CN117769544A - 多取代噻唑衍生物及其在疾病治疗中的应用 - Google Patents
多取代噻唑衍生物及其在疾病治疗中的应用 Download PDFInfo
- Publication number
- CN117769544A CN117769544A CN202280050499.XA CN202280050499A CN117769544A CN 117769544 A CN117769544 A CN 117769544A CN 202280050499 A CN202280050499 A CN 202280050499A CN 117769544 A CN117769544 A CN 117769544A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- alkyl
- hydrogen
- compounds
- 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
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 12
- 238000011282 treatment Methods 0.000 title claims abstract description 12
- 201000010099 disease Diseases 0.000 title claims abstract description 11
- 150000007979 thiazole derivatives Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 105
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 108010052167 Dihydroorotate Dehydrogenase Proteins 0.000 claims abstract description 21
- 102100032823 Dihydroorotate dehydrogenase (quinone), mitochondrial Human genes 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 230000009385 viral infection Effects 0.000 claims abstract description 6
- 208000036142 Viral infection Diseases 0.000 claims abstract description 5
- 230000001404 mediated effect Effects 0.000 claims abstract description 5
- -1 fluoro-substituted cyclopropyl Chemical group 0.000 claims description 117
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 4
- 208000026278 immune system disease Diseases 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 32
- 230000005764 inhibitory process Effects 0.000 description 25
- 238000000034 method Methods 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 22
- 230000000694 effects Effects 0.000 description 21
- 238000012360 testing method Methods 0.000 description 20
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- FYDUUODXZQITBF-UHFFFAOYSA-N 1-[2-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=CC=C1C(F)(F)F FYDUUODXZQITBF-UHFFFAOYSA-N 0.000 description 16
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000013641 positive control Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000005711 Benzoic acid Substances 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 235000010233 benzoic acid Nutrition 0.000 description 7
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 6
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000003833 cell viability Effects 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 229960000684 cytarabine Drugs 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- 230000004614 tumor growth Effects 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 238000010171 animal model Methods 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 239000000460 chlorine Chemical group 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000002719 pyrimidine nucleotide Substances 0.000 description 5
- 150000003230 pyrimidines Chemical class 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Chemical group 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- MWIQPUXVXAVFRM-KEBDBYFISA-N 2-[(E)-[[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-methylhydrazinylidene]methyl]benzoic acid Chemical compound ClC1=C(C=CC=C1)C=1N=C(SC=1)N(/N=C/C1=C(C=CC=C1)C(=O)O)C MWIQPUXVXAVFRM-KEBDBYFISA-N 0.000 description 3
- KWZCBMKXNYOQAK-UHFFFAOYSA-N 2-bromo-1-[2-(trifluoromethyl)phenyl]ethanone Chemical compound FC(F)(F)C1=CC=CC=C1C(=O)CBr KWZCBMKXNYOQAK-UHFFFAOYSA-N 0.000 description 3
- XDDFSGQCTAMHGZ-UHFFFAOYSA-N 2-bromo-4-(2-chlorophenyl)-1,3-thiazole Chemical compound ClC1=CC=CC=C1C1=CSC(Br)=N1 XDDFSGQCTAMHGZ-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 229940083266 Dihydroorotate dehydrogenase inhibitor Drugs 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 101100246662 Homo sapiens DHODH gene Proteins 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000012054 celltiter-glo Methods 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 229940126086 compound 21 Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 3
- 229960005420 etoposide Drugs 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 108010082117 matrigel Proteins 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 3
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- BUZYGTVTZYSBCU-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1 BUZYGTVTZYSBCU-UHFFFAOYSA-N 0.000 description 2
- YXWWHNCQZBVZPV-UHFFFAOYSA-N 2'-methylacetophenone Chemical compound CC(=O)C1=CC=CC=C1C YXWWHNCQZBVZPV-UHFFFAOYSA-N 0.000 description 2
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 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
- 206010024305 Leukaemia monocytic Diseases 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-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
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzenecarbonitrile Natural products N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000010241 blood sampling Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000012200 cell viability kit Methods 0.000 description 2
- 230000019522 cellular metabolic process Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 150000002169 ethanolamines Chemical class 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 102000054896 human PML Human genes 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229960000681 leflunomide Drugs 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- FSPSELPMWGWDRY-UHFFFAOYSA-N m-Methylacetophenone Chemical compound CC(=O)C1=CC=CC(C)=C1 FSPSELPMWGWDRY-UHFFFAOYSA-N 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
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 201000006894 monocytic leukemia Diseases 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000006824 pyrimidine synthesis Effects 0.000 description 2
- 230000000284 resting effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- 229960000331 teriflunomide Drugs 0.000 description 2
- UTNUDOFZCWSZMS-YFHOEESVSA-N teriflunomide Chemical compound C\C(O)=C(/C#N)C(=O)NC1=CC=C(C(F)(F)F)C=C1 UTNUDOFZCWSZMS-YFHOEESVSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000005760 tumorsuppression Effects 0.000 description 2
