CN111233837A - 一种缩氨基硫脲的化合物及其制备方法和用途 - Google Patents
一种缩氨基硫脲的化合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN111233837A CN111233837A CN202010080559.5A CN202010080559A CN111233837A CN 111233837 A CN111233837 A CN 111233837A CN 202010080559 A CN202010080559 A CN 202010080559A CN 111233837 A CN111233837 A CN 111233837A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutically acceptable
- cancer
- compound
- acceptable salts
- formula
- 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.)
- Pending
Links
- -1 Thiosemicarbazone compound Chemical class 0.000 title abstract description 10
- 238000002360 preparation method Methods 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 6
- 229910052805 deuterium Inorganic materials 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 230000001613 neoplastic effect Effects 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 206010004593 Bile duct cancer 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
- 208000000461 Esophageal Neoplasms 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
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms 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
- 208000026900 bile duct neoplasm Diseases 0.000 claims description 2
- 201000007983 brain glioma Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 201000001475 prostate lymphoma Diseases 0.000 claims 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 abstract description 15
- 229910052742 iron Inorganic materials 0.000 abstract description 8
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- 229910021645 metal ion Inorganic materials 0.000 abstract description 3
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 229960000958 deferoxamine Drugs 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000010609 cell counting kit-8 assay Methods 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 4
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- OEUUFNIKLCFNLN-LLVKDONJSA-N chembl432481 Chemical compound OC(=O)[C@@]1(C)CSC(C=2C(=CC(O)=CC=2)O)=N1 OEUUFNIKLCFNLN-LLVKDONJSA-N 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 239000012737 fresh medium Substances 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 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 4
- 239000000375 suspending agent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010065973 Iron Overload Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- FMSOAWSKCWYLBB-VBGLAJCLSA-N deferasirox Chemical compound C1=CC(C(=O)O)=CC=C1N(N\C(N\1)=C\2C(C=CC=C/2)=O)C/1=C\1C(=O)C=CC=C/1 FMSOAWSKCWYLBB-VBGLAJCLSA-N 0.000 description 3
- 229960001489 deferasirox Drugs 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 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
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 2
