CN110464722B - 一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 - Google Patents
一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 Download PDFInfo
- Publication number
- CN110464722B CN110464722B CN201910493676.1A CN201910493676A CN110464722B CN 110464722 B CN110464722 B CN 110464722B CN 201910493676 A CN201910493676 A CN 201910493676A CN 110464722 B CN110464722 B CN 110464722B
- Authority
- CN
- China
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- cancer
- compound
- small molecule
- 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.)
- Active
Links
- 206010027476 Metastases Diseases 0.000 title claims abstract description 27
- 230000009401 metastasis Effects 0.000 title claims abstract description 27
- 239000003814 drug Substances 0.000 title claims abstract description 24
- 150000003839 salts Chemical class 0.000 title claims abstract description 19
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- -1 small molecule compound Chemical class 0.000 title claims description 21
- 229940079593 drug Drugs 0.000 title abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 201000007270 liver cancer Diseases 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 208000014018 liver neoplasm Diseases 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 3
- 206010005949 Bone cancer Diseases 0.000 claims description 2
- 208000018084 Bone neoplasm Diseases 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 29
- 210000004881 tumor cell Anatomy 0.000 abstract description 10
- 201000011510 cancer Diseases 0.000 abstract description 9
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 9
- 230000003013 cytotoxicity Effects 0.000 abstract description 9
- 230000005012 migration Effects 0.000 abstract description 6
- 238000013508 migration Methods 0.000 abstract description 6
- 238000000338 in vitro Methods 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 4
- 230000009545 invasion Effects 0.000 abstract description 4
- 230000033001 locomotion Effects 0.000 abstract description 3
- 125000000217 alkyl group Chemical group 0.000 description 24
- 229910052739 hydrogen Inorganic materials 0.000 description 21
- 239000001257 hydrogen Substances 0.000 description 21