- 230000029812 viral genome replication Effects 0.000 description 2
- 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
- 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 1
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- 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 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
- 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
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-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
- SRSHBZRURUNOSM-DEOSSOPVSA-N (4-chlorophenyl) (1s)-6-chloro-1-(4-methoxyphenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate Chemical compound C1=CC(OC)=CC=C1[C@H]1C(NC=2C3=CC(Cl)=CC=2)=C3CCN1C(=O)OC1=CC=C(Cl)C=C1 SRSHBZRURUNOSM-DEOSSOPVSA-N 0.000 description 1
- UFIVEPVSAGBUSI-REOHCLBHSA-N (S)-dihydroorotic acid Chemical compound OC(=O)[C@@H]1CC(=O)NC(=O)N1 UFIVEPVSAGBUSI-REOHCLBHSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- JYAQYXOVOHJRCS-UHFFFAOYSA-N 1-(3-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(Br)=C1 JYAQYXOVOHJRCS-UHFFFAOYSA-N 0.000 description 1
- BAYUSCHCCGXLAY-UHFFFAOYSA-N 1-(3-methoxyphenyl)ethanone Chemical compound COC1=CC=CC(C(C)=O)=C1 BAYUSCHCCGXLAY-UHFFFAOYSA-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
- UYHTUQHYGKAYJM-UHFFFAOYSA-N 1-[3-(trifluoromethoxy)phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(OC(F)(F)F)=C1 UYHTUQHYGKAYJM-UHFFFAOYSA-N 0.000 description 1
- ABXGMGUHGLQMAW-UHFFFAOYSA-N 1-[3-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(C(F)(F)F)=C1 ABXGMGUHGLQMAW-UHFFFAOYSA-N 0.000 description 1
- HHAISVSEJFEWBZ-UHFFFAOYSA-N 1-[4-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=C(C(F)(F)F)C=C1 HHAISVSEJFEWBZ-UHFFFAOYSA-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
- IIGQLQZSWDUOBI-UHFFFAOYSA-N 1-amino-1-methylthiourea Chemical compound CN(N)C(N)=S IIGQLQZSWDUOBI-UHFFFAOYSA-N 0.000 description 1
- MPEOPBCQHNWNFB-UHFFFAOYSA-N 1-chloro-2-iodobenzene Chemical compound ClC1=CC=CC=C1I MPEOPBCQHNWNFB-UHFFFAOYSA-N 0.000 description 1
- UIQNFNIICOIPOM-UHFFFAOYSA-N 1-phenyl-2-(trifluoromethoxy)ethanone Chemical compound FC(F)(F)OCC(=O)C1=CC=CC=C1 UIQNFNIICOIPOM-UHFFFAOYSA-N 0.000 description 1
- CCBICDLNWJRFPO-UHFFFAOYSA-N 2,6-dichloroindophenol Chemical compound C1=CC(O)=CC=C1N=C1C=C(Cl)C(=O)C(Cl)=C1 CCBICDLNWJRFPO-UHFFFAOYSA-N 0.000 description 1
- OMPATGZMNFWVOH-UHFFFAOYSA-N 2-[2,6-difluoro-4-(3-methoxyphenyl)anilino]pyridine-3-carboxylic acid Chemical compound COC1=CC=CC(C=2C=C(F)C(NC=3C(=CC=CN=3)C(O)=O)=C(F)C=2)=C1 OMPATGZMNFWVOH-UHFFFAOYSA-N 0.000 description 1
- XPRDUGXOWVXZLL-UHFFFAOYSA-N 2-[[2-fluoro-4-(3-methoxyphenyl)phenyl]carbamoyl]cyclopentene-1-carboxylic acid Chemical compound COC1=CC=CC(C=2C=C(F)C(NC(=O)C=3CCCC=3C(O)=O)=CC=2)=C1 XPRDUGXOWVXZLL-UHFFFAOYSA-N 0.000 description 1
- WZWWEVCLPKAQTA-UHFFFAOYSA-N 2-bromo-1-(2-chlorophenyl)ethanone Chemical compound ClC1=CC=CC=C1C(=O)CBr WZWWEVCLPKAQTA-UHFFFAOYSA-N 0.000 description 1
- KJVRURZDIOVSSQ-UHFFFAOYSA-N 2-bromo-1-(3-chlorophenyl)ethanone Chemical compound ClC1=CC=CC(C(=O)CBr)=C1 KJVRURZDIOVSSQ-UHFFFAOYSA-N 0.000 description 1
- NHWQMJMIYICNBP-UHFFFAOYSA-N 2-chlorobenzonitrile Chemical compound ClC1=CC=CC=C1C#N NHWQMJMIYICNBP-UHFFFAOYSA-N 0.000 description 1
- YOMBUJAFGMOIGS-UHFFFAOYSA-N 2-fluoro-1-phenylethanone Chemical compound FCC(=O)C1=CC=CC=C1 YOMBUJAFGMOIGS-UHFFFAOYSA-N 0.000 description 1
- YRNDGUSDBCARGC-UHFFFAOYSA-N 2-methoxyacetophenone Chemical compound COCC(=O)C1=CC=CC=C1 YRNDGUSDBCARGC-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 1
- VMEGFMNVSYVVOM-UHFFFAOYSA-N 6-decylubiquinone Chemical compound CCCCCCCCCCC1=C(C)C(=O)C(OC)=C(OC)C1=O VMEGFMNVSYVVOM-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 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
- 108020004414 DNA Proteins 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 208000001490 Dengue Diseases 0.000 description 1
- 206010012310 Dengue fever Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010014935 Enzyme abnormality Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 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
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010062016 Immunosuppression 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- KNVJMHHAXCPZHF-JTQLQIEISA-N N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-1,2,4-triazol-1-yl]-5-fluoro-2-[(2S)-1,1,1-trifluoropropan-2-yl]oxybenzamide Chemical compound ClC1=C(C(=CC=C1)F)NC(C1=C(C=C(C(=C1)F)N1N=C(N(C1=O)CC)CO)O[C@H](C(F)(F)F)C)=O KNVJMHHAXCPZHF-JTQLQIEISA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 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
- 241000233805 Phoenix Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- 241000700605 Viruses Species 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
- 238000002835 absorbance Methods 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 150000008359 benzonitriles Chemical class 0.000 description 1
- ZJRCIQAMTAINCB-UHFFFAOYSA-N benzoylacetonitrile Chemical compound N#CCC(=O)C1=CC=CC=C1 ZJRCIQAMTAINCB-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
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- PHEZJEYUWHETKO-UHFFFAOYSA-N brequinar Chemical compound N1=C2C=CC(F)=CC2=C(C(O)=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PHEZJEYUWHETKO-UHFFFAOYSA-N 0.000 description 1
- 229950010231 brequinar Drugs 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 description 1
- 208000025729 dengue disease Diseases 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- WUHVJSONZHSDFC-UHFFFAOYSA-N ethyl 2-chloro-2-fluoroacetate Chemical compound CCOC(=O)C(F)Cl WUHVJSONZHSDFC-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 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
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 238000002796 luminescence method Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 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
