonoid and sulfonylureas | |
CN112494490B (en) | Application of pimavanserin tartrate in preparation of drug for treating glioma | |
CN108623560A (en) | A kind of Quinolone acid analog derivative and its preparation method and application | |
RU2731535C1 (en) | Combination, use thereof and method of treating | |
WO2021027582A1 (en) | Combination product containing limonin compound and thiazolidinedione | |
CN106167464A (en) | One class quinoline derivatives, Preparation Method And The Use | |
CN108623591A (en) | A kind of purposes of piperazine Nino peace compound | |
CN101423519A (en) | Tetrandrine organic acid salt as well as preparation method and application | |
CN101233125A (en) | Antitumoral compounds | |
US20230064254A1 (en) | Therapeutic agent containing fused pyrimidine compound as active ingredient | |
JPH02304058A (en) | Xanthocillin x monomethyl ether derivative and antineoplastic agent | |
CN115990162B (en) | Application of 4-hydroxy-2-pyridone alkaloid in preparation of medicines for treating gastric cancer | |
CN111995629B (en) | Germacrene leaf derivative, pharmaceutical composition thereof and application thereof in medicine | |
CN102276625B (en) | Thiadiazole derivative | |
JP2010500387A5 (en) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190305 |