CN116253695A - Hsp90抑制剂及其制备方法和用途 - Google Patents
Hsp90抑制剂及其制备方法和用途 Download PDFInfo
- Publication number
- CN116253695A CN116253695A CN202211634345.3A CN202211634345A CN116253695A CN 116253695 A CN116253695 A CN 116253695A CN 202211634345 A CN202211634345 A CN 202211634345A CN 116253695 A CN116253695 A CN 116253695A
- Authority
- CN
- China
- Prior art keywords
- compound
- para
- meta
- ethyl acetate
- pharmaceutically acceptable
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 134
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 16
- 206010016654 Fibrosis Diseases 0.000 claims abstract description 10
- 230000004761 fibrosis Effects 0.000 claims abstract description 10
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 9
- 210000000056 organ Anatomy 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims description 22
- -1 methylene, ethylene, vinyl Chemical group 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 21
- 201000010099 disease Diseases 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 12
- 230000005764 inhibitory process Effects 0.000 abstract description 11
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 abstract description 10
- 101710113864 Heat shock protein 90 Proteins 0.000 abstract description 9
- 241000894006 Bacteria Species 0.000 abstract description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 230000001093 anti-cancer Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 225
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 68
- 239000000243 solution Substances 0.000 description 52
- 238000000034 method Methods 0.000 description 48
- 239000000203 mixture Substances 0.000 description 45
- 239000007787 solid Substances 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 44
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 239000000047 product Substances 0.000 description 36
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 34
- 239000003208 petroleum Substances 0.000 description 34
- 238000004440 column chromatography Methods 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 24
- 229910052786 argon Inorganic materials 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 239000010410 layer Substances 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- 239000012154 double-distilled water Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 239000011780 sodium chloride Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 14
- 238000001816 cooling Methods 0.000 description 13
- 239000012467 final product Substances 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- PHRZTXWNFAEVIA-UHFFFAOYSA-N hydroxylamine;potassium Chemical compound [K].ON PHRZTXWNFAEVIA-UHFFFAOYSA-N 0.000 description 10
- 239000007791 liquid phase Substances 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 108010006654 Bleomycin Proteins 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 229960001561 bleomycin Drugs 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 208000005069 pulmonary fibrosis Diseases 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 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 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229940125773 compound 10 Drugs 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 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 4
- 210000004072 lung Anatomy 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229940126086 compound 21 Drugs 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000000155 isotopic effect Effects 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- 150000002894 organic compounds Chemical group 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 208000024891 symptom Diseases 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