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- VNDUHYWEWRRBFJ-UHFFFAOYSA-N pp-001 Drugs S1C=CC(C(=O)NC=2C(=C(F)C(=C(F)C=2F)C=2C=C(OC(F)(F)F)C=CC=2)F)=C1C(=O)O VNDUHYWEWRRBFJ-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- DRDVJQOGFWAVLH-UHFFFAOYSA-N tert-butyl n-hydroxycarbamate Chemical compound CC(C)(C)OC(=O)NO DRDVJQOGFWAVLH-UHFFFAOYSA-N 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- 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
- A61P31/12—Antivirals
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
- C07D277/38—Nitrogen atoms
- C07D277/50—Nitrogen atoms bound to hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
本申请属于药物领域,涉及一种多取代噻唑衍生物及其在疾病治疗中的应用。具体地,涉及式I化合物或其药学上可接受的盐、包含式I化合物或其药学上可接受的盐的药物组合物、及其在治疗或预防二氢乳清酸脱氢酶介导的疾病方面的应用,其中包括肿瘤、病毒感染及免疫性疾病。
Description
本申请属于药物领域,涉及一种多取代噻唑衍生物及其在疾病治疗中的应用。具体地,涉及式I化合物或其药学上可接受的盐、包含式I化合物或其药学上可接受的盐的药物组合物、及其在治疗或预防二氢乳清酸脱氢酶介导的疾病方面的应用,其中包括肿瘤、病毒感染及免疫性疾病。
二氢乳清酸脱氢酶(dihydroorotate dehydrogenase,DHODH)是存在于线粒体内膜的一种含铁的黄素依赖酶,可催化嘧啶核苷酸从头合成途径的第4步反应。而嘧啶核苷酸可用于DNA、RNA、糖蛋白和磷脂生物合成,对于细胞代谢和细胞增殖至关重要。
DHODH与多种肿瘤的发生、发展密切相关,因此抑制或下调DHODH可以降低肿瘤细胞增殖,诱导其凋亡或者增加其他靶点药物的抗肿瘤效果。小分子DHODH抑制剂布喹那临床上被用于乳腺癌、头颈癌、结肠癌、胃肠癌、肺癌、卵巢癌等。还有报道称DHODH抑制剂可通过诱导白血病细胞分化,用于急性髓系白血病(AML)的治疗。并且据报道,多个药物,如ASLAN003、BAY 2402234、PTC299、RP7214、JNJ-74856665、以及WO2018192535A1等用于AML的治疗。
人体中静息淋巴细胞主要通过补救合成途径获取细胞代谢所需嘧啶核苷酸,但是,在免疫激活状态下,淋巴细胞对于嘧啶核苷酸的需求可达静息状态下的8倍以上,此时淋巴细胞增殖和各种免疫功能的完成都需要启动从头合成途径补充嘧啶核苷酸。抑制DHODH可以阻断新生嘧啶合成,致使DNA合成障碍,抑制活化的T淋巴细胞、B淋巴细胞,从而在免疫抑制中起重要作用。来氟米特是第一个上市的DHODH抑制剂,用于治疗类风湿性关节炎。特立氟胺是来氟米特的活性代谢产物,于2012年获批上市,用于治疗多发性硬化症。此外,还有IMU-838和PP-001处于临床阶段,分别用于治疗溃疡性结肠炎和非感染性葡萄膜炎。
DHODH抑制剂可防止病毒复制。从头进行嘧啶合成途径的简化及其在病毒复制中的作用。DHODH抑制剂可阻止多种病毒的复制,包括负链RNA病毒(如甲乙型流感病毒)、正链RNA病毒(丙型肝炎病毒与登革热病毒)与DNA病毒(牛痘病毒与腺病毒)等。现有上市的DHODH抑制剂仅有来氟米特和特立氟胺,两者均有明显的毒副作用,如腹泻、肝酶异常、皮疹以及高血压等。因此,开发高效、低毒的DHODH抑制剂具有重要的商业价值与现实意义。
发明内容
本申请一方面提供作为新的DHODH抑制剂的式I化合物或其药学上可接受的盐:
其中,
R
1或R
2独立选自氢、卤素、C
1-6烷基、C
1-6烷氧基和氰基中的任一种;
R
3为-(NR
7)
p-O-R
5;R
5或R
7独立选自氢或C
1-6烷基;
R
4任意选自C
1-6烷基或C
3-6环烷基;
M是氮原子或者CR
6;R
6任意选自氢、卤素和C
1-6烷基中的任一种;
m或n任意为0-5的整数;并且p为0或1。
作为本申请的优选方案,本申请提供一种式I化合物或其药学上可接受的盐,
其中,
R
1或R
2任意选自氢、卤素、C
1-3烷基、C
1-3烷氧基或氰基;
R
3为-(NR
7)p-O-R
5;R
5、R
7任意选自氢或C
1-3烷基;
R
4任意选自C
1-4烷基或C
3-6环烷基;
M是氮原子或CR
6;R
6任意选自氢、卤素和C
1-3烷基中的任一种;
m或n为0-3的任意整数;并且p为0或1;
作为本申请的优选方案,本申请的式I化合物具有如下式Ia结构,
其中,
X为卤素;
R
1或R
2独立选自氢、卤素、C
1-6烷基、C
1-6烷氧基和氰基中的任一种;
R
3为-(NR
7)
p-O-R
5;R
5或R
7独立选自氢或C
1-6烷基;
R
4任意选自C
1-6烷基或C
3-6环烷基;
M是氮原子或者CR
6;R
6任意选自氢、卤素和C
1-6烷基中的任一种;
m或n为0-5的任意整数;并且p为0或1。
作为本申请的优选方案,本申请的式I化合物具有如下式Ib结构,
其中,
R
1或R
2独立选自氢、卤素、C
1-6烷基、C
1-6烷氧基和氰基中的任一种;
R
3为-(NR
7)
p-O-R
5;R
5或R
7独立选自氢或C
1-6烷基;
R
4是C
3-6环烷基;
R
6任意选自氢或C
1-6烷基;
m或n为0-5的任意整数;并且p为0或1。
作为本申请的优选方案,本申请的式I化合物具有如下是Ic结构,
其中,
R
1或R
2独立选自氢、卤素、C
1-6烷基、C
1-6烷氧基和氰基中的任一种;
R
3为-(NR
7)
p-O-R
5;R
5或R
7独立选自氢或C
1-6烷基;
R
4任意选自氢、C
1-6烷基和C
3-6环烷基中的任一种;
m或n为0-5的任意整数;并且p为0或1。
作为本申请的优选方案,化合物式I中,R
1或R
2是氢、卤素、甲基、甲氧基、三氟甲基、三氟甲氧基和氰基中的任一种;
X为氟、氯或溴;
R
3为羟基或-NR
7-O-R
5;
R
5为氢、甲基、乙基、正丙基或异丙基;优选地,R
5为氢、甲基或乙基;
R
7选自氢、甲基或乙基;
R
4为甲基、乙基、丙基、未取代或卤素取代的环丙基、环丁基、环戊基或环己基;优选地,R
4为甲基、乙基、丙基、2-氟代环丙基或2,2-二氟代环丙基;其中当R
4的环烷基具有手性中心时,本申请还进一步包括其相应的立体异构体;
R
6为氢、氟、氯、甲基或乙基;优选地,R
6为氢、氟或甲基;
m或n是0、1或2;并且
p是0或1。
本申请的式I化合物包括但不限于以下化合物:
本申请优选的式I化合物包括以下化合物:
本申请另一方面提供一种式I化合物的制备方法,所述方法包括:式II与式III反应制备得到式I所示化合物。
其中,R
1、R
2、R
3、R
4、M、m、n具有与式I相同的定义范围,R
8是氨基保护基或氢,所述保护基包括但不限于,叔丁氧基羰基、苄氧基羰基等;当R
8为保护基时,式II先脱除保护基后再与式III反应;当R
3为羟基时,可进一步与任选自NH
2OH、NH
2OR
5以及NHR
7OR
5或其相应的盐反应,以制备式I化合物。
当M为CR
6时,式II化合物可通过式IV与式V在金属催化下发生偶联反应得到。金属催化剂优选以三(二亚苄基茚丙酮)二钯、2-二环己基磷-2′,6′-二异丙氧基-1,1′-联苯作为配体,以碱金属碳酸盐作为碱。
其中,R
2、R
4、R
6、R
8、n具有前述结构相同的定义范围。
当M为CR
6,且R
6为卤素,如氟取代时,式IV可通过将式VI与式VII反应制备得到。
当M为氮原子时,所述式II通过下述方法制备:
通过R
2取代苯腈在双三甲基硅基胺基锂催化下反应得到式XX;再与R
4取代异氰酸酯XXI在碱的条件下反应制备式XXII,所述碱是,例如有机碱,所述有机碱包括但不限于,三乙胺、二异丙基乙基胺等。式XXII在单质碘和无机碱的催化下反应得到式XXIII,所述的无机碱,包括但不限于,碳酸钾,碳酸铯等。式XXIII与亚硝酸盐,如亚硝酸钠等,反应制备得到式XXIV;再经金属还原剂还原得到式II,所述金属还原剂包括但不限于,铁粉、锌粉。所述过程表述如下:
本申请再一方面提供一种式II化合物,
其中,
M为氮或CR
6,R
6任意选自氢、C
1-3烷基和氟原子中的任一种;
R
2任意选自氢、卤素、C
1-3烷基、C
1-3烷氧基、氰基中的任一种;
R
4任意选自C
1-4烷基或C
3-6环烷基;
R
8为氨基的保护基或氢原子,所述保护基包括但不限于,叔丁氧基羰基、苄氧羰基等;并且
m任意为0、1、2或3。
本申请式I化合物还包括立体异构体和光学异构体。本申请化合物药学上可接受的盐可以是与无机碱或无机酸形成的盐、与有机碱形成的盐,并且可通过已知的常规方法将式I化合物转化成对应的盐。所述与无机碱形成的盐包括但不限于:钠盐、钾盐、钙盐、盐酸盐、硫酸盐、磷酸盐等;所述与有机碱形成的盐包括但不限于:乙醇胺盐、铵盐、以及与各种氨基酸形成的盐等;作为优选的实施例,本申请式I药学上可接受的盐为钠盐、钾盐、钙盐、乙醇胺盐。
本申请再一方面提供一种药物组合物,所述组合物含有式I化合物或其药学上可接受的盐,所述组合物可以溶液、悬浮液、吸入剂等形式吸入给药;或以片剂、胶囊剂、颗粒剂等形式口服给药;或以栓剂的形式直肠给药或经皮给药;或以注射液形式给药。
本申请的药物组合物制备成口服制剂时,该组合物中可进一步含有药学上可接受的稀释剂,所述稀释剂包括但不限于赋形剂、粘合剂、崩解剂、润滑剂等。所述赋形剂包括乳糖、淀粉、葡萄糖、甘露醇、微晶纤维素、羟丙基纤维素等;所述粘合剂包括聚乙烯醇、乙基纤维素、甲基纤维素、羟丙基纤维素等;所述崩解剂包括淀粉、微晶纤维素、低取代羟丙基纤维素、交联羧甲基纤维素钠等;所述润滑剂包括硬脂酸镁、滑石、聚乙二醇等。将上述稀释剂与药物组合物混合后,可用常规方法压成片剂。如果需要包衣,可将前述片芯用明胶、二氧化钛等糖溶液包衣。或者将本申请化合物与稀释剂充分混合后,直接填充胶囊,制备成胶囊剂。
本申请所述式I化合物或其药学上可接受的盐,以及含有本申请式I化合物或其药学上可接受的盐的药物组合可作为治疗或预防DHODH介导的疾病,所述疾病包括但不限于:自 身免疫疾病、肿瘤、病毒感染等。所述自身免疫疾病包括类风湿性关节炎、银屑病等;所述病毒感染疾病包括流感病毒、冠状病毒等感染引起的疾病。
术语解释:
本申请中,“烷基”是指具有1至6个碳原子的饱和烷烃,如直链烷烃或支链烷烃;“烷氧基”是指具有1至6个碳原子的饱和烷基氧基,如直链烷氧基或支链烷氧基。具体的烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基等。具体的烷氧基包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁基氧基等。
本申请中,“卤素”是指氟、氯、溴、碘;优选地,本申请的卤素为氟、氯、溴。
本申请中,“环烷基”是指含有3至6个碳原子的饱和环烷基,包括环丙基、环丁基、环戊基、环己基。
本申请所述的烷基、烷氧基、环烷基可以是未取代的,或任选可被一个或多个取代基取代;作为本申请优选方案,所述取代基为卤素,如氟,氯,溴;作为本申请优选方案,所述烷基、烷氧基、环烷基为三氟甲基、三氟甲氧基、2-氟代环丙基、2,2-二氟代环丙基等。
图1示出了本申请的两个实施例分别对人单核细胞白血病THP-1细胞在小鼠异体移植瘤模型CB17 SCID的疗效。
图2示出了本申请的两个实施例对人原髓细胞白血病HL-60细胞在小鼠异体移植瘤模型的疗效。
图3示出了本申请的两个实施例对人小细胞肺癌细胞NCI-H82在小鼠异体移植瘤模型的疗效。
为了更好地理解本申请,下文将结合具体实施例和附图描述本申请具体的技术方案。但是,应理解,并不以此限定本申请。除非特别说明,本申请实施例所使用的化合物、试剂、实验动物等均可商购获得。
在此,本申请以整体引入的方式,组合被申请发明人先前的专利申请CN107382902A。具体地,部分化合物的合成可参考CN107382902A中描述的方法,例如,制备参考例化合物(E)-4-(2-氯苯基)-2-[1-甲基-2-(2-羧基苄叉基)肼基]噻唑。
实施例1:
(E)-4-(2-氯苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(1)
步骤(a)叔丁基(对甲苯磺酰基)氨基甲酸酯(1b)
称取20g(0.15mol)羟基氨基甲酸叔丁酯1a置于500mL三口瓶中,加入30mL二氯甲烷,在0℃搅拌状态下加入32.5g(0.165mol)对甲苯磺酰氯的二氯甲烷溶液20mL,搅拌5分钟后,加入15.2g(0.15mol)N-甲基吗啉,反应液升温至室温并反应16个小时。在0℃ 下反应液用水(10mL)淬灭,混合物用二氯甲烷(15mL)萃取三次,有机相合并后用无水硫酸钠干燥、过滤,滤液减压浓缩,得到白色粉状固体的标题化合物1b(34g),收率79.1%。
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),7.79(d,J=8.4Hz,2H),7.49(d,J=8.1Hz,2H),2.43(s,3H),1.23(s,9H).
步骤(b)叔丁基-2-环丙基肼基碳酸酯(1c)
称取9.93g(0.17mol)环丙胺置于500mL三口瓶中,加入20mL四氢呋喃,在-5℃搅拌状态下加入3.52g(34.8mmol)N-甲基吗啉,然后在-5℃搅拌下加入10g(34.8mmol)中间体1b的四氢呋喃溶液20mL,反应液升温至室温并反应16个小时。在0℃下反应液用水(10mL)淬灭,混合物用二氯甲烷(15mL)萃取三次,有机相合并后用无水硫酸钠干燥、过滤,滤液减压浓缩,得到黄色油状的标题化合物1c(2.5g),收率41.7%。
1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),6.44(d,J=2.8Hz,1H),1.12(s,9H),0.57(td,J=7.0,4.6Hz,2H),0.47-0.40(m,2H).