- TZXKOCQBRNJULO-UHFFFAOYSA-N Ferriprox Chemical compound CC1=C(O)C(=O)C=CN1C TZXKOCQBRNJULO-UHFFFAOYSA-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
- 108010010803 Gelatin Proteins 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000006057 Non-nutritive feed additive Substances 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 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 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000002903 Thalassemia Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- 235000012216 bentonite Nutrition 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 229960003266 deferiprone Drugs 0.000 description 2
- 230000005595 deprotonation Effects 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-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
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000008297 liquid dosage form 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
- 239000000463 material Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000003605 opacifier Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 230000005588 protonation Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000011200 topical administration Methods 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
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 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
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-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
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-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
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- ANPAWAXFULSFEF-UHFFFAOYSA-N 5-bromo-3-[4-(prop-2-enoylamino)piperidin-1-yl]sulfonyl-1H-indole-2-carboxamide Chemical compound C(C=C)(=O)NC1CCN(CC1)S(=O)(=O)C1=C(NC2=CC=C(C=C12)Br)C(=O)N ANPAWAXFULSFEF-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 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
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 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
- 230000006820 DNA synthesis Effects 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
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 102000008857 Ferritin Human genes 0.000 description 1
- 238000008416 Ferritin Methods 0.000 description 1
- 108050000784 Ferritin Proteins 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
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 206010025323 Lymphomas Diseases 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 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
- 208000031306 Rare hereditary hemochromatosis Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum 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
- 229920001615 Tragacanth Polymers 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- XMYKNCNAZKMVQN-NYYWCZLTSA-N [(e)-(3-aminopyridin-2-yl)methylideneamino]thiourea Chemical compound NC(=S)N\N=C\C1=NC=CC=C1N XMYKNCNAZKMVQN-NYYWCZLTSA-N 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 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
- 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
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- GPRLELGTCFFNHU-UHFFFAOYSA-N aminothiourea;iron Chemical compound [Fe].NNC(N)=S GPRLELGTCFFNHU-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 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
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- HCIBTBXNLVOFER-UHFFFAOYSA-N diphenylcyclopropenone Chemical compound O=C1C(C=2C=CC=CC=2)=C1C1=CC=CC=C1 HCIBTBXNLVOFER-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 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
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- UTDAKQMBNSHJJB-JWGURIENSA-N n-[(z)-6,7-dihydro-5h-quinolin-8-ylideneamino]-4-pyridin-2-ylpiperazine-1-carbothioamide Chemical compound C/1CCC2=CC=CN=C2C\1=N/NC(=S)N(CC1)CCN1C1=CC=CC=N1 UTDAKQMBNSHJJB-JWGURIENSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960005526 triapine Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种下式(I)表示的化合物及其异构体或药学上可接受的盐。所述化合物可以用于螯合肿瘤细胞内的金属离子，尤其是铁离子以及治疗相关的癌症
Description
技术领域
本发明涉及药物合成领域，具体而言，涉及一种可以用于螯合金属离子的缩氨基硫脲化合物及其制备方法和用途。
背景技术
硫代氨基脲铁螯合剂是一类在体外和体内对许多不同的肿瘤细胞都具有极强选择性的抗肿瘤药物。这些化合物的功能是靶向铁，这是DNA合成的必需元素
铁螯合剂最初是针对铁超负荷疾病（如地中海贫血）开发的，目前有三个铁螯合药物已被批准用来降低铁过载，包括祛铁胺（DFO）、祛铁酮（deferiprone，DFP）和地拉罗司(deferasirox，DFX)。DFO可与铁蛋白或含铁血黄素中的铁结合，转变成铁草胺分子并经肾脏排出，铁草胺的产生可阻止铁的化学反应，从而减少活性氧形成。祛铁胺可皮下或静脉注射，使用剂量20~60mg/kg，由于半衰期仅20分钟，需长时间持续用药，较为不便。祛铁酮为口服药物，半衰期2~3小时，剂量50~100mg/kg每日，分3次口服，胃肠道副反应较多。地拉罗司是由瑞士诺华制药公司研究开发的铁螯合剂产品，是美国 FDA 批准的第一个能够常规使用的口服驱铁剂，获准在≥2岁、输血造成的慢性铁负荷过多的患者中使用, 在欧洲它被推荐作为 6 岁以上地中海贫血铁过载患者的一线用药，临床依从性较好，然而价格昂贵。
然而，在祛铁胺DFO治疗神经母细胞瘤的临床试验中发现，这种药物在某些患者中可以有效抑制此肿瘤的进展。这项研究开启了铁螯合剂治疗肿瘤的新篇章，其中，硫代氨基脲铁螯合剂更是有多个开始进入临床，如Triapine、DPC和COTI-2。
这些硫代氨基脲铁螯合剂能够与其他化疗药物联合在治疗血液肿瘤方面有较好的疗效，然而在实体瘤方面却由于生物活性低、药代性质差而进展较慢。因此，有必要开发活性更高、成药性质更好的结构新颖的硫代氨基脲铁螯合剂。
通过螯合肿瘤细胞中的铁等金属离子，从而抑制癌症细胞的生长，进而治疗肺癌、胰腺癌、结直肠癌等癌症看起来是一个很有希望的治疗手段。因此，该领域存在潜在的远未被满足的巨大药物需求。
发明内容
为解决以上技术问题，本发明采取如下技术方案：
根据本发明的一个方面，本发明提供了一种以下式(I)表示的化合物及其异构体或其药学上可接受的盐，
(I)
其中，
R1选自氢、氘、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、苯基或吡啶；所述苯基或吡啶可被一个或多个选自卤素、羟基、C1-3烷氧基、-NR3aR3b的取代基取代；所述R3a和R3b独立地选自氢、C1-6烷基或C3-6环烷基，或者R3a、R3b与其共同相连的-N-一起组成一个四至八元饱和或不饱和杂环；
R2为1个或多个选自氢、氘、卤素、氰基、C1-3烷基或-OC1-3烷基的基团；
m为0，1或2；
n为1，2或3。
根据本发明的另一个方面，优选地，在式(I)所示的结构中，R1选自苯基或吡啶；所述苯基或吡啶可被一个或多个选自卤素、羟基、C1-3烷氧基、-NR3aR3b的取代基取代；所述R3a和R3b独立地选自氢、C1-6烷基或C3-6环烷基，或者R3a、R3b与其共同相连的-N-一起组成一个四至八元饱和或不饱和杂环；
进一步优选地，R1选自苯基或吡啶；
更进一步优选地，R1为吡啶；
根据本发明的另一个方面，优选地，在式(I)所示的结构中，R2为1个选自氢、氘、卤素、氰基、C1-3烷基或-OC1-3烷基的基团；。
进一步优选地，R2选自氢；
根据本发明的另一个方面，优选地，在式(I)所示的结构中，m为0或1；
根据本发明的另一个方面，优选地，在式(I)所示的结构中，n为1，2或3；
根据本发明的另一个方面，优选地，由式(I)表示的化合物及其异构体或其药学上可接受的盐由选自以下化合物中：
根据本发明的另一个方面，本发明提供了由式(I)表示的化合物及其药学上可接受的盐在制备肿瘤疾病治疗药物中的用途；
优选地，根据所述用途，所述肿瘤疾病选自：肺癌、结直肠癌、胰腺癌、胰腺癌、肝癌、胃癌、食道癌、胆管癌、乳腺癌、卵巢癌、子宫颈癌、黑色素瘤、脑胶质瘤、前列腺癌、淋巴癌、白血病；
根据本发明的另一个方面，本发明提供了一种药物组合物，所述药物组合物包括治疗有效量的由式(I)表示的化合物及其药学上可接受的盐以及药学上可接受的辅料；
根据本发明的另一个方面，本发明提供了一种治疗肿瘤相关疾病的方法，所述方法包括向受试者施用有效量的由式(I)表示的化合物及其药学上可接受的盐作为活性成分的药物组合物。
根据本发明的另一个方面，本发明提供了式(I)表示的所述化合物的制备方法，所述制备方法通过当X=-CH2CH2-时的结构化合物制备举例如下：
1）将胺I-1溶解到氢氧化钠水溶液中，10℃以下加入二硫化碳并在室温搅拌1h。随后加入氯乙酸钠并继续搅拌过夜，经后处理得到中间体I-2；
2）将中间体I-2溶于水，加入85%水合肼，升温至80℃反应2h，待降温后抽滤得到目标中间体I-3，直接用于下一步反应；
3）将中间体I-3、酮或醛I-4溶解于乙醇/水/醋酸的混合溶剂中，升温至70℃反应6h。经后处理得到目标产物I。
具体实施方式
以下，将详细地描述本发明。在进行描述之前，应当理解的是，在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义，而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上，根据与本发明的技术方面相应的含义和概念进行解释。因此，这里提出的描述仅仅是出于举例说明目的的优选实例，并非意图限制本发明的范围，从而应当理解的是，在不偏离本发明的精神和范围的情况下，可以由其获得其他等价方式或改进方式。
根据本发明，如果无另外说明，这里引用的所有术语具有与那些本领域的熟练人员理解本发明相同的含义。
如本文所用的术语“盐”是指含阳离子和阴离子的化合物，其可通过可接受质子部位的质子化和/或可供质子部位的去质子化来产生。值得注意的是，可接受质子部位的质子化导致形成阳离子类物质，其电荷通过生理阴离子的存在而平衡，而可供质子部位的去质子化导致形成阴离子类物质，其电荷通过生理阳离子的存在而平衡。
术语“药学上可接受的盐”指所述盐是药学上可接受的。药学上可接受的盐的例子包括但不限于：（1）酸加成盐，与无机酸形成，如盐酸、氢溴酸、硫酸、硝酸、磷酸等等；或与有机酸形成，如羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羟基乙烷磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4对甲苯磺酸、樟脑酸、十二烷基硫酸、葡萄糖酸、谷氨酸、水杨酸、顺式-已二烯二酸等等；或（2）碱加成盐，和上述无机酸的任一种的共轭碱形成，其中共轭碱包含选自Na+、K+、Mg2+、Ca2+、NHxR4-x +中的阳离子组分，其中NHxR4-x +( R是C1-4烷基，下标x是选自0、1、2、3或4的整数)表示季铵盐中的阳离子。应该理解，所有涉及药学上可接受的盐都包括相同酸加成盐的本文中所定义的溶剂加成形式（溶剂化物）或晶体形式（多晶型物）。
术语“C1-M烷基”是指包含1-M个碳原子的烷基，例如其中M是具有下列数值的整数：2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30。例如术语“C1-6烷基”是指含有1-6个碳原子的烷基。烷基的例子包括但不限于低级烷基，包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基或戊基、异戊基、新戊基、己基、庚基和辛基。
术语“元”意为表示构成环的骨架原子的数量。如，环己基，吡啶基，吡喃基，噻喃基是六元环，环戊基，吡咯基，呋喃基和噻吩基是五元环。
术语“取代”指参考基团可以被一个或多个额外基团所取代，额外基团单独地且独立的选自于，烷基，环烷基，芳基，杂芳基，杂脂环烃，羟基，烷氧基，烷硫基，芳硫基，烷亚砜基，芳亚砜基，烷砜基，芳砜基，氰基，卤基，羰基，硫代羰基，硝基，卤烷基，氟烷基和氨基，包括单取代和双取代的氨基基团及其被保护的衍生物。
本发明所提供的由式(I)表示的化合物或其药学上可接受的盐，和包含该化合物的药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中以及适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。例如其制剂配方的单位剂量中包含0.05-200mg式(I)的化合物或其药学上可接受的盐，优选地，制剂配方的单位剂量中包含0.1mg-100mg式(I)的化合物。
本发明的由通式(I)表示的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺、或者胃肠道等的给药途径。最优选为口服。最佳优选日剂量为0.01-200 mg/kg体重，一次性服用，或0.01-100 mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。
本发明中，术语“有效量”可指为实现预期的效果所需的剂量和时段的有效的量。此有效量可能因某些因子而产生不同的变化，如疾病的种类或治疗时疾病的病症、被施用的特定标的器官的构造、病人个体大小、或疾病或症状的严重性。本领域具有通常知识者不需要过度实验即可凭经验决定特定化合物的有效量。
典型的配方是通过混合本发明的通式(I)表示的化合物及载体、稀释剂或赋形剂制备而成。适宜的载体、稀释剂或赋形剂是本领域技术人员所熟知的，包括诸如碳水化合物、蜡、水溶性及/或可膨胀性聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等物质。
所用的特定载体、稀释剂或赋形剂，将根据本发明的化合物的使用方式和目的而定。一般以本领域技术人员认为可安全有效地给药至哺乳类动物的溶剂为基础而选择溶剂。一般而言，安全的溶剂是无毒性含水溶剂诸如水，以及其他可溶于水或与水混溶的无毒性溶剂。适宜的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(如PEG400、PEG300)等中的一种或多种。该配方也可包括一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使该药物以可被接受的形式制造或使用。
本发明所述的如式(I)的化合物与至少一种其它药物的组合使用时，两种药物或多种药物可以分开使用也可以组合使用，优选以药学组合物的形式给药。本发明的如式(I)的化合物或药物组合物能以任一已知的口服、静脉注射、直肠给药、阴道给药、透皮吸收、其它局部或全身给药形式，分开或一起给药至受试者。
这些药物组合物亦可含有一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使该药物组合物以可被接受的形式制造或使用。
本发明药物优选口服给药途径。用于口服给药的固态剂型可包括胶囊、片剂、粉末或颗粒制剂。在固态剂型中，本发明的化合物或药物组合物与至少一种惰性赋形剂、稀释剂或载剂混合。适宜的赋形剂、稀释剂或载剂包括诸如柠檬酸钠或磷酸二钙的物质，或淀粉、乳糖、蔗糖、甘露糖醇、硅酸等；粘合剂如羧甲基纤维素、褐藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等；湿润剂如甘油等；崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、特定的络合硅酸盐、碳酸钠等；溶液阻滞剂如石蜡等；吸收促进剂如季铵化合物等；吸附剂如高岭土、膨润土等；润滑剂如滑石、硬脂酸钙、硬脂酸镁、固态聚乙二醇、月桂基硫酸钠等。在胶囊与片剂的情况下，该剂型亦可包括缓冲剂。类似类型的固态组合物亦可作为软式与硬式填充明胶胶囊中的填料，其使用乳糖以及高分子量聚乙二醇等作为赋形剂。
用于口服给药的液态剂型包括药学上可接受的乳化液、溶液、悬浮液、糖浆液与酏剂。除了本发明的化合物或其药物组合物之外，该液态剂型可含有本领域中常用的惰性稀释剂，诸如水或其他溶剂；增溶剂及乳化剂诸如乙醇、异丙基醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺；油类（如棉籽油、落花生油、玉米胚芽油、橄榄油、蓖麻油、芝麻油等）；甘油；四氢糠基醇；聚乙二醇与脱水山梨糖醇的脂肪酸酯；或这些物质中的几种的混合物等。
除了这些惰性稀释剂之外，该组合物也可包括赋形剂，诸如润湿剂、乳化剂、悬浮剂、增甜剂、调味剂与香料剂中的一种或多种。
就悬浮液而言，除了本发明的由通式(I)表示的化合物或其药学上可接受的盐或者包含其的药物组合物之外，可进一步含有载剂诸如悬浮剂，如乙氧基化异硬脂醇、聚氧乙烯山梨醣醇、脱水山梨醣醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及黄耆胶，或这些物质中几种的混合物等。
本发明的由通式(I)表示的化合物或其药学上可接受的盐或者包含其的药物组合物可采用其它局部给药剂型给药，包括膏、粉末、喷剂及吸入剂。该药物可在无菌条件下与药学上可接受的赋形剂、稀释剂或载剂以及所需要的任一防腐剂、缓冲剂或推进剂混合。眼用配方、眼用油膏、粉末与溶液，亦意欲涵盖于本发明的范围内。
此外，本公开还涵盖了试剂盒（例如制药包装）。提供的试剂盒可以包含本文所述的药物组合物或化合物和容器(例如，药瓶、安瓿、瓶子、注射器和/或分装包装或其它合适的容器)。在一些实施方式中，提供的试剂盒可以任选地进一步包括第二容器，其包含用于稀释或悬浮本文所述的药物组合物或化合物的药用赋形剂。在一些实施方式中，设置在第一容器和第二容器中的本文所述的药物组合物或化合物组合形成一个单元剂量形式。
在某些实施方式中，本文所述试剂盒进一步包括包含于试剂盒中的用于使用所述化合物或药物组合物的用法说明。本文所述的试剂盒还可以包括管理机构（如美国食品药品监督管理局(FDA)）所要求的信息。在某些实施方式中，在试剂盒中包括的信息为处方信息。在某些实施方式中，试剂盒和用法说明提供用于治疗需要其的受试者的增殖性疾病和/或预防需要其的受试者的增殖性疾病。本文所述的试剂盒可以包含一种或多种额外的药物制剂作为单独的组合物。
以下结合具体的实施例对本发明做进一步详细的说明，但本发明不限于以下实施例，实施例是为了更好的阐释本发明的某些具体体现而不能被解释为以任何方式限定本发明的范围。实施例中未注明的条件为常规条件。除非特别说明，以下实施例中使用的试剂和仪器均为市售可得产品。
以下实施例中化合物的结构是通过核磁共振（NMR）或/和质谱（MS）来确定的。NMR位移（δ）以10-6（ppm）的单位给出。NMR的测定使用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲亚砜（DMSO-d6）、氘代氯仿（CDCl3）、氘代甲醇（CD3OD），内标为四甲基硅烷（TMS）。
MS的测定用FINNIGAN LCQAd（ESI）质谱仪（生产商：Thermo，型号：Finnigan LCQadvantage MAX）。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法（TLC）使用的硅胶板采用的规格是0.15 mm-0.2 mm，薄层层析分离纯化产品采用的规格是0.4 mm-0.5 mm。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例中无特殊说明，反应的温度为室温，为20摄氏度-30摄氏度。
实施例中的反应进程的检测采用薄层色谱法（TLC），所使用的展开剂体系，以及纯化化合物采用的柱层析的洗脱机体系包括有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮和石油醚体系，溶剂的体积比例根据化合物的极性不同而进行调节。
实验中所用缩写语：eq，当量；h，小时；DCM，二氯甲烷。
实施例1：化合物1的制备
按照如下路线制备化合物1。
步骤1：中间体1-2的合成
将化合物1-1（4 g，18.5 mmol）溶于乙酸乙酯（70 ml）中，加入水（35 ml）、碳酸氢钠固体（4.66 g，55.5 mmol）、苄氧羰基氯（3.42 ml，24 mmol），室温搅拌2小时。反应结束后，分液得有机相，用水（100 ml *2）洗涤，干燥，浓缩，柱层析（石油醚:乙酸乙酯=10:1~5:1）得中间体1-2（6.83 g，无色液体）。
往三口烧瓶中加入20ml水和0.67g氢氧化钠（1eq），搅拌溶清后，加入胺1-1（2g，1eq）。将体系冷至10℃，加入二硫化碳（1.34g，1.05eq），加毕室温搅拌1h后，加入氯乙酸钠（2.15g，1.1eq），室温搅拌过夜。次日TLC检测（DCM:MeOH=20:1）原料消失后将体系用冰水浴冷却，加盐酸调pH至1-2，有固体析出来，抽滤，得到滤饼1-2。不用烘干和纯化，直接投入下一步反应。
步骤2：中间体1-3的合成
将上述得到的滤饼转移到单口烧瓶里，加入20ml水， 85%水合肼（3.9g，4eq），升温至80℃反应2h，体系先溶清，然后开始析出固体。TLC（DCM:MeOH=20：1）检测原料消失后将体系用水浴冷却，抽滤，得滤饼1-3（5.6g），直接用于下一步反应。
MS m/z (ESI): 194.1[M+1].
步骤3：化合物1的合成
将中间体1-3（439mg，1eq）溶于乙醇（6 ml）和水（6ml）中，加入3滴冰醋酸，然后加入二吡啶酮1-4（500mg，1.1eq）。体系升温至70℃反应6h。TLC(DCM:MeOH=20:1)检测原料消失后，将体系用冰水浴冷却，抽滤，滤饼烘干，得到367.9mg化合物1，黄色固体。
1H NMR (400 MHz,DMSO-d 6): 14.99 (s, 1H), 8.80 (d, J=8.0Hz, 1H), 8.63(d, J=8.0Hz, 1H), 8.44 (brs, 1H), 8.02-7.92 (m, 3H), 7.62-7.59 (m, 2H), 7.51(d, J=12.0Hz, 1H), 7.34 (d, J=8.0Hz, 1H), 7.23-7.20 (m, 1H), 7.10-7.06 (m,1H), 4.46 (t, J=8.0Hz, 2H), 3.32 (d, J=8.0Hz, 2H).
MS m/z (ESI): 360.1[M+1].
以下实施例2-12的化合物使用类似于实施例1描述的合成路线制备，仅对涉及到的部分原料进行替换。实施例编号、化合物结构和结构表征列于下表：
测试实施例1：化合物对RKO细胞的抑制活性试验
本实验旨在验证本发明化合物对人结肠癌细胞RKO的抑制活性。
主要试剂：
细胞株RKO、EMEM培养基、FBS、Cell Counting Kit-8 (CCK-8)、DPBS、TrypLETMExpress Enzyme。
主要耗材与仪器：
T75细胞培养瓶、96孔细胞培养板、CO2恒温培养箱、Eppendorf 离心机、酶标仪（BioTekCytation 3，配备活细胞培养装置，软件版本Gen5 3.05）。
实验方法：
2 x 106 RKO细胞（购自ATCC）接种于T75培养瓶，用加10%FBS、1%青霉素链霉素的EMEM（均购自Gibco）培养2天，37度，5% CO2。第3天时，倒去培养基，并用DPBS洗一次。加入2mlTrypLETM Express Enzyme（购自Gibco）在室温消化至细胞变圆。加入5 ml新鲜培养基，吹打并收集细胞。1000 rpm离心5分钟。弃去上清，用新鲜培养基重悬细胞并计数。在96孔板中每孔接种200 µl 10000个细胞，37度，5% CO2培养过夜。第二天，吸弃孔中培养基后，排枪加入200 µl每孔的梯度培养基稀释化合物（1% DMSO，起始终浓度200 nM，5倍稀释，3复孔，共6个浓度点），继续培养72小时。加入 CCK-8 试剂 10 μl/孔，放回CO2恒温培养箱100 min后，将该板置于Cytation 3 酶标仪上，读取450 nm 吸光值。
数据分析：IC50结果由GraphPad Prism 8.0软件进行分析。
具体测试数据见下表1。
结论：本发明中化合物显示了良好的结肠癌细胞抑制活性。
测试实施例2：化合物对A549细胞的抑制活性试验
本实验旨在验证本发明化合物对人非小细胞肺癌A549的抑制活性。
主要试剂：
细胞株A549、F12K培养基、FBS、Cell Counting Kit-8 (CCK-8)、DPBS、TrypLETMExpress Enzyme。
主要耗材与仪器：
T75细胞培养瓶、96孔细胞培养板、CO2恒温培养箱、Eppendorf 离心机、酶标仪（BioTekCytation 3，配备活细胞培养装置，软件版本Gen5 3.05）。
实验方法：
2 x 106 RKO细胞（购自ATCC）接种于T75培养瓶，用加10%FBS、1%青霉素链霉素的F12K（均购自Gibco）培养2天，37度，5% CO2。第3天时，倒去培养基，并用DPBS洗一次。加入2mlTrypLETM Express Enzyme（购自Gibco）在室温消化至细胞变圆。加入5 ml新鲜培养基，吹打并收集细胞。1000 rpm离心5分钟。弃去上清，用新鲜培养基重悬细胞并计数。在96孔板中每孔接种200 µl 5000个细胞，37度，5% CO2培养过夜。第二天，吸弃孔中培养基后，排枪加入200 µl每孔的梯度培养基稀释化合物（1% DMSO，起始浓度200 nM，5倍稀释，3复孔，共6个浓度点），继续培养72小时。加入 CCK-8 试剂 10 μl/孔，放回CO2恒温培养箱100 min后，将该板置于Cytation 3 酶标仪上，读取450 nm 吸光值。
数据分析：IC50结果由GraphPad Prism 8.0软件进行分析。
具体测试数据见下表2。
结论：本发明中化合物显示了良好的非小细胞肺癌细胞抑制活性。
测试实施例3：药代动力学评价：
供试品配制：
配制终浓度为3mg/mL的供试品用于口服给药。
口服组供试品配制溶剂为含0.5% 羟丙基甲基纤维素，10%乙醇，10%吐温80和79.5%蒸馏水的混合溶液，给药体积为0.2mL。
实验动物：
种属&品系：ICR小鼠
实验动物来源：上海西普尔-必凯实验动物有限公司。
给药时周龄：给药开始时6-8 周。
给药时体重：给药开始时 17-21g。
动物数与性别：9只，雄性，其中3只为备用小鼠。
实验方案：
实验选用9只体重相近的ICR雄性小鼠，口服给予剂量为16mg/kg 化合物3，单次给药。给药后0.5h、1h、2h、4h、8h、24h采集血样。采用LC-MS/MS分析方法检测血浆中化合物3的含量，血浆定量下限为10ng/mL。使用代谢动力学数据分析软件WinNonlin 7.0对血浆浓度数据进行统计，利用非房室模型法（NCA）计算药代参数。
化合物3在ICR小鼠血浆的主要药代动力学参数见下表：
结论：本发明的化合物药代吸收良好，具有良好的成药性质。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
Claims (10)
1.一种以下式(I)表示的化合物及其异构体或其药学上可接受的盐，
(I)
其中，
R1选自氢、氘、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、苯基或吡啶；所述苯基或吡啶可被一个或多个选自卤素、羟基、C1-3烷氧基、-NR3aR3b的取代基取代；所述R3a和R3b独立地选自氢、C1-6烷基或C3-6环烷基，或者R3a、R3b与其共同相连的-N-一起组成一个四至八元饱和或不饱和杂环；
R2为1个或多个选自氢、氘、卤素、氰基、C1-3烷基或-OC1-3烷基的基团；
m为0，1或2；
n为1，2或3。
2.根据权利要求1所述的由式(I)表示的化合物及其异构体或其药学上可接受的盐，其特征在于，R1选自苯基或吡啶；所述苯基或吡啶可被一个或多个选自卤素、羟基、C1-3烷氧基、-NR3aR3b的取代基取代；所述R3a和R3b独立地选自氢、C1-6烷基或C3-6环烷基，或者R3a、R3b与其共同相连的-N-一起组成一个四至八元饱和或不饱和杂环。
3.根据权利要求2所述的由式(I)表示的化合物及其异构体或其药学上可接受的盐，其特征在于，R1选自苯基或吡啶。
4.根据权利要求1所述的由式(I)表示的化合物及其异构体或其药学上可接受的盐，其特征在于，R2为1个选自氢、氘、卤素、氰基、C1-3烷基或-OC1-3烷基的基团。
5.根据权利要求1所述的由式(I)表示的化合物及其异构体或其药学上可接受的盐，其特征在于，m为0或1。
6.根据权利要求1所述的由式(I)表示的化合物及其异构体或其药学上可接受的盐，其特征在于，n为1，2或3。
7.根据权利要求1-6所述的由式(I)表示的化合物及其异构体或其药学上可接受的盐，其特征在于，选自于以下化合物：
8.根据权利要求1至7中任意一项所述的化合物及其药学上可接受的盐在制备肿瘤疾病治疗药物中的用途。
9.根据权利要8所述的化合物及其药学上可接受的盐在制备肿瘤疾病治疗药物中的用途，所述肿瘤疾病选自：肺癌、结直肠癌、胰腺癌、胰腺癌、肝癌、胃癌、食道癌、胆管癌、乳腺癌、卵巢癌、子宫颈癌、黑色素瘤、脑胶质瘤、前列腺癌、淋巴癌、白血病。
10.一种药物组合物，所述药物组合物包括治疗有效量的根据权利要求1至9中任意一项所述的化合物及其药学上可接受的盐以及药学上可接受的辅料。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010080559.5A CN111233837A (zh) | 2020-02-05 | 2020-02-05 | 一种缩氨基硫脲的化合物及其制备方法和用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010080559.5A CN111233837A (zh) | 2020-02-05 | 2020-02-05 | 一种缩氨基硫脲的化合物及其制备方法和用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111233837A true CN111233837A (zh) | 2020-06-05 |
Family
ID=70871455
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010080559.5A Pending CN111233837A (zh) | 2020-02-05 | 2020-02-05 | 一种缩氨基硫脲的化合物及其制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111233837A (zh) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4207400A1 (de) * | 1992-03-09 | 1993-09-16 | Bayer Ag | Hydrazone |
| WO2007027421A2 (en) * | 2005-08-16 | 2007-03-08 | Trustees Of Dartmouth College | Method for diagnosing non-small cell lung carcinoma |
| WO2010000008A1 (en) * | 2008-06-30 | 2010-01-07 | Desi Raymond Richardson | Thiosemicarbazone compounds and use thereof |
| WO2017058748A1 (en) * | 2015-09-29 | 2017-04-06 | Oncochel Therapeutics, Llc | Thiosemicarbazones |
| CN110713500A (zh) * | 2019-11-15 | 2020-01-21 | 广西师范大学 | 以2-苯甲酰吡啶缩氨基硫脲的钯配合物及其合成方法 |
-
2020
- 2020-02-05 CN CN202010080559.5A patent/CN111233837A/zh active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4207400A1 (de) * | 1992-03-09 | 1993-09-16 | Bayer Ag | Hydrazone |
| WO2007027421A2 (en) * | 2005-08-16 | 2007-03-08 | Trustees Of Dartmouth College | Method for diagnosing non-small cell lung carcinoma |
| WO2010000008A1 (en) * | 2008-06-30 | 2010-01-07 | Desi Raymond Richardson | Thiosemicarbazone compounds and use thereof |
| WO2017058748A1 (en) * | 2015-09-29 | 2017-04-06 | Oncochel Therapeutics, Llc | Thiosemicarbazones |
| CN110713500A (zh) * | 2019-11-15 | 2020-01-21 | 广西师范大学 | 以2-苯甲酰吡啶缩氨基硫脲的钯配合物及其合成方法 |
Non-Patent Citations (3)
| Title |
|---|
| ADELINE Y. LUKMANTARA等: "Structure–activity studies of 4-phenyl-substituted 2-benzoylpyridine thiosemicarbazones with potent and selective anti-tumour activity", 《ORG. BIOMOL. CHEM.》 * |
| DANIEL L. KLAYMAN等: "2-Acetylpyridine thiosemicarbazones. 2. N4,N4-Disubstituted derivatives as potential antimalarial agents", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| MOHAN, M.等: "Synthesis, characterization, and antitumor properties of some metal complexes of 2,6-diacetylpyridine bis(N4-azacyclic thiosemicarbazones)", 《JOURNAL OF INORGANIC BIOCHEMISTRY》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2021175199A1 (zh) | 一类芳香杂环类化合物及其在药物中的应用 | |
| WO2021143693A1 (zh) | 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用 | |
| TWI272272B (en) | Camptothecin derivatives having antitumor activity | |
| WO2021129824A1 (zh) | 新型K-Ras G12C抑制剂 | |
| CN112390788A (zh) | 一种用于抑制krasg12c突变蛋白的化合物及其制备方法和用途 | |
| US20230159529A1 (en) | Aromatic compound and application thereof in antitumor drug | |
| CN115433187B (zh) | 稠合的四环或五环二氢二氮杂䓬并咔唑酮的盐的结晶形式组合物及其用途 | |
| CN112300153B (zh) | 一种杂环化合物、药物组合物和用途 | |
| CN113880827A (zh) | 一种用于抑制krasg12c突变蛋白的化合物及其制备方法和用途 | |
| WO2021249563A1 (zh) | 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用 | |
| CN114195788A (zh) | 一类四环化合物及其用途 | |
| WO2024008129A1 (zh) | 作为kat6抑制剂的化合物 | |
| WO2020156189A1 (zh) | 喜树碱衍生物及其水溶性前药、包含其的药物组合物及其制备方法和用途 | |
| CN110003204B (zh) | 一种bet蛋白抑制剂、其制备方法及用途 | |
| CN112243437B (zh) | 含丙烯酰基的核转运调节剂及其用途 | |
| JP6854497B2 (ja) | インドールアミン−２，３−ジオキシゲナーゼ阻害剤としてのスルホニルアミディーン及びその製造方法と用途 | |
| CN111233837A (zh) | 一种缩氨基硫脲的化合物及其制备方法和用途 | |
| EP4116300A1 (en) | Crystal of tricyclic compound acting on crbn protein and preparation method therefor | |
| JP7329052B2 (ja) | フッ素含有置換ベンゾチオフェン化合物ならびにその医薬組成物および応用 | |
| WO2009033396A1 (en) | Dithiolopyrrolone compounds, the preparation and the use thereof | |
| JP2021531302A (ja) | アゼチジン誘導体のボレート | |
| WO2014183670A1 (zh) | 苯并咪唑酰胺类化合物及其制备方法和应用 | |
| CN116249683B (zh) | 氘甲基取代吡嗪并吡嗪并喹啉酮类衍生物、其制备方法及其在医药上的应用 | |
| CN113831346B (zh) | 多靶点抗肿瘤小分子及其衍生物、制法、药物组合物和应用 | |
| CN114409653A (zh) | 一种桥环并嘧啶并环类化合物及其用途 |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200605 |