- 125000000547 substituted alkyl group Chemical group 0.000 description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 20
- 125000003545 alkoxy group Chemical group 0.000 description 19
- 230000012292 cell migration Effects 0.000 description 19
- 230000000694 effects Effects 0.000 description 19
- 150000002431 hydrogen Chemical class 0.000 description 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 11
- 229910052736 halogen Inorganic materials 0.000 description 10
- 150000002367 halogens Chemical class 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 229930182470 glycoside Natural products 0.000 description 8
- 150000002338 glycosides Chemical class 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 239000004017 serum-free culture medium Substances 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000003041 virtual screening Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NRTGZESAIDNRFP-UHFFFAOYSA-N (1-ethylcyclopentyl) acetate Chemical compound CC(=O)OC1(CC)CCCC1 NRTGZESAIDNRFP-UHFFFAOYSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- MPXTYZZFIJTPPA-UHFFFAOYSA-N 3beta,16beta,17alpha-trihydroxycholest-5-en-22-one 16-O-(2-O-(4-methoxybenzoyl)-beta-D-xylopyranosyl)-(1-3)-(2-O-acetyl-alpha-arabinopyranoside) Natural products C1=CC(OC)=CC=C1C(=O)OC1C(OC2C(C(OC3C(C4(C)CCC5C6(C)CCC(O)CC6=CCC5C4C3)(O)C(C)C(=O)CCC(C)C)OCC2O)OC(C)=O)OCC(O)C1O MPXTYZZFIJTPPA-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- MAGWLGAJMLWPLZ-UHFFFAOYSA-N OSW-1 Natural products COc1ccc(cc1)C(=O)OC2C(O)C(O)COC2OC3C(O)COC(OC4CC5C6CC=C7CC(O)CCC7(C)C6CCC5(C)C4(O)OC(C)C(=O)CCC(C)C)C3OC(=O)C MAGWLGAJMLWPLZ-UHFFFAOYSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 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
- 241001448530 Rohdea japonica Species 0.000 description 1
- MPXTYZZFIJTPPA-JOQRFCRPSA-N [(2s,3r,4s,5r)-2-[(2s,3r,4s,5s)-3-acetyloxy-2-[[(3r,8s,9r,10r,13s,14r,16r,17s)-3,17-dihydroxy-10,13-dimethyl-17-[(2s)-6-methyl-3-oxoheptan-2-yl]-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-16-yl]oxy]-5-hydroxyoxan-4-yl]oxy-4,5-dihydro Chemical compound C1=CC(OC)=CC=C1C(=O)O[C@H]1[C@H](O[C@@H]2[C@H]([C@H](O[C@H]3[C@]([C@@]4(C)CC[C@H]5[C@@]6(C)CC[C@@H](O)CC6=CC[C@@H]5[C@H]4C3)(O)[C@H](C)C(=O)CCC(C)C)OC[C@@H]2O)OC(C)=O)OC[C@@H](O)[C@@H]1O MPXTYZZFIJTPPA-JOQRFCRPSA-N 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000010232 migration assay Methods 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 208000011581 secondary neoplasm Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
-
- 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
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用。所述化合物的结构如式(Ⅰ)所示；所述小分子化合物或其药学上可接受的盐，在体外可显著抑制肿瘤细胞的侵袭、迁移和水平运动能力；且细胞毒性较小，对正常细胞安全性高，具有很好的成药特性，可制备成为抗肿瘤药物和/或抗肿瘤转移药物进行应用，用于防治中晚期恶性肿瘤病人的肿瘤细胞的转移；同时，所述小分子化合物或其药学上可接受的盐的结构简单、易于合成，可大规模工业化生产制备，易于推广应用。
Description
技术领域
本发明涉及抗肿瘤医药技术领域，更具体地，涉及一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用。
背景技术
肿瘤是当今世界危及人类健康的一种最常见、最严重的疾病，其发病率仅次于心血管疾病。肿瘤转移是指恶性肿瘤细胞脱离其原发部位，在体内通过各种途径(如血液、淋巴等)的转运，到达远端其它组织继续增殖生长，形成继发肿瘤的全过程。侵袭与转移是恶性肿瘤区别于良性肿瘤的最主要的特征之一。据估计，90％肿瘤病人的死亡是源于癌细胞转移。因此，研究如何抑制和/或预防肿瘤细胞的转移是抗肿瘤药物研发的重要方向。
以原发性肝癌(Hepatocellular carcinoma，HCC)为例，虽然目前对于诊断和治疗肝癌的技术手段有了很大的提高，最主要的手段还是手术切除，但是只有大约20％～30％的肝癌患者能够在其患病的早期阶段被诊断出来，进而有机会采取最有效的治疗手段。不同阶段的肝癌患者对于同一种治疗手段的预后情况大大不同，如同样是手术切除治疗，中晚期肝癌患者即使采取手术治疗手段，复发的几率很大。因为术后残留的肝癌细胞会转移到其它组织，最常见的是肺转移，通过浸润到其它组织的细胞群中，引发了更加严重的癌症，加大了治疗的难度。无论在长期的细胞培养中还是动物模型体内，肝癌细胞都有很强的迁移和侵润能力，使得普通的治疗手段，如切除手术、放疗、化疗等效果不明显。从而使肝癌患者治疗预后差，复发率高。
因此，寻找抑制肿瘤细胞转移，是治疗肿瘤的一项重要的手段，新型抗肿瘤转移药物的发现对挽救恶性肿瘤患者的生命具有至关重要的临床意义和社会价值。
发明内容
本发明的目的在于提供一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用。本发明化合物在体外可显著抑制肿瘤细胞的侵袭、迁移和水平运动能力；且细胞毒性较小，对正常细胞安全性高，具有很好的成药特性，可制备成为抗肿瘤药物和/或抗肿瘤转移药物进行应用，用于防治中晚期恶性肿瘤病人的肿瘤细胞的转移本发明的另一目的在于提供由所述小分子化合物或其药学上可接受的盐制备的药物组合物。
本发明的上述目的是通过以下方案予以实现的：
一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用，所述化合物的结构如式(Ⅰ)所示：
其中所述X、Y、Z分别独立地为C、N、O或S；
R1为氢、羟基、C1-6烷基、C1-6取代烷基、C1-6烷氧基、C3-6环烷基、苯基、取代苯基、苄基、取代苄基、胺基、取代胺基、苯酯基、
或糖苷；其中R4为C3-9环烷基或
其中R6为氢、卤素、羟基、硝基、C1-4烷基、C1-4取代烷基或C1-4烷氧基，n为0～4的整数；R5为羟基、C1-6烷基、C1-6取代烷基、C1-6烷氧基、C3-6环烷基或苯基；
R2为氢、羟基、硝基、C1-6烷基、C1-6取代烷基、C1-6烷氧基、C3-6环烷基、苯基、取代苯基或
其中R7为C1-4烷基、C1-4取代烷基、C1-4烷氧基或C3-6环烷基；
R3为氢、羟基、硝基、羰基、C1-6烷基、C1-6取代烷基、C1-6烷氧基、苯基、
或糖苷；其中R8和R9分别独立地为氢、羟基、硝基、卤素、C1-4烷基、C1-4烷氧基；n为0～4的整数；
所述C1-4取代烷基、C1-6取代烷基、取代苯基、取代苄基、取代胺基中的取代基为卤素、羟基、苯基、C1-4烷基、C1-4烷氧基或C3-6环烷基。
优选地，所述X、Y、Z分别独立地为C或N。
优选地，当X、Y和Z均为N时，化合物的结构如式(Ⅱ)所示：
R1为氢、羟基、C1-6烷基、C1-6取代烷基、苯基、取代苯基、苄基、胺基、取代胺基、苯酯基、
或糖苷；其中R4为C3-9环烷基或
其中R6为氢、卤素、羟基或硝基，n为0～4的整数；R5为C1-6烷基、C1-6取代烷基、C1-6烷氧基或C3-6环烷基；
当Y为N，X和Z均为C时，化合物的结构如式(Ⅲ)所示：
R1为羟基、C1-4烷基或
其中n为0～4的整数，R6为氢、卤素、羟基、硝基、C1-4烷基或C1-4烷氧基；
R2为氢；R3为氢、C1-6烷基、C1-6取代烷基、C1-6烷氧基或糖苷；
当Y为C，X和Z均为N时，化合物的结构如式(Ⅳ)所示：
R1为羟基、C1-4烷基或
其中n为0～4的整数，R6为氢、卤素、羟基、硝基、C1-4烷基或-COOCH3；
R2为氢；R3为氢或C1-6取代烷基；C1-6取代烷基中的取代基为卤素、羟基、苯基；
当X为C，Y和Z均为N时，化合物的结构如式(Ⅴ)所示：
R1为羟基或C1-4烷基；R2为氢；R3为氢或糖苷。
优选地，当X、Y和Z均为N时，R1为氢、羟基、甲基、乙基、丙基、异丙基、乙酸基、乙基环戊烷、苯基、取代苯基、苄基、胺基、
或糖苷；其中R4为
取代苯基中的取代基为氟、氯、溴、硝基、羟基、甲基、乙基、甲氧基或乙氧基中的一个或多个。
优选地，所述小分子化合物为以下结构中的一种：
优选地，所述其药学上可接受的盐是由所述小分子化合物与酸或者碱反应制备得到。
更优选地，所述酸为盐酸、硫酸或氢溴酸；所述碱为氢氧化钠、氢氧化钙或氢氧化钾。
优选地，所述抗肿瘤转移为抗肝癌、乳腺癌、肺癌、胃癌、宫颈癌、卵巢癌、食管癌、大肠癌、鼻咽癌、脑癌或骨癌中的一种或多种的转移。
本发明同时还保护由所述小分子化合物或其药学上可接受的盐制备的药物组合物，所述药物组合物包含治疗有效量的式(Ⅰ)所示小分子化合物和/或其药学上可接受的盐：
其中所述X、Y、Z分别独立地为C、N、O或S；
R1为氢、羟基、C1-6烷基、C1-6取代烷基、C1-6烷氧基、C3-6环烷基、苯基、取代苯基、苄基、取代苄基、胺基、取代胺基、苯酯基、
或糖苷；其中R4为C3-9环烷基或
其中R6为氢、卤素、羟基、硝基、C1-4烷基、C1-4取代烷基或C1-4烷氧基，n为0～4的整数；R5为羟基、C1-6烷基、C1-6取代烷基、C1-6烷氧基、C3-6环烷基或苯基；
R2为氢、羟基、硝基、C1-6烷基、C1-6取代烷基、C1-6烷氧基、C3-6环烷基、苯基、取代苯基或
其中R7为C1-4烷基、C1-4取代烷基、C1-4烷氧基或C3-6环烷基；
R3为氢、羟基、硝基、羰基、C1-6烷基、C1-6取代烷基、C1-6烷氧基、苯基、
或糖苷；其中R8和R9分别独立地为氢、羟基、硝基、卤素、C1-4烷基、C1-4烷氧基；n为0～4的整数；
所述C1-4取代烷基、C1-6取代烷基、取代苯基、取代苄基、取代胺基中的取代基为卤素、羟基、苯基、C1-4烷基、C1-4烷氧基或C3-6环烷基。
哟选地，所述药物组合物可制备成为注射剂、乳剂、片剂、散剂、颗粒剂、软膏、脂质体或口服液。
与现有技术相比，本发明具有以下有益效果：
本发明所述小分子化合物或其药学上可接受的盐，在体外可显著抑制肿瘤细胞的侵袭、迁移和水平运动能力；且细胞毒性较小，对正常细胞安全性高，具有很好的成药特性，可制备成为抗肿瘤药物和/或抗肿瘤转移药物进行应用，用于防治中晚期恶性肿瘤病人的肿瘤细胞的转移；
同时，所述小分子化合物或其药学上可接受的盐的结构简单、易于合成，可大规模工业化生产制备，易于推广应用。
附图说明
图1为不同浓度的化合物1对HepG2细胞迁移的影响。
图2为不同浓度的化合物2对HepG2细胞迁移的影响。
图3为不同浓度的化合物3对HepG2细胞迁移的影响。
图4为不同浓度的化合物4对HepG2细胞迁移的影响。
图5为不同浓度的化合物5对HepG2细胞迁移的影响。
图6为不同浓度的化合物7对HepG2细胞迁移的影响。
图7为不同浓度的化合物8对HepG2细胞迁移的影响。
图8为不同浓度的化合物11对HepG2细胞迁移的影响。
图9为不同浓度的化合物28对HepG2细胞迁移的影响。
图10为不同浓度的化合物32对HepG2细胞迁移的影响。
图11为不同浓度的化合物33对HepG2细胞迁移的影响。
图12为通过划痕实验测定不同浓度的化合物1对HepG2细胞迁移的影响。
图13为通过划痕实验测定不同浓度的化合物32对HepG2细胞迁移的影响。
图14为通过划痕实验测定不同浓度的化合物33对HepG2细胞迁移的影响。
具体实施方式
下面结合具体实施例对本发明做出进一步地详细阐述，所述实施例只用于解释本发明，并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，为可从商业途径得到的试剂和材料。
实施例1
化合物的筛选，步骤如下：
1、化合物库预处理：虚拟筛选化合物库为实验室自备化合物数据库。化合物库作如下处理：去除离子及络合水分子、加电荷、质子化、产生三维构象。这些流程均在药物设计软件包Discovery Studio 3.0中完成。其中质子化在pH 6.5-8.5条件下进行。准备好的小分子库用于虚拟筛选。
2.以基于虎眼万年青皂甙(OSW-1)的结构进行相似度匹配的数据库搜寻，找出结构类似的化合物。
筛选得到的化合物结构如表1所示。
表1化合物结构
实施例2化合物细胞毒性测定
以实施例1筛选的化合物进行进一步的筛选，测试化合物的细胞毒性，具体过程如下：
1.细胞培养：体外培养HepG2细胞，使用含有10％胎牛血清的DMEM培养基，在37℃，5％二氧化碳浓度条件下进行常规维持培养和传代。
2.药物干预：将HepG2细胞铺板至96孔板，每孔1×103细胞；次日，分别使用不同浓度梯度的小分子化合物处理细胞，每个浓度设3个平行复孔。
3.测试方法：72小时后，用CCK-8试剂盒检测细胞毒性。
按照10％的比例，每100uL培养基中加入10uL CCK-8，并于37℃进行孵育2小时后，用酶标仪检测吸收光值(OD450)。
相对于对照组的吸光值，分别计算出不同化合物在不同浓度的作用下的细胞毒性。以相对值为纵坐标，药物浓度为横坐标绘制各化合物对细胞生长率作用的曲线图，并计算各药物使50％细胞死亡时的药物浓度(CC50)以评价各化合物的细胞毒性。
每种化合物的每个浓度至少进行3次重复实验。
实施例3化合物抑制HepG2细胞迁移能力
以实施例2筛选的化合物为测试对象，测试其抑制HepG2细胞迁移的能力，实验具体过程如下：
1.细胞培养：体外培养HepG2细胞，使用含有10％胎牛血清，100U/mL青霉素，100μg/mL链霉素的高糖DMEM培养基，在37℃，5％二氧化碳浓度条件下进行常规维持培养和传代。
2.Transwell迁移实验：用胰酶消化细胞后离心收集2×106细胞；用1mL PBS缓冲液洗涤细胞一次，离心收集细胞；加入1mL无血清培养基重悬细胞；用完全培养基配置不同浓度的各种化合物，取0.6mL至24孔板后，放入细胞培养小室。取0.1mL重悬的细胞加入小室上室，置于37℃，5％CO2的环境中培养。24小时后取出小室，用PBS清洗干净，风干；用4％PFA固定细胞20min后，用PBS将小室清洗干净，风干；取1％结晶紫/2％(v/v)甲醇染色30min，用PBS清洗干净，风干后拍照。重复3次独立实验。
4.结果处理：Transwell迁移实验拍照，每个样品随机选取10个视野拍照(放大倍数：100×；标尺：200μm)。用image pro plus 6.0对每个视野的细胞数进行统计。计算各化合物的抑制50％癌症细胞迁移的起效浓度，以评价各化合物的作用。
划痕实验具体过程如下：
(1)先用marker笔在6孔板背后，用直尺比着，均匀得划横线，大约每隔0.5～1cm一道，横穿过孔。每孔至少穿过5条线；
(2)每孔中加入约5x105个细胞，掌握为过夜培养贴壁；
(3)第二天用枪头比着直尺，尽量垂至于背后的横线划痕；
(4)用PBS洗细胞3次，去处划下的细胞，加入无血清培养基；
(5)放入37度5％CO2培养箱，培养。按0，48，72小时拍照取样。
每种化合物的每个浓度至少进行3次重复实验。
实施例2和3的测试结果如表2所示。
表2化合物的细胞毒性和抑制HepG2细胞迁移试验结果
化合物1～33的测试结果如表1所示，部分化合物的测试结果如图1～11所示，图1～11分别是化合物1、2、3、4、5、7、8、11、28、32、33实验的测试结果；图12～14分别是化合物1、32、33划痕实验得到测试结果。
从表1中可知，实施例提供的大部分化合物的细胞毒性较低，甚至部分化合物对于细胞没有任何的毒性；同时大部分化合物对HepG2细胞具有较好的抑制转移作用，其中尤其是化合物1、32、33，没有或较低的细胞毒性，而对于HepG2细胞表现出优异的抑制转移作用，且在纳摩尔浓度条件下就能起效，化合物1、32、33的划痕实验也验证了这个结论。
综上，上述实施例提供的大部分化合物对于细胞的毒性较低，甚至没有毒性，同时能够很好的抑制HepG2细胞迁移，可制备成为抗肿瘤药物和/或抗肿瘤转移药物进行应用，用于防治中晚期恶性肿瘤病人的肿瘤细胞的转移。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，对于本领域的普通技术人员来说，在上述说明及思路的基础上还可以做出其它不同形式的变化或变动，这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。
Claims (5)
1.一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用，其特征在于，所述小分子化合物为以下结构中的一种：
2.根据权利要求1所述小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用，其特征在于，所述其药学上可接受的盐是由所述小分子化合物与酸或者碱反应制备得到。
3.根据权利要求1所述小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用，其特征在于，所述抗肿瘤转移为抗肝癌、乳腺癌、肺癌、胃癌、宫颈癌、卵巢癌、食管癌、大肠癌、鼻咽癌、脑癌或骨癌中的一种或多种的转移。
4.一种药物组合物，其特征在于，所述药物组合物包含治疗有效量的以下任意一种结构的小分子化合物和/或其药学上可接受的盐：
5.根据权利要求4所述药物组合物，其特征在于，所述药物组合物可制备成为注射剂、乳剂、片剂、散剂、颗粒剂、软膏、脂质体或口服液。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910493676.1A CN110464722B (zh) | 2019-06-06 | 2019-06-06 | 一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 |
| PCT/CN2020/076031 WO2020244253A1 (zh) | 2019-06-06 | 2020-02-20 | 一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910493676.1A CN110464722B (zh) | 2019-06-06 | 2019-06-06 | 一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110464722A CN110464722A (zh) | 2019-11-19 |
| CN110464722B true CN110464722B (zh) | 2023-05-23 |
Family
ID=68506733
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910493676.1A Active CN110464722B (zh) | 2019-06-06 | 2019-06-06 | 一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN110464722B (zh) |
| WO (1) | WO2020244253A1 (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110464722B (zh) * | 2019-06-06 | 2023-05-23 | 暨南大学 | 一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 |
| CN111349096B (zh) * | 2020-04-14 | 2021-03-09 | 石河子大学 | 一种吲哚类化合物及其制备方法、应用 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1507435A (zh) * | 2001-03-29 | 2004-06-23 | ����˹�ж�-����˹˹������˾ | 新型氰基取代的二氢嘧啶化合物及其治疗疾病的用途 |
| WO2006018435A1 (en) * | 2004-08-18 | 2006-02-23 | Altana Pharma Ag | Benzothienopyridines for use as inhibitors of eg5 kinesin |
| WO2006079645A1 (en) * | 2005-01-27 | 2006-08-03 | Nycomed Gmbh | Novel indolopyridines , benzofuranopyridines and benzothienopyridines |
| WO2009024613A1 (en) * | 2007-08-22 | 2009-02-26 | 4Sc Ag | Tetracyclic indolopyridines as eg5 inhibitors |
| CN106727489A (zh) * | 2016-12-24 | 2017-05-31 | 广州中大南沙科技创新产业园有限公司 | 2‑呋喃丙烯醛类化合物在制备抗人类γ疱疹病毒药物中的应用 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2239013B (en) * | 1989-11-01 | 1993-06-02 | Toyama Chemical Co Ltd | Novel isoindole derivatives and salts thereof,processes for producing the same and antitumor agent comprising the same |
| JP2007529533A (ja) * | 2004-03-15 | 2007-10-25 | ピーティーシー セラピューティクス，インコーポレーテッド | 血管新生の抑制に有用なテトラサイクリックカルボリン誘導体 |
| WO2008015265A1 (de) * | 2006-08-04 | 2008-02-07 | Æterna Zentaris Gmbh | Anthracen-derivate und deren verwendung zur behandlung gutartiger und bösartiger tumorerkrankungen |
| JP2010536807A (ja) * | 2007-08-22 | 2010-12-02 | ４エスツェー アクチェンゲゼルシャフト | キネシンスピンドルタンパク質（ｅｇ５）の阻害剤としてのインドロピリジン |
| WO2015061321A1 (en) * | 2013-10-21 | 2015-04-30 | Northeastern University | Hypoxia-targeted delivery system for pharmaceutical agents |
| CN110464722B (zh) * | 2019-06-06 | 2023-05-23 | 暨南大学 | 一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 |
-
2019
- 2019-06-06 CN CN201910493676.1A patent/CN110464722B/zh active Active
-
2020
- 2020-02-20 WO PCT/CN2020/076031 patent/WO2020244253A1/zh active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1507435A (zh) * | 2001-03-29 | 2004-06-23 | ����˹�ж�-����˹˹������˾ | 新型氰基取代的二氢嘧啶化合物及其治疗疾病的用途 |
| WO2006018435A1 (en) * | 2004-08-18 | 2006-02-23 | Altana Pharma Ag | Benzothienopyridines for use as inhibitors of eg5 kinesin |
| WO2006079645A1 (en) * | 2005-01-27 | 2006-08-03 | Nycomed Gmbh | Novel indolopyridines , benzofuranopyridines and benzothienopyridines |
| WO2009024613A1 (en) * | 2007-08-22 | 2009-02-26 | 4Sc Ag | Tetracyclic indolopyridines as eg5 inhibitors |
| CN106727489A (zh) * | 2016-12-24 | 2017-05-31 | 广州中大南沙科技创新产业园有限公司 | 2‑呋喃丙烯醛类化合物在制备抗人类γ疱疹病毒药物中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110464722A (zh) | 2019-11-19 |
| WO2020244253A1 (zh) | 2020-12-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI652060B (zh) | 阿折地平藥物應用於癌症治療 | |
| CN110464722B (zh) | 一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 | |
| CN110357885A (zh) | 一种蝶啶类化合物及其在药学上的应用 | |
| WO2018209961A1 (zh) | 烷氧端基寡peg修饰的氨基嘧啶衍生物及抗肿瘤应用 | |
| CN112494467A (zh) | 香兰素在制备尼克酰胺-n-甲基转移酶抑制剂中的应用 | |
| CN112656795A (zh) | 防己诺林碱在抗结膜黑色素瘤中的作用机制及应用 | |
| CN114010630B (zh) | 槲皮素的氧甲基修饰物在制备抑制肿瘤细胞增殖的药物中的应用 | |
| CN111803493A (zh) | 马来酸替加色罗在制备抗肿瘤药物中的应用 | |
| CN111712245A (zh) | 用于肝细胞癌的治疗剂 | |
| CN114195779A (zh) | 9-0-乙基乙醚小檗红碱的合成方法及其在制备抗肿瘤药物中的用途 | |
| CN101967142A (zh) | 噻唑酰胺类化合物及其在治疗恶性肿瘤中的药物用途 | |
| CN112516164B (zh) | 一种抑制肿瘤转移的氨基富勒烯材料 | |
| WO2018058863A1 (zh) | 聚醚类化合物用途 | |
| WO2019007003A1 (zh) | 烷硫端基寡PEG修饰的氨基吡唑并[3,4-d]嘧啶衍生物及抗非小细胞肺癌的应用 | |
| CN114948964A (zh) | 多靶点蛋白激酶抑制剂的用途 | |
| CN111773220A (zh) | 阿帕替尼或其可药用盐的药物新用途 | |
| CN113893263A (zh) | 一种抗肿瘤的药物组合物及其应用 | |
| CN107260752B (zh) | 一种协同抗胰腺癌的药物组合物 | |
| CN113662939B (zh) | 去甲基斑蝥素酸镁和索拉菲尼的组合物在制备抗肝癌药物中的应用 | |
| CN111875606B (zh) | 一种基于虚拟对接获得的嘌呤类化合物及其制备方法和应用 | |
| RU2809720C2 (ru) | Применение производного инденофлуорена для ингибирования и/или элиминации опухолевых клеток | |
| RU2777535C2 (ru) | Терапевтическое средство для лечения гепатоцеллюлярной карциномы | |
| CN112142742B (zh) | Ctcf转录因子抑制剂及其应用 | |
| CN109172570B (zh) | 一种生物碱在制备防治肺癌患者顺铂耐药性的药物中的应用 | |
| CN117045803A (zh) | γ-氨基丁酸受体拮抗剂组合物及其在制备治疗胃癌药物中的应用 |
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 |