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-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
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 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
- 229930006000 Sucrose Natural products 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002671 adjuvant 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
- 239000002585 base Substances 0.000 description 2
- 125000006278 bromobenzyl group Chemical group 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 2
- 229960004884 fluconazole Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 230000000670 limiting effect Effects 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
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinyl group Chemical group C1(O)=CC(O)=CC=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 238000012384 transportation and delivery Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- 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 1
- HHXBZEIOUIMZET-UHFFFAOYSA-N (2,3-dichlorophenyl)-phenylphosphane Chemical compound ClC1=CC=CC(PC=2C=CC=CC=2)=C1Cl HHXBZEIOUIMZET-UHFFFAOYSA-N 0.000 description 1
- 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 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- 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 1
- 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 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 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
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 238000011752 CBA/J (JAX™ mouse strain) Methods 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 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-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 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
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 102100032510 Heat shock protein HSP 90-beta Human genes 0.000 description 1
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 1
- 101001016856 Homo sapiens Heat shock protein HSP 90-beta Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 206010023421 Kidney fibrosis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 101000988090 Leishmania donovani Heat shock protein 83 Proteins 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
- 206010025323 Lymphomas Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010062129 Tongue neoplasm Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 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
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000002411 adverse Effects 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
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000004075 alteration Effects 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
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-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
- 239000011230 binding agent Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 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
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000009787 cardiac fibrosis Effects 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 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
- 229940120124 dichloroacetate Drugs 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
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 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
- 239000008101 lactose Substances 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000314 lubricant Substances 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
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 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
- 238000000465 moulding Methods 0.000 description 1
- VQSRKMNBWMHJKY-YTEVENLXSA-N n-[3-[(4ar,7as)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H](CN(C2)C=2N=CC(F)=CN=2)CSC(N)=N3)=C1 VQSRKMNBWMHJKY-YTEVENLXSA-N 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002916 oxazoles Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001184 polypeptide 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
- 239000013641 positive control Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 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
- 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
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000012747 synergistic agent Substances 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
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-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
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229940075466 undecylenate Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/65031—Five-membered rings having the nitrogen atoms in the positions 1 and 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/653—Five-membered rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了HSP90抑制剂、或其药用盐,或包含其的药物组合物及其制备方法和用途。本发明提供的通式(I)的化合物可用作HSP90抑制剂,其可用于预防和/或治疗HSP90相关的疾病,比如肿瘤、癌症、器官纤维化,还可用于抗菌。本发明中涉及的所有通式(I)的化合物都为HSP90抑制剂,具有更强的HSP90抑制活性,尤其是抗肿瘤、抗癌、抗器官纤维化和抗菌活性。
Description
技术领域
本发明涉及药物合成领域,具体涉及HSP90抑制剂或其药用盐,及其制备方法和用途。
背景技术
HSP90是一种重要的治疗多种人类疾病的靶标,包括抗肿瘤、抗器官纤维化、抗菌等。目前还没有任何一款HSP90抑制剂上市用于治疗疾病,因此仍然急需开发新型的HSP90抑制剂。
发明内容
基于上述现有技术的需要,本发明提供一种HSP90抑制剂或其药用盐,包含其的药物组合物及其制备方法和用途。
本发明的第一方面提供一种通式(I)所示的化合物或其药用盐:
其中:R1选自烷基、芳基、亚甲基芳基和卤素组成的组;优选地,卤素为氟原子、氯原子;
R2选自对位或间位-O-Ph-CONHOH、对位或间位-O-CH2-Ph-CONHOH、对位或间位-O-Ph-CH=CH-CONHOH、对位或间位-CONHOH、对位或间位-CH=CH-CONHOH、对位或间位-SOCH3、对位或间位-SO2CH3、对位或间位-PO(CH3)2和对位或间位-NO2组成的组;
L为不存在任何取代基或者L选自烷基、乙烯基、乙炔基组成的组;其中烷基优选为-(CH2)n-,最优选为-(CH2)1-2-;
X为O或NH。
优选地,所述R1选自C1-6烷基、C6-10芳基、亚甲基(C6-10芳基)、氟原子、氯原子组成的组。
优选地,所述R2选自对位或间位-O-Ph-CONHOH、对位或间位-O-CH2-Ph-CONHOH、对位或间位-O-Ph-CH=CH-CONHOH、对位或间位-CONHOH、对位或间位-CH=CH-CONHOH、对位或间位-SOCH3、对位或间位-SO2CH3、对位或间位-PO(CH3)2和对位或间位-NO2组成的组
优选地,所述X为O或NH。
优选地,所述L为不存在任何取代基或者L选自亚甲基、乙撑基、乙烯基、乙炔基组成的组。
在本发明的一些实施方案中,所述化合物或其药用盐中的化合物选自表1。
本发明的第二方面提供一种药物组合物,其包含有效量的上述化合物或其药用盐,和任选的药用赋形剂或药用载体。
本发明的第三方面提供上述化合物或其药用盐,或上述药物组合物在制备HSP90抑制剂中的用途。
本发明的第四方面提供所述HSP90抑制剂用于预防和/或治疗肿瘤、癌症或器官纤维化。
本发明的第五方面提供所述HSP90抑制剂用于抗菌的用途。
本发明的有益效果至少包括:
本发明的HSP90抑制剂或其药用盐、或药物组合物可用于预防和/或治疗HSP90相关的疾病,比如肿瘤、癌症、器官纤维化,还可用于抗菌。本发明涉及的所有通式(I)的化合物都为HSP90抑制剂,具有更强的HSP90抑制活性,尤其是抗肿瘤、抗癌、抗器官纤维化和抗菌活性。
本发明的特征和优点将在随后的具体实施方式部分予以详细说明。
附图说明
图1(a)和图1(b)显示本发明中112个代表化合物对HSP90在200nM下的抑制率结果。
图2(a)和图2(b)显示本发明中112个代表化合物对A549肺癌细胞和肺成纤维细胞HLF-1的增殖抑制活性。
图3显示化合物HH-69对肿瘤的抑制活性。
图4显示化合物HH-69逆转小鼠肺纤维化。
具体实施方式
为了使本发明的目的、技术方案和有益效果更加清楚,下面结合附图和具体的实施方式对本发明作进一步详细的说明。所述实施例的示例在附图中示出。应理解,在下述本发明的实施方式中描述的具体的实施例仅作为本发明的具体实施方式的示例性说明,旨在用于解释本发明,而不构成对本发明的限制。
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值,这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说,各个范围的端点值之间、各个范围的端点值和单独的点值之间,以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围,这些数值范围应被视为在本文中具体公开。在本申请的描述中,除非另有说明,“一个/一种”、“多个/多种”等类似用词的含义是两个/种或两个/种以上。
【术语说明】
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本领域普通技术人员通常理解的含义。
如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。选自组成的组是指选自所列各项的至少一种或各项之一。
如本文所用,可在本领域的参考文献中找到对标准化学术语(如基团)的定义。
除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
如本文所用,术语“本发明的化合物”或“本发明的活性成分”可互换使用,指通式化合物的立体异构体、对映异构体,或其药用盐。该术语还包括外消旋体、光学异构体、同位素化合物(如氘代化合物)或前药。
“立体异构体”是指由相同原子组成,通过相同的键键合,但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时,除非另有说明,否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子,且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体,以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术进行拆分,例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成,或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)。
本发明还包括同位素标记的化合物,等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素。本发明中的化合物,或对映体,非对映体,异构体,或药用盐或溶剂化物,其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物,例如放射性同位素也在其中,在药物和底物的组织分布实验中是有用的。例如氚,即3H和碳14,即14C,它们的制备和检测比较容易。是同位素中的首选。此外,较重同位素取代如氘,即2H,由于其很好的代谢稳定性在某些疗法中有优势,例如在体内增加半衰期或减少用量,因此,在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法,通过用易得的同位素标记试剂替换为非同位素的试剂,用披露在示例中的方案可以制备。在本申请中,术语“药用盐”包括药用酸加成盐和药用碱加成盐。
“药用酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等。有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟甲酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、焦谷氨酸、枸橼酸盐、甲磺酸盐、苯磺酸盐、对甲基苯磺酸盐、羟乙磺酸盐等。这些盐可通过本专业已知的方法制备。
“药用碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,诸如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺等。这些盐可通过本专业已知的方法制备。
如本文所述,本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常,术语“取代”不论在术语“可选”前面或后面出现,在本发明配方中包括取代基的通式,是指用指定结构取代基,代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时,取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲,允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的,芳环的和非芳环的有机化合物。在本发明中,如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外,本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物,在足够长的时间内检测足以维持化合物结构的完整性,最好是在足够长的时间内都在效,本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本申请的权利要求中。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗癌症、肿瘤、器官纤维化以及抗菌等。在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。本文所用术语“药用”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中,“药用赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“癌症”或“肿瘤”包括但不限于淋巴瘤、肉瘤、黑色素瘤、肺癌、肝癌、乳腺癌、卵巢癌、前列腺癌、膀胱癌、胰腺癌、甲状腺癌、喉癌、舌癌、多发性骨髓瘤、白血病。适应症还包括器官纤维化,例如囊性纤维化、肺纤维化、心脏纤维化、肝脏纤维化、肾脏纤维化。适应症还包括抗菌,包括细菌(各种革兰氏阴性菌和革兰氏阳性菌)和真菌。
本文所用术语“预防”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术。在优选的实施方案中,本发明的化合物和组合物通过口服施用,适合用于口服施用的本文披露的化合物的配制品可以离散单元呈现,如各自含有预定量的活性成分的片剂、胶囊剂或扁囊剂。在其他优选的实施方案中,本发明的化合物和组合物是注射剂和粉剂。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。
除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。
活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为25-500mg,优选100-250mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法,包括步骤:将药用载体与本发明所述通式(I)化合物或其晶型、药用盐、水合物或溶剂合物进行混合,从而形成药物组合物。
本发明还提供了一种治疗方法,它包括步骤:给需要治疗的对象施用本发明中所述的化合物,或其药用盐,或施用本发明所述的药物组合物,用于抑制HSP90。
代表化合物编号、命名、结构及高分辨质谱结果如下表1所示:
通式(I)化合物的制备方法
需要注意的是,下面实施例中所用的各种材料和试剂都是本领域中常用的材料和试剂,均可通过市售获得;以下实施例中所提到的倍量为摩尔倍量。
合成路线一:
制备例1中间体1(本制备例中的产物6)的制备方法
方法与试剂:A:BF3OEt2,AcOH,90℃,16h;B:无水N,N-二甲基甲酰胺(dry DMF),BnBr,K2CO3,Ar,140℃,24h;C:NaH,无水四氢呋喃(dry THF),草酸二乙酯,Ar,0℃,0.5h,90℃,3h,回流(reflux);D:NH2OH.HCl,无水乙醇(dry CH3CH2OH),90℃,4h,回流(reflux);E:i):四氢呋喃(THF),H2O,LiOH,RT,24h;ii)EtNH2.HCl,HOBT,EDCI,ET3N,无水二氯甲烷(dryDCM),0℃,0.5h,RT 24h;F:CAN,NIS,无水乙腈(dry CH3CN),RT,24h。
具体步骤包括:
原料化合物(1倍量)溶于醚合三氟化硼(15倍量),并加入乙酸(5倍量)于圆底烧瓶中,用气球接收气体。90℃下搅拌反应16h。冷却至室温后,加入10%的NaOAC溶液适量,室温下搅拌半小时,混合液用乙酸乙酯萃取,饱和的氯化钠水溶液洗涤三次,乙酸乙酯层用无水硫酸钠干燥,经过柱层析纯化(石油醚:乙酸乙酯=30:1)得到纯品产物1位褐色固体。
化合物1(1倍量)溶于无水二氯甲烷,室温下并将无水碳酸钾(2.2倍量)、溴苄(2.2倍量)加入圆底烧瓶中,置换氩气,140℃下加热搅拌过夜。冷至室温,反应液中加水,有固体析出,抽滤,滤饼依次用水洗涤三次,石油醚洗涤三次,经过柱层析纯化(石油醚:乙酸乙酯=20:1),得到纯品土黄色化合物2。
化合物2(1倍量)溶于无水N,N-二甲基甲酰胺中,将针缓慢滴加入置换氩气后的氢化钠(4.0倍量)的两口瓶中,室温搅拌反应半小时,针缓慢加入草酸二乙酯(1.5倍量),90℃搅拌回流3h。冷至室温,用乙酸调PH至弱酸(PH=5),混合液中加水,乙酸乙酯萃取,饱和氯化钠溶液洗涤有机层三次,乙酸乙酯层用无水硫酸钠干燥半小时,经硅胶柱层析纯化(石油醚:乙酸乙酯=15:1),得到纯品产物3为亮黄色固体。
化合物3(1倍量)溶于无水乙醇,室温下将盐酸羟胺(1.5倍量)加入反应液中,90℃回流4h。冷至室温,浓缩反应液,加水,乙酸乙酯萃取,饱和氯化钠洗涤有机层,乙酸乙酯层用无水硫酸钠干燥。经硅胶柱层析纯化(石油醚:乙酸乙酯=10:1),得到纯品产物4为黄色化合物。
化合物4(1倍量)加入圆底烧瓶,加入四氢呋喃、1M氢氧化锂和水的混合液(v/v/v=2:1:1)。室温搅拌过夜。浓缩反应液,浓缩液加水,用1mol/L HCl调PH至酸性后,乙酸乙酯萃取,饱和氯化钠水溶液洗涤,无水硫酸钠干燥。干燥后的有机液过滤,浓缩后干燥箱干燥后置于圆底烧瓶中,用无水二氯甲烷溶解,冰浴下依次将乙胺盐酸盐(1.5倍量)、HOBT(1.5倍量)、EDCI(2倍量)、三乙胺(3.5倍量)加入反应液中,0℃反应半小时,撤掉冰浴,室温搅拌过夜,浓缩反应液,经硅胶柱层析纯化(石油醚:乙酸乙酯=8:1),得到产物5为黄色化合物。
将NIS(2.0倍量)、CAN(0.05倍量)加入化合物5(1倍量)的无水乙腈溶液,室温搅拌过夜,避光。蒸去乙腈,乙酸乙酯萃取,饱和氯化钠溶液洗涤有机层三次,乙酸乙酯层用无水硫酸钠干燥。经硅胶柱层析纯化(石油醚:乙酸乙酯=10:1),得到纯品产物6为白色化合物。
制备例2中间体2(本制备例中的终产物)的制备方法
方法与试剂:A:NaHCO3,Pd(PPh3)2Cl2,N,N-二甲基甲酰胺(DMF),H2O,Ar,80℃,24h;B:BCl3,无水二氯甲烷(dry DCM),-78℃,1h,RT,2h;C:NHOK,RT,24h。
具体步骤包括:
化合物6(1倍量)、化合物7(1.5倍量)、碳酸氢钠(3倍量)和双三苯基膦二氯化钯(0.01倍量)置于双口瓶中。将瓶中空气置换成氩气。加入氩气排过气的N,N-二甲基甲酰胺和水的混合液(v/v=5:1)。混合物于90℃反应过夜。冷却至室温后,用硅藻土过滤反应液,并用乙酸乙酯冲洗滤饼至没有荧光洗出。收集滤液用饱和氯化钠水溶液洗涤3次,乙酸乙酯层用无水硫酸钠干燥,经过柱层析纯化(石油醚:乙酸乙酯=15:1)得到纯品产物8为黄色固体。
化合物8(1倍量)用无水二氯甲烷溶解后,-78℃下,缓慢滴加三氯化硼(4倍量),搅拌反应1h,室温反应2h。浓缩反应液,后用甲醇溶解,再次浓缩,反复三次。经硅胶柱层析纯化(石油醚:乙酸乙酯=2:1)得到纯品产物9为淡黄色化合物。
最终化合物9溶于羟胺钾的无水甲醇溶液,室温搅拌过夜。减压蒸除甲醇后,加入双蒸水使残渣溶解,用1M HCl溶液调制PH值至6~7。过滤生成的固体,并用双蒸水清洗4次得到粗品终产物,粗品终产物利用高效液相纯化(甲醇:水=65%:35%)得到纯品白色固体终产物。
制备例3本发明的一种化合物的制备方法,其中,所述化合物的R2为对位-O-CH2-Ph-CONHOH,L为不存在任何取代基,X为O:
方法与试剂:A:K2CO3,CH3CN,RT,24h;B:BCl3;无水二氯甲烷(dry DCM),-78℃,1h,RT,2h;C:NaCO3,Pd(PPh3)2Cl2,二氧六环(dioxane),H2O,Ar,80℃,24h;D:NHOK,RT,24h。
具体步骤包括:
A:化合物10(1倍量)、化合物11(1.2倍量)、无水碳酸钾(3倍量)置于圆底烧瓶中,加入适量乙腈使之溶解,室温搅拌过夜。蒸去乙腈,加双蒸水,乙酸乙酯萃取,饱和氯化钠溶液洗涤三次,乙酸乙酯层用无水硫酸钠干燥。经过柱层析纯化(石油醚:乙酸乙酯=20:1)得到纯品产物12为白色固体。
化合物6(1倍量)用无水二氯甲烷溶解后,-78℃下,缓慢滴加三氯化硼(4倍量),搅拌反应1h,转至室温继续搅拌反应2h。浓缩反应液,后用甲醇溶解,再次浓缩,反复三次。残留物二氯甲烷溶解后经硅胶柱层析纯化(石油醚:乙酸乙酯=3:1)得到纯品产物13位淡黄色油状化合物。
化合物13(1倍量)、化合物12(2倍量)、无水碳酸钠(3倍量)和双三苯基膦二氯化钯(0.02倍量)置于双口瓶中。将瓶中空气置换成氩气。加入氩气排过气的二氧六环和水的混合液(v/v=4:1)。混合物于80℃反应过夜。冷却至室温后,用硅藻土过滤反应液,并用乙酸乙酯冲洗滤饼至没有荧光洗出。收集滤液用饱和氯化钠水溶液洗涤3次,乙酸乙酯层用无水硫酸钠干燥,经高效液相纯化(甲醇:水=70%:30%)得到纯品产物14位白色固体。
最终化合物14溶于羟胺钾的无水甲醇溶液,室温搅拌过夜。减压蒸除甲醇后,加入双蒸水使残渣溶解,用1M HCl溶液调制PH值至6~7。过滤生成的固体,并用双蒸水清洗4次得到粗品终产物,粗品终产物利用高效液相纯化(甲醇:水=65%:35%)得到纯品白色固体终产物。
R2为间位-O-CH2-Ph-CONHOH的产物制备方法与上述对位-O-CH2-Ph-CONHOH的制备方法一致,只是原料中化合物10的羟基为间位。
制备例4本发明的一种化合物的制备方法,其中,所述化合物的R2为对位-CH=CH-CONHOH,L为不存在任何取代基,X为O:
方法与试剂:A:Na2CO3,Pd(PPh3)2Cl2,DMF,H2O,Ar,80℃,5h;B:BCl3,无水二氯甲烷(dry DCM),-78℃,1h,RT,2h;C:NHOK,RT,24h。
具体步骤包括:
化合物6(1倍量)、化合物15(1.5倍量)、碳酸氢钠(3倍量)和双三苯基膦二氯化钯(0.02倍量)置于双口瓶中。将瓶中空气置换成氩气。加入氩气排过气的N,N-二甲基甲酰胺(DMF)和水的混合液(v/v=5:1)。混合物于80℃反应5h。冷却至室温后,用硅藻土过滤反应液,并用乙酸乙酯冲洗滤饼至没有荧光洗出。收集滤液用饱和氯化钠水溶液洗涤3次,乙酸乙酯层用无水硫酸钠干燥,经过柱层析纯化(石油醚:乙酸乙酯=10:1)得到纯品产物16为黄色油状化合物。
化合物16(1倍量)用无水二氯甲烷溶解后,-78℃下,缓慢滴加三氯化硼(4倍量),搅拌反应1h,室温反应2h。浓缩反应液,后用甲醇溶解,再次浓缩,反复三次。经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1)得到纯品产物17为淡黄色固体化合物。
最终化合物17溶于羟胺钾的无水甲醇溶液,室温搅拌过夜。减压蒸除甲醇后,加入双蒸水使残渣溶解,用1M HCl溶液调制PH值至6~7。过滤生成的固体,并用双蒸水清洗4次得到粗品终产物,粗品终产物利用高效液相纯化(甲醇:水=65%:35%)得到纯品为橘黄色固体。
R2为间位-CH=CH-CONHOH的产物的制备方法与对位-CH=CH-CONHOH的制备方法一致,只是原料中化合物15的-CH=CH-COOCH3为间位。
制备例5本发明的一种化合物的制备方法,其中,所述化合物的R2为对位-CONHOH,L为烷基,X为O:
方法与试剂:A:碳酸钠,四三苯基膦钯,二氧六环,水,氩气,90℃,24h;B:三氯化硼,无水二氯甲烷,-78℃,1h,室温,2h;C:羟胺钾,无水甲醇,室温,过夜。
具体步骤包括:
化合物6(1倍量)、化合物18(1.5倍量)、无水碳酸钠(3倍量)和四三苯基膦钯(0.02倍量)置于双口瓶中。将瓶中空气置换成氩气。注射加入氩气排过气的二氧六环和水的混合液(v/v=5:1)。混合物于90℃反应过夜。冷却至室温后,用硅藻土过滤反应液,并用乙酸乙酯冲洗滤饼至没有荧光洗出。收集滤液用饱和氯化钠水溶液洗涤3次,乙酸乙酯层用无水硫酸钠干燥,经过柱层析纯化(石油醚:乙酸乙酯=10:1)得到纯品产物19为白色固体化合物。
化合物19(1倍量)用无水二氯甲烷溶解后,-78℃下,缓慢滴加三氯化硼(4倍量),搅拌反应1h,转至室温后继续反应2h。浓缩反应液,后用甲醇溶解,再次浓缩,反复三次。经硅胶柱层析纯化(石油醚:乙酸乙酯=3:1)得到纯品产物20为淡黄色固体化合物。
最终化合物20溶于羟胺钾的无水甲醇溶液,室温搅拌过夜。减压蒸除甲醇后,加入双蒸水使残渣溶解,用1M HCl溶液调制PH值至6~7。过滤生成的固体,并用双蒸水清洗4次得到粗品终产物,粗品终产物利用高效液相纯化(甲醇:水=65%:35%)得到纯品为淡黄色固体终产物。
R2为间位-CONHOH终产物的制备方法与对位-CONHOH的制备方法一致,只是原料中化合物18的-COOCH3为间位。
制备例6本发明的一种化合物的制备方法,其中,所述化合物的R2为对位-O-Ph-CONHOH,L为不存在任何取代基,X为O:
方法与试剂:A:NaHCO3,Pd(PPh3)2Cl2,DMF,H2O,Ar,80℃,24h;B:Cu(OAc)2,吡啶,无水二氯甲烷,分子筛,氧气,RT,24h;C:BCl3,无水二氯甲烷(dry DCM),-78℃,1h,RT,2h;D:NHOK,无水甲醇,RT,24h。
具体步骤包括:
(一)化合物6(1倍量)、化合物10(2倍量)、碳酸氢钠(3倍量)和双三苯基膦二氯化钯(0.02倍量)置于双口瓶中。将瓶中空气置换成氩气。加入氩气排过气的N,N-二甲基甲酰胺和水的混合液(v/v=5:1)。混合物于80℃反应过夜。冷却至室温后,用硅藻土过滤反应液,并用乙酸乙酯冲洗滤饼至没有荧光洗出。收集滤液用饱和氯化钠水溶液洗涤3次,乙酸乙酯层用无水硫酸钠干燥,经过柱层析纯化(石油醚:乙酸乙酯=6:1)得到纯品产物21为黄色固体化合物。
化合物21(1倍量)、化合物7(1.1倍量)、醋酸铜(1.1倍量)和一定量的型分子筛置于双口瓶中。将瓶中空气置换成氧气。针管加入吡啶(5倍量)、无水二氯甲烷适量。混合物于室温搅拌反应过夜。用硅藻土过滤反应液,并用乙酸乙酯冲洗滤饼至没有荧光洗出。收集滤液用饱和氯化钠水溶液洗涤3次,乙酸乙酯层用无水硫酸钠干燥,经过柱层析纯化(石油醚:乙酸乙酯=8:1)得到纯品产物22为黄色固体化合物。
化合物22(1倍量)用无水二氯甲烷溶解后,-78℃下,缓慢滴加三氯化硼(4倍量),搅拌反应1h,室温反应2h。浓缩反应液,后用甲醇溶解,再次浓缩,反复三次。经硅胶柱层析纯化(石油醚:乙酸乙酯=1:1)得到纯品产物23为淡黄色固体化合物。
最终化合物23溶于羟胺钾的无水甲醇溶液,室温搅拌过夜。减压蒸除甲醇后,加入双蒸水使残渣溶解,用1M HCl溶液调制PH值至6~7。过滤生成的固体,并用双蒸水清洗4次得到粗品终产物,粗品终产物利用高效液相纯化(甲醇:水=65%:35%)得到纯品白色固体终产物。
R2为间位-O-Ph-CONHOH的产物的制备方法与R2为对位-O-Ph-CONHOH的制备方法一致,只是化合物10中的羟基为间位。
化合物21(1倍量)、化合物24(1.1倍量)、醋酸铜(1.1倍量)和一定量的型分子筛置于双口瓶中。将瓶中空气置换成氧气。针管加入吡啶(5倍量)、无水二氯甲烷适量。混合物于室温搅拌反应过夜。用硅藻土过滤反应液,并用乙酸乙酯冲洗滤饼至没有荧光洗出。收集滤液用饱和氯化钠水溶液洗涤3次,乙酸乙酯层用无水硫酸钠干燥,经过柱层析纯化(石油醚:乙酸乙酯=8:1)得到纯品产物25为黄色固体化合物。
化合物25(1倍量)用无水二氯甲烷溶解后,-78℃下,缓慢滴加三氯化硼(4倍量),搅拌反应1h,室温反应2h。浓缩反应液,后用甲醇溶解,再次浓缩,反复三次。经硅胶柱层析纯化(石油醚:乙酸乙酯=1:1)得到纯品产物26为淡黄色固体化合物。
最终化合物26溶于羟胺钾的无水甲醇溶液,室温搅拌过夜。减压蒸除甲醇后,加入双蒸水使残渣溶解,用1M HCl溶液调制PH值至6~7。过滤生成的固体,并用双蒸水清洗4次得到粗品终产物,粗品终产物利用高效液相纯化(甲醇:水=65%:35%)得到纯品白色固体终产物。
R2为间位-O-Ph-CH=CH-CONHOH的产物的制备方法与R2为对位-O-Ph-CH=CH-CONHOH的制备方法一致,只是化合物21中的羟基为间位。
制备例7本发明的一种化合物的制备方法,其中,所述化合物的R2为对位-CONHOH,L为烷基、烯基或炔基,X为O:
方法与试剂:A:CuI,Pd(PPh3)2Cl2,Et3N,MeCN,Ar,70℃,12h;B:BCl3,无水二氯甲烷(dry DCM),-78℃,1h,RT,2h;C:NHOK,RT,24h;D:Pd(OAc)2,PPh3,K2CO3,DMF,H2O;E:H2,10%Pd/C,CH3OH,RT,1h。
具体步骤包括:
化合物6(1倍量)、化合物27(1.2倍量)、碘化亚铜(0.05倍量)、二氯二三苯基膦钯(0.05倍量)置于双口瓶中。将瓶中空气置换成氩气。针管加入无水三乙胺(3倍量)、氩气鼓泡后的乙腈。混合物于70℃搅拌反应12h。用硅藻土过滤反应液,并用乙酸乙酯冲洗滤饼至没有荧光洗出。收集滤液用饱和氯化钠水溶液洗涤3次,乙酸乙酯层用无水硫酸钠干燥,经过柱层析纯化(石油醚:乙酸乙酯=10:1)得到纯品产物28为淡黄色固体。
化合物28(1倍量)用无水二氯甲烷溶解后,-78℃下,缓慢滴加三氯化硼(4倍量),搅拌反应1h,室温反应2h。浓缩反应液,后用甲醇溶解,再次浓缩,反复三次。经硅胶柱层析纯化(石油醚:乙酸乙酯=2:1)得到纯品产物29为淡黄色固体。
最终化合物29溶于羟胺钾的无水甲醇溶液,室温搅拌过夜。减压蒸除甲醇后,加入双蒸水使残渣溶解,用1M HCl溶液调制PH值至6~7。过滤生成的固体,并用双蒸水清洗4次得到粗品终产物,粗品终产物利用高效液相纯化(甲醇:水=60%:40%)得到纯品为淡黄色固体。
化合物6(1倍量)、化合物30(1.2倍量)、醋酸钯(0.05倍量)和三苯基膦(0.1倍量)置于双口瓶中。将瓶中空气置换成氩气。加入氩气排过气的N,N-二甲基甲酰胺和水的混合液(v/v=5:1)。混合物于100℃搅拌反应过夜。用硅藻土过滤反应液,并用乙酸乙酯冲洗滤饼至没有荧光洗出。收集滤液用饱和氯化钠水溶液洗涤3次,乙酸乙酯层用无水硫酸钠干燥,经过柱层析纯化(石油醚:乙酸乙酯=10:1)得到纯品产物31为淡黄色固体。
化合物31(1倍量)用无水二氯甲烷溶解后,-78℃下,缓慢滴加三氯化硼(4倍量),搅拌反应1h,室温反应2h。浓缩反应液,后用甲醇溶解,再次浓缩,反复三次。经硅胶柱层析纯化(二氯甲烷:甲醇=80:1)得到纯品产物32为淡黄色固体化合物。
最终化合物32溶于羟胺钾的无水甲醇溶液,室温搅拌过夜。减压蒸除甲醇后,加入双蒸水使残渣溶解,用1M HCl溶液调制PH值至6~7。过滤生成的固体,并用双蒸水清洗4次得到终产物粗品,终产物粗品利用高效液相纯化(甲醇:水=65%:35%)得到纯品灰白色固体终产物。
化合物31(1倍量)溶于甲醇溶液,加入10%钯碳(0.1倍量),置换瓶中空气为氢气,室温搅拌反应1小时,用硅藻土过滤反应液,并用甲醇冲洗滤饼至没有荧光洗出。经硅胶柱层析纯化(二氯甲烷:甲醇=40:1),得到纯品33为淡黄色固体化合物。
最终化合物33溶于羟胺钾的无水甲醇溶液,室温搅拌过夜。减压蒸除甲醇后,加入双蒸水使残渣溶解,用1M HCl溶液调制PH值至6~7。过滤生成的固体,并用双蒸水清洗4次得到粗品终产物,粗品终产物利用高效液相纯化(甲醇:水=70%:30%)得到纯品灰白色固体终产物。
R2为间位取代基的制备方法与R2为对位的制备方法一致,只要化合物27、30中的-COOCH3为间位。
制备例8本发明的一种化合物的制备方法,其中,所述化合物的R2为对位-SO2CH3、对位-SOCH3、对位-PO(CH3)2或对位-NO2,L为不存在任何取代基,X为O:
方法与试剂:A:NaHCO3,Pd(PPh3)2Cl2,DMF,H2O,Ar,90℃,24h;B:BCl3,无水二氯甲烷(dry DCM),-78℃,1h,RT,2h。
具体步骤包括:
化合物6(1倍量)、化合物34或37或40或43(2倍量)、碳酸氢钠(3倍量)和双三苯基膦二氯化钯(0.01倍量)置于双口瓶中。将瓶中空气置换成氩气。加入氩气排过气的N,N-二甲基甲酰胺和水的混合液(v/v=5:1)。混合物于80℃反应过夜。冷却至室温后,用硅藻土过滤反应液,并用乙酸乙酯冲洗滤饼至没有荧光洗出。收集滤液用饱和氯化钠水溶液洗涤3次,乙酸乙酯层用无水硫酸钠干燥,经过柱层析纯化(石油醚:乙酸乙酯=8:1)得到纯品产物35或38或41或44为黄色固体化合物。
化合物35或38或41或44(1倍量)用无水二氯甲烷溶解后,-78℃下,缓慢滴加三氯化硼(4倍量),搅拌反应1h,室温反应2h。浓缩反应液,后用甲醇溶解,再次浓缩,反复三次。经硅胶柱层析纯化(石油醚:乙酸乙酯=2:1)得到纯品36或39或42或45为白色固体。
制备例9本发明的一种化合物的制备方法,其中,所述化合物的R2为间位-SO2CH3、间位-SOCH3、间位-PO(CH3)2或间位-NO2,L为不存在任何取代基,X为O:
方法与试剂:A:NaHCO3,Pd(PPh3)2Cl2,DMF,H2O,Ar,90℃,24h;B:BCl3,无水二氯甲烷,-78℃,1h,RT,2h。。
具体步骤包括:
化合物6(1倍量)、化合物46或49或52或55(2倍量)、碳酸氢钠(3倍量)和双三苯基膦二氯化钯(0.1倍量)置于双口瓶中。将瓶中置换成氩气。加入氩气排过气的N,N-二甲基甲酰胺和水的混合液(v/v=5:1)。混合物于80℃反应过夜。冷却至室温后,用硅藻土过滤反应液,并用乙酸乙酯冲洗滤饼至没有荧光洗出。收集滤液用饱和氯化钠水溶液洗涤3次,乙酸乙酯层用无水硫酸钠干燥,经过柱层析纯化(石油醚:乙酸乙酯=8:1)得到纯品产物47或50或53或56为黄色固体化合物。
化合物47或50或53或56(1倍量)用无水二氯甲烷溶解后,-78℃下,缓慢滴加三氯化硼(4倍量),搅拌反应1h,室温反应2h。浓缩反应液,后用甲醇溶解,再次浓缩,反复三次。经硅胶柱层析纯化(石油醚:乙酸乙酯=2:1)得到纯品48或51或54或57为黄色固体。
合成路线二:
制备例10中间体3的制备方法
方法与试剂:A:BF3OEt2,AcOH,90℃,16h;B:无水N,N-二甲基甲酰胺,BnBr,K2CO3,Ar,140℃,24h;C:NaH,无水四氢呋喃,草酸二乙酯,氩气,0℃,0.5h,90℃,3h,回流;D:水合肼,乙醇,90℃,4h,回流;E:i):THF,H2O,LiOH,RT,24h;ii)乙胺盐酸盐,HOBt,EDCI,三乙胺,无水二氯甲烷,0℃,0.5h,室温,24h;F:CAN,NIS,无水乙腈,室温,24h;
具体步骤包括:
将合成路线一的制备例中的原料化合物6位R取代的间苯二酚(1倍量)溶于醚合三氟化硼(15倍量),并加入乙酸(5倍量)于圆底烧瓶中,用气球接收气体。90℃下搅拌反应16h。冷却至室温后,加入10%的NaOAC溶液适量,室温下搅拌半小时,混合液用乙酸乙酯萃取,饱和的氯化钠水溶液洗涤三次,乙酸乙酯层用无水硫酸钠干燥,经过柱层析纯化(石油醚:乙酸乙酯=30:1)得到纯品产物1为褐色固体。
化合物1(1倍量)溶于无水二氯甲烷,室温下并将无水碳酸钾(2.2倍量)、溴苄(2.2倍量,)加入圆底烧瓶中,置换氩气,140℃下加热搅拌过夜。冷至室温,反应液中加水,有固体析出,抽滤,滤饼依次用水洗涤三次,石油醚洗涤三次,经过柱层析纯化(石油醚:乙酸乙酯=20:1),得到纯品土黄色化合物2。
化合物2(1倍量)溶于无水N,N-二甲基甲酰胺中,将针缓慢滴加入置换氩气后的氢化钠(4.0倍量)的两口瓶中,室温搅拌反应半小时,针缓慢加入草酸二乙酯(1.5倍量),90℃搅拌回流3h。冷至室温,用乙酸调PH至弱酸(PH=5),混合液中加水,乙酸乙酯萃取,饱和氯化钠溶液洗涤有机层三次,乙酸乙酯层用无水硫酸钠干燥半小时,经硅胶柱层析纯化(石油醚:乙酸乙酯=15:1),得到纯品产物3为亮黄色固体。
化合物3(1倍量)溶于无水乙醇,室温下将水合肼(1.5倍量)加入反应液中,90℃回流4h。冷至室温,浓缩反应液,加水,乙酸乙酯萃取,饱和氯化钠洗涤有机层,乙酸乙酯层用无水硫酸钠干燥。经硅胶柱层析纯化(石油醚:乙酸乙酯=10:1),得到纯品产物58为黄色化合物。
化合物58(1倍量)加入圆底烧瓶,加入四氢呋喃、氢氧化锂和水的混合液(v/v/v=2:1:1)。室温搅拌过夜。浓缩反应液,浓缩液加水,用1mol/L HCl调PH至酸性后,乙酸乙酯萃取,饱和氯化钠水溶液洗涤,无水硫酸钠干燥。干燥后的有机液过滤,浓缩后干燥箱干燥后置于圆底烧瓶中,用无水二氯甲烷溶解,冰浴下依次将乙胺盐酸盐(1.5倍量)、HOBt(1.5倍量)、EDCI(2倍量)、三乙胺(3.5倍量)加入反应液中,0℃反应半小时,撤掉冰浴,室温搅拌过夜,浓缩反应液,经硅胶柱层析纯化(石油醚:乙酸乙酯=8:1),得到产物59为黄色化合物。
将NIS(2.0倍量)、CAN(0.05倍量)加入化合物5(1倍量)的无水乙腈溶液,室温搅拌过夜,避光。蒸去乙腈,乙酸乙酯萃取,饱和氯化钠溶液洗涤有机层三次,乙酸乙酯层用无水硫酸钠干燥。经硅胶柱层析纯化(石油醚:乙酸乙酯=10:1),得到纯品产物60为棕色化合物。
该吡唑系列的剩余所有目标化合物的合成方法与上述第一个噁唑系列的各个终产物的合成方法完全一致,不再赘述。
代表化合物的活性测试结果:
(一)活性抑制实验
首先测试了112个代表化合物对HSP90的单浓度抑制率,给药浓度为200nM,具体步骤包括:将100mM TrisCl pH7.4、20mM KCl、6mM MgCl2、5ug/ml BSA、25nM全长Hsp90、10nMVER-51001(荧光探针)混合,总体积为50μL;将此混合液在黑暗中用384孔板室温下平衡30分钟;然后加入200nM的化合物,并在室温下黑暗中再平衡30分钟(DMSO的终浓度为2%);使用Fusion平板读取器(Perkin Elmer;吸收波长485nm,发射波长535nm)测量荧光偏振,计算抑制率。结果如图1(a)和图1(b)所示。从结果中可以看出,所有的化合物对HSP90在200nM浓度下的抑制率都高于85%。证明112个代表化合物具有极高的HSP90抑制活性。
然后测试了112个化合物对A549肺癌细胞和肺成纤维细胞HLF-1的增殖抑制活性,具体步骤包括:用含10%胎小牛血清得培养液配成单个细胞悬液,以每孔10000个细胞接种到96孔板,每孔体积200微升。加入不同浓度的化合物后,孵育72小时。每孔加MTT溶液(5mg/ml用PBS配)20微升。继续孵育4小时,终止培养,小心吸弃孔内培养上清液,对于悬浮细胞需要离心后再吸弃孔内培养上清液。每孔加150微升DMSO,振荡10分钟,使结晶物充分融解。选择490nm波长,在酶联免疫监测仪上测定各孔光吸收值,记录结果,以时间为横坐标,吸光值为纵坐标绘制细胞生长曲线,计算了IC50值。结果如图2(a)和图2(b)所示。
从结果中可以看出112个代表化合物对A549细胞和肺成纤维细胞HLF-1都展现出了较强的增殖抑制活性,IC50值均在nM级别,证明了该类化合物有作为抗癌药和肺纤维化药物的潜力。
(二)还选取了代表化合物HH-69测试了其对A549细胞小鼠肿瘤模型的抑制活性,具体步骤包括:将BALB/c小鼠使用随机分配为三个组(每组n=10只小鼠):第1组,生理盐水和二甲基亚砜(5%,v/v);第2组给予10毫克每千克的HH-69和生理盐水和二甲基亚砜(5%,v/v);第3组为给药组,20毫克每千克的HH-69和生理盐水和二甲基亚砜(5%,v/v),每三天给药一次,腹腔注射给药,给药18天;18天后将小鼠处死,取出肿瘤,计算肿瘤体积(长度×宽度2÷2),统计结果如图3所示。
从结果可以看出,通过18天的腹腔注射给药,化合物HH-69不论是在低给药剂量下还是高给药剂量下,都能够显著抑制肿瘤的生长。
(三)此外,还测试了化合物HH-69逆转博来霉素诱导的小鼠肺纤维化,具体步骤包括:CBA/J小鼠随机分为三组,每组6只小鼠;第一组为正常小鼠组,每日只口服给予生理盐水;第二组为博来霉素诱导的纤维化组,博来霉素通过气管注射给药(2.5毫克每千克),注射完后缝合伤口,让小鼠直立3分钟,使博来霉素在肺内均匀分布,三天后可形成肺纤维化病灶;第三组为HH-69给药组,博来霉素造模3天后开始给药,给药剂量为10毫克每千克,腹腔注射给药,每天一次,持续14天;14天后解剖小鼠,取出肺组织,制成切片并进行HE染色,最后在显微镜下观察。结果如图4所示,其中A为正常小鼠,B为博来霉素组,C为博来霉素+HH-69组。从结果中看以看出化合物HH-69能够逆转博来霉素诱导的小鼠肺纤维化。
(四)最后,根据文献报道,HSP90抑制剂具有抗菌活性(J.Med.Chem.2022,65,7,5539–5564),因此我们又继续测试了化合物HH-69是否能够抑制真菌的生长,以氟康唑为阳性对照药。
具体步骤包括:准备10只试管。往第一只试管中加入1mL药品混匀,吸1mL加入第二只试管中,混匀。在第二只试管中吸1mL加入第三只,以此类推,到第10只的时候,吸出1mL弃去。再往10只试管中分别加入1mL菌液(10000fu/ml)混匀,放入保温箱培养24小时,拿出观察哪只试管还澄清,哪只试管的药物浓度就是MIC,实验结果如下表2所示:
从结果可以看出化合物HH-69对两种菌都展现出了较强的抑制活性,活性明显优于氟康唑。
最后说明的是,以上的实施例仅用于说明本发明的技术方案,并不构成对本发明内容的限制。在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,包括各个技术特征以任何其它的合适方式进行组合,这些简单变型和组合同样应当视为本发明所公开的内容,均属于本发明的保护范围。
Claims (10)
2.根据权利要求1所述的通式(I)所示的化合物或其药用盐,其特征在于,所述R1选自C1-6烷基、C6-10芳基、亚甲基(C6-10芳基)、氟原子和氯原子组成的组。
3.根据权利要求1所述的通式(I)所示的化合物或其药用盐,其特征在于,所述R2选自对位或间位-O-Ph-CONHOH、对位或间位-O-CH2-Ph-CONHOH、对位或间位-O-Ph-CH=CH-CONHOH、对位或间位-CONHOH、对位或间位-CH=CH-CONHOH、对位或间位-SOCH3、对位或间位-SO2CH3、对位或间位-PO(CH3)2和对位或间位-NO2组成的组。
4.根据权利要求1所述的通式(I)所示的化合物或其药用盐,其特征在于,所述X为O或NH。
5.根据权利要求1所述的通式(I)所示的化合物或其药用盐,其特征在于,所述L为不存在任何取代基或者L选自亚甲基、乙撑基、乙烯基、乙炔基组成的组。
6.一种化合物或其药用盐,其特征在于,所述化合物选自表1。
7.一种药物组合物,其包含有效量的权利要求1至6中任一项所述的化合物或其药用盐,和任选的药用赋形剂或药用载体。
8.根据权利要求1至6中任一项所述的化合物或其药用盐,或根据权利要求6所述的药物组合物在制备HSP90抑制剂中的用途。
9.根据权利要求1至6中任一项所述的化合物或其药用盐,或根据权利要求7所述的药物组合物用于预防和/或治疗肿瘤、癌症或器官纤维化的用途。
10.根据权利要求1至6中任一项所述的化合物或其药用盐,或根据权利要求7所述的药物组合物用于抗菌的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211634345.3A CN116253695A (zh) | 2022-12-19 | 2022-12-19 | Hsp90抑制剂及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211634345.3A CN116253695A (zh) | 2022-12-19 | 2022-12-19 | Hsp90抑制剂及其制备方法和用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116253695A true CN116253695A (zh) | 2023-06-13 |
Family
ID=86681695
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211634345.3A Pending CN116253695A (zh) | 2022-12-19 | 2022-12-19 | Hsp90抑制剂及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116253695A (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090076006A1 (en) * | 2007-09-10 | 2009-03-19 | Changgeng Qian | Hsp90 inhibitors containing a zinc binding moiety |
CN101641338A (zh) * | 2006-09-11 | 2010-02-03 | 柯瑞斯公司 | 作为抗增殖制剂的多功能小分子 |
CN115381816A (zh) * | 2022-08-04 | 2022-11-25 | 武汉市金银潭医院(武汉市传染病医院) | Ver50589在制备抗肠道病毒71型药物中的应用 |
-
2022
- 2022-12-19 CN CN202211634345.3A patent/CN116253695A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101641338A (zh) * | 2006-09-11 | 2010-02-03 | 柯瑞斯公司 | 作为抗增殖制剂的多功能小分子 |
US20090076006A1 (en) * | 2007-09-10 | 2009-03-19 | Changgeng Qian | Hsp90 inhibitors containing a zinc binding moiety |
CN115381816A (zh) * | 2022-08-04 | 2022-11-25 | 武汉市金银潭医院(武汉市传染病医院) | Ver50589在制备抗肠道病毒71型药物中的应用 |
Non-Patent Citations (1)
Title |
---|
KAIJUN GENG, ET AL.: ""Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2, 4-diaminopyrimidine motifs"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 152, 11 April 2018 (2018-04-11), pages 76 - 86, XP055783259, DOI: 10.1016/j.ejmech.2018.04.019 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112745335B (zh) | 一种三并杂环化合物及其用途 | |
EP3111940B1 (en) | Silicon phthalocyanine complex, preparation method and medicinal application thereof | |
CN112851663B (zh) | 一种并杂环化合物及其用途 | |
CN107382966B (zh) | 一类荜茇酰胺-川芎嗪杂合物、制备方法及医药用途 | |
CN116390728B (zh) | 喹唑啉衍生物及其制备方法和用途 | |
JP2019526605A (ja) | 置換2−h−ピラゾール誘導体の結晶形、塩型及びその製造方法 | |
CN109081852B (zh) | 一种双重靶向酞菁类抗癌光敏剂及其制备方法 | |
EA000033B1 (ru) | Бис-(2-галоидэтил)аминофенилзамещенные производные дистамицина и их применение в качестве противоопухолевого и противовирусного средства | |
WO2020173417A1 (zh) | 含丙烯酰基的核转运调节剂及其用途 | |
CN109942665B (zh) | 雷公藤内酯醇衍生物及其制备方法和应用 | |
CN116041324A (zh) | 一种氘代吡唑二氯苯甲酰胺类化合物、药物组合物和用途 | |
CN116253695A (zh) | Hsp90抑制剂及其制备方法和用途 | |
CN110981865B (zh) | 一种用于治疗脑胶质瘤的药物及其制备方法 | |
JP2023538638A (ja) | ピラゾールボロン酸化合物、それを含有する医薬組成物、及びそれらの使用 | |
CN110256405B (zh) | 5-烃基-n-取代芳基吡啶酮衍生物及其制备方法和用途 | |
CN113999211A (zh) | 一类特异性抗前列腺癌活性的含1,2,3-三氮唑的吲唑骨架衍生物 | |
WO2020087024A1 (en) | Pyrazolyl compounds and methods of use thereof | |
CN104250247B (zh) | 新型槐定碱类衍生物槐定酸、槐定醇、槐定酯、槐定醚及其制备方法和用途 | |
CN114907387B (zh) | 嘧啶并吡咯类kras抑制剂及其制备方法与应用 | |
CN114907189B (zh) | 多酚取代的3-芳基-2-芳基甲基丙烯类化合物及其制备方法和应用 | |
CN115974855A (zh) | Ezh2和hdac双靶点抑制剂、其药物组合物及其制备方法和用途 | |
JPH05504345A (ja) | 新規ジヒドロピリジン | |
CN113929729B (zh) | 一种藜芦胺类化合物、其制备方法及其应用 | |
CN112778393B (zh) | 欧夹竹桃苷衍生物及其制备方法、药物组合物和用途 | |
CN117624161A (zh) | 一种吡啶羧酸胺衍生物及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |