CN116925009A - 一种含4-甲硫基苄基化合物及其制备方法与用途 - Google Patents
一种含4-甲硫基苄基化合物及其制备方法与用途 Download PDFInfo
- Publication number
- CN116925009A CN116925009A CN202310895118.4A CN202310895118A CN116925009A CN 116925009 A CN116925009 A CN 116925009A CN 202310895118 A CN202310895118 A CN 202310895118A CN 116925009 A CN116925009 A CN 116925009A
- Authority
- CN
- China
- Prior art keywords
- compound
- cancer
- acid
- pharmaceutically acceptable
- methylthiobenzyl
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 84
- -1 4-methylthio benzyl Chemical group 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 102000004243 Tubulin Human genes 0.000 claims abstract description 7
- 108090000704 Tubulin Proteins 0.000 claims abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- 239000011734 sodium Substances 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- 229940024606 amino acid Drugs 0.000 claims description 5
- 235000001014 amino acid Nutrition 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 229960005261 aspartic acid Drugs 0.000 claims description 3
- 235000003704 aspartic acid Nutrition 0.000 claims description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 235000014304 histidine Nutrition 0.000 claims description 3
- 229960002885 histidine Drugs 0.000 claims description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 3
- 229960003136 leucine Drugs 0.000 claims description 3
- 235000018977 lysine Nutrition 0.000 claims description 3
- 229960003646 lysine Drugs 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
- 208000037848 Metastatic bone disease Diseases 0.000 claims description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004473 Threonine Substances 0.000 claims description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 2
- 229960003767 alanine Drugs 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 229960003121 arginine Drugs 0.000 claims description 2
- 235000009697 arginine Nutrition 0.000 claims description 2
- 229960001230 asparagine Drugs 0.000 claims description 2
- 235000009582 asparagine Nutrition 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- 229960002433 cysteine Drugs 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 229960002989 glutamic acid Drugs 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 2
- 235000004554 glutamine Nutrition 0.000 claims description 2
- 229960002743 glutamine Drugs 0.000 claims description 2
- 229960002449 glycine Drugs 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 229960000310 isoleucine Drugs 0.000 claims description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 229930182817 methionine Natural products 0.000 claims description 2
- 229960004452 methionine Drugs 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 2
- 235000008729 phenylalanine Nutrition 0.000 claims description 2
- 229960005190 phenylalanine Drugs 0.000 claims description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 2
- 229960002429 proline Drugs 0.000 claims description 2
- 229960001153 serine Drugs 0.000 claims description 2
- 235000004400 serine Nutrition 0.000 claims description 2
- 235000008521 threonine Nutrition 0.000 claims description 2
- 229960002898 threonine Drugs 0.000 claims description 2
- 229960004799 tryptophan Drugs 0.000 claims description 2
- 229960004441 tyrosine Drugs 0.000 claims description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 2
- 235000002374 tyrosine Nutrition 0.000 claims description 2
- 229960004295 valine Drugs 0.000 claims description 2
- 239000004474 valine Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- VPXGOSNPXCNGAI-UHFFFAOYSA-N (4-methylsulfanylphenyl)methyl 2-morpholin-4-yl-5-nitrobenzoate Chemical compound C1=CC(SC)=CC=C1COC(=O)C1=CC([N+]([O-])=O)=CC=C1N1CCOCC1 VPXGOSNPXCNGAI-UHFFFAOYSA-N 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- AAPRNHKWNGDTOT-DVRVPOOOSA-N 2-[(3s)-3-(aminomethyl)piperidine-1-carbonyl]-n-[1-(cyclononen-1-ylmethyl)piperidin-4-yl]-9h-xanthene-9-carboxamide Chemical compound C1[C@H](CN)CCCN1C(=O)C1=CC=C(OC=2C(=CC=CC=2)C2C(=O)NC3CCN(CC=4CCCCCCCC=4)CC3)C2=C1 AAPRNHKWNGDTOT-DVRVPOOOSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 231100000782 microtubule inhibitor Toxicity 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 235000010980 cellulose Nutrition 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
- 238000000605 extraction Methods 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 3
- 229960004528 vincristine Drugs 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- 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 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102000029749 Microtubule Human genes 0.000 description 2
- 108091022875 Microtubule Proteins 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229940122429 Tubulin inhibitor Drugs 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 2
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000007928 intraperitoneal injection 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
- 230000000670 limiting effect Effects 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 210000004688 microtubule Anatomy 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-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
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 description 1
- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical class NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- AWQSAIIDOMEEOD-UHFFFAOYSA-N 5,5-Dimethyl-4-(3-oxobutyl)dihydro-2(3H)-furanone Chemical compound CC(=O)CCC1CC(=O)OC1(C)C AWQSAIIDOMEEOD-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 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
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 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
- 229920002261 Corn starch Polymers 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-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 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
- 229920002307 Dextran Polymers 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 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
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 239000001692 EU approved anti-caking agent Substances 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical class [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000021309 Germ cell tumor Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 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
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 229960000250 adipic acid Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 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
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-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
- 235000010233 benzoic acid Nutrition 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 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
- 150000001719 carbohydrate derivatives Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- WOWBFOBYOAGEEA-UHFFFAOYSA-N diafenthiuron Chemical compound CC(C)C1=C(NC(=S)NC(C)(C)C)C(C(C)C)=CC(OC=2C=CC=CC=2)=C1 WOWBFOBYOAGEEA-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 210000004024 hepatic stellate cell Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- DQOCFCZRZOAIBN-WZHZPDAFSA-L hydroxycobalamin Chemical compound O.[Co+2].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O DQOCFCZRZOAIBN-WZHZPDAFSA-L 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 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
- 239000004615 ingredient Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004924 lung microvascular endothelial cell Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 150000002696 manganese Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 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
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- GRRYSIXDUIAUGY-UHFFFAOYSA-N n-methylcarbamoyl chloride Chemical compound CNC(Cl)=O GRRYSIXDUIAUGY-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-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
- 229930014626 natural product Natural products 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 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
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 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
- 230000001717 pathogenic effect Effects 0.000 description 1
- 201000002628 peritoneum cancer Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000014101 wine Nutrition 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic 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
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种含4‑甲硫基苄基化合物及其制备方法与用途,所述含4‑甲硫基苄基化合物的结构式如式I所示,本发明所提供的含4‑甲硫基苄基化合物或其药用盐具有良好的微管蛋白抑制活性和优秀的抗肿瘤活性,可修饰性强,为抗肿瘤药物的进一步开发提供了研究基础。
Description
技术领域
本发明属于医药技术领域,具体地说,本发明涉及一种含4-甲硫基苄基化合物及其制备方法与抗肿瘤、抑制微管蛋白的用途。
背景技术
微管是细胞骨架的主要组成部分,在维持细胞形态、细胞分裂、信号转导等过程中起着重要作用,因此,微管蛋白是一个非常有前景的新型化疗药物的靶标。多种微管抑制剂已被用于一线治疗肿瘤,如紫杉醇用于治疗卵巢癌、乳腺癌、肺癌、大肠癌及黑色素瘤等,长春新碱用于治疗急性白血病、恶性淋巴瘤、生殖细胞肿瘤、小细胞肺癌及乳腺癌等,微管是肿瘤化疗中最成功的靶点之一。
尽管微管抑制剂在临床上广泛用于癌症治疗,但是耐药性肿瘤的出现限制了微管抑制剂在临床上的应用。瘤细胞中P-糖蛋白(P-glycoprotein)的高表达是耐药的重要原因之一。紫杉醇和长春新碱都是P-糖蛋白的底物,P-糖蛋白外排这些药物,降低药物在胞内的浓度,进而降低药物的抗肿瘤活性。临床常用微管抑制剂还存在其它技术缺陷,例如神经毒性、水溶性差以及难于合成纯化等。
IMB5046是本所研究发现的具有优秀抗肿瘤活性的微管蛋白抑制剂。研究发现,IMB5046靶向作用于秋水仙碱口袋,对A-431,HT-1080,HT29以及A549等肿瘤细胞均具有优秀的抑制活性(IC50=0.037-0.426μM)。值得一提的是,IMB5046对秋水仙碱,长春新碱,以及紫杉醇耐药的肿瘤细胞KBV200和MCF7/ADR均具有优秀的抑制活性(Resistance index=1.1-1.4)。另外,体内活性研究表明,IMB5046可显著抑制肿瘤的生长,在H460细胞裸鼠皮下移植瘤模型中,IMB5046腹腔注射给药20mg/kg抑瘤率达83%;在小鼠表皮癌细胞KB模型中,IMB5046腹腔注射给药15mg/kg抑瘤率达65.6%(Scitific Reports,2016,6,31472)。IMB5046相对于以上天然产物来源的微管蛋白抑制剂,具有结构简单,易合成的特点。然而,该化合物较差的水溶性(S<0.1mg/mL)限制了其进一步开发。
发明内容
本发明的目的之一是提供一组含4-甲硫基苄基化合物或其药用盐。
本发明的又一目是提供所述含4-甲硫基苄基化合物的合成方法。
本发明的再一目是提供含有所述含4-甲硫基苄基化合物或其药用盐的组合物。
本发明的另一目是提供以所述含4-甲硫基苄基化合物或其药用盐作为活性成分的药物组合物或药物制剂,以及该药物组合物在制备治疗或预防肿瘤相关疾病和抑制微管蛋白抑制药物方面的应用。
术语定义
在本文中用于本发明描述中的术语仅是为了描述具体实施方案而不作为对本发明的限制。本文所用命名和在本文所述的有机化学、药物化学、生物学中的实验室操作是本领域熟知的和常用的。除非另外提及,本文所用的全部技术和科学术语与本领域所属技术领域的一般技术人员通常所理解的具有相同的含义。
如在本发明实施方案和所附权利要求的描述中所用,单数形式的“一”、“一种”、“该”、“其”是指该冠词的单数和复数,除非上下文另外明确提及。例如,一种化合物包括一种或多于一种化合物。
如本文所用,“和/或”是指和包括一或多个相关的所列项目的任意和所有可能的组合。
如本文所用,术语“疾病”是指身体状态或一些器官的任意改变,中断或干扰其功能的实施和/或引起症状。
如本文所用,术语“肿瘤”是指机体在各种致病因素作用下,细胞异常增殖而形成的局部肿块,包括良性肿瘤、恶性肿瘤和交界肿瘤。包括但不局限于乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。
如本文所用,术语“治疗”目的是减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物或其药学上可接受的盐、异构体、多晶型物、溶剂合物、同位素标记的化合物、代谢物或前药,或其药物组合物,该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善,则受试者被成功地“治疗”了。还应当理解,所述的疾病状态或病症的治疗的不仅包括完全地治疗,还包括未达到完全地治疗,但实现了一些生物学或医学相关的结果。
如本文所用,术语“受试者”可以指患者或者其它接受本发明组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物,在本发明中尤其指人类和哺乳动物。
技术主题一
本发明提供了具有如式I所示结构的含4-甲硫基苄基化合物或其药用盐:
其中,X代表O或NH;
R1代表NO2、F或者CF3;
R2代表H、磷酰基、磺酰基、C1-C5烷基取代磺酰基、Ra和/或Rb取代的氨基甲酰基,或R2与其键连的O形成氨基酸酯基;
Ra和Rb独立的代表H、C1-C5烷基、羟基取代的C1-C5烷基、C1-C3烷基取代或未取代的氨基取代的C1-C5烷基,或Ra、Rb和它们共同键连的N连接成C1-C3取代或未取代的含氮五元或六元杂环。
在本发明的一些优选实施方案中,所述所述C1-C5烷基代表:
―CH3、―CH2CH3、―CH(CH3)2、―(CH2)2CH3、―(CH2)3CH3、―(CH2)4CH3、―CH(CH3)CH2CH3、―CH2CH(CH3)CH3、―C(CH3)3、―CH(CH3)(CH2)2CH3、
―CH2CH(CH3)CH2CH3、―CH2CH2CH(CH3)CH3、―C(CH3)2CH2CH3、―CH2C(CH3)2CH3、―CH2C(CH2)3;
所述C1-C5烷基取代磺酰基代表甲磺酰基、乙磺酰基、丙磺酰基、丁磺酰基、异丁磺酰基、戊磺酰基、异戊磺酰基;
所述氨基酸代表甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸(蛋氨酸)、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、苯丙氨酸、天冬酰胺、谷氨酰胺、苏氨酸、天门冬氨酸、谷氨酸、赖氨酸、精氨酸和组氨酸。
所述含氮五元-六元杂环代表哌嗪、哌啶、吗啉。
在本发明的一些优选实施方案中,所述R2选自
在本发明的一些优选实施方案中,所述式I所示的含4-甲硫基苄基化合物或其药用盐选自如下:
如本文所用,“药用盐”是指保留目标化合物的所需生物活性并表现出最小的不希望的毒理学效应的盐。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与本发明化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱包括无机碱及有机碱制备的盐,所述的无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。所述的有机无毒碱的盐,包括伯胺、仲胺和叔胺的盐,包括取取代胺和环状胺。例如:N,N'-二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺等。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例盐酸、氢溴酸、氢碘酸、硫酸、磷酸或硝酸等;有机酸例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡萄糖酸、3-羟基-2-萘甲酸、烟酸、巴莫酸、果胶酯酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、胺基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对-甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、海藻酸、马来酸、富马酸、D-葡萄糖酸、扁桃酸、抗坏血酸、葡庚糖酸、甘油磷酸、天冬胺酸、磺基水杨酸等包括钠、钾、镁、锂、铝、钙、锌、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因等形成的盐。
在本发明的一些优选实施方案中,所述药用盐选自钠盐、钾盐、钙盐、盐酸盐、磷酸盐或硫酸盐。
技术主题二
本发明还提供了式I所示含4-甲硫基苄基化合物的合成方法,虽然本发明化合物可通过如下的方法制得,然而该方法的条件,例如反应物、溶剂、酸、碱、所用化合物的量、反应温度、反应时间等不限于以下的描述。还可以任选将本说明书中描述的或本领域技术人员已知的各种合成方法的组合来方便地制得本发明的化合物,本发明所属领域的技术人员可以容易地进行上述组合。
路线2
路线3
技术主题三
本发明提供一种药物组合物,其包含式I所示的含4-甲硫基苄基化合物或其药用盐,以及药学上可以接受的载体或赋形剂。
如本文所用,“药物组合物”其中含有治疗有效量的所述式I所示含4-甲硫基苄基化合物或其药用盐,以及一种或多种药学上可接受的载体,制备成片剂、胶囊、颗粒剂、散剂、混悬剂、乳剂、粉剂、溶液、凝胶剂、糖浆剂、丸剂、酊剂、酒剂、煎膏剂、锭剂、合剂、栓剂、注射剂、吸入剂或喷雾剂等形式。该药物组合物优选含有重量比为0.1%-99.5%的本发明含4-甲硫基苄基化合物或其药用盐作为活性成分,更优选含有重量比为0.5%-99.5%的活性成分。
如本文所用,“药学上可接受的载体或赋形剂”包括:稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、粒化剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、增甜剂、调味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂,本领域技术人员将理解,某些药学上可接受的赋形剂可以以多于一种功能和以替代性功能来使用,取决于所述赋形剂在制剂中存在多少和在制剂中存在何种其它成分。例如:当用于口服时,可以制成口服制剂,如片剂、胶囊剂、颗粒剂和丸剂等,包含填充剂(例如糖类衍生物如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇;淀粉衍生物如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉;纤维素衍生物如结晶纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠;阿拉伯胶;右旋糖酐;硅酸盐衍生物如偏硅酸镁铝;磷酸盐衍生物如磷酸钙;碳酸盐衍生物如碳酸钙;硫酸盐衍生物如硫酸钙等)、粘合剂(例如明胶、聚乙烯吡咯烃酮和聚乙二醇)、崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烃酮)、润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)、矫味剂(例如常用的甜味剂、酸味剂和香料等)。当用于肠胃外时,可以制成注射剂,包括注射用无菌粉末与注射用溶剂,所用载体或赋形剂包含无菌水、林格氏液和等渗氯化钠溶液,也可根据药物的性质加入适宜的附加剂例如抗氧化剂、缓冲剂和抑菌剂。当用于直肠给药时,所述药物可以制成栓剂等。用于经肺给药时,所述药物可以制成吸入剂或喷雾剂等。有许多本领域技术人员可用的资源,这些资源描述了药学上可接受的赋形剂且其可用于选择合适的药学上可接受的赋形剂,例如《雷明登药学大全》、《中国药学年鉴》、《药剂学》等书籍。
本发明可以通过本领域已知的任何合适的方法来施用,例如,口服、静脉内、腹膜内、肌肉内、局部、透皮、经眼、经鼻、吸入、皮下、肌内、口含、舌下、直肠给予等方式,可以以1μg~2000mg/kg受试者体重的任何量施用如上所述的化合物,例如以1μg~1000mg/kg体重/天,50μg~1000mg/kg体重/天,100μg~1000mg/kg体重/天,1~500mg/kg体重/天,2~200mg/kg体重/天,5~100mg/kg体重/天量施用如上所述的化合物。在本发明的一些的实施方案中,可以以每日4次、每日3次、每日2次、每日1次、每两日1次、每周1次或其他间隔的方式施用如上所述的化合物,任选地酌情每周或每月重复如上所述的给药方案。在本发明中,所述化合物的给药剂量可根据患者或受试者的病情轻重、年龄、体重、性别、给药方式及疗程等因素进行调整。
本发明化合物可以单独使用,经也可以和另一种或多种其它活性成分联合用于治疗、预防、抑制或者改善疾病或者病状,其中药物的联合使用比任何一种药物的单独使用更为安全或者更为有效。这种其它药物可以以对此通常使用的途径和量与本发明的化合物同时或者依次给药。当本发明的化合物与一种或者多种其它药物同时使用时,在单位剂型中含有该其它药物和本发明的化合物的药物组合物是优选的,特别是与药学可接受的载体联合。然而,联合治疗还可以包括在不同重叠日程中给予本发明的化合物和一种或者多种其它药物的治疗。还可以预期,当与一种或者多种其它活性成分联合使用时,本发明化合物和其它活性成分可以以比各自单独使用时更低的剂量使用。因此,除了本发明的化合物外,本发明药物组合物还包括含有一种或者多种其它活性成分的那些组合物。
技术主题四
本发明还提供了式I所示含4-甲硫基苄基化合物或其药用盐在制备抑制微管蛋白活性药物中的应用。
进一步的,还提供了式I所示含4-甲硫基苄基化合物或其药用盐在抗肿瘤药物中的应用。
在一些实施方案中,所述肿瘤包括结直肠癌、乳腺癌、胃癌、肺癌前列腺癌、胰腺癌、肝癌、卵巢癌、黑色素瘤、脑癌、转移性骨病、A型淋巴瘤、胃肠癌、白血病。
发明的有益效果
本发明研制开发的化合物经验证对微管蛋白具有良好的抑制性,具有优秀的抗肿瘤活性,本申请系列化合物可进一步结构修饰形成磷酸酯盐或者氨基酸前药,从而提高水溶性,有望成为潜在的抗肿瘤药物。
具体实施方式
以下结合具体实施例阐述本发明,这些实施例不旨在限制本发明的范围,而是为本领域技术人员制备和使用本发明化合物、组合物和方法提供指导。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
本申请中描述的化合物的化学名称通常从ChemDraw Ultra(ChambridgeSoft)和生成/或通常遵循IUPAC命名法的原理。
实施例1化合物1a
室温下,向化合物3(10g,51mmol)的乙腈(130mL)溶液中加入3-溴丙烯(9.2g,76mmol),碳酸钾(14g,101mmol),在56℃下搅拌13小时。冷却反应液至室温,硅藻土过滤,滤液减压浓缩,乙酸乙酯(30mL)萃取三次,饱和食盐水水洗一次有机层,无水Na2SO4干燥,过滤,减压浓缩,进行柱层析(V石油醚:V乙酸乙酯=5:1)纯化得到化合物4,淡黄色固体(9.4g,收率78%)。
b)室温下,向化合物4(3.5g,14.7mmol)的DMF溶液(40mL)中加入甲硫醇钠(1.5g,21.4mmol),在45℃下搅拌过夜。次日冷却反应液至室温,加入200mL水,乙酸乙酯(40mL)萃取三次,饱和食盐水水洗一次有机层,无水Na2SO4干燥,过滤,减压浓缩,进行柱层析(V石油醚:V乙酸乙酯=2:1)纯化得到化合物5,白色固体(2.4g,收率69%)。
c)室温下,向化合物5(5.3g,22.3mmol)的甲醇:H2O(30mL:10mL)溶液中加入氢氧化锂(1.6g,66.9mmol),在45℃下搅拌3小时。反应液冷却至室温,减压浓缩除去甲醇,1MHCl调节pH=3,有固体析出,过滤,滤饼水洗,干燥得化合物6,白色固体。
d)氩气保护,0℃下向化合物6(840mg,4mmol)的无水THF(30mL)溶液中加入氢化铝锂(455mg,12mmol),搅拌10分钟后转移到室温下进行反应4小时。0℃下加入水(1mL),滴加10%NaOH(1mL),再分别加入两次水(1mL),室温下搅拌15分钟,硅藻土过滤,乙酸乙酯(20mL)萃取三次,饱和食盐水水洗一次有机层,无水Na2SO4干燥,过滤,减压浓缩,进行柱层析(V石油醚:V乙酸乙酯=2:1)纯化得化合物7,无色油状物(480mg,收率61%)。
e)室温下,向化合物7(420mg,2mmol)的二氯甲烷(15mL)溶液中加入8(756mg,3mmol)、EDCI(1.15g,6mmol)和催化量的DMAP,室温下搅拌过夜。用二氯甲烷(25mL)萃取三次,饱和食盐水水洗一次合并的有机层,无水Na2SO4干燥,过滤,减压浓缩,残留物进行柱层析(V石油醚:V乙酸乙酯=5:1)纯化得到化合物9,黄色油状(560mg,收率63%)。
f)氩气保护,向化合物9(4g,9mmol)的甲醇溶液(15mL)中加入(PPh3)4Pd(693mg,0.6mmol)搅拌5分钟后,再加入碳酸钾(3.7g,26.7mmol),室温下反应1小时。加入1M HCl调pH,二氯甲烷(25mL)萃取三次,饱和食盐水水洗一次合并的有机层,无水Na2SO4干燥,过滤,减压浓缩,柱层析(V石油醚:V乙酸乙酯=3:1)纯化得到化合物1a,黄色固体(1.2g,收率34%)。
1H NMR(500MHz,CDCl3)δ8.64(d,J=2.8Hz,1H),8.23(dd,J=9.2,2.8Hz,1H),7.50(d,J=7.9Hz,1H),7.07(s,1H),7.00–6.92(m,2H),6.66(s,1H),5.30(s,2H),3.77(t,J=4.7Hz,4H),3.19(t,J=4.7Hz,4H),2.34(s,3H);
13C NMR(151MHz,CDCl3)δ165.72,156.39,156.19,139.82,138.09,134.88,128.52,128.07,121.58,120.80,120.63,117.49,114.73,66.65,66.34,51.80,19.73;
MS-ESI(m/z):403.2[M-H]-。
实施例2化合物1b
制备方法同化合物1a,使用2-吗啉-5-氟苯甲酸为原料可制得无色油状化合物1b。
1H NMR(500MHz,CDCl3)δ7.52–7.44(m,2H),7.14(td,J=10.9,9.8,5.5Hz,1H),7.10–7.02(m,2H),6.96(d,J=7.9Hz,1H),6.66(s,1H),5.28(s,2H),3.74(t,J=4.5Hz,4H),2.96(t,J=4.6Hz,4H),2.33(s,3H);
13C NMR(151MHz,CDCl3)δ166.00,165.99,158.63,157.02,156.37,148.86,148.84,138.53,134.76,126.61,126.56,121.29,121.12,121.07,120.64,119.53,119.39,117.92,117.76,114.55,67.00,66.28,53.33,19.73;
MS-ESI(m/z):376.0[M-H]-
实施例3化合物2a
a)室温下,向化合物10(1g,7.3mmol)的乙腈(25mL)溶液中加入碳酸钾(2g,14.5mmol)和3-溴丙烯(1.3g,10.7mmol),57℃下反应3小时。反应液冷却至室温,硅藻土过滤,滤液减压浓缩,柱层析(V石油醚:V乙酸乙酯=5:1)纯化得到化合物11,白色固体(1.29g,收率100%)。
b)室温下,向化合物11(7.55g,42.6mmol)的DMF(50mL)溶液中加入甲硫醇钠(2.98g,42.5mmol),45℃下反应4小时。加入水(250mL),乙酸乙酯(50mL)萃取三次,饱和食盐水水洗一次有机层,无水Na2SO4干燥,过滤,滤液减压浓缩,柱层析(V石油醚:V乙酸乙酯=5:1)纯化得到化合物12,白色固体(7.29g,收率84%)。
c)氩气保护,0℃下向化合物12(2g,9.8mmol)的无水THF(30mL)溶液中加入氢化铝锂(1.1g,29.4mmol),0℃下搅拌10分钟后转移至室温,室温下反应5小时。0℃下加入水(2mL),再加入10%NaOH(2mL),最后再加入水(2mL)两次,室温下搅拌15分钟,硅藻土过滤,减压浓缩,乙酸乙酯(30mL)萃取三次,饱和食盐水水洗一次有机层,无水Na2SO4干燥,过滤,减压浓缩,残留物柱层析(V二氯甲烷:V甲醇:V氨水=10:1:0.05)纯化得到化合物13。
d)室温下,向化合物13(2.58g,12.3mmol)的二氯甲烷(35mL)溶液中加入EDCI(11.8g,61.5mmol)、化合物8(4.6g,18.3mmol)和催化剂量DMAP,室温下反应4小时。二氯甲烷(30mL)萃取三次,饱和食盐水水洗一次合并的有机层,无水Na2SO4干燥,过滤,滤液减压浓缩,残留物柱层析(V石油醚:V乙酸乙酯=3:1)纯化得到化合物14。
e)室温下,向化合物14(1.71g,3.9mmol)的甲醇(20mL)溶液中加入(PPh3)4Pd(222mg,0.2mmol)搅拌5分钟,随后加入K2CO3(1.6g,11.7mmol),室温下反应3小时,1M HCl调节pH,减压浓缩,乙酸乙酯(20mL)萃取三次,饱和食盐水水洗一次合并的有机层,无水Na2SO4干燥,过滤,滤液减压浓缩,残留物柱层析(V石油醚:V乙酸乙酯=3:1)纯化得到化合物2a,黄色固体(715mg,收率46%)。
1H NMR(500MHz,CDCl3)δ8.78(d,J=2.8Hz,1H),8.63(s,1H),8.22(dd,J=8.9,2.8Hz,1H),7.44(d,J=7.9Hz,1H),7.16(d,J=8.9Hz,1H),6.98(s,1H),6.95–6.85(m,2H),4.58(d,J=5.8Hz,2H),3.58(t,J=4.6Hz,4H),3.03(t,J=4.6Hz,4H),2.32(s,3H);
13C NMR(151MHz,CDCl3)δ164.78,156.69,155.46,143.60,140.73,135.23,128.30,127.45,126.97,120.88,120.66,119.53,114.39,66.41,52.88,43.61,19.85;
MS-ESI(m/z):402.0[M-H]-。
实施例4化合物2b
制备方法同化合物2a,使用2-吗啉-5-氟苯甲酸为原料可制得白色固体化合物2b:
1H NMR(500MHz,CDCl3)δ10.46(s,1H),7.95(dd,J=9.7,3.2Hz,1H),7.46(d,J=7.9Hz,1H),7.22(dd,J=8.8,4.8Hz,1H),7.14(ddd,J=8.8,7.2,3.2Hz,1H),7.00(d,J=1.9Hz,1H),6.90(dd,J=7.9,1.9Hz,1H),6.83(s,1H),4.59(d,J=5.5Hz,2H),3.52(t,J=4.6Hz,4H),2.88(t,J=4.6Hz,4H),2.31(s,3H);
13C NMR(126MHz,CDCl3)δ164.64,161.13,159.18,156.67,146.80,141.26,135.06,129.95,129.89,123.02,122.96,120.68,120.66,119.04,118.86,118.47,118.28,114.42,77.21(d,J=31.9Hz),66.89,53.70,43.56,19.88;
实施例5化合物2b-P
a)0℃下,向化合物2b(237mg,0.63mmol)的乙腈(8mL)溶液中滴加DIEA(220μl,1.26mmol),搅拌5分钟后滴加POCl3(193mg,1.25mmol),搅拌10分钟后转移至室温反应8小时。0℃下滴加饱和NaHCO3溶液(1mL),搅拌过夜。乙酸乙酯(20mL)萃取三次,保留水层,1MHCl调pH=3,乙酸乙酯(20mL)萃取两次,无水Na2SO4干燥合并的有机层,过滤,滤液减压浓缩。将残留物溶于甲醇,加入NaOH(50mg,1.25mg)室温搅拌30min,浓缩反应液,加入无水乙醚将残留物固化,过滤,甲醇冲洗滤饼,干燥滤饼,得到白色固体2b-P。
1H NMR(500MHz,D2O)δ7.52–7.39(m,2H),7.23(dt,J=13.4,5.1Hz,3H),7.09(d,J=7.8Hz,1H),4.52(s,2H),3.51(t,J=4.8Hz,4H),2.84(t,J=4.7Hz,4H),2.41(s,3H);
13C NMR(126MHz,D2O)δ158.06,146.91,135.37,126.18,122.71,122.35,119.10,118.95,118.78,116.45,116.26,66.66,52.61,43.34,13.81;
实施例6化合物2b-1
室温下,向化合物2b(100mg,0.27mmol)的二氯甲烷溶液(10mL)中加入三乙胺(111μl,0.81mmol)和DMAP(19mg,0.16mmol),随后加入甲氨基甲酰氯(50mg,0.54mmol),室温下反应5小时。反应液减压浓缩,柱层析(V二氯甲烷:V甲醇=80:1)纯化得到无色油状化合物2b-CH3(70mg,收率60%)。
1H NMR(500MHz,CDCl3)δ10.45(s,1H),7.95(dd,J=9.7,3.1Hz,1H),7.20(d,J=10.4Hz,3H),7.14(qd,J=7.3,6.4,3.2Hz,2H),4.61(d,J=5.6Hz,2H),3.53(s,4H),2.88(dt,J=7.1,3.6Hz,7H),2.43(s,3H)。
实施例7化合物2b-2
制备方法同化合物2b-1,使用二甲氨基甲酰氯和2b为原料可制得白色固体化合物2b-(CH3)2:
1H NMR(500MHz,CDCl3)δ10.43(s,1H),7.95(dd,J=9.7,3.1Hz,1H),7.23–7.18(m,3H),7.16–7.11(m,2H),4.61(d,J=5.6Hz,2H),3.55(t,J=4.4Hz,4H),3.13(s,3H),2.99(s,3H),2.88(t,J=4.6Hz,4H),2.42(s,3H)。
实施例8化合物2b-3
制备方法同化合物2b-1,使用1-哌啶酰氯和2b为原料可制得白色固体化合物2b-3。
1HNMR(500MHz,CDCl3)δ10.41(s,1H),7.95(dd,J=9.7,3.1Hz,1H),7.23–7.18(m,3H),7.17–7.10(m,2H),4.61(d,J=5.6Hz,2H),3.69–3.46(m,8H),2.88(t,J=4.6Hz,4H),2.42(s,3H),1.65(s,6H)。
实施例9化合物2b-4
制备方法同化合物2b-1,使用4-甲基哌嗪-1-甲酰氯和2b为原料可制得白色固体化合物2b-4:
1HNMR(500MHz,CDCl3)δ10.43(t,J=5.7Hz,1H),7.95(dd,J=9.7,3.1Hz,1H),7.22–7.18(m,3H),7.17–7.11(m,2H),4.61(d,J=5.6Hz,2H),3.73(s,2H),3.54(dd,J=11.0,6.6Hz,6H),2.87(t,J=4.6Hz,4H),2.46(d,J=16.8Hz,4H),2.42(s,3H),2.34(s,3H);
实施例10化合物2b-5
制备方法同化合物2b-1,使用二异丙基甲胺酰氯和2b为原料可制得白色固体化合物2b-5:
1HNMR(500MHz,CDCl3)δ10.40(s,1H),7.95(dd,J=9.7,3.2Hz,1H),7.22–7.20(m,3H),7.16–7.10(m,2H),4.62(d,J=5.6Hz,2H),4.12(s,1H),3.94(s,1H),3.57(t,J=4.3Hz,4H),2.88(t,J=4.6Hz,4H),2.42(s,3H),1.31(dd,J=29.6,6.8Hz,12H);
实施例11化合物2b-6
制备方法同化合物2b-1,使用N,N-二乙基氯甲酰胺和2b为原料可制得白色固体化合物2b-6:
1H NMR(500MHz,CDCl3)δ10.42(s,1H),7.95(dd,J=9.7,3.1Hz,1H),7.23–7.18(m,3H),7.17–7.09(m,2H),4.61(d,J=5.6Hz,2H),3.59–3.53(m,4H),3.47(q,J=7.1Hz,2H),3.36(q,J=7.1Hz,2H),2.88(t,J=4.6Hz,4H),2.42(s,3H),1.29(t,J=7.1Hz,3H),1.18(t,J=7.1Hz,3H);
实施例12化合物2b-7
制备方法同化合物2b-1,使用4-吗啉碳酰氯和2b为原料可制得白色固体化合物2b-7:
1H NMR(500MHz,CDCl3)δ10.44(s,1H),7.95(dd,J=9.7,3.1Hz,1H),7.24–7.19(m,3H),7.18–7.11(m,2H),4.61(d,J=5.6Hz,2H),3.73(d,J=16.9Hz,6H),3.58–3.52(m,6H),2.88(t,J=4.6Hz,4H),2.43(s,3H);
实施例13化合物2b-NH2.2HCl
a)室温下,向化合物2b(200mg,0.53mmol)的二氯甲烷溶液(10mL)中加入EDCI(508mg,2.65mmol)、DMAP(39mg,0.32mmol)和化合物15(230mg,1.06mmol),室温下反应三小时。二氯甲烷(20mL)萃取三次,饱和食盐水洗有机层,无水Na2SO4干燥,过滤,浓缩,柱层析(二氯甲烷/甲醇=100:1),得到无色油状化合物16。
b)室温下,向化合物16(190mg,0.33mmol)的二氯甲烷的溶液(8mL)中加入4M HCl的乙醚溶液(2mL),室温下搅拌4小时,过滤,二氯甲烷冲洗滤饼,干燥得白色固体2b-NH2.HCl。(107mg,收率68%)
1H NMR(500MHz,D2O)δ7.71–7.62(m,2H),7.51–7.38(m,3H),7.21(d,J=1.8Hz,1H),4.57(s,2H),4.40(d,J=4.2Hz,1H),3.83(t,J=4.6Hz,4H),3.33(t,J=4.4Hz,4H),2.62(tt,J=11.0,5.6Hz,1H),2.46(s,3H),1.18(t,J=7.4Hz,6H).
生物实施例1化合物对NCI-H460细胞毒活性
细胞培养:人肺癌细胞NCI-H460及A549、人肝癌细胞HepG2及SMMC-7721用含10%胎牛血清的RPMI-1640培养基(Hyclone公司)培养于37℃、5% CO2培养箱中。人乳腺癌细胞MCF7及MDA-MB-231、人微血管内皮细胞HMEC-1及人肝星状细胞LX2用含10%胎牛血清的DMEM培养基(Hyclone公司)培养于37℃、5% CO2培养箱。
细胞毒活性分析:取对数生长期的细胞按4000个/孔种96孔板,细胞贴壁过夜。加入不同待测药物,同时以IMB5046作为对照,设3个复孔。培养箱培养48小时,加入MTT(5mg/mL,20μL),继续培养4小时。酶标仪上(Multiskan MK3 microplate reader,ThermoLabsystems,Franklin,MA)检测570nm的光吸收值。
本发明设计合成了一系列含4-甲硫苄基化合物。部分化合物体外具有优秀的抗肿瘤活性,其中化合物2b(IC50=60nM)和2b-CH3(IC50=37nM)具有优于先导物的细胞毒活性。
表1化合物对NCI-H460细胞体外活性
生物实施例2化合物的水溶性
试验方法:称取样品6mg,将样品溶于1mL乙腈(HPLC)中,依次分别配置6mg/mL、0.6mg/mL、0.06mg/mL和0.006mg/mL的四个样品溶液。通过液相色谱在254nm下检测四个样品溶液,根据样品浓度和相应峰面积得到一条标准曲线。
再次称取样品6mg,在样品中加入1mL纯净水,超声24小时后通过液相色谱在254nm下检测样品溶液的峰面积。将样品水溶液的峰面积带入标准曲线,得到相应的水溶性。
表1-2化合物2b、2b-P和2b-NH2.HCl的水溶性
化合物 | 水溶性(mg/mL) |
2b | <0.1 |
2b-P | >5.0 |
2b-NH2.HCl | >0.5 |
IMB5046 | <0.1 |
最后应说明的是:以上实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明实施例技术方案的精神和范围。
Claims (10)
1.式I所示结构的含4-甲硫基苄基化合物或其药用盐:
其中,X代表O或NH;
R1代表NO2、F或者CF3;
R2代表H、磷酰基、磺酰基、C1-C5烷基取代磺酰基、Ra和/或Rb取代的氨基甲酰基,或R2与其键连的O形成氨基酸酯基;
Ra和Rb独立的代表H、C1-C5烷基、羟基取代的C1-C5烷基、C1-C3烷基取代或未取代的氨基取代的C1-C5烷基,或Ra、Rb和它们共同键连的N连接成C1-C3取代或未取代的含氮五元或六元杂环。
2.根据权利要求1所述的式I所示结构的含4-甲硫基苄基化合物或其药用盐,其特征在于,所述C1-C5烷基代表:
―CH3、―CH2CH3、―CH(CH3)2、―(CH2)2CH3、―(CH2)3CH3、―(CH2)4CH3、―CH(CH3)CH2CH3、―CH2CH(CH3)CH3、―C(CH3)3、―CH(CH3)(CH2)2CH3、―CH2CH(CH3)CH2CH3、―CH2CH2CH(CH3)CH3、―C(CH3)2CH2CH3、―CH2C(CH3)2CH3、―CH2C(CH2)3;
所述C1-C5取代磺酰基代表甲磺酰基、乙磺酰基、丙磺酰基、丁磺酰基、异丁磺酰基、戊磺酰基、异戊磺酰基;
所述氨基酸代表甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸(蛋氨酸)、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、苯丙氨酸、天冬酰胺、谷氨酰胺、苏氨酸、天门冬氨酸、谷氨酸、赖氨酸、精氨酸和组氨酸。
所述含氮五元或六元杂环代表哌嗪、哌啶、吗啉。
3.根据权利要求1所述的式I所示结构的含4-甲硫基苄基化合物或其药用盐,其特征在于,所述R2选自
4.根据权利要求1所述的式I所示结构的含4-甲硫基苄基化合物或其药用盐,其特征在于,所述药用盐选自钠盐、钾盐、钙盐、盐酸盐、磷酸盐或硫酸盐。
5.根据权利要求1所述的式I所示结构的含4-甲硫基苄基化合物或其药用盐,其特征在于,选自如下:
6.一种如权利要求1所述的化合物的制备方法,其特征在于,选自任一如下路线:路线1
路线2
路线3
7.药物组合物,其包含权利要求1-5任一项所述的式I所示结构的含4-甲硫基苄基化合物或其药用盐,以及任选地,一种或多种药学上可接受的载体或赋形剂。
8.根据权利要求1-5任一项所述的式I所示结构的含4-甲硫基苄基化合物或其药用盐在制备抑制微管蛋白的药物中的应用。
9.根据权利要求1-5任一项所述的式I所示结构的含4-甲硫基苄基化合物或其药用盐在制备抗肿瘤药物中的应用。
10.根据权利要求9所述应用,其特征在于,所述肿瘤包括结直肠癌、乳腺癌、胃癌、肺癌前列腺癌、胰腺癌、肝癌、卵巢癌、黑色素瘤、脑癌、转移性骨病、A型淋巴瘤、胃肠癌或白血病。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310895118.4A CN116925009A (zh) | 2023-07-20 | 2023-07-20 | 一种含4-甲硫基苄基化合物及其制备方法与用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310895118.4A CN116925009A (zh) | 2023-07-20 | 2023-07-20 | 一种含4-甲硫基苄基化合物及其制备方法与用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116925009A true CN116925009A (zh) | 2023-10-24 |
Family
ID=88387353
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310895118.4A Pending CN116925009A (zh) | 2023-07-20 | 2023-07-20 | 一种含4-甲硫基苄基化合物及其制备方法与用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116925009A (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10025830A1 (de) * | 1999-08-17 | 2001-02-22 | Novartis Ag | Neue Herbizide |
CN101287729A (zh) * | 2005-06-30 | 2008-10-15 | 普罗西迪恩有限公司 | Gpcr激动剂 |
CN105012307A (zh) * | 2015-07-08 | 2015-11-04 | 中国医学科学院医药生物技术研究所 | Imb5046化合物在制备抗肿瘤药物中的用途 |
CN109678815A (zh) * | 2019-01-09 | 2019-04-26 | 中国药科大学 | N-苄基苯甲酰胺类衍生物及其制备方法与制药用途 |
CN116283831A (zh) * | 2023-03-13 | 2023-06-23 | 中国医学科学院医药生物技术研究所 | 一种对硝基苯衍生物及其制备方法和应用 |
-
2023
- 2023-07-20 CN CN202310895118.4A patent/CN116925009A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10025830A1 (de) * | 1999-08-17 | 2001-02-22 | Novartis Ag | Neue Herbizide |
CN101287729A (zh) * | 2005-06-30 | 2008-10-15 | 普罗西迪恩有限公司 | Gpcr激动剂 |
CN105012307A (zh) * | 2015-07-08 | 2015-11-04 | 中国医学科学院医药生物技术研究所 | Imb5046化合物在制备抗肿瘤药物中的用途 |
CN109678815A (zh) * | 2019-01-09 | 2019-04-26 | 中国药科大学 | N-苄基苯甲酰胺类衍生物及其制备方法与制药用途 |
CN116283831A (zh) * | 2023-03-13 | 2023-06-23 | 中国医学科学院医药生物技术研究所 | 一种对硝基苯衍生物及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
JINXIN CHE ET AL.: "Discovery of 1, 5-Dihydro ‑ 4 H‑ imidazol-4-one Derivatives as Potent, Selective Antagonists of CXC Chemokine Receptor 2", ACS MEDICINAL CHEMISTRY LETTERS, vol. 12, pages 836 - 845 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106866571B (zh) | 杂环脲类化合物及其药物组合物和应用 | |
JP2008546653A (ja) | N2−キノリン又はイソキノリン置換のプリン誘導体及びその製造方法並びにその用途 | |
CN102153564B (zh) | 含氮原子的青蒿素二聚体、其制备方法及用途 | |
JPH11269146A (ja) | 分化誘導剤 | |
WO2016008411A1 (en) | 5-amino-4-carbamoyl-pyrazole compounds as selective and irreversible t790m over wt-egfr kinase inhibitors and use thereof | |
CN102131814B (zh) | 新型表鬼臼毒素的(多)氨基烷基氨基烷基酰胺、烷基-脲或烷基-磺酰胺衍生物、其制备方法及其作为抗癌剂在治疗中的用途 | |
CN106243183B (zh) | 熊果酸-硫化氢供体试剂衍生物及其合成方法 | |
US8470763B2 (en) | Alpha-amino-N-substituted amides, pharmaceutical composition containing them and uses thereof | |
CN116096372A (zh) | 一种egfr抑制剂、其制备方法和在药学上的应用 | |
US9353146B2 (en) | Acylation derivatives of paridis saponins I, preparation method therefor and application thereof | |
CN110981882B (zh) | 一类白屈菜碱一氧化氮供体衍生物及其制备方法和用途 | |
CN110183503B (zh) | 磺酰氮杂螺癸二烯酮类化合物及其用途 | |
KR20010013164A (ko) | 세포 증식 억제제로서의 시아노구아니딘 | |
CN116925009A (zh) | 一种含4-甲硫基苄基化合物及其制备方法与用途 | |
CN111961048B (zh) | 含取代β-咔啉结构的三氟甲基吡唑酰胺及其制备方法和应用 | |
CN113717138B (zh) | 一类氮芥类色原酮衍生物与应用 | |
CN103304575A (zh) | 新藤黄酸衍生物、其制备方法及医药用途 | |
CN110143934A (zh) | 一种含氟紫杉烷类化合物及其制备方法与应用 | |
CN110283174B (zh) | 一类PI3Kδ抑制剂及其用途 | |
CN118206507A (zh) | 一种含硒化合物及其制备方法与用途 | |
Zhao et al. | Discovery and optimization of 2-thio-5-amino substituted benzoquinones as potent anticancer agents | |
CN101230015B (zh) | 含酰胺取代基的取代桂皮酸衍生物及其肿瘤细胞毒性 | |
CN111393416B (zh) | 含1-甲基吡啶-3-(4-氯苯基)吡唑单元的吡唑化合物的制备方法和应用 | |
KR20200140248A (ko) | 비타민 c-백금 착체, 이의 중간체, 이의 제조 방법, 약물 조성물 및 용도 | |
PL225349B1 (pl) | Pochodne 2’,5’-dideoksy-5-fluorourydyny o działaniu cytotoksycznym, sposób ich wytwarzania i zastosowanie |
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 |