步骤(c)1-(2-氯苯基)-2-硫氰酸乙烷-1-酮(1e)
称取4g(17.1mmol)1d(2-溴-1-(2-氯苯基)乙酮)置于100mL单口瓶中,加入50mL无水乙醇,在室温搅拌状态下加入4.0g(41.2mmol)硫氰酸钾,反应液在85℃回流反应3个小时。反应液减压浓缩,柱层析分离得到黄色油状产物1e(3.8g),收率97%。LCMS:211.9,213.9([M+H]+).
步骤(d)2-溴-4-(2-氯苯基)噻唑(1f)
称取3.8g(18.0mmol)中间体1e置于100mL单口瓶中,加入50mL冰醋酸,在室温搅拌状态下加入40mL醋酸的氢溴酸溶液,反应液在140℃回流反应3个小时。反应液倾倒入(100mL)冰水中,混合液用乙酸乙酯(50mL)分别萃取三次,有机相合并后用无水硫酸钠干燥、过滤、滤液浓缩,得到粗品用柱层析分离得到黄色油状产物(2.5g),收率51%。LCMS:273.9,275.9([M+H]+).
步骤(e)2-(4-(2-氯苯基)噻唑-2-基)-2-环丙基肼-1-羧酸叔丁酯(1g)
称取3g(11mmol)中间体2-溴-4-(2-氯苯基)噻唑1f置于500mL单口瓶中,加入1.9g(11mmol)中间体1c,0.51g(0.55mmol)的三(二亚苄基茚丙酮)二钯,0.51g(1.10mmol)的2-二环己基磷-2′,6′-二异丙氧基-1,1′-联苯和7.19g(22mmol)的碳酸铯,反应液在室温搅拌下,用氮气置换三次,反应液在100℃下搅拌反应16个小时,反应液硅藻土过滤,滤液减压浓缩,得到的粗品用柱层析分离得到黄色固体中间体1g(100mg,收率:3%)。LCMS:366.1,368.1([M+H]+).
步骤(f)4-(2-氯代苯基)-2-(1-环丙基肼)噻唑(1h)
称取100mg(0.27mmol)的中间体2-(4-(2-氯苯基)噻唑-2-基)-2-环丙基肼-1-羧酸叔丁酯1g置于100mL单口瓶中,加入10mL二氯甲烷,在室温搅拌状态下加入2mL三氟乙酸,反应液在室温搅拌反应2个小时。反应液减压浓缩,得到黄色油状中间体1h(70mg)收率97.2%。LCMS:266.0,268.0([M+H]+).
步骤(g)(E)-4-(2-氯苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(1)
称取70mg(0.26mmol)的中间体4-(2-氯代苯基)-2-(1-环丙基肼)噻唑1h置于100mL单口瓶中,加入5mL二氯甲烷和44mg(0.26mmol)的3-氟-6-醛基苯甲酸,反应液在室温下搅拌反应2个小时。反应液减压浓缩,用高效液相制备色谱法纯化得到白色固体目标化合物 1(27mg,收率:25%)。
1H NMR(400MHz,DMSO-d
6)δ13.67(s,1H),9.09(s,1H),8.05(dd,J=8.8,5.7Hz,1H),7.94(dd,J=7.7,1.7Hz,1H),7.68(dd,J=9.5,2.8Hz,1H),7.60-7.50(m,2H),7.50-7.39(m,2H),7.36(td,J=7.6,1.8Hz,1H),2.91-2.83(m,1H),1.27-1.17(m,2H),1.08-0.98(m,2H).
实施例2:
(E)-4-(2-氯苯基)-2-[1-环丙基-2-(2-羧基-4-氯苄叉基)肼基]噻唑(2)
与实施例1的方法类似,用2-氯-6醛基苯甲酸替代2-氟-6-醛基苯甲酸与中间体1h反应得到42mg的标题化合物2。
1H NMR(400MHz,DMSO-d
6)δ13.72(s,1H),9.09(s,1H),8.02(d,J=8.6Hz,1H),7.98-7.86(m,2H),7.75(dd,J=8.5,2.3Hz,1H),7.62-7.27(m,4H),2.98-2.78(m,1H),1.31-1.12(m,2H),1.10-0.95(m,2H).
实施例3:
(E)-4-(2-氯苯基)-2-[1-环丁基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(3)
与中间体1c方法类似,采用环丁基胺替代环丙胺与中间体1b反应得到3c;与实施例1方法类似,得到27mg的标题化合物3。
1H NMR(400MHz,DMSO-d
6)δ13.66(s,1H),8.76(s,1H),8.02(dd,J=8.7,5.8Hz,1H),7.96-7.88(m,1H),7.66(d,J=7.2Hz,1H),7.57-7.46(m,3H),7.47-7.38(m,1H),7.40-7.31(m,1H),4.83(s,1H),2.89-2.74(m,2H),2.61-2.52(m,2H),1.90-1.75(m,2H).
实施例4:
(E)-4-(3-氯苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(4)
与实施例1方法类似,采用2-溴-1-(3-氯苯基)乙酮4d替代1d,得到29mg的标题化合物4。
1H NMR(400MHz,DMSO-d
6)δ13.71(s,1H),9.13(s,1H),8.04(dd,J=8.8,5.7Hz,1H),7.95(t,J=1.7Hz,1H),7.88(d,J=7.8Hz,1H),7.67(dd,J=9.5,2.8Hz,1H),7.62(s,1H),7.53(td,J=8.5,2.8Hz,1H),7.46(t,J=7.9Hz,1H),7.40-7.33(m,1H),2.91(tt,J=6.8,3.8Hz,1H),1.31-1.21(m,2H),1.10-0.99(m,2H).
实施例5:
2-溴-1-(2-三氟甲基苯基)乙酮(5d)
称取10g(53.2mmol)2-三氟甲基苯乙酮(5c)置于500mL单口瓶中,加入50mL甲醇,在室温搅拌状态下加入5.68g(58.5mmol)溴化铵和35.98g(58.5mmol)过氧单磺酸钾,反应液室温搅拌下,置换氩气三次,反应液在65℃反应16个小时。反应液过滤,滤液用水(10mL)淬灭,混合物用二氯甲烷(15mL×3)萃取,有机相合并后用无水硫酸钠干燥、过滤,滤液减压浓缩,得到油状中间体5d(15g)收率71%。
(E)-4-(2-三氟甲基苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(5)
与实施例1方法类似,采用2-溴-1-(2-三氟甲基苯基)乙酮5d替代1d,得到38mg的标题化合物5。
1H NMR(400MHz,DMSO-d
6)δ13.66(s,1H),9.08(s,1H),8.04(dd,J=8.8,5.7Hz,1H),7.83(d,J=7.8Hz,1H),7.76-7.64(m,3H),7.65-7.50(m,2H),7.11(s,1H),2.91-2.75(m,1H),1.22-1.09(m,2H),1.10-0.90(m,J=3.8Hz,2H).
实施例6:
(E)-4-(2-甲苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(6)
与实施例5的方法类似,采用2-甲基苯乙酮(6c)替代2-三氟甲基苯乙酮(5c),得到标题化合物6。
1H NMR(400MHz,DMSO-d
6)δ13.56(s,1H),9.08(s,1H),8.05(dd,J=8.8,5.7Hz,1H),7.68(dd,J=9.5,2.8Hz,1H),7.64-7.51(m,2H),7.31-7.19(m,3H),7.10(s,1H),2.91-2.79(m,1H),2.48(s,14H),1.26-1.16(m,2H),1.09-0.94(m,2H).
实施例7:
(E)-4-(4-氯苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(7)
与实施例5的方法类似,采用4-氯苯乙酮(7c)替代2-三氟甲基苯乙酮(5c),得到标题化合物7。
1H NMR(400MHz,DMSO-d
6)δ13.68(s,1H),9.11(s,1H),8.04(dd,J=8.8,5.7Hz,1H),7.93(d,J=8.5Hz,2H),7.67(dd,J=9.5,2.8Hz,1H),7.58-7.52(m,2H),7.48(d,J=8.6Hz,2H),2.99-2.81(m,1H),1.27-1.22(m,2H),1.04(q,J=6.5,5.5Hz,2H).
实施例8:
(E)-4-(3-甲基苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(8)
与实施例5的方法类似,采用3-甲基苯乙酮(8c)替代2-三氟甲基苯乙酮(5c),得到标题化合物8。
1H NMR(400MHz,DMSO-d
6)δ9.10(s,1H),8.04(s,1H),7.75-7.63(m,2H),7.61-7.48 (m,2H),7.43(s,1H),7.35-7.25(m,1H),7.16-7.08(m,1H),2.92-2.85(m,1H),2.36(s,3H),1.28-1.21(m,2H),1.10-0.98(m,2H).
实施例9:
(E)-4-(2-甲氧基苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(9)
与实施例5的方法类似,用2-甲氧基苯乙酮替代2-三氟甲基苯乙酮,得到标题化合物9。
1H NMR(400MHz,DMSO-d
6)δ9.09(s,1H),8.15(dd,J=7.6,1.8Hz,1H),8.01(dd,J=8.9,5.7Hz,1H),7.76-7.60(m,2H),7.55-7.45(m,2H),7.33-7.23(m,1H),7.09(d,J=8.3Hz,1H),7.06-6.98(m,1H),3.90(s,3H),2.91-2.82(m,1H),1.26-1.17(m,2H),0.95-0.86(m,2H).
实施例10:
(E)-4-(2-三氟甲氧基苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(10)
与实施例5的方法类似,用2-三氟甲氧基苯乙酮替代2-三氟甲基苯乙酮,得到标题化合物10。
1H NMR(400MHz,DMSO-d
6)δ9.09(s,1H),8.14-8.06(m,1H),8.06-7.97(m,1H),7.70-7.61(m,1H),7.57-7.39(m,4H),7.30(s,1H),2.91-2.80(m,1H),1.27-1.16(m,2H),1.05-0.95(m,2H).
实施例11:
(E)-4-(3-甲氧基苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(11)
与实施例5的方法类似,采用3-甲氧基苯乙酮替代2-三氟甲基苯乙酮,得到标题化合物11。
1H NMR(400MHz,DMSO-d
6)δ9.11(s,1H),8.11-8.00(m,1H),7.82-7.60(m,2H),7.60-7.44(m,3H),7.41-7.29(m,1H),6.89(d,J=8.2Hz,1H),3.81(s,3H),2.94-2.83(m,1H),1.30-1.20(m,2H),1.08-1.01(m,2H).
实施例12:
(E)-4-(3-三氟甲氧基苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(12)
与实施例5的方法类似,采用3-三氟甲氧基苯乙酮替代2-三氟甲基苯乙酮,得到标题化合物12。
1H NMR(400MHz,DMSO-d
6)δ9.12(s,1H),8.04(dd,J=8.7,5.6Hz,1H),7.95(d,J=7.5Hz,1H),7.87(s,1H),7.74-7.62(m,3H),7.60-7.50(m,2H),7.30(d,J=7.9Hz,1H),2.95- 2.87(m,1H),1.27-1.20(m,4H),1.08-1.01(m,2H).
实施例13:
(E)-4-(2-氟苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(13)
与实施例5的方法类似,采用2-氟苯乙酮替代2-三氟甲基苯乙酮,得到标题化合物13。
1H NMR(400MHz,DMSO-d
6)δ9.12(s,1H),8.19-8.07(m,1H),8.05-7.95(m,1H),7.68-7.59(m,1H),7.57-7.44(m,2H),7.40-7.15(m,3H),2.92-2.83(m,1H),1.28-1.17(m,2H),1.09-0.98(m,2H).
实施例14:
(E)-4-(2-氰基苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(14)
与实施例5的方法类似,采用2-氰基苯乙酮替代2-三氟甲基苯乙酮,得到标题化合物14。
1H NMR(400MHz,DMSO-d
6)δ9.14(s,1H),8.09-7.97(m,2H),7.90(dd,J=7.3,2.0Hz,1H),7.81-7.73(m,1H),7.71-7.64(m,1H),7.61(d,J=5.2Hz,1H),7.59-7.50(m,2H),2.92-2.82(m,2H),1.26-1.17(m,2H),1.11-1.02(m,2H).
实施例15:
(E)-4-(2-溴苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(15)
与实施例5的方法类似,采用2-溴苯乙酮替代2-三氟甲基苯乙酮,得到标题化合物15。
实施例16:
(E)-4-(3-三氟甲基苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(16)
与实施例5方法类似,采用3-三氟甲基苯乙酮替代2-三氟甲基苯乙酮,得到标题化合物16。
1H NMR(400MHz,DMSO-d
6)δ9.11(s,1H),8.07-7.99(m,1H),7.81-7.74(m,1H),7.72(d,J=7.9Hz,1H),7.70-7.63(m,1H),7.59-7.51(m,1H),7.51-7.42(m,1H),7.37(s,1H),7.34-7.25(m,1H),2.85(s,1H),1.21(d,J=14.2Hz,2H),1.03(s,2H).
实施例17:
(E)-4-(3-溴苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(17)
与实施例5的方法类似,采用3-溴苯乙酮替代2-三氟甲基苯乙酮,得到标题化合物17。
1H NMR(400MHz,DMSO-d
6)δ9.13(s,1H),8.11-8.07(m,1H),8.07-7.98(m,1H),7.96-7.88(m,1H),7.70-7.60(m,2H),7.56-7.46(m,2H),7.43-7.34(m,1H),2.95-2.85(m,2H),1.29-1.20(m,4H),1.08-0.98(m,2H).
实施例18:
(E)-4-(4-甲基苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(18)
与实施例5的方法类似,用4-甲基苯乙酮替代2-三氟甲基苯乙酮,得到标题化合物18。
1H NMR(400MHz,DMSO-d
6)δ9.10(s,1H),8.03-7.96(m,1H),7.78(d,J=7.9Hz,2H),7.63(dd,J=12.4,3.0Hz,1H),7.54-7.44(m,1H),7.35(s,1H),7.20(d,J=7.9Hz,2H),2.91-2.81(m,1H),2.30(s,3H),1.27-1.17(m,2H),1.07-0.97(m,2H).
实施例19:
(E)-4-(4-三氟甲基苯基)-2-[1-环丙基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(19)
与实施例5的方法类似,采用4-三氟甲基苯乙酮替代2-三氟甲基苯乙酮,得到标题化合物19。
1H NMR(400MHz,DMSO-d
6)δ9.11(s,1H),8.10(d,J=8.2Hz,2H),8.01(dd,J=8.8,5.5Hz,1H),7.76(d,J=8.2Hz,2H),7.69(s,1H),7.65(dd,J=9.4,3.0Hz,2H),7.52(s,1H),2.94-2.84(m,1H),1.27-1.18(m,4H),1.06-0.99(m,2H).
实施例20:
(E)-5-氟-4-(2-氯苯基)-2-[1-甲基-2-(2-羧基苄叉基)肼基]噻唑(20)
2-氯-2-氟-1-(2-氯苯基)乙酮
称取10.0g(41.9mmol)的邻氯碘苯置于250mL三口瓶中,加入超干THF(100mL),搅拌至溶清。氩气保护下,降温至-78℃,滴加入20.1mL的正丁基锂溶液(2.5M in hexane)。加毕,在-78℃条件下反应40min,再滴加入10.0g(71.2mmol)的氯氟乙酸乙酯,加完后, 在-78℃下再反应40min。用饱和氯化铵(200mL)淬灭,乙酸乙酯萃取三次(120mL*3),合并有机相,无水硫酸钠干燥,过滤,浓缩,柱分离(EA/PE,0%-10%),得无色液体5.8g,收率67.0%。
1H NMR(400MHz,CDCl3)δ7.66(dd,J=8.0,1.0Hz,1H),7.54-7.46(m,2H),7.43-7.37(m,1H),7.00(d,J=50.5Hz,1H).
4-(2-氯苯基)-5-氟-2-(1-甲基肼基)噻唑
称取500mg(2.4mmol)的中间体2-氯-2-氟-1-(2-氯苯基)乙酮置于25mL的茄形瓶中,加入380mg(3.6mmol)的2-甲基氨基硫脲和10mL的超干四氢呋喃,在氮气保护下80℃反应25小时。将反应也冷却至室温,浓缩出去溶剂,加100mL水,用乙酸乙酯萃取三次(50mL*3),合并有机相浓缩,柱层析分离,得到灰色固体220mg,收率35.3%。
(E)-5-氟-4-(2-氯苯基)-2-[1-甲基-2-(2-羧基苄叉基)肼基]噻唑
称取100mg(0.39mmol)的中间体4-(2-氯苯基)-5-氟-2-(1-甲基肼基)噻唑置于25mL的茄形瓶中,加入87.5mg(0.58mmol)的2-醛基苯甲酸,64mg(0.78mmol)的醋酸钠和10mL甲醇。在氮气保护下于室温下反应16小时。浓缩除去溶剂,加入50mL的水(50mL),用乙酸乙酯萃取三次(50mL*3),合并有机相浓缩,柱层析分离得黄色固体50mg的标题化合物,收率32.3%。
1H NMR(400MHz,DMSO-d
6)δ8.59(s,1H),7.94(d,J=7.9Hz,1H),7.89(dd,J=7.9,1.4Hz,1H),7.63(t,J=7.6Hz,1H),7.59-7.52(m,2H),7.51-7.39(m,3H),3.51(s,3H).
实施例21:
(E)-5-氟-4-(2-氯苯基)-2-[1-甲基-2-(2-羧基-4-氟苄叉基)肼基]噻唑(21)
与实施例20的方法类似,采用2-醛基-4-氟苯甲酸替代2-醛基苯甲酸,得到标题化合物21。
1H NMR(400MHz,DMSO-d
6)δ13.64(s,2H),8.54-8.50(m,1H),7.98(dd,J=8.8,5.6Hz,1H),7.64(dd,J=9.4,2.9Hz,1H),7.59-7.48(m,3H),7.47-7.39(m,2H),3.51(s,3H).
实施例22:
(E)-2-((2-(4-(2-氯苯基)噻唑-2-基)-2-甲基肼叉基)甲基)-N-羟基苯甲酰胺(22)
参考文献报道的合成方法,得到中间体化合物(E)-4-(2-氯苯基)-2-[1-甲基-2-(2-羧基苄叉基)肼基]噻唑。
称取1.0g(2.6mmol)的上述中间体化合物置于100mL茄形瓶中,加入30mL的四氢呋喃,室温下搅拌至固体完全溶解。加入484mg(3.0mmol)羰基二咪唑,室温下反应16小时后,冰水浴下将反应液滴加到20mL的50%的羟胺水溶液中,并搅拌1小时。加入50mL饱和食盐水溶液,并用乙酸乙酯萃取三次(50mL*3),合并有机相浓缩,柱层析分离得到黄色固体135mg的标题化合物,收率13%。
1H NMR(400MHz,Methanol-d
4,DMSO-d
6)δ8.46(s,1H),8.11(d,J=8.0Hz,1H),7.99(dd,J=7.8,1.8Hz,1H),7.91-7.84(m,1H),7.67(t,J=7.6Hz,1H),7.56-7.29(m,5H),3.73(s,3H).
实施例23:
(E)-2-((2-(4-(2-氯苯基)噻唑-2-基)-2-甲基肼叉基)甲基)-N-甲氧基苯甲酰胺(23)
称取(E)-4-(2-氯苯基)-2-[1-甲基-2-(2-羧基苄叉基)肼基]噻唑500mg(1.3mmol)置于100mL茄形瓶中,加入25mL四氢呋喃,室温下搅拌至固体完全溶解,加入512mg(1.3mmol)HATU,271mg(2.6mmol)的三乙胺和167mg(2.0mmol)的O-甲基羟胺盐酸盐,室温下反应16小时。加入50mL水并用乙酸乙酯萃取三次(50mL*3),合并有机相浓缩,柱层析分离得到白色固体167mg的标题化合物,收率30%。
1H NMR(400MHz,DMSO-d
6)δ7.81(dd,J=7.7,2.0Hz,1H),7.77(d,J=7.3Hz,1H),7.72-7.62(m,2H),7.60-7.52(m,1H),7.47(dd,J=7.8,1.5Hz,1H),7.39-7.23(m,3H),6.94(d,J=3.4Hz,1H),5.97(d,J=3.3Hz,1H),3.91(s,3H),3.21(s,3H).
实施例24:
(E)-2-((2-(3-(2-氯苯基)-1,2,4-噻二唑-5-基)-2-甲基肼叉基)甲基)苯甲酸(133)
步骤(a)2-氯苯基甲脒
量取73.0mL的双三甲基硅基胺基锂的四氢呋喃溶液(2.0M,146.0mmol)置于500mL反应瓶中,加入150mL的四氢呋喃。氮气保护下,控温0-10℃,缓慢滴加入2-氯苯腈10.0g(73.0mmol)的四氢呋喃(50mL)溶液。TLC检测原始物料完全消耗,浓缩除去反应溶剂,加入200mL纯化水,并用二氯甲烷萃取三次(200mL*3).合并有机相后,并分别用2M的盐酸(200mL)和饱和食盐水(300mL)各洗涤一次。浓缩除去溶剂得到9.5克黄色固体,直接投下一步反应。LCMS:155.1([M+H]
+).
步骤(b)2-氯-N-(甲基硫脲基)苯基甲脒
称取2-氯苯基甲脒(9.5g,61.3mmol)和甲基异氰酸酯(6.8g,92.5mmol)置于500mL反应瓶中,加入乙腈(170mL)。控温20℃以下,缓慢滴加入三乙胺(18.7g,185.1mmol)。滴加完毕后,反应液在室温下反应3小时。LCMS监控原料完全消耗后,浓缩出去反应溶剂,并用柱层析纯化(石油醚∶乙酸乙酯=20∶1)得到黄色固体10.0克。该两步反应,总收率60.4%。
1H NMR(300MHz,DMSO-d6):δ9.03(d,J=2.3Hz,1H),8.60-8.56(m,1H),7.52-7.32(m,5H),2.84(d,J=2.3Hz,3H).LCMS:228.1([M+H]+).
步骤(c)3-(2-氯苯基)-N-甲基-1,2,4-噻二唑-5-胺
称取2-氯-N-(甲基硫脲基)苯基甲脒(10.0g,44.1mmol)和单质碘(13.4g,52.9mmol)置于250mL的反应瓶中,加入乙腈(100mL)和碳酸钾(9.1g,66.1mmol)。室温下搅拌0.5小时后,LCMS监控原料消耗完全。向反应溶液中加入水(200mL),并用乙酸乙酯萃取 三次(200mL*3)。合并有机相并用饱和食盐水洗涤两次(200mL*2),并用无水硫酸钠干燥,浓缩后,柱层析纯化(石油醚∶乙酸乙酯=5∶1)得到黄色固体5.0克,收率50.4%。
1H NMR(300MHz,DMSO-d
6):δ8.49(brs,1H),7.78-7.75(m,1H),7.55-7.53(m,1H),7.46-7.41(m,2H),2.94(d,J=4.8Hz,3H).LCMS:226.0([M+H]
+).
步骤(d)N-(3-(2-氯苯基)-1,2,4-噻二唑-5-基)-N-甲基一氧化二氮酰胺
称取3-(2-氯苯基)-N-甲基-1,2,4-噻二唑-5-胺(500mg,2.2mmol)置于50mL反应瓶中,0℃下加入2M盐酸(5mL),并逐滴加入亚硝酸钠(150mg,2.2mmol)的水溶液(2mL)。混合溶液在0-5℃下保温反应1小时。LCMS监控反应原料完全消耗后,将反应液倾到入2mL水中,并用乙酸乙酯萃取三次(5mL*3),合并有机相并用饱和食盐水(10mL)洗涤一次,用无水硫酸钠干燥后,柱层析(石油醚∶乙酸乙酯=1∶1)得到200mg的白色固体,收率35.4%。
1H NMR(300MHz,DMSO-d
6):δ8.02-7.99(m,1H),7.73-7.70(m,1H),7.66-7.56(m,2H),4.62(s,3H).LCMS:255.0([M+H]
+).
步骤(f)3-(2-氯苯基)-5-(1-甲基肼基)-1,2,4-噻二唑
称取锌粉(100mg,1.57mmol)和冰醋酸(2mL)置于25mL反应瓶中,并加热到45℃,缓慢滴加入N-(3-(2-氯苯基)-1,2,4-噻二唑-5-基)-N-甲基一氧化二氮酰胺(200mg,0.79mmol)的冰醋酸溶液(2mL),混合溶液在45-50℃条件下搅拌12小时。LCMS监控原料完全消耗后,过滤除去锌粉并用乙酸乙酯洗涤两次(20mL*2),母液分别用饱和碳酸钠溶液洗涤三次(10mL*3),饱和食盐水洗涤三次(10ml*),并用无水硫酸钠干燥后,用柱层析纯化(石油醚∶乙酸乙酯=1∶1)得到64mg的白色固体,收率67.7%。
1H NMR(300MHz,DMSO-d
6):δ7.74(dd,J=7.4,2.0Hz,1H),7.53(dd,J=7.8,1.4Hz,1H),7.47-7.38(m,2H),5.65(s,2H).LCMS:241.1([M+H]
+).
步骤(g)(E)-2-((2-(3-(2-氯苯基)-1,2,4-噻二唑-5-基)-2-甲基肼叉基)甲基)苯甲酸
称取3-(2-氯苯基)-5-(1-甲基肼基)-1,2,4-噻二唑(60mg,0.25mmol)和邻醛基苯甲酸(45mg,0.3mmol)和四氢呋喃(3mL)置于10mL反应瓶中,升温至60℃反应6小时。LCMS监控原料完全消耗后,浓缩出去反应溶剂,残留固体用甲醇(5mL)打浆后得到标题化合物41mg的的白色固体。
1H NMR(400MHz,DMSO-d
6):δ13.39(brs,1H),8.78(s,1H),7.98-7.94(m,2H),7.88(dd,J=7.6,2.0Hz,1H),7.71(t,J=7.5Hz,1H),7.62-7.43(m,4H),3.73(s,3H).LCMS:373.0([M+H]
+).
实施例25:盐的制备
称取化合物21(E)-5-氟-4-(2-氯苯基)-2-[1-甲基-2-(2-羧酸-4-氟苄叉基)肼基]噻唑(300mg,0.74mmol)溶于四氢呋喃(5mL)中,加入氢氧化钠(29.5mg,0.74mmol)。室温下搅拌2小时,浓缩除去溶剂,得到化合物21的钠盐淡黄色固体328mg(收率99%)。
1H NMR(400MHz,DMSO-d
6)δ9.09(s,1H),7.84(dd,J=8.8,5.9Hz,1H),7.64-7.38(m,5H),7.17(td,J=8.5,2.8Hz,1H),3.47(s,3H).
参考上述方法,可将本申请化合物与不同的碱反应,转化为药学上可接受的盐。
活性测试1:本申请化合物对人DHODH酶抑制活性测试
该方法是将DHODH酶的活性与染料2,6-二氯苯酚靛酚(DCIP)显色联系起来。具体地,将纯化的重组人DHODH用测试缓冲液(含50mM三(羟基甲基)氨基甲烷,150mM氯化钾, 0.1%TritonX-100,pH 8.0)稀释至0.4μg/mL;另外用上述相同的测试缓冲液配置含有2mM的L-二氢乳清酸、0.2mM的癸基泛醌和0.12mM的DCIP的底物溶液;向96孔板的每个孔中加入50μL的DHODH酶溶液和50μL底物溶液,充分混合5秒钟,即使用Spectramax分光光度计读取600nM出的吸光度测量值。加入不同的测试化合物,通过不同吸光度值即可计算酶活性。纯化的重组人DHODH酶购自R&D SYSTEMS(目录号:10062-DD),其他试剂均购自Sigma-Aldrich。实验中,采用Brequinar(购自Sigma-Aldrich)作为阳性对照。根据细胞活力来计算化合物对细胞增殖的抑制率;并根据不同浓度化合物的抑制率拟合半数抑制浓度IC
50值(详见表1)。
表1
活性测试2:本申请化合物对人单核细胞白血病细胞THP-1抗细胞增殖活性测试
在96孔板中将5000个细胞/孔的THP-1细胞接种于90%的RPMI 1640(Gibco,货号22400-089)、10%的胎牛血清(Coming,货号35-076-CV)和0.05mM的巯基乙醇(Sigma-Aldrich,货号63689),并培养过夜。将细胞用不同浓度的测试化合物孵育72小时。使用Promega CellTiter-Glo发光法细胞活性检测试剂盒(Promega-G7573),按照供应商提供的说明书分析细胞活力。根据细胞活力来计算化合物对细胞增殖的抑制率;并根据不同浓度化合物的抑制率拟合半数抑制浓度IC
50值(详见表2)。实验中,选取Staurosporine作为阳性对照化合物。
表2
活性测试3:本申请化合物对人原髓细胞白血病细胞HL-60抗细胞增殖活性测试
在96孔板中将2500个细胞/孔的HL-60细胞接种于80%的IMDM(Gibco,货号12440053)和20%的胎牛血清(Corning,货号35-076-CV),并培养过夜。将细胞用不同浓度的测试化合物孵育72小时。使用Promega CellTiter-Glo发光法细胞活性检测试剂盒(Promega-G7573),按照供应商提供的说明书分析细胞活力。根据细胞活力来计算化合物对细胞增殖的抑制率;并根据不同浓度化合物的抑制率拟合半数抑制浓度IC
50值(详见表3)。实验中,选取Staurosporine作为阳性对照化合物。
表3
活性测试4:本申请化合物对人小细胞肺癌细胞NCI-H82抗细胞增殖活性测试
在96孔板中将5000个细胞/孔的NCI-H82细胞接种于90%的RPMI 1640(Gibco,货号 22400-089)和10%的胎牛血清(Corning,货号35-076-CV),并培养过夜。将细胞用不同浓度的测试化合物孵育72小时。使用Promega CellTiter-Glo发光法细胞活性检测试剂盒(Promega-G7573),按照供应商提供的说明书分析细胞活力。根据细胞活力来计算化合物对细胞增殖的抑制率;并根据不同浓度化合物的抑制率拟合半数抑制浓度IC
50值(详见表4)。实验中,选取Staurosporine作为阳性对照化合物。
表4
从酶水平的活性数据来看,本申请化合物具有良好的DHOHD酶抑制活性,部分化合物的酶活性≤5nM。本申请的化合物具有良好的肿瘤细胞抗增殖活性,测试的化合物IC
50在约1μM以下。
活性测试5:本申请化合物对THP-1细胞异种型移植瘤模型的疗效
选取CB17 SCID小鼠,雌性,6-8周龄,体重18-22克。将THP-1细胞(10×10^6cells/0.2mL with Matrigel)皮下接种于每只小鼠。待小鼠成瘤后,肿瘤平均值达到100-150mm
3时,开始给药。
考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为:V=0.5a×b
2,a和b分别表示肿瘤的长径和短径。实施例20、21和阳性对照化合物阿糖胞苷对该动物模型的结果如图1。
选取实施例20及21制备的化合物,口服给药29天后,可剂量依耐性的抑制肿瘤生长。实施例20(给药剂量9mg/kg)抑瘤率(TG)可达到97%;实施例21(给药剂量15mg/kg)抑瘤率可达到85%。阳性对照化合物阿糖胞苷(10mg/kg)抑瘤率为45%。两个化合物的抑瘤率均超出阿糖胞苷。
活性测试6:本申请化合物对HL-60细胞异种型移植瘤模型的疗效
选取Balb/c裸小鼠,雌性,6-8周龄,体重18-22克。HL-60细胞(10×10^6cells/0.2mL with Matrigel)皮下接种于每只小鼠。待小鼠成瘤后,肿瘤平均值达到100-150mm
3时,开始给药。
考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为:V=0.5a×b
2,a和b分别表示肿瘤的长径和短径。实施例20、21和阳性对照 化合物阿糖胞苷对该动物模型的结果如图2。
选取实施例20及21制备的化合物,口服给药18天后,可剂量依耐性的抑制肿瘤生长。实施例20(给药剂量22.5mg/kg)抑瘤率(TG)可达到101.6%;实施例21(给药剂量36mg/kg)抑瘤率可达到102.4%。阳性对照化合物阿糖胞苷(25mg/kg)抑瘤率为77.9%。这两个化合物的抑瘤率均超出阿糖胞苷。
活性测试7:本申请化合物对NCI-H82细胞异种型移植瘤模型的疗效
Balb/c裸小鼠,雌性,6-8周龄,体重18-22克。NCI-H82细胞(5×10^6cells/0.2mL with Matrigel)皮下接种于每只小鼠。待小鼠成瘤后,肿瘤平均值达到100-150mm
3时,开始给药。
考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为:V=0.5a×b
2,a和b分别表示肿瘤的长径和短径。实施例20、21和阳性对照化合物顺铂+依托泊苷对该动物模型的结果如图3。
选取实施例20及21制备的化合物,口服给药31天后,可剂量依赖性的抑制肿瘤生长。实施例20(给药剂量22.5mg/kg)的抑瘤率(TG)可达到96.2%;实施例21(给药剂量36mg/kg)抑瘤率分别为95.3%。阳性对照化合物顺铂和依托泊苷联用(2mg/kg+4mg/kg)抑瘤率为58.7%。这两个化合物的抑瘤率均超出顺铂和依托泊苷联用组。
通过小鼠的异体移植瘤模型数据,本申请化合物在动物模型上显示出了优秀的抗肿瘤增殖活性。
活性测试8:本申请化合物在小鼠上的药物代谢动力学实验
将化合物溶于含有5%的DMSO和10%的Solutol的生理盐水中(所属百分比均为体积比),分别配置成0.2mg/mL和1mg/mL的溶液,其中0.2mg/mL溶液用于静脉给药,1mg/mL溶液用于灌胃给药。
药代动力学实验在ICR小鼠上进行,每组3只,静脉注射剂量为5mL/kg,口服灌胃给药剂量为10mL/kg。静脉给药的采血时间点是给药后0、0.083、0.25、0.5、1、2、4、8和24小时,口服给药后的采血时间点是给药后0、0.25、0.5、1、2、4、6、8和24小时。经眶静脉丛采血,每个时间点取样0.03mL。样品被放置在含有K2-EDTA的试管中,并在冰中保存直到离心。样品在采集后1小时内,于2-8℃条件下,4000RPM离心6分钟,离心完毕后样品置于约-80℃冷冻保存。分离上清液用于LC/MS/MS分析。LC/MS/MS系统型号为LC-MS/MS-23(TQ6500+Triple quad)。样品在Acquity UPLC BEH C18、1.7μM、50×2.1mm柱上分离,从30%流动相B开始以线性梯度洗脱,其中流动相A是含有0.1%甲酸的水溶液、流动相B是含有0.1%甲酸的乙腈溶液。采用正离子模式的电喷雾电离来获取LC/MS/MS数据,使用标准曲线分别定量化合物的血浆浓度。得到各时间点的血药浓度后,采用FDA认证的药代动力学程序Phoenix WinNonlin 7.0(Pharsight,美国)拟合得到T
1/2、C
max、T
max及生物利用度(F%)等药代动力学参数。
其中,部分实施例化合物的药物代谢动力学结果详见表5。
表5
参考例 | 实施例1 | 实施例20 | 实施例21 | |
F(%) | 30.99±4.62 | 19.43±2.64 | 56.75±5.05 | 73.06±11.73 |
从代谢数据可知,相较于参考例化合物,选取实施例20和21制备的化合物,口服给药后,生物利用度(F(%))显著提高。
作为本申请的具体实施例,参照上述合成方法,优选地,通式Ib化合物进一步包括表6所示实施例制备的化合物:
表6
作为本申请的具体实施例,参照上述合成方法,优选地,通式Ia化合物进一步包括表7所示实施例制备的化合物:
表7
作为本申请的具体实施例,参照上述合成方法,优选地,通式Ic化合物进一步包括表8所示实施例制备的化合物:
表8
从上述活性测试结果可知,本申请的化合物具备及其优异的DHODH抑制活性,其中一些化合物抑制DHODH的IC
50值甚至达到小于1nM的级别。因此,本申请的化合物成为低毒性、高安全性的新的DHODH抑制剂,可以作为抗炎剂、自身免疫疾病治疗剂、免疫抑制剂、抗癌剂、病毒感染治疗剂等应用。
应理解,在阅读了本申请的上述公开内容之后,在不脱离本申请的方面构思和精神的情况下,本领域普通技术人员可以对本申请的技术方案作各种改动、调整等,或做组合灯,这些等价形式同样落于本申请要求保护的范围内。
Claims (11)
- 一种如下式I所示的化合物或其药学上可接受的盐,其中,R 1或R 2独立选自氢、卤素、C 1-6烷基、C 1-6烷氧基、和氰基中的任一种;R 3为-(NR 7) p-O-R 5;R 5或R 7独立选自氢或C 1-6烷基;R 4任意选自C 1-6烷基或C 3-6环烷基;M是氮原子或者CR 6;R 6任意选自氢、卤素和C 1-6烷基中任一种;m或n任意为0-5的整数;并且p为0或1。
- 如权利要求1所述的式I所示的化合物,其中,所述化合物任选自式Ia、式Ib、式Ic化合物或其药学上可接受的盐,其中,R 1或R 2独立选自氢、卤素、C 1-6烷基、C 1-6烷氧基和氰基中的任一种;R 3为-(NR 7) p-O-R 5;R 4任意选自C 1-6烷基或C 3-6环烷基;R 5或R 7独立选自氢或C 1-6烷基;R 6任意选自氢或C 1-6烷基;X为卤素;m或n任意为0-5的整数;并且p为0或1。
- 如权利要求1或2任一项所述的化合物,其中,R 1或R 2是氢、卤素、甲基、甲氧基、三氟甲基、三氟甲氧基、和氰基中的任一种;并且m或n是0或1或2。
- 如权利要求1或2任一项所述的化合物,其中,R 4为C 1-3烷基、未取代的环丙基、环丁基、氟取代的环丙基、和环丁基中的任一种。
- 如权利要求1或2任一项所述的化合物,其中,R 3为羟基或NR 7-O-R 5;R 5或R 7独立选自氢、甲基和乙基中的任一种;
- 如权利要求2所述的化合物,其中,在式Ia化合物中,X是氟,R 4是C 1-4烷基、环丙基、环丁基;在式Ib化合物中,R 4是环丙基、环丁基。
- 如权利要求1或2任一项所述的化合物,其中,所述化合物是以下化合物或其药学上可接受的盐:
- 一种式II化合物,其中,M为氮或CR 6,R 6任意选自氢、C 1-3烷基和氟中任一种;R 2任意选自氢、卤素、C 1-3烷基、C 1-3烷氧基和氰基中的任一种;R 4任意选自C 1-4烷基或C 3-6环烷基;R 8为氨基保护基或氢原子;并且m任意为0、1、2或3。
- 一种药物组合物,其包含如权利要求1或2任一所述的式I化合物或其药学上可接受的盐或药学上可接受的载体。
- 如权利要求9所述的药物组合物在制备治疗或预防DHODH介导的疾病的药物中的用途。
- 如权利要求10所述的用途,其中,所述DHODH介导的疾病包括自身免疫疾病、肿瘤和病毒感染。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2021108830833 | 2021-08-02 | ||
CN202110883083.3A CN115701427A (zh) | 2021-08-02 | 2021-08-02 | 多取代噻唑衍生物及其在疾病治疗中的应用 |
PCT/CN2022/108625 WO2023011312A1 (zh) | 2021-08-02 | 2022-07-28 | 多取代噻唑衍生物及其在疾病治疗中的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117769544A true CN117769544A (zh) | 2024-03-26 |
Family
ID=85142584
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110883083.3A Pending CN115701427A (zh) | 2021-08-02 | 2021-08-02 | 多取代噻唑衍生物及其在疾病治疗中的应用 |
CN202280050499.XA Pending CN117769544A (zh) | 2021-08-02 | 2022-07-28 | 多取代噻唑衍生物及其在疾病治疗中的应用 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110883083.3A Pending CN115701427A (zh) | 2021-08-02 | 2021-08-02 | 多取代噻唑衍生物及其在疾病治疗中的应用 |
Country Status (2)
Country | Link |
---|---|
CN (2) | CN115701427A (zh) |
WO (1) | WO2023011312A1 (zh) |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4319026A (en) * | 1980-08-14 | 1982-03-09 | Gulf Oil Corporation | Heterocyclic-substituted hydrazides and hydrazones as plant growth regulators |
CN103058949A (zh) * | 2011-10-18 | 2013-04-24 | 华东理工大学 | 做为dhodh抑制剂的噻唑衍生物及其应用 |
CN106892878B (zh) * | 2015-12-18 | 2020-01-10 | 华东理工大学 | 噻唑类衍生物及其在抑制二氢乳清酸脱氢酶中的应用 |
CN107382902B (zh) * | 2016-05-17 | 2022-08-12 | 华东理工大学 | 噻唑类衍生物及其应用 |
CN107459496B (zh) * | 2016-06-03 | 2022-07-19 | 华东理工大学 | 噻唑类衍生物在治疗病毒感染中的应用 |
CN108721283A (zh) * | 2017-04-20 | 2018-11-02 | 华东理工大学 | 噻唑衍生物在治疗非淋巴细胞性白血病中的应用 |
EP4116296A1 (en) * | 2020-03-02 | 2023-01-11 | East China University of Science and Technology | Anti-rna virus drug and application thereof |
CN112707874A (zh) * | 2020-12-29 | 2021-04-27 | 广东中科药物研究有限公司 | 一种抗病毒化合物及其制备方法 |
-
2021
- 2021-08-02 CN CN202110883083.3A patent/CN115701427A/zh active Pending
-
2022
- 2022-07-28 CN CN202280050499.XA patent/CN117769544A/zh active Pending
- 2022-07-28 WO PCT/CN2022/108625 patent/WO2023011312A1/zh active Application Filing
Also Published As
Publication number | Publication date |
---|---|
CN115701427A (zh) | 2023-02-10 |
WO2023011312A1 (zh) | 2023-02-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11672799B2 (en) | 1,4-disubstituted pyridazine quinolne analogs there of and methods for treating SMN-deficiency-related conditions | |
US20230113085A1 (en) | Novel small molecule inhibitors of tead transcription factors | |
EP1986633B1 (en) | Treatment of duchenne muscular dystrophy | |
CA2998803A1 (en) | Hepatitis b core protein modulators | |
JP5580834B2 (ja) | 新規イソインドリン−1−オン誘導体 | |
JP2011526294A (ja) | ホスホジエステラーゼ10阻害剤としての二置換フェニル化合物 | |
EA028918B1 (ru) | Производные 5-аминотетрагидрохинолин-2-карбоновых кислот и их применение в качестве активатора растворимой гуанилатциклазы | |
WO2019101086A1 (zh) | 卤代烯丙基胺类ssao/vap-1抑制剂及其应用 | |
KR20150061644A (ko) | 지방산 신타아제 저해제로서의 히드로피롤로피롤 유도체 | |
EP3398942B1 (en) | Substituted oxadiazole chemical compound and composition containing said chemical compound and use thereof | |
EP2964225B1 (en) | CaMKII INHIBITORS AND USES THEREOF | |
JP2008520673A (ja) | Hcv阻害剤 | |
CN117203205A (zh) | 三唑酮、四唑酮和咪唑酮或它们的盐,以及包含它们的药物组合物 | |
CN117769544A (zh) | 多取代噻唑衍生物及其在疾病治疗中的应用 | |
EP1742947B1 (fr) | Derives de pyridoindolone substitues en -6, leur preparation, leur application en therapeutique. | |
CA2956464C (en) | Bisamidinium-based inhibitors for the treatment of myotonic dystrophy | |
EP3998255A1 (en) | Small-molecule regulator of tlr8 | |
CA3178647A1 (en) | Substituted tricyclic amides, analogues thereof, and methods using same | |
JP2018087173A (ja) | 悪性脳腫瘍治療薬 | |
MXPA02008418A (es) | Medicamentos para enfermedades virales. | |
US20230312481A1 (en) | Substituted (phthalazin-1-ylmethyl)ureas, substituted n-(phthalazin-1-ylmethyl)amides, and analogues thereof | |
CN111662275B (zh) | 苯磺酰胺类idh突变体抑制剂、其制备方法和用途 | |
CN111559982B (zh) | 2-(2-取代-4-羟基嘧啶-5-甲酰胺基)乙酸类化合物及其制备方法与用途 | |
TWI828289B (zh) | 作為tyk2/jak1假激酶結構域抑制劑的化合物及合成和使用方法 | |
WO2010060277A1 (zh) | 取代乙酰肼类衍生物及其制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |