CN111655685A - 噻吩衍生物及其用途 - Google Patents
噻吩衍生物及其用途 Download PDFInfo
- Publication number
- CN111655685A CN111655685A CN201980010101.8A CN201980010101A CN111655685A CN 111655685 A CN111655685 A CN 111655685A CN 201980010101 A CN201980010101 A CN 201980010101A CN 111655685 A CN111655685 A CN 111655685A
- Authority
- CN
- China
- Prior art keywords
- triazol
- dione
- piperidine
- thiophen
- benzyloxy
- 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.)
- Granted
Links
- 150000003577 thiophenes Chemical class 0.000 title abstract description 8
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 25
- 230000002489 hematologic effect Effects 0.000 claims abstract description 20
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 20
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- 230000006433 tumor necrosis factor production Effects 0.000 claims abstract description 10
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 9
- 206010009900 Colitis ulcerative Diseases 0.000 claims abstract description 8
- 208000011231 Crohn disease Diseases 0.000 claims abstract description 8
- 201000006704 Ulcerative Colitis Diseases 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 160
- 239000001257 hydrogen Substances 0.000 claims description 115
- 229910052739 hydrogen Inorganic materials 0.000 claims description 115
- 238000000034 method Methods 0.000 claims description 86
- 229910052736 halogen Inorganic materials 0.000 claims description 81
- 150000002367 halogens Chemical class 0.000 claims description 81
- 150000002431 hydrogen Chemical class 0.000 claims description 81
- -1 hydrogen Chemical class 0.000 claims description 76
- 150000003839 salts Chemical class 0.000 claims description 73
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 60
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 47
- 239000003814 drug Substances 0.000 claims description 47
- 125000001424 substituent group Chemical group 0.000 claims description 47
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 28
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 claims description 22
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 20
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 19
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 19
- 229910052794 bromium Inorganic materials 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 19
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 208000023275 Autoimmune disease Diseases 0.000 claims description 15
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 14
- 206010025323 Lymphomas Diseases 0.000 claims description 14
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 208000027866 inflammatory disease Diseases 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 208000034578 Multiple myelomas Diseases 0.000 claims description 10
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 10
- GYIOTIGHJSIQBM-AQKKSAQBSA-N 3-[4-[4-[[4-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]phenyl]methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound C[C@@H]1O[C@@H](CN(C1)CC1=CC=C(COC=2C(=CSC=2)C=2N=NN(C=2)C2C(NC(CC2)=O)=O)C=C1)C GYIOTIGHJSIQBM-AQKKSAQBSA-N 0.000 claims description 9
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 9
- 201000005787 hematologic cancer Diseases 0.000 claims description 9
- 229940124597 therapeutic agent Drugs 0.000 claims description 9
- SKUSCUALKIOIST-UHFFFAOYSA-N 3-[4-(4-methoxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound COC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O SKUSCUALKIOIST-UHFFFAOYSA-N 0.000 claims description 8
- NEYLNUDXHJZGQU-UHFFFAOYSA-N 3-[4-[4-[[4-(methoxymethyl)phenyl]methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound COCC1=CC=C(COC=2C(=CSC=2)C=2N=NN(C=2)C2C(NC(CC2)=O)=O)C=C1 NEYLNUDXHJZGQU-UHFFFAOYSA-N 0.000 claims description 8
- 208000032839 leukemia Diseases 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- DHJYAECRJZDUBS-UHFFFAOYSA-N 3-[4-(4-phenylmethoxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound C(C1=CC=CC=C1)OC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O DHJYAECRJZDUBS-UHFFFAOYSA-N 0.000 claims description 7
- BBJBZSIMNQIPRI-UHFFFAOYSA-N 3-[4-(5-bromo-4-methoxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound BrC1=C(C(=CS1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O)OC BBJBZSIMNQIPRI-UHFFFAOYSA-N 0.000 claims description 7
- ZSXWHDGBJSYIGI-UHFFFAOYSA-N 3-[4-(5-methoxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound COC1=CC(=CS1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O ZSXWHDGBJSYIGI-UHFFFAOYSA-N 0.000 claims description 7
- LPLLYDCCDLOHJR-UHFFFAOYSA-N 3-[4-[4-(1-benzothiophen-2-ylmethoxy)thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound S1C2=C(C=C1COC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O)C=CC=C2 LPLLYDCCDLOHJR-UHFFFAOYSA-N 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- GCBMOTDOCNMCFZ-UHFFFAOYSA-N 3-[4-[4-[[4-(pyrrolidin-1-ylmethyl)phenyl]methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound N1(CCCC1)CC1=CC=C(COC=2C(=CSC=2)C=2N=NN(C=2)C2C(NC(CC2)=O)=O)C=C1 GCBMOTDOCNMCFZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
- HTVDYCWSHTVTEC-UHFFFAOYSA-N 3-[4-(4-butoxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound C(CCC)OC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O HTVDYCWSHTVTEC-UHFFFAOYSA-N 0.000 claims description 5
- FMOMPMDQXOVEAS-UHFFFAOYSA-N 3-[4-(4-cyclopentyloxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound C1(CCCC1)OC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O FMOMPMDQXOVEAS-UHFFFAOYSA-N 0.000 claims description 5
- XHDCLSOMGHYDTH-UHFFFAOYSA-N 3-[4-(4-propan-2-yloxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound C(C)(C)OC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O XHDCLSOMGHYDTH-UHFFFAOYSA-N 0.000 claims description 5
- OHTZYARSHWISJC-UHFFFAOYSA-N 3-[4-(5-ethoxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound C(C)OC1=CC(=CS1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O OHTZYARSHWISJC-UHFFFAOYSA-N 0.000 claims description 5
- RBXFEJBRBRJAJN-UHFFFAOYSA-N 3-[4-[4-(cyclohexylmethoxy)thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound C1(CCCCC1)COC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O RBXFEJBRBRJAJN-UHFFFAOYSA-N 0.000 claims description 5
- MWXIATPVHBNZHB-UHFFFAOYSA-N 3-[4-[4-(cyclopentylmethoxy)thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound C1(CCCC1)COC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O MWXIATPVHBNZHB-UHFFFAOYSA-N 0.000 claims description 5
- HZJFTWKSXUDUKW-UHFFFAOYSA-N 3-[4-[4-(cyclopropylmethoxy)thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound C1(CC1)COC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O HZJFTWKSXUDUKW-UHFFFAOYSA-N 0.000 claims description 5
- DVNLDLFIAXARNX-UHFFFAOYSA-N 3-[4-[4-(pyridin-2-ylmethoxy)thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound N1=C(C=CC=C1)COC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O DVNLDLFIAXARNX-UHFFFAOYSA-N 0.000 claims description 5
- GQUKMMDZYLQTOS-UHFFFAOYSA-N 3-[4-[4-(pyridin-3-ylmethoxy)thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound N1=CC(=CC=C1)COC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O GQUKMMDZYLQTOS-UHFFFAOYSA-N 0.000 claims description 5
- GURSTJOQVOVFAQ-UHFFFAOYSA-N 3-[4-[4-(pyridin-4-ylmethoxy)thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound N1=CC=C(C=C1)COC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O GURSTJOQVOVFAQ-UHFFFAOYSA-N 0.000 claims description 5
- FUKAEXJEQUFSJB-UHFFFAOYSA-N 3-[4-[4-[(4-chlorophenyl)methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound ClC1=CC=C(COC=2C(=CSC=2)C=2N=NN(C=2)C2C(NC(CC2)=O)=O)C=C1 FUKAEXJEQUFSJB-UHFFFAOYSA-N 0.000 claims description 5
- JVECXQTZSKVUAT-UHFFFAOYSA-N 3-[4-[4-[(4-methoxyphenyl)methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound COC1=CC=C(COC=2C(=CSC=2)C=2N=NN(C=2)C2C(NC(CC2)=O)=O)C=C1 JVECXQTZSKVUAT-UHFFFAOYSA-N 0.000 claims description 5
- COESVKOQORAESL-UHFFFAOYSA-N 3-[4-[4-[[2-(morpholin-4-ylmethyl)phenyl]methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound O1CCN(CC1)CC1=C(COC=2C(=CSC=2)C=2N=NN(C=2)C2C(NC(CC2)=O)=O)C=CC=C1 COESVKOQORAESL-UHFFFAOYSA-N 0.000 claims description 5
- QNKTURROPWVXKI-UHFFFAOYSA-N 3-[4-[4-[[3-(morpholin-4-ylmethyl)phenyl]methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound O1CCN(CC1)CC=1C=C(COC=2C(=CSC=2)C=2N=NN(C=2)C2C(NC(CC2)=O)=O)C=CC=1 QNKTURROPWVXKI-UHFFFAOYSA-N 0.000 claims description 5
- CLSPMJQWVLSVMZ-UHFFFAOYSA-N 3-[4-[4-[[4-(morpholin-4-ylmethyl)phenyl]methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound O1CCN(CC1)CC1=CC=C(COC=2C(=CSC=2)C=2N=NN(C=2)C2C(NC(CC2)=O)=O)C=C1 CLSPMJQWVLSVMZ-UHFFFAOYSA-N 0.000 claims description 5
- LDHONPFNTLTROG-UHFFFAOYSA-N 3-[4-[4-[[4-(piperidin-1-ylmethyl)phenyl]methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound N1(CCCCC1)CC1=CC=C(COC=2C(=CSC=2)C=2N=NN(C=2)C2C(NC(CC2)=O)=O)C=C1 LDHONPFNTLTROG-UHFFFAOYSA-N 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 208000019420 lymphoid neoplasm Diseases 0.000 claims description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- MJAVSTOYMNIMJK-UHFFFAOYSA-N 3-(5-bromo-4-thiophen-3-yltriazol-1-yl)piperidine-2,6-dione Chemical compound BrC1=C(N=NN1C1C(NC(CC1)=O)=O)C1=CSC=C1 MJAVSTOYMNIMJK-UHFFFAOYSA-N 0.000 claims description 4
- XWDDXZCCMGZUGZ-UHFFFAOYSA-N 3-[4-[4-(1-phenylethoxy)thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound C1(=CC=CC=C1)C(C)OC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O XWDDXZCCMGZUGZ-UHFFFAOYSA-N 0.000 claims description 4
- KYIPTANZBFHHGN-UHFFFAOYSA-N 3-[4-[4-[[4-(2-morpholin-4-ylethyl)phenyl]methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound O1CCN(CC1)CCC1=CC=C(COC=2C(=CSC=2)C=2N=NN(C=2)C2C(NC(CC2)=O)=O)C=C1 KYIPTANZBFHHGN-UHFFFAOYSA-N 0.000 claims description 4
- CGKLRUHMCLTLBF-UHFFFAOYSA-N 3-[4-[4-[[4-[(dimethylamino)methyl]phenyl]methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound CN(C)CC1=CC=C(COC=2C(=CSC=2)C=2N=NN(C=2)C2C(NC(CC2)=O)=O)C=C1 CGKLRUHMCLTLBF-UHFFFAOYSA-N 0.000 claims description 4
- NODPLDAFIWXVAU-UHFFFAOYSA-N 3-[5-iodo-4-(4-methoxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound IC1=C(N=NN1C1C(NC(CC1)=O)=O)C1=CSC=C1OC NODPLDAFIWXVAU-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 210000003519 mature b lymphocyte Anatomy 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 230000000069 prophylactic effect Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 4
- WIBXNHMQDGRIDN-UHFFFAOYSA-N 2-chloro-3-methoxythiophene Chemical compound COC=1C=CSC=1Cl WIBXNHMQDGRIDN-UHFFFAOYSA-N 0.000 claims 1
- 102100040247 Tumor necrosis factor Human genes 0.000 claims 1
- 230000009702 cancer cell proliferation Effects 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 250
- 238000005160 1H NMR spectroscopy Methods 0.000 description 185
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 150
- 239000000203 mixture Substances 0.000 description 122
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 116
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- 239000000243 solution Substances 0.000 description 99
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 81
- 239000007787 solid Substances 0.000 description 73
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 58
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 53
- 239000011541 reaction mixture Substances 0.000 description 52
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 239000002609 medium Substances 0.000 description 34
- 239000003921 oil Substances 0.000 description 34
- 235000019198 oils Nutrition 0.000 description 34
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 33
- 238000004440 column chromatography Methods 0.000 description 32
- 239000012044 organic layer Substances 0.000 description 30
- 239000012300 argon atmosphere Substances 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- UFTXASQYKJFRKI-UHFFFAOYSA-N methyl 4-bromo-3-hydroxythiophene-2-carboxylate Chemical compound COC(=O)C=1SC=C(Br)C=1O UFTXASQYKJFRKI-UHFFFAOYSA-N 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- 150000001721 carbon Chemical group 0.000 description 12
- 201000010099 disease Diseases 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 11
- 230000004663 cell proliferation Effects 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 10
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 9
- 239000006285 cell suspension Substances 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 7
- XRFYBLAXLGAQRA-UHFFFAOYSA-N 3-azidopiperidine-2,6-dione Chemical compound O=C1NC(CCC1N=[N+]=[N-])=O XRFYBLAXLGAQRA-UHFFFAOYSA-N 0.000 description 7
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 7
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 238000007865 diluting Methods 0.000 description 7
- 238000010790 dilution Methods 0.000 description 7
- 239000012895 dilution Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 229940125773 compound 10 Drugs 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 5
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 5
- 239000003124 biologic agent Substances 0.000 description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 5
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 4
- WGBMKGMEHJIMEJ-UHFFFAOYSA-N 3-[4-(2-methoxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound COC=1SC=CC=1C=1N=NN(C=1)C1C(NC(CC1)=O)=O WGBMKGMEHJIMEJ-UHFFFAOYSA-N 0.000 description 4
- UMHODGBXTIJRCE-UHFFFAOYSA-N 3-[4-(4-ethoxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound C(C)OC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O UMHODGBXTIJRCE-UHFFFAOYSA-N 0.000 description 4
- ROOIIRRKNQTAGM-UHFFFAOYSA-N 3-[4-(4-methoxy-5-methylthiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound COC=1C(=CSC=1C)C=1N=NN(C=1)C1C(NC(CC1)=O)=O ROOIIRRKNQTAGM-UHFFFAOYSA-N 0.000 description 4
- CSROZJGOUIWLNI-UHFFFAOYSA-N 3-[4-(4-propoxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound C(CC)OC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O CSROZJGOUIWLNI-UHFFFAOYSA-N 0.000 description 4
- MUKPGYWMEFTAIP-UHFFFAOYSA-N 3-[4-(5-chloro-4-methoxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound ClC1=C(C(=CS1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O)OC MUKPGYWMEFTAIP-UHFFFAOYSA-N 0.000 description 4
- ZRRITICBFNCZPV-UHFFFAOYSA-N 3-[4-(5-chlorothiophen-2-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound ClC1=CC=C(S1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O ZRRITICBFNCZPV-UHFFFAOYSA-N 0.000 description 4
- CLIGYUJHYAYYGK-UHFFFAOYSA-N 3-[4-(5-methylthiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound CC1=CC(=CS1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O CLIGYUJHYAYYGK-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 229940124599 anti-inflammatory drug Drugs 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 4
- 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 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 210000005087 mononuclear cell Anatomy 0.000 description 4
- 229960004641 rituximab Drugs 0.000 description 4
- 229910001958 silver carbonate Inorganic materials 0.000 description 4
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- YEENEYXBHNNNGV-XEHWZWQGSA-M sodium;3-acetamido-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoate;(2r,3r,4s,5s,6r)-2-[(2r,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound [Na+].CC(=O)N(C)C1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I.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 YEENEYXBHNNNGV-XEHWZWQGSA-M 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- RKEPWQUJGOTPTB-OKILXGFUSA-N (2S,6R)-4-[[4-[(4-bromothiophen-3-yl)oxymethyl]phenyl]methyl]-2,6-dimethylmorpholine Chemical compound BrC=1C(=CSC=1)OCC1=CC=C(CN2C[C@@H](O[C@@H](C2)C)C)C=C1 RKEPWQUJGOTPTB-OKILXGFUSA-N 0.000 description 3
- GVPCOFMAPDQIMI-UHFFFAOYSA-N 3-(4-thiophen-2-yltriazol-1-yl)piperidine-2,6-dione Chemical compound S1C(=CC=C1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O GVPCOFMAPDQIMI-UHFFFAOYSA-N 0.000 description 3
- PGEUBQZQGXWTFO-UHFFFAOYSA-N 3-(4-thiophen-3-yltriazol-1-yl)piperidine-2,6-dione Chemical compound S1C=C(C=C1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O PGEUBQZQGXWTFO-UHFFFAOYSA-N 0.000 description 3
- FMIUUWYSYOGKGK-UHFFFAOYSA-N 3-(5-chloro-4-thiophen-3-yltriazol-1-yl)piperidine-2,6-dione Chemical compound ClC1=C(N=NN1C1C(NC(CC1)=O)=O)C1=CSC=C1 FMIUUWYSYOGKGK-UHFFFAOYSA-N 0.000 description 3
- BLFYFOIRUSHFCF-UHFFFAOYSA-N 3-[4-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound O1C=2C(OCC1)=C(SC=2)C=1N=NN(C=1)C1C(NC(CC1)=O)=O BLFYFOIRUSHFCF-UHFFFAOYSA-N 0.000 description 3
- FXSPXUVLTVUUCB-UHFFFAOYSA-N 3-[4-(2,5-dibromothiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound BrC=1SC(=CC=1C=1N=NN(C=1)C1C(NC(CC1)=O)=O)Br FXSPXUVLTVUUCB-UHFFFAOYSA-N 0.000 description 3
- PPPDVMPXLUOKPR-UHFFFAOYSA-N 3-[4-(4-bromothiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound BrC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O PPPDVMPXLUOKPR-UHFFFAOYSA-N 0.000 description 3
- XNRMQBRNAFPGAM-UHFFFAOYSA-N 3-[4-(4-chlorothiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound ClC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O XNRMQBRNAFPGAM-UHFFFAOYSA-N 0.000 description 3
- IKMCNWXOYROHAP-UHFFFAOYSA-N 3-[4-(4-methylthiophen-3-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound CC=1C(=CSC=1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O IKMCNWXOYROHAP-UHFFFAOYSA-N 0.000 description 3
- VXCRMWYWWXOCJJ-UHFFFAOYSA-N 3-[4-(5-acetylthiophen-2-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound C(C)(=O)C1=CC=C(S1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O VXCRMWYWWXOCJJ-UHFFFAOYSA-N 0.000 description 3
- VYEQWLPDESYKON-UHFFFAOYSA-N 3-[4-(5-bromothiophen-2-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound BrC1=CC=C(S1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O VYEQWLPDESYKON-UHFFFAOYSA-N 0.000 description 3
- UXZNZXIGKIQJRR-UHFFFAOYSA-N 3-[4-(5-methylthiophen-2-yl)triazol-1-yl]piperidine-2,6-dione Chemical compound CC1=CC=C(S1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O UXZNZXIGKIQJRR-UHFFFAOYSA-N 0.000 description 3
- CVLRTBPAFJRHGA-UHFFFAOYSA-N 3-[4-[5-(hydroxymethyl)thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione Chemical compound OCC1=CC(=CS1)C=1N=NN(C=1)C1C(NC(CC1)=O)=O CVLRTBPAFJRHGA-UHFFFAOYSA-N 0.000 description 3
- HAYBTWOBFZGUIG-UHFFFAOYSA-N 3-bromo-4-[(4-chlorophenyl)methoxy]thiophene Chemical compound BrC1=CSC=C1OCC1=CC=C(C=C1)Cl HAYBTWOBFZGUIG-UHFFFAOYSA-N 0.000 description 3
- MJHLPKWONJUCFK-UHFFFAOYSA-N 3-ethynylthiophene Chemical compound C#CC=1C=CSC=1 MJHLPKWONJUCFK-UHFFFAOYSA-N 0.000 description 3
- BXYHAVFIFJDEIJ-UHFFFAOYSA-N 4-[[2-[(4-bromothiophen-3-yl)oxymethyl]phenyl]methyl]morpholine Chemical compound BrC=1C(=CSC=1)OCC1=C(CN2CCOCC2)C=CC=C1 BXYHAVFIFJDEIJ-UHFFFAOYSA-N 0.000 description 3
- IUPBULNOCRVXSH-UHFFFAOYSA-N 4-[[4-[(4-bromothiophen-3-yl)oxymethyl]phenyl]methyl]morpholine Chemical compound BrC=1C(=CSC=1)OCC1=CC=C(CN2CCOCC2)C=C1 IUPBULNOCRVXSH-UHFFFAOYSA-N 0.000 description 3
- SLVYMCDGYSJHRF-UHFFFAOYSA-N 4-bromo-2-(chloromethyl)-3-methoxythiophene Chemical compound BrC=1C(=C(SC=1)CCl)OC SLVYMCDGYSJHRF-UHFFFAOYSA-N 0.000 description 3
- KHIZKHJPMHLIBX-UHFFFAOYSA-N 4-bromo-3-(pyridin-4-ylmethoxy)thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1=CC=NC=C1 KHIZKHJPMHLIBX-UHFFFAOYSA-N 0.000 description 3
- UIAPIGAOSZOXHH-UHFFFAOYSA-N 4-bromo-3-[[4-(2-morpholin-4-ylethyl)phenyl]methoxy]thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1=CC=C(C=C1)CCN1CCOCC1 UIAPIGAOSZOXHH-UHFFFAOYSA-N 0.000 description 3
- ZWUFRKNZOOTSSH-UHFFFAOYSA-N 4-bromo-3-[[4-(methoxymethyl)phenyl]methoxy]thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1=CC=C(C=C1)COC ZWUFRKNZOOTSSH-UHFFFAOYSA-N 0.000 description 3
- WUUDFAPRORFLEN-BETUJISGSA-N 4-bromo-3-[[4-[[(2S,6R)-2,6-dimethylmorpholin-4-yl]methyl]phenyl]methoxy]thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1=CC=C(C=C1)CN1C[C@@H](O[C@@H](C1)C)C WUUDFAPRORFLEN-BETUJISGSA-N 0.000 description 3
- CWLRRXNVZBFRDX-UHFFFAOYSA-N 4-bromo-3-cyclopentyloxythiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OC1CCCC1 CWLRRXNVZBFRDX-UHFFFAOYSA-N 0.000 description 3
- AFGBVOQLKUEKQC-UHFFFAOYSA-N 4-methoxythiophene-3-carbaldehyde Chemical compound COC1=CSC=C1C=O AFGBVOQLKUEKQC-UHFFFAOYSA-N 0.000 description 3
- FLJUBMBXNFLNDM-UHFFFAOYSA-N 4-propan-2-yloxythiophene-3-carbaldehyde Chemical compound CC(C)OC1=CSC=C1C=O FLJUBMBXNFLNDM-UHFFFAOYSA-N 0.000 description 3
- GJZYULNTPIBSKV-UHFFFAOYSA-N 5-bromo-4-methoxythiophene-3-carbaldehyde Chemical compound COC1=C(SC=C1C=O)Br GJZYULNTPIBSKV-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
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 101100356020 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) recA gene Proteins 0.000 description 3
- 208000017604 Hodgkin disease Diseases 0.000 description 3
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 3
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 101100042680 Mus musculus Slc7a1 gene Proteins 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000004012 Tofacitinib Substances 0.000 description 3
- VBWXDDWVLZXGDG-UHFFFAOYSA-N [4-[(4-bromothiophen-3-yl)oxymethyl]phenyl]methanol Chemical compound BrC=1C(=CSC=1)OCC1=CC=C(C=C1)CO VBWXDDWVLZXGDG-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 210000000601 blood cell Anatomy 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 210000001102 germinal center b cell Anatomy 0.000 description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical group O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 229960004942 lenalidomide Drugs 0.000 description 3
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- VUQDWWAXCWAUTG-UHFFFAOYSA-N methyl 4-[1-(2,6-dioxopiperidin-3-yl)triazol-4-yl]-3-methoxythiophene-2-carboxylate Chemical compound O=C1NC(CCC1N1N=NC(=C1)C=1C(=C(SC=1)C(=O)OC)OC)=O VUQDWWAXCWAUTG-UHFFFAOYSA-N 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- NSEVIVKAZHFLBF-UHFFFAOYSA-N piperidine-2,6-dione;hydrochloride Chemical compound Cl.O=C1CCCC(=O)N1 NSEVIVKAZHFLBF-UHFFFAOYSA-N 0.000 description 3
- 238000004393 prognosis Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 230000003637 steroidlike Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- VHJLUFNXQYIJRA-UHFFFAOYSA-N (4-bromo-3-methoxythiophen-2-yl)methanol Chemical compound COC=1C(Br)=CSC=1CO VHJLUFNXQYIJRA-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HPMWZCLCPNXGCU-UHFFFAOYSA-N 1-(5-ethynylthiophen-2-yl)ethanone Chemical compound CC(=O)C1=CC=C(C#C)S1 HPMWZCLCPNXGCU-UHFFFAOYSA-N 0.000 description 2
- OHKRABLXDKDBGF-UHFFFAOYSA-N 1-[4-[(4-ethynylthiophen-3-yl)oxymethyl]phenyl]-N,N-dimethylmethanamine Chemical compound C(#C)C=1C(=CSC=1)OCC1=CC=C(C=C1)CN(C)C OHKRABLXDKDBGF-UHFFFAOYSA-N 0.000 description 2
- PVODDFJLNVTZDX-UHFFFAOYSA-N 1-[[4-[(4-bromothiophen-3-yl)oxymethyl]phenyl]methyl]piperidine Chemical compound BrC=1C(=CSC=1)OCC1=CC=C(CN2CCCCC2)C=C1 PVODDFJLNVTZDX-UHFFFAOYSA-N 0.000 description 2
- BGZPKQBSVBAONY-UHFFFAOYSA-N 2,5-dibromo-3-ethynylthiophene Chemical compound BrC1=CC(C#C)=C(Br)S1 BGZPKQBSVBAONY-UHFFFAOYSA-N 0.000 description 2
- MEHLMGBLXFGQBM-UHFFFAOYSA-N 2-(5-chlorothiophen-2-yl)ethynyl-trimethylsilane Chemical compound C[Si](C)(C)C#Cc1ccc(Cl)s1 MEHLMGBLXFGQBM-UHFFFAOYSA-N 0.000 description 2
- GRDXTXRQXDSFAQ-UHFFFAOYSA-N 2-bromo-4-(dimethoxymethyl)thiophene Chemical compound COC(OC)c1csc(Br)c1 GRDXTXRQXDSFAQ-UHFFFAOYSA-N 0.000 description 2
- WQWZHRJLJWMSLF-UHFFFAOYSA-N 3-(1-benzothiophen-2-ylmethoxy)-4-bromothiophene-2-carboxylic acid Chemical compound S1C2=C(C=C1COC1=C(SC=C1Br)C(=O)O)C=CC=C2 WQWZHRJLJWMSLF-UHFFFAOYSA-N 0.000 description 2
- KOXINGYFNBODNV-UHFFFAOYSA-N 3-(2-iodoethynyl)-4-methoxythiophene Chemical compound IC#CC1=CSC=C1OC KOXINGYFNBODNV-UHFFFAOYSA-N 0.000 description 2
- PQGOWCMRDQFVQL-UHFFFAOYSA-N 3-[4-[4-[[4-(2-morpholin-4-ylethyl)phenyl]methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione hydrochloride Chemical compound Cl.O1CCN(CC1)CCC1=CC=C(COC=2C(=CSC=2)C=2N=NN(C=2)C2C(NC(CC2)=O)=O)C=C1 PQGOWCMRDQFVQL-UHFFFAOYSA-N 0.000 description 2
- ZKADAAVXJWMTBB-UHFFFAOYSA-N 3-[4-[4-[[4-(piperidin-1-ylmethyl)phenyl]methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione hydrochloride Chemical compound C1CCN(CC1)CC2=CC=C(C=C2)COC3=CSC=C3C4=CN(N=N4)C5CCC(=O)NC5=O.Cl ZKADAAVXJWMTBB-UHFFFAOYSA-N 0.000 description 2
- NEHDVYZLLJXMLM-UHFFFAOYSA-N 3-[4-[4-[[4-(pyrrolidin-1-ylmethyl)phenyl]methoxy]thiophen-3-yl]triazol-1-yl]piperidine-2,6-dione hydrochloride Chemical compound C1CCN(C1)CC2=CC=C(C=C2)COC3=CSC=C3C4=CN(N=N4)C5CCC(=O)NC5=O.Cl NEHDVYZLLJXMLM-UHFFFAOYSA-N 0.000 description 2
- KLVPTCPNUVPNON-UHFFFAOYSA-N 3-bromo-4-(dimethoxymethyl)thiophene Chemical compound COC(OC)C1=CSC=C1Br KLVPTCPNUVPNON-UHFFFAOYSA-N 0.000 description 2
- AHFBURSRHVTIPC-UHFFFAOYSA-N 3-bromo-4-[[4-(methoxymethyl)phenyl]methoxy]thiophene Chemical compound BrC1=CSC=C1OCC1=CC=C(C=C1)COC AHFBURSRHVTIPC-UHFFFAOYSA-N 0.000 description 2
- PPEVSCXBBKUJOG-UHFFFAOYSA-N 3-bromo-4-cyclopentyloxythiophene Chemical compound BrC1=CSC=C1OC1CCCC1 PPEVSCXBBKUJOG-UHFFFAOYSA-N 0.000 description 2
- UKIBAXPBJSDMHV-UHFFFAOYSA-N 3-butoxy-4-(diethoxymethyl)thiophene Chemical compound C(CCC)OC1=CSC=C1C(OCC)OCC UKIBAXPBJSDMHV-UHFFFAOYSA-N 0.000 description 2
- FCFLLTDYVPFSCF-UHFFFAOYSA-N 3-ethynyl-4-methoxythiophene Chemical compound C(#C)C=1C(=CSC=1)OC FCFLLTDYVPFSCF-UHFFFAOYSA-N 0.000 description 2
- GJWIHYJXWDRTMO-UHFFFAOYSA-N 4-(dimethoxymethyl)-2-ethoxythiophene Chemical compound COC(C=1C=C(SC=1)OCC)OC GJWIHYJXWDRTMO-UHFFFAOYSA-N 0.000 description 2
- WJCSZOZQMLDCQT-UHFFFAOYSA-N 4-[(4-bromothiophen-3-yl)oxymethyl]pyridine Chemical compound BrC=1C(=CSC=1)OCC1=CC=NC=C1 WJCSZOZQMLDCQT-UHFFFAOYSA-N 0.000 description 2
- FKVFCRSNTZHJIM-UHFFFAOYSA-N 4-[2-[4-[(4-bromothiophen-3-yl)oxymethyl]phenyl]ethyl]morpholine hydrochloride Chemical compound Cl.BrC=1C(=CSC=1)OCC1=CC=C(CCN2CCOCC2)C=C1 FKVFCRSNTZHJIM-UHFFFAOYSA-N 0.000 description 2
- XHQKRGOPDKQYBJ-UHFFFAOYSA-N 4-[2-[4-[(4-ethynylthiophen-3-yl)oxymethyl]phenyl]ethyl]morpholine Chemical compound C(#C)C=1C(=CSC=1)OCC1=CC=C(C=C1)CCN1CCOCC1 XHQKRGOPDKQYBJ-UHFFFAOYSA-N 0.000 description 2
- UMGMSWIHHGTFNO-UHFFFAOYSA-N 4-bromo-3-[[4-(hydroxymethyl)phenyl]methoxy]thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1=CC=C(C=C1)CO UMGMSWIHHGTFNO-UHFFFAOYSA-N 0.000 description 2
- PHNZVBKQFPIIPP-UHFFFAOYSA-N 4-bromo-3-methoxy-2-methylthiophene Chemical compound COC1=C(C)SC=C1Br PHNZVBKQFPIIPP-UHFFFAOYSA-N 0.000 description 2
- RFPGIOQHVDAYEC-UHFFFAOYSA-N 5-chloro-4-methoxythiophene-3-carbaldehyde Chemical compound COC1=C(Cl)SC=C1C=O RFPGIOQHVDAYEC-UHFFFAOYSA-N 0.000 description 2
- XDDDEXITDCJJJC-UHFFFAOYSA-N 5-ethoxythiophene-3-carbaldehyde Chemical compound CCOC1=CC(=CS1)C=O XDDDEXITDCJJJC-UHFFFAOYSA-N 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 2
- 208000011691 Burkitt lymphomas Diseases 0.000 description 2
- 201000004085 CLL/SLL Diseases 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 229940123907 Disease modifying antirheumatic drug Drugs 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- 208000016937 Extranodal nasal NK/T cell lymphoma Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 208000009359 Sezary Syndrome Diseases 0.000 description 2
- 208000021388 Sezary disease Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ONHDMTVVNVPHFY-UHFFFAOYSA-N [4-[[4-(2-trimethylsilylethynyl)thiophen-3-yl]oxymethyl]phenyl]methanol Chemical compound C[Si](C)(C)C#CC=1C(=CSC=1)OCC1=CC=C(C=C1)CO ONHDMTVVNVPHFY-UHFFFAOYSA-N 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940125644 antibody drug Drugs 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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
- 229960002438 carfilzomib Drugs 0.000 description 2
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 description 2
- 108010021331 carfilzomib Proteins 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- MQMQNIQJGNBEMG-ONEVTFJLSA-M chlororuthenium;(1z,5z)-cycloocta-1,5-diene;1,2,3,4,5-pentamethylcyclopentane Chemical compound [Ru]Cl.C\1C\C=C/CC\C=C/1.C[C]1[C](C)[C](C)[C](C)[C]1C MQMQNIQJGNBEMG-ONEVTFJLSA-M 0.000 description 2
- 208000024207 chronic leukemia Diseases 0.000 description 2
- 208000023738 chronic lymphocytic leukemia/small lymphocytic lymphoma Diseases 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 2
- 229960002204 daratumumab Drugs 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 239000002988 disease modifying antirheumatic drug Substances 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 229960000403 etanercept Drugs 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 230000005496 eutectics Effects 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 201000003444 follicular lymphoma Diseases 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 230000002584 immunomodulator Effects 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 229960000598 infliximab Drugs 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 229960002373 loxoprofen Drugs 0.000 description 2
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 description 2
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- JPVJINONGKVQQR-UHFFFAOYSA-N methyl 3-(1-benzothiophen-2-ylmethoxy)-4-bromothiophene-2-carboxylate Chemical compound S1C2=C(C=C1COC1=C(SC=C1Br)C(=O)OC)C=CC=C2 JPVJINONGKVQQR-UHFFFAOYSA-N 0.000 description 2
- USXIWRWDISOALI-UHFFFAOYSA-N methyl 4-bromo-3-(pyridin-4-ylmethoxy)thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC1=CC=NC=C1 USXIWRWDISOALI-UHFFFAOYSA-N 0.000 description 2
- IFTGGENQEGTCII-UHFFFAOYSA-N methyl 4-bromo-3-cyclopentyloxythiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OC1CCCC1 IFTGGENQEGTCII-UHFFFAOYSA-N 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 201000005962 mycosis fungoides Diseases 0.000 description 2
- 210000000822 natural killer cell Anatomy 0.000 description 2
- 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 2
- 239000008188 pellet Substances 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000000109 phenylethoxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])O* 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229960001350 tofacitinib Drugs 0.000 description 2
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- RWQWHKSMZLFSMQ-UHFFFAOYSA-N trimethyl-[2-(4-methylthiophen-3-yl)ethynyl]silane Chemical compound C[Si](C#CC1=CSC=C1C)(C)C RWQWHKSMZLFSMQ-UHFFFAOYSA-N 0.000 description 2
- FQTYBHVSVMOOOT-UHFFFAOYSA-N trimethyl-[2-(5-methylthiophen-2-yl)ethynyl]silane Chemical compound CC1=CC=C(C#C[Si](C)(C)C)S1 FQTYBHVSVMOOOT-UHFFFAOYSA-N 0.000 description 2
- JHPWAEIKVVYNAF-UHFFFAOYSA-N trimethyl-[2-[4-[[4-(2-morpholin-4-ylethyl)phenyl]methoxy]thiophen-3-yl]ethynyl]silane Chemical compound C[Si](C)(C)C#CC=1C(=CSC=1)OCC1=CC=C(C=C1)CCN1CCOCC1 JHPWAEIKVVYNAF-UHFFFAOYSA-N 0.000 description 2
- XSIQYIQYLNOAIG-UHFFFAOYSA-N trimethyl-[2-[4-[[4-(morpholin-4-ylmethyl)phenyl]methoxy]thiophen-3-yl]ethynyl]silane Chemical compound C[Si](C)(C)C#CC=1C(=CSC=1)OCC1=CC=C(CN2CCOCC2)C=C1 XSIQYIQYLNOAIG-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 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
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- 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
- 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
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- GFDULHHVTZGHBC-IYBDPMFKSA-N (2R,6S)-4-[[4-[(4-ethynylthiophen-3-yl)oxymethyl]phenyl]methyl]-2,6-dimethylmorpholine Chemical compound C(#C)C=1C(=CSC=1)OCC1=CC=C(CN2C[C@@H](O[C@@H](C2)C)C)C=C1 GFDULHHVTZGHBC-IYBDPMFKSA-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
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- HNVIQLPOGUDBSU-OLQVQODUSA-N (2s,6r)-2,6-dimethylmorpholine Chemical compound C[C@H]1CNC[C@@H](C)O1 HNVIQLPOGUDBSU-OLQVQODUSA-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
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- PTHGDVCPCZKZKR-UHFFFAOYSA-N (4-chlorophenyl)methanol Chemical compound OCC1=CC=C(Cl)C=C1 PTHGDVCPCZKZKR-UHFFFAOYSA-N 0.000 description 1
- GCCQKPVRICDXCJ-UHFFFAOYSA-N (4-ethynylthiophen-2-yl)methanol Chemical compound OCC1=CC(C#C)=CS1 GCCQKPVRICDXCJ-UHFFFAOYSA-N 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
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SQHSJJGGWYIFCD-UHFFFAOYSA-N (e)-1-diazonio-1-dimethoxyphosphorylprop-1-en-2-olate Chemical compound COP(=O)(OC)C(\[N+]#N)=C(\C)[O-] SQHSJJGGWYIFCD-UHFFFAOYSA-N 0.000 description 1
- RBZMSGOBSOCYHR-UHFFFAOYSA-N 1,4-bis(bromomethyl)benzene Chemical group BrCC1=CC=C(CBr)C=C1 RBZMSGOBSOCYHR-UHFFFAOYSA-N 0.000 description 1
- IGBZCOWXSCWSHO-UHFFFAOYSA-N 1-(5-bromothiophen-2-yl)ethanone Chemical compound CC(=O)C1=CC=C(Br)S1 IGBZCOWXSCWSHO-UHFFFAOYSA-N 0.000 description 1
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- 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 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
- MVDFYXDOROJHIJ-UHFFFAOYSA-N 1-[5-(2-trimethylsilylethynyl)thiophen-2-yl]ethanone Chemical compound CC(=O)C1=CC=C(C#C[Si](C)(C)C)S1 MVDFYXDOROJHIJ-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
- SKQDZNVRFFTYFC-UHFFFAOYSA-N 1-[[4-[(4-ethynylthiophen-3-yl)oxymethyl]phenyl]methyl]piperidine Chemical compound C(#C)C=1C(=CSC=1)OCC1=CC=C(CN2CCCCC2)C=C1 SKQDZNVRFFTYFC-UHFFFAOYSA-N 0.000 description 1
- KKILRGOQPVOJDF-UHFFFAOYSA-N 1-[[4-[(4-ethynylthiophen-3-yl)oxymethyl]phenyl]methyl]pyrrolidine Chemical compound C(#C)C=1C(=CSC=1)OCC1=CC=C(CN2CCCC2)C=C1 KKILRGOQPVOJDF-UHFFFAOYSA-N 0.000 description 1
- SUHKSQTXXZQEBH-UHFFFAOYSA-N 1-benzothiophen-2-ylmethanol Chemical compound C1=CC=C2SC(CO)=CC2=C1 SUHKSQTXXZQEBH-UHFFFAOYSA-N 0.000 description 1
- 125000005976 1-phenylethyloxy group Chemical group 0.000 description 1
- GBJBDOWMZMXKCD-UHFFFAOYSA-N 2,5-dibromothiophene-3-carbaldehyde Chemical compound BrC1=CC(C=O)=C(Br)S1 GBJBDOWMZMXKCD-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- UVAOUSVMYDAWTC-UHFFFAOYSA-N 2-(4-cyclopentyloxythiophen-3-yl)ethynyl-trimethylsilane Chemical compound C1(CCCC1)OC=1C(=CSC=1)C#C[Si](C)(C)C UVAOUSVMYDAWTC-UHFFFAOYSA-N 0.000 description 1
- XKSYIRNYMKWUSR-UHFFFAOYSA-N 2-(4-ethoxythiophen-3-yl)ethynyl-trimethylsilane Chemical compound C(C)OC=1C(=CSC=1)C#C[Si](C)(C)C XKSYIRNYMKWUSR-UHFFFAOYSA-N 0.000 description 1
- DQIBQOMDCMGMDH-UHFFFAOYSA-N 2-(4-methoxy-5-methylthiophen-3-yl)ethynyl-trimethylsilane Chemical compound COC=1C(=CSC=1C)C#C[Si](C)(C)C DQIBQOMDCMGMDH-UHFFFAOYSA-N 0.000 description 1
- JQDNCGRNPYKRAO-UHFFFAOYSA-N 2-(bromomethyl)pyridine;hydron;bromide Chemical compound Br.BrCC1=CC=CC=N1 JQDNCGRNPYKRAO-UHFFFAOYSA-N 0.000 description 1
- FHQJDYUROMAVHN-UHFFFAOYSA-N 2-[(4-bromothiophen-3-yl)oxymethyl]-1-benzothiophene Chemical compound BrC=1C(=CSC=1)OCC1=CC2=C(S1)C=CC=C2 FHQJDYUROMAVHN-UHFFFAOYSA-N 0.000 description 1
- IRMSYPWLJHJJNQ-UHFFFAOYSA-N 2-[(4-bromothiophen-3-yl)oxymethyl]pyridine Chemical compound BrC=1C(=CSC=1)OCC1=NC=CC=C1 IRMSYPWLJHJJNQ-UHFFFAOYSA-N 0.000 description 1
- GOLWJVMEIIEQEQ-UHFFFAOYSA-N 2-[(4-ethynylthiophen-3-yl)oxymethyl]-1-benzothiophene Chemical compound C(#C)C=1C(=CSC=1)OCC1=CC2=C(S1)C=CC=C2 GOLWJVMEIIEQEQ-UHFFFAOYSA-N 0.000 description 1
- HIOZSYGINFWTDF-UHFFFAOYSA-N 2-[(4-ethynylthiophen-3-yl)oxymethyl]pyridine Chemical compound C(#C)C=1C(=CSC=1)OCC1=NC=CC=C1 HIOZSYGINFWTDF-UHFFFAOYSA-N 0.000 description 1
- LKQXCVDYDRKEJK-UHFFFAOYSA-N 2-[4-(cyclohexylmethoxy)thiophen-3-yl]ethynyl-trimethylsilane Chemical compound C1(CCCCC1)COC=1C(=CSC=1)C#C[Si](C)(C)C LKQXCVDYDRKEJK-UHFFFAOYSA-N 0.000 description 1
- FIACBFZUHUJENE-UHFFFAOYSA-N 2-[4-(cyclopentylmethoxy)thiophen-3-yl]ethynyl-trimethylsilane Chemical compound C1(CCCC1)COC=1C(=CSC=1)C#C[Si](C)(C)C FIACBFZUHUJENE-UHFFFAOYSA-N 0.000 description 1
- ROOAZQKRBLGBLE-UHFFFAOYSA-N 2-[4-(cyclopropylmethoxy)thiophen-3-yl]ethynyl-trimethylsilane Chemical compound C1(CC1)COC=1C(=CSC=1)C#C[Si](C)(C)C ROOAZQKRBLGBLE-UHFFFAOYSA-N 0.000 description 1
- RHFQTUHJEBJFSA-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methoxy]thiophen-3-yl]ethynyl-trimethylsilane Chemical compound ClC1=CC=C(COC=2C(=CSC=2)C#C[Si](C)(C)C)C=C1 RHFQTUHJEBJFSA-UHFFFAOYSA-N 0.000 description 1
- QQCMPKFOHDGFHT-UHFFFAOYSA-N 2-[4-[(4-methoxyphenyl)methoxy]thiophen-3-yl]ethynyl-trimethylsilane Chemical compound COC1=CC=C(COC=2C(=CSC=2)C#C[Si](C)(C)C)C=C1 QQCMPKFOHDGFHT-UHFFFAOYSA-N 0.000 description 1
- VNSDNLJFRHHKCV-KDURUIRLSA-N 2-[4-[[4-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]phenyl]methoxy]thiophen-3-yl]ethynyl-trimethylsilane Chemical compound C[C@H]1CN(C[C@H](O1)C)CC1=CC=C(C=C1)COC1=CSC=C1C#C[Si](C)(C)C VNSDNLJFRHHKCV-KDURUIRLSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-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
- BRDXOEHQYVBYQI-UHFFFAOYSA-N 2-bromo-4-ethynyl-3-methoxythiophene Chemical compound BrC=1SC=C(C=1OC)C#C BRDXOEHQYVBYQI-UHFFFAOYSA-N 0.000 description 1
- ZFAJPWYXLYGUJU-UHFFFAOYSA-N 2-bromo-5-chlorothiophene Chemical compound ClC1=CC=C(Br)S1 ZFAJPWYXLYGUJU-UHFFFAOYSA-N 0.000 description 1
- UYVDCGFLVLPESJ-UHFFFAOYSA-N 2-bromo-5-ethynylthiophene Chemical compound BrC1=CC=C(C#C)S1 UYVDCGFLVLPESJ-UHFFFAOYSA-N 0.000 description 1
- ACDLOOGOFKSUPO-UHFFFAOYSA-N 2-bromo-5-methylthiophene Chemical compound CC1=CC=C(Br)S1 ACDLOOGOFKSUPO-UHFFFAOYSA-N 0.000 description 1
- XLPCKKCIIHURJL-UHFFFAOYSA-N 2-chloro-4-ethynyl-3-methoxythiophene Chemical compound ClC=1SC=C(C=1OC)C#C XLPCKKCIIHURJL-UHFFFAOYSA-N 0.000 description 1
- SDVHVQQEXLEHGZ-UHFFFAOYSA-N 2-chloro-5-ethynylthiophene Chemical compound ClC1=CC=C(C#C)S1 SDVHVQQEXLEHGZ-UHFFFAOYSA-N 0.000 description 1
- RZFURNNLOJDXQI-UHFFFAOYSA-N 2-ethoxy-4-ethynylthiophene Chemical compound C(C)OC=1SC=C(C=1)C#C RZFURNNLOJDXQI-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- UIUKIKLGNRUZJK-UHFFFAOYSA-N 2-methoxythiophene-3-carbaldehyde Chemical compound COC=1SC=CC=1C=O UIUKIKLGNRUZJK-UHFFFAOYSA-N 0.000 description 1
- YSNRUIFOACFNEJ-UHFFFAOYSA-N 3-(2-bromoethynyl)thiophene Chemical compound BrC#Cc1ccsc1 YSNRUIFOACFNEJ-UHFFFAOYSA-N 0.000 description 1
- VISMUHDPHAIMFG-UHFFFAOYSA-N 3-(2-chloroethynyl)thiophene Chemical compound ClC#CC1=CSC=C1 VISMUHDPHAIMFG-UHFFFAOYSA-N 0.000 description 1
- FNHPUOJKUXFUKN-UHFFFAOYSA-N 3-(bromomethyl)pyridine;hydron;bromide Chemical compound Br.BrCC1=CC=CN=C1 FNHPUOJKUXFUKN-UHFFFAOYSA-N 0.000 description 1
- CJCLIVOYZPZLFC-UHFFFAOYSA-N 3-(cyclohexylmethoxy)-4-ethynylthiophene Chemical compound C1(CCCCC1)COC1=CSC=C1C#C CJCLIVOYZPZLFC-UHFFFAOYSA-N 0.000 description 1
- BFGJOATVQLNKDK-UHFFFAOYSA-N 3-(cyclopentylmethoxy)-4-ethynylthiophene Chemical compound C1(CCCC1)COC1=CSC=C1C#C BFGJOATVQLNKDK-UHFFFAOYSA-N 0.000 description 1
- NIRBOJZQLBDWFB-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-ethynylthiophene Chemical compound C1(CC1)COC1=CSC=C1C#C NIRBOJZQLBDWFB-UHFFFAOYSA-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
- ONNNNPMLTVXZKD-UHFFFAOYSA-N 3-[(4-bromothiophen-3-yl)oxymethyl]pyridine Chemical compound BrC=1C(=CSC=1)OCC=1C=NC=CC=1 ONNNNPMLTVXZKD-UHFFFAOYSA-N 0.000 description 1
- YGXCKARMVMNSAY-UHFFFAOYSA-N 3-[(4-chlorophenyl)methoxy]-4-ethynylthiophene Chemical compound ClC1=CC=C(COC2=CSC=C2C#C)C=C1 YGXCKARMVMNSAY-UHFFFAOYSA-N 0.000 description 1
- AHWXYRYOSCAGFI-UHFFFAOYSA-N 3-[(4-ethynylthiophen-3-yl)oxymethyl]pyridine Chemical compound C(#C)C=1C(=CSC=1)OCC=1C=NC=CC=1 AHWXYRYOSCAGFI-UHFFFAOYSA-N 0.000 description 1
- BGAJNPLDJJBRHK-UHFFFAOYSA-N 3-[2-[5-(3-chloro-4-propan-2-yloxyphenyl)-1,3,4-thiadiazol-2-yl]-3-methyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propanoic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C1=NN=C(N2C(=C3CN(CCC(O)=O)CCC3=N2)C)S1 BGAJNPLDJJBRHK-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
- SGMHUUCJAVGNAG-UHFFFAOYSA-N 3-bromo-4-(1-phenylethoxy)thiophene Chemical compound BrC1=CSC=C1OC(C)C1=CC=CC=C1 SGMHUUCJAVGNAG-UHFFFAOYSA-N 0.000 description 1
- DKGSNRJFTNGCON-UHFFFAOYSA-N 3-bromo-4-(cyclohexylmethoxy)thiophene Chemical compound BrC1=CSC=C1OCC1CCCCC1 DKGSNRJFTNGCON-UHFFFAOYSA-N 0.000 description 1
- KJTQZXYWLHYENS-UHFFFAOYSA-N 3-bromo-4-(cyclopentylmethoxy)thiophene Chemical compound BrC1=CSC=C1OCC1CCCC1 KJTQZXYWLHYENS-UHFFFAOYSA-N 0.000 description 1
- XWGGHIHHBHFVRI-UHFFFAOYSA-N 3-bromo-4-(cyclopropylmethoxy)thiophene Chemical compound BrC1=CSC=C1OCC1CC1 XWGGHIHHBHFVRI-UHFFFAOYSA-N 0.000 description 1
- AKDNDWACGKDMRW-UHFFFAOYSA-N 3-bromo-4-(diethoxymethyl)thiophene Chemical compound CCOC(OCC)C1=CSC=C1Br AKDNDWACGKDMRW-UHFFFAOYSA-N 0.000 description 1
- YRAJHVDHJQOPNC-UHFFFAOYSA-N 3-bromo-4-[(4-methoxyphenyl)methoxy]thiophene Chemical compound BrC1=CSC=C1OCC1=CC=C(C=C1)OC YRAJHVDHJQOPNC-UHFFFAOYSA-N 0.000 description 1
- FFVWRPRFYKPFLA-UHFFFAOYSA-N 3-bromo-4-ethoxythiophene Chemical compound CCOC1=CSC=C1Br FFVWRPRFYKPFLA-UHFFFAOYSA-N 0.000 description 1
- KDGDRHOXZMXUGL-UHFFFAOYSA-N 3-bromo-4-ethynylthiophene Chemical compound BrC1=CSC=C1C#C KDGDRHOXZMXUGL-UHFFFAOYSA-N 0.000 description 1
- MBUSOPVRLCFJCS-UHFFFAOYSA-N 3-bromo-4-methylthiophene Chemical compound CC1=CSC=C1Br MBUSOPVRLCFJCS-UHFFFAOYSA-N 0.000 description 1
- JKKDMCDIUUARGO-UHFFFAOYSA-N 3-bromo-4-phenylmethoxythiophene Chemical compound C(C1=CC=CC=C1)OC1=CSC=C1Br JKKDMCDIUUARGO-UHFFFAOYSA-N 0.000 description 1
- RYSICGXZRVMXDP-UHFFFAOYSA-N 3-bromopiperidine-2,6-dione Chemical compound BrC1CCC(=O)NC1=O RYSICGXZRVMXDP-UHFFFAOYSA-N 0.000 description 1
- LQLRPYRVXZPVAN-UHFFFAOYSA-N 3-butoxy-4-ethynylthiophene Chemical compound C(CCC)OC1=CSC=C1C#C LQLRPYRVXZPVAN-UHFFFAOYSA-N 0.000 description 1
- WOBRAFNXVCKLQV-UHFFFAOYSA-N 3-cyclopentyloxy-4-ethynylthiophene Chemical compound C1(CCCC1)OC1=CSC=C1C#C WOBRAFNXVCKLQV-UHFFFAOYSA-N 0.000 description 1
- UHYSBCQXJLLBEC-UHFFFAOYSA-N 3-ethoxy-4-ethynylthiophene Chemical compound C(C)OC1=CSC=C1C#C UHYSBCQXJLLBEC-UHFFFAOYSA-N 0.000 description 1
- LWUMKYTZKGAUOO-UHFFFAOYSA-N 3-ethynyl-2-methoxythiophene Chemical compound C(#C)C1=C(SC=C1)OC LWUMKYTZKGAUOO-UHFFFAOYSA-N 0.000 description 1
- RSAQGVAWISZYSZ-UHFFFAOYSA-N 3-ethynyl-4-(1-phenylethoxy)thiophene Chemical compound C(#C)C1=CSC=C1OC(C)C1=CC=CC=C1 RSAQGVAWISZYSZ-UHFFFAOYSA-N 0.000 description 1
- QTTOMURXRCBFNL-UHFFFAOYSA-N 3-ethynyl-4-[(4-methoxyphenyl)methoxy]thiophene Chemical compound C(#C)C1=CSC=C1OCC1=CC=C(C=C1)OC QTTOMURXRCBFNL-UHFFFAOYSA-N 0.000 description 1
- LJRVXMNIAYWFRU-UHFFFAOYSA-N 3-ethynyl-4-[[4-(methoxymethyl)phenyl]methoxy]thiophene Chemical compound C(#C)C1=CSC=C1OCC1=CC=C(C=C1)COC LJRVXMNIAYWFRU-UHFFFAOYSA-N 0.000 description 1
- RTRFMDZMKYAFOL-UHFFFAOYSA-N 3-ethynyl-4-phenylmethoxythiophene Chemical compound C(C1=CC=CC=C1)OC1=CSC=C1C#C RTRFMDZMKYAFOL-UHFFFAOYSA-N 0.000 description 1
- YTKCCASOXQTBLI-UHFFFAOYSA-N 3-ethynyl-4-propan-2-yloxythiophene Chemical compound C(#C)C1=CSC=C1OC(C)C YTKCCASOXQTBLI-UHFFFAOYSA-N 0.000 description 1
- SVJQKSKOSQKQJD-UHFFFAOYSA-N 3-ethynyl-4-propoxythiophene Chemical compound C(#C)C1=CSC=C1OCCC SVJQKSKOSQKQJD-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical compound [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- VAJUUDUWDNCECT-UHFFFAOYSA-N 4-(bromomethyl)pyridine;hydron;bromide Chemical compound Br.BrCC1=CC=NC=C1 VAJUUDUWDNCECT-UHFFFAOYSA-N 0.000 description 1
- UURVDJKPQMQLLM-UHFFFAOYSA-N 4-[(4-ethynylthiophen-3-yl)oxymethyl]pyridine Chemical compound C(#C)C=1C(=CSC=1)OCC1=CC=NC=C1 UURVDJKPQMQLLM-UHFFFAOYSA-N 0.000 description 1
- JFOHSGRPBHBPNT-UHFFFAOYSA-N 4-[[2-[(4-ethynylthiophen-3-yl)oxymethyl]phenyl]methyl]morpholine Chemical compound C(#C)C=1C(=CSC=1)OCC1=C(CN2CCOCC2)C=CC=C1 JFOHSGRPBHBPNT-UHFFFAOYSA-N 0.000 description 1
- UVDXNADRRAOUTQ-UHFFFAOYSA-N 4-[[3-[(4-bromothiophen-3-yl)oxymethyl]phenyl]methyl]morpholine Chemical compound BrC=1C(=CSC=1)OCC=1C=C(CN2CCOCC2)C=CC=1 UVDXNADRRAOUTQ-UHFFFAOYSA-N 0.000 description 1
- CJEUIPPLIHDDCJ-UHFFFAOYSA-N 4-[[3-[(4-ethynylthiophen-3-yl)oxymethyl]phenyl]methyl]morpholine Chemical compound C(#C)C=1C(=CSC=1)OCC=1C=C(CN2CCOCC2)C=CC=1 CJEUIPPLIHDDCJ-UHFFFAOYSA-N 0.000 description 1
- YASREBUUWWVFRL-UHFFFAOYSA-N 4-[[4-[(4-ethynylthiophen-3-yl)oxymethyl]phenyl]methyl]morpholine Chemical compound C(#C)C=1C(=CSC=1)OCC1=CC=C(CN2CCOCC2)C=C1 YASREBUUWWVFRL-UHFFFAOYSA-N 0.000 description 1
- ABMUSXPGSSMPLK-UHFFFAOYSA-N 4-bromo-2-methylthiophene Chemical compound CC1=CC(Br)=CS1 ABMUSXPGSSMPLK-UHFFFAOYSA-N 0.000 description 1
- CFBONFRLHROEAF-UHFFFAOYSA-N 4-bromo-3-(1-phenylethoxy)thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OC(C)C1=CC=CC=C1 CFBONFRLHROEAF-UHFFFAOYSA-N 0.000 description 1
- LOJXTWDZINYZQW-UHFFFAOYSA-N 4-bromo-3-(cyclohexylmethoxy)thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1CCCCC1 LOJXTWDZINYZQW-UHFFFAOYSA-N 0.000 description 1
- HBDKJLLEIMXKAT-UHFFFAOYSA-N 4-bromo-3-(cyclopentylmethoxy)thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1CCCC1 HBDKJLLEIMXKAT-UHFFFAOYSA-N 0.000 description 1
- PKAFYIDMODWKKW-UHFFFAOYSA-N 4-bromo-3-(cyclopropylmethoxy)thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1CC1 PKAFYIDMODWKKW-UHFFFAOYSA-N 0.000 description 1
- UXTXHZXNAKFHFU-UHFFFAOYSA-N 4-bromo-3-(pyridin-2-ylmethoxy)thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1=NC=CC=C1 UXTXHZXNAKFHFU-UHFFFAOYSA-N 0.000 description 1
- UGZUNPGRIPQVQZ-UHFFFAOYSA-N 4-bromo-3-(pyridin-3-ylmethoxy)thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC=1C=NC=CC=1 UGZUNPGRIPQVQZ-UHFFFAOYSA-N 0.000 description 1
- YFZMVJGBFABQNP-UHFFFAOYSA-N 4-bromo-3-[(4-chlorophenyl)methoxy]thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1=CC=C(C=C1)Cl YFZMVJGBFABQNP-UHFFFAOYSA-N 0.000 description 1
- GJJBZTJIQYVPTP-UHFFFAOYSA-N 4-bromo-3-[(4-methoxyphenyl)methoxy]thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1=CC=C(C=C1)OC GJJBZTJIQYVPTP-UHFFFAOYSA-N 0.000 description 1
- ZSJHUCKVOXNZQH-UHFFFAOYSA-N 4-bromo-3-[[3-(morpholin-4-ylmethyl)phenyl]methoxy]thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1=CC(=CC=C1)CN1CCOCC1 ZSJHUCKVOXNZQH-UHFFFAOYSA-N 0.000 description 1
- ZWIAFYNXJBVFGI-UHFFFAOYSA-N 4-bromo-3-[[4-(morpholin-4-ylmethyl)phenyl]methoxy]thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1=CC=C(C=C1)CN1CCOCC1 ZWIAFYNXJBVFGI-UHFFFAOYSA-N 0.000 description 1
- RLYAZPJPYINLED-UHFFFAOYSA-N 4-bromo-3-[[4-(pyrrolidin-1-ylmethyl)phenyl]methoxy]thiophene-2-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C(=O)O)OCC1=CC=C(C=C1)CN1CCCC1 RLYAZPJPYINLED-UHFFFAOYSA-N 0.000 description 1
- XQTDBVMCRWTBHL-UHFFFAOYSA-N 4-bromo-3-phenylmethoxythiophene-2-carboxylic acid Chemical compound OC(=O)c1scc(Br)c1OCc1ccccc1 XQTDBVMCRWTBHL-UHFFFAOYSA-N 0.000 description 1
- NOUGYWJLOPDMRG-UHFFFAOYSA-N 4-butoxythiophene-3-carbaldehyde Chemical compound CCCCOC1=CSC=C1C=O NOUGYWJLOPDMRG-UHFFFAOYSA-N 0.000 description 1
- JWLYTBFYJPSVEB-UHFFFAOYSA-N 4-ethynyl-2-methoxythiophene Chemical compound C(#C)C=1C=C(SC=1)OC JWLYTBFYJPSVEB-UHFFFAOYSA-N 0.000 description 1
- PMKNFARXRZOJKB-UHFFFAOYSA-N 4-ethynyl-3-methoxy-2-methylthiophene Chemical compound C(#C)C=1C(=C(SC=1)C)OC PMKNFARXRZOJKB-UHFFFAOYSA-N 0.000 description 1
- NZOIUCVTBFWRCS-UHFFFAOYSA-N 4-iodomorpholine;hydroiodide Chemical compound I.IN1CCOCC1 NZOIUCVTBFWRCS-UHFFFAOYSA-N 0.000 description 1
- HJKMXEMFPYMIHZ-UHFFFAOYSA-N 4-propoxythiophene-3-carbaldehyde Chemical compound CCCOC1=CSC=C1C=O HJKMXEMFPYMIHZ-UHFFFAOYSA-N 0.000 description 1
- ZKLBPUYMTHPNOQ-UHFFFAOYSA-N 5-bromothiophene-3-carbaldehyde Chemical compound BrC1=CC(C=O)=CS1 ZKLBPUYMTHPNOQ-UHFFFAOYSA-N 0.000 description 1
- IAIRWQIVQJQYQT-UHFFFAOYSA-N 5-ethynyl-2,3-dihydrothieno[3,4-b][1,4]dioxine Chemical compound O1CCOC2=C(C#C)SC=C21 IAIRWQIVQJQYQT-UHFFFAOYSA-N 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 208000016683 Adult T-cell leukemia/lymphoma Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000036170 B-Cell Marginal Zone Lymphoma Diseases 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 229940125814 BTK kinase inhibitor Drugs 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- SZRAYPQTNCETBP-UHFFFAOYSA-N ClC1=CSC=C1C#C Chemical compound ClC1=CSC=C1C#C SZRAYPQTNCETBP-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 206010061850 Extranodal marginal zone B-cell lymphoma (MALT type) Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 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 1
- 229940122245 Janus kinase inhibitor Drugs 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 201000003791 MALT lymphoma Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000027190 Peripheral T-cell lymphomas Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000031672 T-Cell Peripheral Lymphoma Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 206010070517 Type 2 lepra reaction Diseases 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
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- BEGWYRFEYSJEPO-UHFFFAOYSA-N [4-(2-morpholin-4-ylethyl)phenyl]methanol Chemical compound C1=CC(CO)=CC=C1CCN1CCOCC1 BEGWYRFEYSJEPO-UHFFFAOYSA-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
- 230000009471 action Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 201000006966 adult T-cell leukemia Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005818 alkanylalkoxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 235000003704 aspartic acid Nutrition 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
- 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
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 description 1
- UUWSLBWDFJMSFP-UHFFFAOYSA-N bromomethylcyclohexane Chemical compound BrCC1CCCCC1 UUWSLBWDFJMSFP-UHFFFAOYSA-N 0.000 description 1
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006251 butylcarbonyl group Chemical group 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007665 chronic toxicity Effects 0.000 description 1
- 231100000160 chronic toxicity Toxicity 0.000 description 1
- 208000013056 classic Hodgkin lymphoma Diseases 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 229940125904 compound 1 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
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 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
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000001880 copper compounds Chemical class 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000062 cyclohexylmethoxy group Chemical group [H]C([H])(O*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229960004137 elotuzumab Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 208000024386 fungal infectious disease Diseases 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000007674 genetic toxicity Effects 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000008187 granular material Substances 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
- 238000010438 heat treatment Methods 0.000 description 1
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004871 hexylcarbonyl group Chemical group C(CCCCC)C(=O)* 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- 102000057041 human TNF Human genes 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- DUMSKQUKLVSSII-UHFFFAOYSA-N iodomethylcyclopentane Chemical compound ICC1CCCC1 DUMSKQUKLVSSII-UHFFFAOYSA-N 0.000 description 1
- 125000006328 iso-butylcarbonyl group Chemical group [H]C([H])([H])C([H])(C(*)=O)C([H])([H])[H] 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005932 isopentyloxycarbonyl group Chemical group 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 201000007919 lymphoplasmacytic lymphoma Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- GKEFGJCQPBYKNK-UHFFFAOYSA-N methyl 3-methoxy-4-(2-trimethylsilylethynyl)thiophene-2-carboxylate Chemical compound COC1=C(SC=C1C#C[Si](C)(C)C)C(=O)OC GKEFGJCQPBYKNK-UHFFFAOYSA-N 0.000 description 1
- RMXZWHDXTQWQAN-UHFFFAOYSA-N methyl 4-bromo-3-(1-phenylethoxy)thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OC(C)C1=CC=CC=C1 RMXZWHDXTQWQAN-UHFFFAOYSA-N 0.000 description 1
- NXLYEVFGNIXJNJ-UHFFFAOYSA-N methyl 4-bromo-3-(cyclohexylmethoxy)thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC1CCCCC1 NXLYEVFGNIXJNJ-UHFFFAOYSA-N 0.000 description 1
- WWOLKOVBEGXEJR-UHFFFAOYSA-N methyl 4-bromo-3-(cyclopentylmethoxy)thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC1CCCC1 WWOLKOVBEGXEJR-UHFFFAOYSA-N 0.000 description 1
- MAENZDRZFKXLOU-UHFFFAOYSA-N methyl 4-bromo-3-(cyclopropylmethoxy)thiophene-2-carboxylate Chemical compound S1C=C(Br)C(OCC2CC2)=C1C(=O)OC MAENZDRZFKXLOU-UHFFFAOYSA-N 0.000 description 1
- DOOIEUFUPNEZLY-UHFFFAOYSA-N methyl 4-bromo-3-(pyridin-2-ylmethoxy)thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC1=NC=CC=C1 DOOIEUFUPNEZLY-UHFFFAOYSA-N 0.000 description 1
- WGXDAOKOEABEMF-UHFFFAOYSA-N methyl 4-bromo-3-(pyridin-3-ylmethoxy)thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC=1C=NC=CC=1 WGXDAOKOEABEMF-UHFFFAOYSA-N 0.000 description 1
- TYNQLLPTYDYGFV-UHFFFAOYSA-N methyl 4-bromo-3-[(4-chlorophenyl)methoxy]thiophene-2-carboxylate Chemical compound S1C=C(Br)C(OCC=2C=CC(Cl)=CC=2)=C1C(=O)OC TYNQLLPTYDYGFV-UHFFFAOYSA-N 0.000 description 1
- UQNZOOQZHLBHER-UHFFFAOYSA-N methyl 4-bromo-3-[(4-methoxyphenyl)methoxy]thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC1=CC=C(C=C1)OC UQNZOOQZHLBHER-UHFFFAOYSA-N 0.000 description 1
- HFTDEQXKBSURQX-UHFFFAOYSA-N methyl 4-bromo-3-[[2-(bromomethyl)phenyl]methoxy]thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC1=C(C=CC=C1)CBr HFTDEQXKBSURQX-UHFFFAOYSA-N 0.000 description 1
- ZLKHIIUUOGGJQR-UHFFFAOYSA-N methyl 4-bromo-3-[[2-(morpholin-4-ylmethyl)phenyl]methoxy]thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC1=C(C=CC=C1)CN1CCOCC1 ZLKHIIUUOGGJQR-UHFFFAOYSA-N 0.000 description 1
- QVANWESDWHLSEQ-UHFFFAOYSA-N methyl 4-bromo-3-[[3-(bromomethyl)phenyl]methoxy]thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC1=CC(=CC=C1)CBr QVANWESDWHLSEQ-UHFFFAOYSA-N 0.000 description 1
- VIBOEPDKNFFFPK-UHFFFAOYSA-N methyl 4-bromo-3-[[3-(morpholin-4-ylmethyl)phenyl]methoxy]thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC1=CC(=CC=C1)CN1CCOCC1 VIBOEPDKNFFFPK-UHFFFAOYSA-N 0.000 description 1
- JSMQHQFTQDZNLL-UHFFFAOYSA-N methyl 4-bromo-3-[[4-(2-morpholin-4-ylethyl)phenyl]methoxy]thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC1=CC=C(C=C1)CCN1CCOCC1 JSMQHQFTQDZNLL-UHFFFAOYSA-N 0.000 description 1
- WISYPXBUQVFHNT-UHFFFAOYSA-N methyl 4-bromo-3-[[4-(pyrrolidin-1-ylmethyl)phenyl]methoxy]thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC1=CC=C(C=C1)CN1CCCC1 WISYPXBUQVFHNT-UHFFFAOYSA-N 0.000 description 1
- PEGFRXUFEQUKRP-OKILXGFUSA-N methyl 4-bromo-3-[[4-[[(2S,6R)-2,6-dimethylmorpholin-4-yl]methyl]phenyl]methoxy]thiophene-2-carboxylate Chemical compound BrC=1C(=C(SC=1)C(=O)OC)OCC1=CC=C(C=C1)CN1C[C@@H](O[C@@H](C1)C)C PEGFRXUFEQUKRP-OKILXGFUSA-N 0.000 description 1
- AAUKODCGPDBXCN-UHFFFAOYSA-N methyl 4-bromo-3-methoxythiophene-2-carboxylate Chemical compound COC(=O)C=1SC=C(Br)C=1OC AAUKODCGPDBXCN-UHFFFAOYSA-N 0.000 description 1
- KZQRMNKCFAXILO-UHFFFAOYSA-N methyl 4-ethynyl-3-methoxythiophene-2-carboxylate Chemical compound C(#C)C=1C(=C(SC=1)C(=O)OC)OC KZQRMNKCFAXILO-UHFFFAOYSA-N 0.000 description 1
- PCUVYBUDIWDLNI-UHFFFAOYSA-N methyl n-(n'-chloro-n-methoxycarbonylcarbamimidoyl)carbamate Chemical compound COC(=O)NC(=NCl)NC(=O)OC PCUVYBUDIWDLNI-UHFFFAOYSA-N 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
- PGXWDLGWMQIXDT-UHFFFAOYSA-N methylsulfinylmethane;hydrate Chemical compound O.CS(C)=O PGXWDLGWMQIXDT-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 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
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005933 neopentyloxycarbonyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 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
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000004675 pentylcarbonyl group Chemical group C(CCCC)C(=O)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003304 ruthenium compounds Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- SYIKUFDOYJFGBQ-YLAFAASESA-N tofacitinib citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 SYIKUFDOYJFGBQ-YLAFAASESA-N 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- OQUBLKNISPLGJP-UHFFFAOYSA-N trimethyl(2-thiophen-2-ylethynyl)silane Chemical compound C[Si](C)(C)C#CC1=CC=CS1 OQUBLKNISPLGJP-UHFFFAOYSA-N 0.000 description 1
- KBRAKDQFUDWYKH-UHFFFAOYSA-N trimethyl-[2-(4-phenylmethoxythiophen-3-yl)ethynyl]silane Chemical compound C(C1=CC=CC=C1)OC=1C(=CSC=1)C#C[Si](C)(C)C KBRAKDQFUDWYKH-UHFFFAOYSA-N 0.000 description 1
- MSGYZWJBOOTWRU-UHFFFAOYSA-N trimethyl-[2-(5-methylthiophen-3-yl)ethynyl]silane Chemical compound CC1=CC(C#C[Si](C)(C)C)=CS1 MSGYZWJBOOTWRU-UHFFFAOYSA-N 0.000 description 1
- WPVZSZKFTHLPKF-UHFFFAOYSA-N trimethyl-[2-[4-(1-phenylethoxy)thiophen-3-yl]ethynyl]silane Chemical compound C[Si](C#CC1=CSC=C1OC(C)C1=CC=CC=C1)(C)C WPVZSZKFTHLPKF-UHFFFAOYSA-N 0.000 description 1
- QZDKVSATUTWTDB-UHFFFAOYSA-N trimethyl-[2-[4-(pyridin-2-ylmethoxy)thiophen-3-yl]ethynyl]silane Chemical compound C[Si](C)(C)C#CC=1C(=CSC=1)OCC1=NC=CC=C1 QZDKVSATUTWTDB-UHFFFAOYSA-N 0.000 description 1
- MOCDMEJABMWIAQ-UHFFFAOYSA-N trimethyl-[2-[4-(pyridin-3-ylmethoxy)thiophen-3-yl]ethynyl]silane Chemical compound C[Si](C)(C)C#CC=1C(=CSC=1)OCC=1C=NC=CC=1 MOCDMEJABMWIAQ-UHFFFAOYSA-N 0.000 description 1
- VMYVSKIFAAQKSM-UHFFFAOYSA-N trimethyl-[2-[4-(pyridin-4-ylmethoxy)thiophen-3-yl]ethynyl]silane Chemical compound C[Si](C)(C)C#CC=1C(=CSC=1)OCC1=CC=NC=C1 VMYVSKIFAAQKSM-UHFFFAOYSA-N 0.000 description 1
- CWWCOUYZHDZHRA-UHFFFAOYSA-N trimethyl-[2-[4-[[2-(morpholin-4-ylmethyl)phenyl]methoxy]thiophen-3-yl]ethynyl]silane Chemical compound C[Si](C)(C)C#CC=1C(=CSC=1)OCC1=C(CN2CCOCC2)C=CC=C1 CWWCOUYZHDZHRA-UHFFFAOYSA-N 0.000 description 1
- OHFPYDILUFRBCJ-UHFFFAOYSA-N trimethyl-[2-[4-[[3-(morpholin-4-ylmethyl)phenyl]methoxy]thiophen-3-yl]ethynyl]silane Chemical compound C[Si](C)(C)C#CC=1C(=CSC=1)OCC=1C=C(CN2CCOCC2)C=CC=1 OHFPYDILUFRBCJ-UHFFFAOYSA-N 0.000 description 1
- HCPJCXHTAWGOMD-UHFFFAOYSA-N trimethyl-[2-[4-[[4-(piperidin-1-ylmethyl)phenyl]methoxy]thiophen-3-yl]ethynyl]silane Chemical compound C[Si](C)(C)C#CC=1C(=CSC=1)OCC1=CC=C(CN2CCCCC2)C=C1 HCPJCXHTAWGOMD-UHFFFAOYSA-N 0.000 description 1
- MLOXLTHDPCQPFV-UHFFFAOYSA-N trimethyl-[2-[4-[[4-(pyrrolidin-1-ylmethyl)phenyl]methoxy]thiophen-3-yl]ethynyl]silane Chemical compound C[Si](C)(C)C#CC=1C(=CSC=1)OCC1=CC=C(CN2CCCC2)C=C1 MLOXLTHDPCQPFV-UHFFFAOYSA-N 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 229940039916 xeljanz Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
-
- 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
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及由下式(I)表示的噻吩衍生物或其盐:
Description
技术领域
本发明涉及医药领域,尤其涉及具有TNF-α产生抑制活性和血液癌症细胞生长抑制活性的新型噻吩衍生物。
背景技术
肿瘤坏死因子-α(TNF-α)是免疫系统细胞释放的炎性细胞因子。已知持续过量地产生TNF-α会引起组织损伤和各种疾病(非专利文献1)。涉及TNF-α的病理状况的实例包括许多病理状况,包括自身免疫性疾病,例如类风湿性关节炎、克罗恩氏病和溃疡性结肠炎。
鉴于上述情况,预期抑制TNF-α产生的化合物在治疗上述疾病中有效,已进行了各种研究。
类风湿性关节炎(代表性的自身免疫性疾病)的治疗剂大致分为以下三种。
第一种治疗剂是抗炎药。抗炎药具有减轻炎症中的疼痛和肿胀的作用。此外,抗炎药分为非类固醇抗炎药(NSAID)和类固醇类抗炎药。NSAID的实例包括塞来昔布(celecoxib)、氯索洛芬(loxoprofen)、吲哚美辛(indomethacin)等。尽管这些药物能立即缓解因炎症引起的肿胀和疼痛,但它们对风湿病的发展具有微弱的抑制作用。另一方面,类固醇类抗炎药能强烈抑制炎症,对疼痛、肿胀和僵硬有效。但是,长期使用大剂量的类固醇类抗炎药可能会引起机会性感染、骨质疏松或动脉硬化的问题。
第二种治疗剂是改善病情的抗风湿药物(disease-modifying anti-rheumaticdrug,DMARD)。DMARD直接作用于免疫疾病、抑制炎症和抑制疾病发展。另一方面,即使个体间的疗效强度差别很大,也会出现例如缺乏预测疗效的方法、起效缓慢以及副作用频发等问题。
第三种治疗剂是生物制剂。市场上有多种生物制剂,例如以REMICADE(注册商标)出售的英夫利昔单抗(infliximab)和以ENBREL(注册商标)出售的依那西普(etanercept)(专利文献1)。生物制剂显示出强大的功效,但问题在于非常昂贵。近年来,JAK抑制剂,例如以XELJANZ(注册商标)出售的小分子化合物托法替尼(tofacitinib),已投放市场并受到关注,因为它们显示出与生物制剂相当的疗效。但是,存在严重感染的风险以剂量依赖性方式增加等问题。因此,期望开发一种新型抗风湿药物,其可以口服施用且具有与生物制剂相当的效果。
血液癌症是分化过程中由血细胞(例如红细胞、白细胞和血小板)癌变而引起的疾病。在血液癌症中,具有特别多的患者的多发性骨髓瘤、恶性淋巴瘤和白血病被称为三大血液癌症。
多发性骨髓瘤是由浆细胞癌变引起的疾病,浆细胞由B细胞(其为血细胞之一的白细胞)分化和成熟。在多发性骨髓瘤的药物治疗中,引入蛋白酶体抑制剂(硼替佐米(bortezomib)、卡非佐米(carfilzomib)、依沙佐米(ixazomib))和免疫调节剂(沙利度胺(thalidomide)、来那度胺(lenalidomide)、泊马度胺(pomalidomide))显著改善了预后并实现长期存活(非专利文献2、3)。然而,多发性骨髓瘤并非可预期治愈的疾病,其主要治疗目的是延长生存期,同时保持复发患者的QOL。此外,已证实,近年来开发的两种抗体药物(依洛托珠单抗(erotuzumab)、达雷木单抗(daratumumab))进一步改善了预后;然而,尚不能完全阻止病态的恶化(非专利文献4)。
恶性淋巴瘤是由淋巴细胞(其为血细胞之一的白细胞)癌变引起的疾病。化学疗法仍占据恶性淋巴瘤药物治疗的核心。即使是可治愈的血液肿瘤,治愈率也依疾病种类而差异很大,一些恶性淋巴瘤难以用化学疗法来治疗(非专利文献5)。对于不能通过化学疗法获得足够的治疗效果的情况,已尝试单独的分子靶向药物或分子靶向药物与化学治疗剂联合。例如,在CD20阳性率为90%以上的B细胞非霍奇金淋巴瘤中,抗CD20抗体药物利妥昔单抗(rituximab)和其他药物的联合使用已成为主流。作为具体实例,对于新诊断患有弥漫性大B细胞淋巴瘤、套细胞淋巴瘤或滤泡性淋巴瘤的患者,建议联合使用利妥昔单抗疗法与化学疗法(例如CHOP治疗),利妥昔单抗被定位为优越的分子靶向药物(非专利文献6)。
引起关注的其他针对B细胞非霍奇金淋巴瘤的分子靶向药物包括依鲁替尼(ibrutinib)(一种布鲁顿酪氨酸激酶(BTK)抑制剂)和来那度胺(一种免疫调节剂)。特别地,来那度胺可改善非生发中心B细胞(GCB)型弥漫性大B细胞淋巴瘤患者的预后,但对GCB型弥漫性大B细胞淋巴瘤的疗效较差;此外,在与靶向复发性套细胞淋巴瘤患者的利妥昔单抗的联合使用试验中,总缓解率为56%,无缓解患者为44%。因此,需要开发对恶性淋巴瘤有效的新型治疗剂(非专利文献7)。
WO 2017/197051(专利文献2)描述了具有戊二酰亚胺基的化合物。但是,并无关于具有噻吩环的本发明化合物的具体公开。
现有技术文献
[专利文献]
专利文献1:国际专利申请号2012-524071的国家公布
专利文件2:WO 2017/197051
[非专利文献]
非专利文献1:Yamazaki,Clinical Immunology,27,1270,1995年
非专利文献2:Terui,Internal Medicine,第120卷,第4期,第875页,2017年
非专利文献3:Shibayama,Internal Medicine,第120卷,第4期,第881页,2017年
非专利文献4:Zhang,Internal Medicine,第120卷,第4期,第887页,2017年
非专利文献5:Suzumiya,The Journal of the Japanese Society of InternalMedicine,第105卷,第9期,第1761页,2016年
非专利文献6:NCCN指南日文版,非霍奇金淋巴瘤,第二版,2015年
非专利文献7:Arora.m.,Ther Adv Hematol,第7卷,第4期,第209页,2016年
发明内容
[技术问题]
本发明旨在提供新型噻吩衍生物及含有该噻吩衍生物的药物,该噻吩衍生物具有TNF-α产生抑制活性且可用于治疗类风湿性关节炎、克罗恩氏病、溃疡性结肠炎或血液癌症。
[技术方案]
为解决上述问题,本发明人进行了深入研究,发现由下式(I)表示的化合物具有优异的TNF-α产生抑制活性。他们进一步对其作为抗癌药的有效性进行了各种研究,完成本发明。因此,本发明提供以下内容。
[1]由下式(I)表示的化合物或其盐(以下有时称为“本发明化合物”):
式中:
R1为氢或卤素;
m个R各自独立地为卤素、C1-6烷基、C1-6羟烷基、可选地具有取代基的C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基,或
相邻的环碳原子上的两个R彼此键合并与它们所连接的碳原子一起形成含有1至2个氧原子的5元环或6元环;以及
m是0、1、2或3。
[2]上述[1]所述的化合物或其盐,其中,由式(I)表示的化合物是由下式(IA)或(IB)表示的化合物:
式中:
R1为氢或卤素;
R2为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基;
R3为氢、卤素、C1-6烷基或可选地具有取代基的C1-6烷氧基;
R4为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基;
R5为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基;
R6为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基,或
R5和R6彼此键合并与它们所连接的碳原子一起形成含有1至2个氧原子的5元环或6元环;以及
R7为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基。
[3]上述[2]所述的化合物或其盐,其中,
R1为氢或卤素;
R2为氢、卤素或C1-6烷氧基;
R3为氢、卤素、C1-6烷基或可选地具有取代基的C1-6烷氧基;
R4为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基或C1-6烷氧羰基;
R5和R6各自为氢,或
R5和R6彼此键合并与它们所连接的碳原子一起形成含有1至2个氧原子的5元环或6元环;以及
R7为氢、卤素、C1-6烷基或C1-6烷基羰基。
[4]上述[1]至[3]中任一项所述的化合物或其盐,其中,R和R3的可选地具有取代基的C1-6烷氧基为C1-6链烷氧基、C3-6环烷氧基,或
由下式表示的烷氧基:-O-X―Y,
式中:
X为直链或支链的C1-6亚烷基;以及
Y为C3-6环烷基,或各自可选地具有取代基的吡啶、萘或苯并噻吩,或由式(II)表示的取代基:
Z为氢、C1-6烷氧基、C1-6烷氧基甲基、卤素或由下式(III)、(IV)、(V)或(VI)表示的取代基:
Z1和Z2各自独立地为氢或C1-6烷基,或
Z1和Z2彼此键合并与它们所连接的氮原子一起形成5元环或6元环;以及
n为1或2;
[5]上述[4]所述的化合物或其盐,其中,X为CH2、CH(CH3)或CH2CH2。
[6]上述[2]至[5]中任一项所述的化合物或其酸加成盐,其中,
R1为氢、碘、溴或氯;
R2为氢、溴或甲氧基;
R3为氢、溴、氯、甲基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、环戊氧基、环丙基甲氧基、环戊基甲氧基、环己基甲氧基、苄氧基、1-苯基乙氧基、吡啶-2-基甲氧基、吡啶-3-基甲氧基、吡啶-4-甲氧基、苯并[b]噻吩-2-基甲氧基、4-甲氧基苄氧基、4-(甲氧基甲基)苄氧基、4-氯苄氧基、4-(吡咯烷-1-基甲基)苄氧基、4-(哌啶-1-基甲基)苄氧基、4-[(二甲氨基)甲基]苄氧基、4-(2-吗啉代乙基)苄氧基、2-(吗啉代甲基)苄氧基、3-(吗啉代甲基)苄氧基、4-(吗啉代甲基)苄氧基或4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基;
R4为氢、溴、氯、甲基、羟甲基、甲氧基、乙氧基或甲氧羰基;
R5和R6各自为氢,或
R5和R6彼此键合并与它们所连接的碳原子一起形成含有2个氧原子的6元环。
R7为氢、氯、溴、甲基或乙酰基。
[7]上述[1]至[6]中任一项所述的化合物或其盐,其中,所述化合物或盐选自:
3-[4-(4-溴噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[5-氯-4-(噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-甲基噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-乙酰基噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-{4-[5-(羟甲基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-[4-(2,3-二氢噻吩并[3,4-b][1,4]二恶英-5-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-氯噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-溴噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(2,5-二溴噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-氯噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-甲氧基-5-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
4-[1-(2,6-二氧代哌啶-3-基)-1H-1,2,3-三唑-4-基]-3-甲氧基噻吩-2-羧酸甲酯、
3-[4-(4-乙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(2-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-丙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-氯-4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-溴-4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-乙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-丁氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-异丙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-{4-[4-(环戊氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(环丙基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(环戊基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(环己基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(4-甲氧基苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(吡啶-4-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(吡啶-2-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(吡啶-3-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-(4-{4-[4-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-(4-{4-[4-(甲氧基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-{4-[4-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-(4-{4-[3-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-(4-{4-[2-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-(4-{4-[4-(吡咯烷-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-(4-{4-[4-(4-哌啶-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-{4-[4-(4-氯苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(1-苯基乙氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-(4-{4-[4-(2-吗啉代乙基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-[4-(4-{4-[(二甲氨基)甲基]苄氧基}噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-{4-[4-(苯并[b]噻吩-2-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-[5-溴-4-(噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮,和
3-[5-碘-4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮,及它们的酸加成盐。
[8]上述[2]所述的化合物或其盐,其中,由式(I)表示的化合物是由下式(IA)表示的化合物:
式中:
R1为氢;
R2为氢;
R3为氢或可选地具有取代基的C1-6烷氧基;以及
R4为氢、C1-6烷氧基或卤素。
[9]上述[8]所述的化合物或其盐,其中,R3为氢、C1-6链烷氧基,或
下式表示的烷氧基:-O-X―Y
式中:
X为直链C1-6亚烷基;以及
Y为苯并噻吩、吡啶或由式(II)表示的取代基:
Z为氢、C1-6链烷氧基甲基或由下式(III)、(IV)、(V)或(VI)表示的取代基:
Z1和Z2各自为C1-6链烷基,或
Z1和Z2彼此键合并与它们所连接的氮原子一起形成5元环或6元环;以及n为1或2;
R4为氢、C1-6烷氧基或卤素。
[10]上述[1]至[9]中任一项所述的化合物或其盐,其中,所述化合物或盐选自:
3-[4-(5-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-溴-4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-{4-[4-(苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-(4-{4-[4-(甲氧基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-{4-[4-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-(4-{4-[4-(吡咯烷-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-(4-{4-[4-(4-哌啶-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-(4-{4-[4-(2-吗啉代乙基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-[4-(4-{4-[(二甲氨基)甲基]苄氧基}噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮,和
3-{4-[4-(苯并[b]噻吩-2-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮,
及它们的酸加成盐。
[11]上述[1]至[9]中任一项所述的化合物或其盐,其中,所述化合物或盐选自:
3-[4-(5-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-(4-{4-[4-(甲氧基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-{4-[4-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-(4-{4-[4-(哌啶-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮,及它们的酸加成盐。
[12]一种药物,其中,所述药物包含上述[1]所述的化合物或其盐作为活性成分。
[13]上述[12]所述的药物,其中,所述药物是TNF-α产生抑制剂。
[14]上述[12]所述的药物,其中,该药物是炎性疾病、自身免疫性疾病或血液癌症的预防剂或治疗剂。
[15]一种药物组合物,其中,所述药物组合物包含上述[1]所述的化合物或其盐作为活性成分以及药学上可接受的载体。
[16]上述[15]所述的药物组合物,其中,所述组合物是TNF-α产生抑制剂。
[17]上述[15]所述的药物组合物,其中,所述组合物是用于炎性疾病、自身免疫性疾病或血液癌症的预防剂或治疗剂。
[18]一种抑制TNF-α产生的方法,其中,所述方法包括向哺乳动物施用有效量的上述[1]所述的化合物或其盐。
[19]一种预防或治疗炎性疾病、自身免疫性疾病或血液癌症的方法,其中,所述方法包括给有此施用需要的哺乳动物施用预防有效量或治疗有效量的上述[1]所述的化合物或其盐。
[20]上述[1]所述的化合物或其盐,用于预防或治疗炎性疾病、自身免疫性疾病或血液癌症。
[21]上述[1]所述的化合物或其盐在制备药物中的用途。
[22]上述[1]所述的化合物或其盐在制备预防或治疗炎性疾病、自身免疫性疾病或血液癌症的药物中的用途。
[23]上述[14]所述的药物、上述[17]所述的药物组合物、上述[19]所述的方法、上述[20]所述的化合物或其盐或上述[22]所述的用途,其中,所述自身免疫性疾病是类风湿性关节炎、克罗恩氏病或溃疡性结肠炎。
[24]上述[14]所述的药物、上述[17]所述的药物组合物、上述[19]所述的方法、上述[20]所述的化合物或其盐或上述[22]所述的用途,其中,所述血液癌症是白血病、恶性淋巴瘤或多发性骨髓瘤。
[25]上述[14]所述的药物、上述[17]所述的药物组合物、上述[19]所述的方法、上述[20]所述的化合物或其盐或上述[22]所述的用途,其中,所述血液癌症是多发性骨髓瘤。
[26]上述[14]所述的药物、上述[17]所述的药物组合物、上述[19]所述的方法、上述[20]所述的化合物或其盐或上述[22]所述的用途,其中,所述血液癌症是恶性淋巴瘤。
[27]上述[14]所述的药物、上述[17]所述的药物组合物、上述[19]所述的方法、上述[20]所述的化合物或其盐或上述[22]所述的用途,其中,所述血液癌症是白血病。
[28]上述[26]所述的药物、上述[26]所述的药物组合物、上述[26]所述的方法、上述[26]所述的化合物或其盐或上述[26]所述的用途,其中,所述恶性淋巴瘤是非霍奇金淋巴瘤。
[29]上述[28]所述的药物、上述[28]所述的药物组合物、上述[28]所述的方法、上述[28]所述的化合物或其盐或上述[28]所述的用途,其中,所述非霍奇金淋巴瘤是前体淋巴样肿瘤(precursor lymphoid neoplasm)或成熟B细胞肿瘤。
[发明的有益效果]
根据本发明,提供了新型噻吩衍生物,其可用于预防或治疗炎性疾病(例如类风湿性关节炎、克罗恩氏病、溃疡性结肠炎等)、自身免疫性疾病和血液癌症(例如多发性骨髓瘤、恶性淋巴瘤、白血病等)等。
具体实施方式
[本发明化合物]
下面详细解释本发明。
下面详细描述本说明书中使用的各个基团的定义。除非特别指出,否则各个基团具有以下定义。
本发明化合物的盐包括酸加成盐、与碱形成的盐、与氨基酸形成的盐等。酸加成盐的实例包括与无机酸(例如盐酸、硫酸、氢溴酸、硝酸等)形成的盐、与有机酸(例如葡糖酸、酒石酸、马来酸、富马酸、琥珀酸、苹果酸、柠檬酸、扁桃酸、乙酸、甲磺酸等)形成的盐等。与碱形成的盐的实例包括与碱金属(例如钠、钾等)形成的盐、与碱土金属(例如钙等)形成的盐等。与氨基酸形成的盐的实例包括与氨基酸(例如甘氨酸、赖氨酸、精氨酸、鸟氨酸、谷氨酸、天冬氨酸等)形成的盐等。上述具体示例并非限制性的。其中,优选酸加成盐。当本发明化合物用作药物时,药学上可接受的盐是特别优选的。
在本发明的化合物中,卤素是氟、氯、溴或碘。
在本发明化合物中,例如,C1-6烷基为具有1至6个碳原子的直链或支链烷基(以下有时称为“C1-6链烷基”)或具有3至6个碳原子的环状烷基(以下有时称为“C3-6环烷基”),例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、2-乙基丁基、环丙基、环丁基、环戊基、环己基等,可选地具有取代基。优选为C1-4链烷基或C3-6环烷基。
在本发明化合物中,C1-6羟烷基是被一个以上羟基取代的上述C1-6烷基。通常,它被1至3个羟基取代,优选被1个羟基取代。例如,它是CH2OH、CH2CH2OH、CH2CH2CH2OH、CH(OH)CH2OH、CH(CH3)OH、CH(CH2OH)2等,可选地具有取代基。优选为C1-4羟基链烷基。
在本发明化合物中,例如,C1-6烷氧基是具有1至6个碳原子的直链或支链烷氧基(以下有时称为“C1-6链烷氧基”)或具有3个碳原子的环状烷氧基。1至6个碳原子(以下有时称为“C3-6环烷氧基”),例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、异戊氧基、新戊氧基、己氧基、环丙氧基、环丁氧基、环戊氧基等,可选地具有取代基。优选为C1-4链烷氧基或C3-6环烷氧基。
在本发明化合物中,C1-6烷基羰基是被C1-6烷基取代的羰基。例如,它是其中烷基部分为具有1至6个碳原子的直链或支链烷基的烷基羰基,例如甲基羰基、乙基羰基、丙基羰基、异丙基羰基、丁基羰基、异丁基羰基、仲丁基羰基、叔丁基羰基、戊基羰基、异戊基羰基、新戊基羰基、己基羰基等,可选地具有取代基。优选为C1-4烷基羰基。
在本发明化合物中,C1-6烷氧羰基是被C1-6烷氧基取代的羰基。例如,它是其中烷氧基部分为具有1至6个碳原子的直链或支链烷氧基的烷氧羰基,例如甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基、叔丁氧羰基、戊氧羰基、异戊氧羰基、新戊氧羰基、己氧羰基等,可选地具有取代基。优选为C1-4烷氧羰基。
在本发明化合物中,例如具,C3-6环烷基是有3至6个碳原子的环烷基,例如环丙基、环丁基、环戊基、环己基等,可选地具有取代基。
在本发明化合物中,例如,C3-6环烷氧基是具有3至6个碳原子的环状烷氧基,例如环丙氧基、环丁氧基、环戊氧基、环己氧基等,可选地具有取代基。
在本发明化合物中,例如,C1-6亚烷基是可通过从作为上述C1-6烷基的实例所列举的基团中除去一个氢原子而形成的二价基团,可选地具有取代基。优选为直链或支链的C1-6亚烷基,更优选为直链或支链的C1-4亚烷基。
“可选地具有取代基”指可不存在取代基或可存在一个以上取代基。存在取代基的一个实例是:当上述式(IA)中的R3是可取代位置被至少一个(优选1至3个)上述式(II)的取代基取代的C1-6烷氧基时。其他取代基可由本领域普通技术人员适当地选自卤素、羟基等。
以下说明由式(I)表示的化合物中的各个符号。
R1为氢或卤素(优选氯、溴、碘)。
m个R各自独立地为卤素、C1-6烷基、C1-6羟烷基、可选地具有取代基的C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基,或相邻的环碳原子上的两个R彼此键合并与它们所连接的碳原子一起形成含有1至2个氧原子的5元环或6元环;m为0、1、2或3。
优选地,m个R各自独立地为:
卤素(例如氯、溴);
C1-6链烷基,更优选为C1-4链烷基(例如甲基);
C1-6羟基链烷基,更优选为C1-4羟基链烷基(例如羟甲基);
C1-6链烷氧基,更优选为C1-4链烷氧基(例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基);
C3-6环烷氧基(例如环戊氧基);
下式表示的烷氧基:-O-X―Y
式中:
X为直链或支链的C1-6亚烷基,更优选直链或支链的C1-4亚烷基(例如亚甲基、甲基亚甲基);以及
Y为C3-6环烷基(例如环丙基、环戊基、环己基),
或各自可选地具有取代基的吡啶、萘或苯并噻吩,优选为吡啶、萘或苯并噻吩,更优选为吡啶或苯并噻吩或由式(II)表示的取代基:
Z为氢、C1-6烷氧基,优选为C1-4链烷氧基(例如甲氧基)、C1-6烷氧基甲基,优选为C1-4链烷氧基甲基(例如甲氧基甲基)、卤素(例如氯)或由下式(III)、(IV)、(V)或(VI)表示的取代基:
Z1和Z2各自独立地为氢或C1-6烷基,优选为氢或C1-6链烷基,更优选为C1-4链烷基(例如甲基);或
Z1和Z2彼此键合并与它们所连接的氮原子一起形成5元环或6元环(优选为饱和的5元环或6元环(例如吡咯烷环、哌啶环));以及
n为1或2,优选为1;
C1-6链烷氧羰基,更优选为C1-4链烷氧羰基(例如甲氧羰基);
C1-6链烷基羰基,更优选为C1-4链烷基羰基(例如乙酰基);或
相邻的环碳原子上的两个R彼此键合并与它们所连接的碳原子一起形成含2个氧原子的饱和6元环,更优选为含OCH2CH2O的6元环(例如1,4-二恶烷环)。
以下说明由式(IA)或(IB)表示的化合物中的各个符号。
R1为氢或卤素;
R2为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基;
R3为氢、卤素、C1-6烷基或可选地具有取代基的C1-6烷氧基;
R4为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基;
R5为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基;
R6为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基,或
R5和R6彼此键合并与它们所连接的碳原子一起形成含有1至2个氧原子的5元环或6元环;以及
R7为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基。
在上述各个符号中,卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、可选地具有取代基的C1-6烷氧基、C1-6烷氧羰基、C1-6烷基羰基以及R5和R6彼此键合并与它们所连接的碳原子一起形成的含1至2个氧原子的5元环或6元环,可为上述由式(I)表示的化合物所解释的那些。
下面说明各个上述符号的优选实施方式。
R1优选为氢、氯、溴或碘。
R2优选为氢、卤素或C1-6链烷氧基。更优选为氢、卤素或C1-4链烷氧基,进一步优选为氢、溴或甲氧基。
R3优选为氢、卤素、C1-6链烷基或可选地具有取代基的C1-6烷氧基。作为卤素,优选为溴或氯。作为C1-6链烷基,优选为C1-4链烷基,更优选为甲基。可选地具有取代基的C1-6烷氧基优选为C1-6链烷氧基、C3-6环烷氧基或由式:-O-X―Y表示的烷氧基。
作为R3的“C1-6链烷氧基”,优选为C1-4链烷氧基,更优选甲氧基、乙氧基、丙氧基、异丙氧基或丁氧基。
作为R3的“C3-6环烷氧基”,优选为环戊氧基。
在R3的“由式:-O-X―Y表示的烷氧基”中,X为直链或支链的C1-6亚烷基。Y为C3-6环烷基或各自可选地具有取代基的吡啶、萘或苯并噻吩,或由下式(II)表示的取代基:
X的“直链或支链的C1-6亚烷基”优选为直链或支链的C1-4亚烷基,更优选为亚甲基(-CH2-)或甲基亚甲基(-CH(CH3)-),进一步优选为亚甲基(-CH2-)。
Y的“C3-6环烷基”优选为环丙基、环戊基或环己基。
Y的“各自可选地具有取代基的吡啶、萘或苯并噻吩”优选为吡啶、萘或苯并噻吩,更优选为吡啶或苯并噻吩。
在Y的“由式(II)表示的取代基”中,Z为氢、C1-6烷氧基、C1-6烷氧基甲基、卤素或由下式(III)、(IV)、(V)或(VI)表示的取代基:
Z的C1-6烷氧基优选为C1-6链烷氧基,更优选为C1-4链烷氧基,最优选为甲氧基。
Z的C1-6烷氧基甲基优选为C1-6链烷氧基甲基,更优选为C1-4链烷氧基甲基,最优选为甲氧基甲基。
Z的卤素优选为氯、溴、碘,更优选为氯。
在由式(III)表示的取代基中,
Z1和Z2各自独立地为氢或C1-6烷基,优选为氢或C1-6链烷基,更优选为C1-4链烷基,最优选为甲基;或
Z1和Z2彼此键合并与它们所连接的氮原子一起形成5元环或6元环,优选为饱和的5元环或6元环,更优选为吡咯烷环或哌啶环;以及
n为1或2,更优选为1。
例如,最优选的“由式:-O-X―Y表示的烷氧基”为:环丙基甲氧基、环戊基甲氧基、环己基甲氧基、苄氧基、苯基乙氧基(特别优选1-苯基乙氧基)、甲氧基苄氧基(特别优选4-甲氧基苄氧基)、甲氧基甲基苄氧基(特别优选4-(甲氧基甲基)苄氧基、氯苄氧基(特别优选4-氯苄氧基)、(吡咯烷-1-基甲基)苄氧基(特别优选4-(吡咯烷-1-基甲基)苄氧基)、(哌啶-1-基甲基)苄氧基(特别优选4-(哌啶-1-基甲基)苄氧基)、[(二甲氨基)甲基]苄氧基(特别优选4-[(二甲氨基)甲基]苄氧基)、吗啉代乙基苄氧基(特别优选4-(2-吗啉代乙基)苄氧基)、吗啉代甲基苄氧基(特别优选2-(吗啉代甲基)苄氧基、3-(吗啉代甲基)苄氧基、4-(吗啉代甲基)苄氧基)或2,6-二甲基吗啉代甲基苄氧基(特别优选4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)。
R4优选为氢、卤素、C1-6链烷基、C1-6羟基链烷基、C1-6链烷氧基或C1-6链烷氧羰基。
R4的卤素更优选为溴或氯。
R4的C1-6链烷基更优选为C1-4链烷基,最优选为甲基。
R4的C1-6羟基链烷基更优选为C1-4羟基链烷基,最优选为羟甲基。
R4的C1-6链烷氧基更优选为C1-4链烷氧基,最优选为甲氧基或乙氧基。
R4的C1-6链烷氧羰基更优选为C1-4链烷氧羰基,最优选为甲氧羰基。
优选R5和R6各自独立地为氢,或
R5和R6彼此键合并与它们所连接的碳原子一起形成含有1至2个氧原子的5元环或6元环。含有1至2个氧原子的5元环或6元环优选为含有两个氧原子的饱和6元环,更优选为含有OCH2CH2O的6元环,最优选为1,4-二恶烷环。
R7优选为氢、卤素、C1-6链烷基或C1-6链烷基羰基,更优选为氢、卤素、C1-4链烷基或C1-4链烷基羰基,最优选为氢、溴、氯、甲基或乙酰基。
由下式(I)表示的化合物的具体优选实例包括以下化合物。
[化合物I-1]
化合物(I),其中,R1为氢或卤素;
m个R各自独立地为卤素、C1-6链烷基、C1-6羟基链烷基、C1-6链烷氧基、C3-6环烷氧基、
下式表示的烷氧基:-O-X―Y
式中:
X为直链或支链的C1-6亚烷基;以及
Y为C3-6环烷基、吡啶、萘或苯并噻吩或由式(II)表示的取代基:
Z为氢、C1-6链烷氧基、C1-6链烷氧基甲基、卤素或由下式(III)、(IV)、(V)或(VI)表示的取代基:
Z1和Z2各自独立地为氢或C1-6链烷基;或
Z1和Z2彼此键合并与它们所连接的氮原子一起形成饱和的5元环或6元环;以及
n为1或2;
C1-6链烷氧羰基,或C1-6链烷基羰基,或
相邻的环碳原子上的两个R彼此键合并与它们所连接的碳原子一起形成含有2个氧原子的饱和6元环;以及
m为0、1、2或3。
[化合物I-2]
化合物(I),其中,R1为氢;
m个R各自独立地为卤素、
C1-6链烷氧基、
下式表示的烷氧基:-O-X―Y
式中:
X为直链C1-6亚烷基;以及
Y为苯并噻吩、吡啶或由式(II)表示的取代基:
Z为氢、C1-6链烷氧基甲基或由下式(III)、(IV)、(V)或(VI)表示的取代基:
Z1和Z2各自为C1-6链烷基;或
Z1和Z2彼此键合并与它们所连接的氮原子一起形成5元环或6元环;以及n为1或2;
m为0、1或2。
在另一个实施方式中,化合物(I)的具体优选实例包括下式表示的化合物(IA)和化合物(IB):
式中,
R1为氢或卤素;
R2为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基;
R3为氢、卤素、C1-6烷基或可选地具有取代基的C1-6烷氧基;
R4为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基;
R5为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基;
R6为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基,或
R5和R6彼此键合并与它们所连接的碳原子一起形成含有1至2个氧原子的5元环或6元环;以及
R7为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基。
化合物(IA)和(IB)的具体优选实例包括以下化合物。
[化合物(IA)-1]和[化合物(IB)-1]
化合物(IA)和化合物(IB),
其中,
R3为氢、卤素、C1-6烷基、C1-6烷氧基或
下式表示的烷氧基:-O-X―Y
式中:
X为直链或支链的C1-6亚烷基;以及
Y为C3-6环烷基或各自可选地具有取代基的吡啶、萘或苯并噻吩(更优选为吡啶、萘或苯并噻吩)或由式(II)表示的取代基:
Z为氢、C1-6烷氧基、C1-6烷氧基甲基、卤素或由下式(III)、(IV)、(V)或(VI)表示的取代基:
Z1和Z2各自独立地为氢或C1-6烷基,或
Z1和Z2彼此键合并与它们所连接的氮原子一起形成5元环或6元环;以及
n为1或2;
[化合物(IA)-2]和[化合物(IB)-2]
化合物(IA)和化合物(IB),
其中,
R1为氢或卤素;
R2为氢、卤素或C1-6烷氧基;
R3为氢、卤素、C1-6烷基或可选地具有取代基的C1-6烷氧基;
R4为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基或C1-6烷氧羰基;
R5和R6各自为氢,或
R5和R6彼此键合并与它们所连接的碳原子一起形成含有1至2个氧原子的5元环或6元环;以及
R7为氢、卤素、C1-6烷基或C1-6烷基羰基。
[化合物(IA)-3]和[化合物(IB)-3]
化合物(IA)和化合物(IB),
其中,
R1为氢或卤素;
R2为氢、卤素或C1-6链烷氧基;
R3为氢、卤素、C1-6链烷基、C1-6链烷氧基,C3-6环烷氧基或
下式表示的烷氧基:-O-X―Y
式中:
X为直链或支链的C1-6亚烷基;以及
Y为C3-6环烷基、吡啶、苯并噻吩或
由式(II)表示的取代基:
Z为氢、C1-6链烷氧基,C1-6链烷氧基甲基、卤素或由下式(III)、(IV)、(V)或(VI)表示的取代基:
Z1和Z2各自独立地为C1-6链烷基;或
Z1和Z2彼此键合并与它们所连接的氮原子一起形成5元环或6元环;以及
n为1或2;
R4为氢、卤素、C1-6链烷基、C1-6羟基链烷基、C1-6链烷氧基或C1-6链烷氧羰基;
R5和R6各自为氢,或
R5和R6彼此键合并与它们所连接的碳原子一起形成含有1至2个氧原子的5元环或6元环;以及
R7为氢、卤素、C1-6链烷基或C1-6链烷基羰基。
[化合物(IA)-4]
化合物(IA),
其中,
R1为氢;
R2为氢;
R3为氢、C1-6链烷氧基或
下式表示的烷氧基:-O-X―Y
式中:
X为直链C1-6亚烷基;以及
Y为苯并噻吩、吡啶或由式(II)表示的取代基:
Z为氢、C1-6链烷氧基甲基或由下式(III)、(IV)、(V)或(VI)表示的取代基:
Z1和Z2各自独立地为C1-6链烷基,或
Z1和Z2彼此键合并与它们所连接的氮原子一起形成5元环或6元环;以及n为1或2;
R4为氢、C1-6烷氧基或卤素。
[本发明化合物的制备方法]
下面说明本发明化合物的制备方法。
以下制备方法中所用原料和试剂以及所得化合物可各自形成盐。此种盐的实例包括与本发明前述化合物的盐相似的那些盐。
当所得本发明化合物为游离化合物时,可通过本身已知的方法将其转化为所需的盐。相反,当各个步骤中所得本发明化合物为盐时,可通过本身已知的方法将其转化为游离形式或其他种类的所需盐。
尽管对本发明化合物的制备方法无特别限制,但该化合物可通过例如使以下化合物(VII)和(VIII)进行加成环化反应形成三唑环来制备。
其中,R、R1和m如上定义。
可通过使用不会对反应产生不利影响的合适溶剂,在搅拌下,以溶液状态或悬浮液状态使化合物(VII)与化合物(VIII)反应来进行该反应。此种合适的溶剂的实例包括醚(例如四氢呋喃等)、乙腈、醇(例如叔丁醇等)、水等。
反应也可在合适催化剂的存在下进行。此种催化剂的实例包括铜化合物(例如碘化铜(I)、乙酸铜(II)、硫酸铜(II))、钌化合物(例如氯(五甲基环戊二烯基)(环辛二烯)钌(II))等。
反应温度无特别限制,例如,反应可在室温至在加热下进行。
本领域技术人员可适当地确定上述反应的各种条件。
当在本发明制备方法中用作起始化合物的化合物(VII)或化合物(VIII)可商购时,可使用商购产品,或可通过本身已知方法、下文“实施例”部分中公开的方法或与其类似的方法由已知化合物制备而适当地获得。
本发明的化合物可为晶体。本发明化合物的晶体可通过应用本身已知的结晶方法使本发明化合物结晶来制备。结晶方法的实例包括溶液的结晶方法、蒸气的结晶方法、熔融形式的结晶方法等。此外,本发明化合物可为药学上可接受的共晶或共晶盐。此处,共晶或共晶盐指在室温下由两种以上独特的固体组成的晶质,两种以上独特的固体各自具有不同的物理性质(例如结构、熔点、熔化热、吸湿性、溶解性、稳定性等)。共晶或共晶盐可根据本身已知的共结晶方法来制备。
本发明的化合物可为水合物、非水合物、溶剂化物和非溶剂化物中的任何一种。
[本发明化合物的用途]
本发明的化合物具有优异的TNF-α产生抑制活性和血液癌症细胞生长抑制活性,因此基于这些活性可用作例如安全药物。预期包含本发明化合物的本发明药物显示出低毒性(例如急性毒性、慢性毒性、遗传毒性、心脏毒性、致癌性等),可用作例如哺乳动物(例如小鼠、大鼠、仓鼠、兔子、猫、狗、牛、绵羊、猴子、人等)的炎性疾病、自身免疫性疾病、血液癌症等的预防剂或治疗剂。
“炎性疾病、自身免疫性疾病”的实例包括类风湿性关节炎、克罗恩氏病、多发性硬化症、溃疡性结肠炎、系统性红斑狼疮、结节性红斑性麻风、骨关节炎、痛风性关节炎、类风湿性脊柱炎、自身免疫性糖尿病等。
“血液癌症”的实例包括白血病、恶性淋巴瘤、多发性骨髓瘤等。白血病分为但不限于急性白血病和慢性白血病。急性白血病包括但不限于急性髓细胞性白血病、急性淋巴细胞性白血病/淋巴母细胞性淋巴瘤和急性早幼粒细胞性白血病。慢性白血病包括但不限于慢性髓细胞性白血病、慢性淋巴细胞性白血病/小淋巴细胞性淋巴瘤。恶性淋巴瘤分为霍奇金淋巴瘤和非霍奇金淋巴瘤。霍奇金淋巴瘤可进一步分为经典霍奇金淋巴瘤和以结节性淋巴细胞为主的霍奇金淋巴瘤。非霍奇金淋巴瘤又分为前体淋巴样肿瘤、成熟B细胞肿瘤和成熟的T/NK细胞肿瘤。前体淋巴样肿瘤分为B细胞淋巴母细胞白血病/淋巴瘤、T细胞淋巴母细胞白血病/淋巴瘤。成熟B细胞肿瘤包括但不限于慢性淋巴细胞性白血病/小淋巴细胞性淋巴瘤、滤泡性淋巴瘤、MALT淋巴瘤、淋巴浆细胞性淋巴瘤、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、伯基特淋巴瘤等。成熟T/NK细胞瘤包括但不限于外周T细胞淋巴瘤、成人T细胞白血病/淋巴瘤、结外NK/T细胞淋巴瘤、结外鼻型NK/T细胞淋巴瘤、真菌性真菌病、塞扎里综合征(Sezary syndrome)等。
如本文所用,“预防”包括预防疾病(所有或一种以上病理状况)的发作和延缓疾病的发作。“预防有效量”指足以达到目的的本发明化合物的剂量。“治疗”包括疾病(所有或一种以上病理状况)的治愈、疾病的改善和抑制疾病严重程度的发展。“治疗有效量”指足以达到目的的本发明化合物的剂量。
当本发明化合物用作药物时,根据作为制备药物制剂方法(例如日本药典等中描述的方法)的本身已知的方法,本发明化合物可单独使用或与广泛用于制药领域的药学上可接受的载体组合用作本发明化合物的药物组合物。在不损害本发明的所需效果的范围内,将药物组合物与药物领域中通常使用的载体、赋形剂、稀释剂、增溶剂等混合,且可以片剂、散剂、颗粒剂、胶囊剂、糖浆剂、溶液剂、注射剂等形式口服或胃肠外施用。剂型可由本领域技术人员根据本发明化合物的预期用途适当地确定。剂量取决于患者的症状、年龄、体重等。通常,成人每天可以一至几份的量施用0.01mg至500mg,优选0.05mg至300mg,更优选0.1mg至150mg,进一步优选0.5mg至100mg。
实施例
下面具体解释本发明的化合物;但是,显然本发明不限于此。
实施例1(化合物1)
3-[4-(4-溴噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(1-1)向丙酮/水(2:1)混合物(120mL)中加入3-溴哌啶-2,6-二酮(9.74g,50.73mmol)和叠氮化钠(16.51g,253.96mmol),将混合物在氩气气氛下于室温搅拌24小时。蒸发丙酮,剩余溶液用乙酸乙酯萃取。有机层用水和饱和盐水洗涤,用无水硫酸镁干燥,用活性炭处理,浓缩。浓缩的残余物从乙酸乙酯中重结晶,得到3-叠氮基哌啶-2,6-二酮(6.26g,80%),为灰色固体。
1H-NMR(DMSO-d6)δ11.06(1H,brs),4.57(1H,dd,J=5.4,11.9Hz),2.45-2.66(2H,m),1.99-2.10(1H,m),1.78-1.93(1H,m)。
(1-2)向3-溴-4-乙炔基噻吩(0.23g,1.23mmol)的乙腈(6mL)溶液中加入3-叠氮基哌啶-2,6-二酮(通过实施例1(1-1)的方法合成)(0.19g,1.23mmol)和碘化铜(I)(23.4mg,0.12mmol),将混合物在氩气气氛下于室温搅拌48小时。浓缩反应混合物,将浓缩的残余物通过柱色谱法纯化(二氯甲烷/甲醇),得到3-[4-(4-溴噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(0.15g,36%),为白色固体。
1H-NMR(DMSO-d6)δ11.17-11.31(1H,br),8.66(1H,s),8.05(1H,d,J=3.5Hz),7.87(1H,d,J=3.5Hz),5.90(1H,dd,J=5.2,12.6Hz),2.65-2.96(3H,m),2.29-2.39(1H,m)。
实施例2(化合物2)
3-[4-(噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
通过类似于实施例1(1-2)的方法,由3-乙炔基噻吩(70mg,0.65mmol)获得3-[4-(噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(99mg,58%),为白色固体。
1H-NMR(DMSO-d6)δ11.27(1H,s),8.54(1H,s),7.87(1H,dd,J=1.2,2.9Hz),7.67(1H,dd,J=3.0,5.0Hz),7.52(1H,dd,J=1.2,5.0Hz),5.85(1H,dd,J=5.2,12.8Hz),2.84-2.95(1H,m),2.61-2.75(2H,m),2.32-2.41(1H,m)。
实施例3(化合物3)
3-[4-(噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
向三甲基(噻吩-2-基乙炔基)硅烷(560mg,3.11mmol)的甲醇(6mL)溶液中加入碳酸钾(858mg,6.21mmol),将混合物在室温搅拌1小时。将水加入到反应混合物中,将混合物用乙醚萃取。有机层用饱和盐水洗涤,用无水硫酸钠干燥,浓缩,得到无色油状物(350mg)。向所得无色油(350mg)的乙腈(3mL)溶液中加入3-叠氮基哌啶-2,6-二酮(通过实施例1(1-1)的方法合成)(479mg,3.11mmol)和碘化铜(I)(59.1mg,0.31mmol),将混合物在室温搅拌20小时。过滤收集沉淀物,用甲醇洗涤,得到3-[4-(噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(429mg,53%),为灰色固体。
1H-NMR(DMSO-d6)δ11.28(1H,brs),8.60(1H,s),7.56(1H,dd,J=0.8,5.0Hz),7.44(1H,d,J=2.9Hz),7.15(1H,dd,J=3.6,5.0Hz),5.86(1H,d,J=8.2Hz),2.80-2.98(1H,m),2.60-2.80(2H,m),2.30-2.45(1H,m)。
实施例4(化合物4)
3-[5-氯-4-(噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
在-78℃下向3-乙炔基噻吩(0.80mL,8.04mmol)的四氢呋喃(12mL)溶液中滴加1.64M正丁基锂/己烷溶液(5.60mL,9.18mmol),在-78℃下搅拌混合物1小时。向反应混合物中滴加N-氯琥珀酰亚胺(2.37g,17.75mmol)在四氢呋喃(30mL)中的悬浮液,将该混合物在-78℃至室温下搅拌19.5小时。向反应混合物中加入己烷,将混合物用饱和盐水和1.0M硫代硫酸钠水溶液洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷/二氯甲烷)纯化,得到3-(氯乙炔基)噻吩混合物(723.3mg),为浅黄色油。
向所得混合物(723.3mg)的乙腈(8mL)溶液中加入3-叠氮基哌啶-2,6-二酮(624.7mg,4.05mmol)和氯(五甲基环戊二烯基)(环辛二烯)钌(II)(78.7mg,0.21mmol),将混合物在70℃下搅拌20天。浓缩反应混合物,将浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到粗产物(137.6mg)。所得粗产物用乙酸乙酯和氯仿洗涤,得到3-[5-氯-4-(噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(44.6mg,2%),为灰色固体。
1H-NMR(DMSO-d6)δ11.34(1H,brs),8.03(1H,dd,J=1.3,2.9Hz),7.76(1H,dd,J=2.9,5.0Hz),7.64(1H,dd,J=1.3,5.0Hz),5.88(1H,dd,J=5.1,12.5Hz),2.69-3.01(3H,m),2.38-2.47(1H,m)。
实施例5(化合物5)
3-[4-(5-甲基噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(5-1)向2-溴-5-甲基噻吩(500mg,2.82mmol)的三乙胺(3mL)溶液中加入三甲基硅基乙炔(333mg,3.39mmol)、碘化铜(I)(53.8mg,0.28mmol)和双(三苯基膦)二氯化钯(II)(99.1mg,0.14mmol),使用微波反应器将混合物在80℃搅拌1小时。通过柱色谱法纯化反应混合物,得到三甲基[(5-甲基噻吩-2-基)乙炔基]硅烷(539mg,98%),为橙色油。
1H-NMR(CDCl3)δ7.23(1H,d,J=1.4Hz),6.76-6.78(1H,m),2.43(3H,d,J=1.0Hz),0.22(9H,s)。
(5-2)通过类似于实施例3的方法,由三甲基[(5-甲基噻吩-2-基)乙炔基]硅烷(539mg,2.77mmol)得到3-[4-(5-甲基噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(291mg,38%),为灰色固体。
1H-NMR(DMSO-d6)δ11.26(1H,s),8.47(1H,s),7.58(1H,d,J=1.3Hz),7.19-7.23(1H,m),5.83(1H,dd,J=5.0,12.4Hz),2.89(1H,ddd,J=4.0,12.8,17.6Hz),2.58-2.77(2H,m),2.49(3H,d,J=0.9Hz),2.29-2.41(1H,m)。
实施例6(化合物6)
3-[4-(5-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
通过类似于实施例5的方法,由4-溴-2-甲基噻吩得到3-[4-(5-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(产率16%),为浅蓝色固体。
三甲基[(5-甲基噻吩-3-基)乙炔基]硅烷
1H-NMR(CDCl3)δ7.23(1H,d,J=1.3Hz),6.75-6.80(1H,m),2.43(3H,d,J=1.0Hz),0.23(9H,s)。
3-[4-(5-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.26(1H,s),8.47(1H,s),7.58(1H,d,J=1.4Hz),7.21(1H,brt,J=1.2Hz),5.83(1H,dd,J=5.1,12.5Hz),2.84-2.94(1H,m),2.60-2.74(2H,m),2.30-2.40(1H,m),2.09(3H,s)。
实施例7(化合物7)
3-[4-(4-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(7-1)通过类似于实施例5(5-1)的方法,由3-溴-4-甲基噻吩(500mg,2.82mmol)得到三甲基[(4-甲基噻吩-3-基)乙炔基]硅烷(293mg,54%),为黄色油。
1H-NMR(CDCl3)δ7.41(1H,d,J=3.1Hz),6.84-6.89(1H,m),2.27(3H,d,J=1.0Hz),0.24(9H,s)。
(7-2)向三甲基[(4-甲基噻吩-3-基)乙炔基]硅烷(423mg,2.18mmol)的甲醇(6mL)溶液中加入碳酸钾(601.6mg,4.35mmol),将混合物在室温下搅拌23小时。将反应混合物过滤,浓缩滤液。浓缩的残余物通过柱色谱法(己烷)纯化,得到黄色油状物(180mg)。通过类似于实施例1(1-2)的方法,由所得油状物获得3-[4-(4-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(117mg,19%),为白色无定形类物质。
1H-NMR(DMSO-d6)δ11.26(1H,s),8.47(1H,s),7.80(1H,d,J=3.3Hz),7.27-7.31(1H,m),5.86(1H,dd,J=5.0,12.5Hz),2.84-2.97(1H,m),2.65-2.79(2H,m),2.31-2.40(4H,m)。
实施例8(化合物8)
3-[4-(5-乙酰基噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(8-1)向2-乙酰基-5-溴噻吩(0.50g,2.44mmol)的四氢呋喃(5mL)溶液中加入二异丙胺(0.51mL,3.63mmol)、三甲基硅基乙炔(0.37mL,2.67mmol)、双(三苯基膦)二氯化钯(II)(86mg,0.12mmol)和碘化铜(I)(12mg,0.06mmol),将混合物在氩气气氛下密封,在室温下搅拌17小时。向反应混合物中加入水,将混合物用二氯甲烷萃取。有机层用水和饱和盐水洗涤,用无水硫酸镁干燥,浓缩,得到1-{5-[([三甲基甲硅烷基)乙炔基]噻吩-2-基}乙酮混合物(0.64g),为棕色固体。所得混合物不进行纯化即用于下一步反应。
1H-NMR(CDCl3)δ7.53(1H,d,J=4.0Hz),7.19(1H,d,J=4.0Hz),2.54(3H,s),0.26(9H,s)。
(8-2)向1-{5-[(三甲基甲硅烷基)乙炔基]噻吩-2-基}乙酮混合物(0.64g)的甲醇(6mL)溶液中加入碳酸钾(0.80g,5.80mmol),将混合物在氩气气氛下于室温搅拌1小时。通过硅藻土过滤反应混合物,浓缩滤液。将水加入浓缩的残余物中,用乙醚萃取。将有机层用水和饱和盐水洗涤,用无水硫酸镁干燥,浓缩,得到1-(5-乙炔基噻吩-2-基)乙酮(0.19g,2步52%),为棕色固体。
1H-NMR(CDCl3)δ7.54(1H,d,J=4.0Hz),7.25(1H,d,J=4.0Hz),3.51(1H,s),2.55(3H,s)。
(8-3)通过类似于实施例1(1-2)的方法,由1-(5-乙炔基噻吩-2-基)乙酮(0.19g,1.26mmol)得到3-[4-(5-乙酰基噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(70.6mg,18%),为浅棕色固体。
1H-NMR(DMSO-d6)δ11.31(1H,s),8.81(1H,s),7.96(1H,d,J=4.0Hz),7.56(1H,d,J=3.9Hz),5.90(1H,dd,J=5.2,12.8Hz),2.83-2.96(1H,m),2.58-2.77(2H,m),2.55(3H,s),2.34-2.43(1H,m)。
实施例9(化合物9)
3-{4-[5-(羟甲基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
通过类似于实施例1(1-2)的方法,由(4-乙炔基噻吩-2-基)甲醇(0.53g,3.84mmol)得到3-{4-[5-(羟甲基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(0.33g,29%),为浅紫色固体。
1H-NMR(DMSO-d6)δ11.26(1H,s),8.50(1H,s),7.72(1H,d,J=1.4Hz),7.32-7.38(1H,m),5.84(1H,dd,J=5.2,12.6Hz),5.55(1H,t,J=5.8Hz),4.66(2H,dd,J=0.7,5.8Hz),2.82-2.96(1H,m),2.60-2.77(2H,m),2.30-2.41(1H,m)。
实施例10(化合物10)
3-[4-(2,3-二氢噻吩并[3,4-b][1,4]二恶英-5-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
通过类似于实施例1(1-2)的方法,由5-乙炔基-2,3-二氢噻吩并[3,4-b][1,4]二恶英(1.36g,8.18mmol)得到3-[4-(2,3-二氢噻吩并[3,4-b][1,4]二恶英-5-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(0.87g,33%),为灰色固体。
1H-NMR(DMSO-d6)δ11.23(1H,s),8.33(1H,s),6.62(1H,s),5.87(1H,dd,J=5.1,12.4Hz),4.20-4.40(4H,m),2.62-2.95(3H,m),2.23-2.36(1H,m)。
实施例11(化合物11)
3-[4-(5-氯噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(11-1)向2-溴-5-氯噻吩(0.50g,2.53mmol)的THF(5mL)溶液中加入二异丙胺(0.53ml,3.77mmol)、双(三苯基膦)二氯化钯(II)(88.9mg,0.13mmol)、碘化铜(I)(12.1mg,0.06mmol)和三甲基硅基乙炔(0.37ml,2.67mmol),将混合物在氩气气氛下密封,在80℃下搅拌5小时。向反应混合物中加入饱和氯化铵水溶液,用乙醚萃取混合物。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷)纯化,得到[(5-氯噻吩-2-基)乙炔基]三甲基硅烷(0.51g,94%),为浅黄色油。
1H-NMR(CDCl3)δ6.99(1H,d,J=3.9Hz),6.76(1H,d,J=3.9Hz),0.24(9H,s)。
(11-2)通过类似于实施例8(8-2、8-3)的方法,由[(5-氯噻吩-2-基)乙炔基]三甲基硅烷得到3-[4-(5-氯噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(产率23%),为灰色固体。
2-氯-5-乙炔基噻吩
1H-NMR(CDCl3)δ7.05(1H,d,J=3.8Hz),6.79(1H,d,J=3.9Hz),3.32(1H,s)。
3-[4-(5-氯噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.28(1H,s),8.64(1H,s),7.32(1H,d,J=3.9Hz),7.17(1H,d,J=3.9Hz),5.87(1H,dd,J=5.1,12.6Hz),2.82-2.95(1H,m),2.60-2.75(2H,m),2.31-2.41(1H,m)。
实施例12(化合物12)
3-[4-(5-溴噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
通过类似于实施例1(1-2)的方法,由2-溴-5-乙炔基噻吩(0.13g,0.69mmol)得到3-[4-(5-溴噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(101.7mg,43%),为灰色固体。
1H-NMR(DMSO-d6)δ11.28(1H,s),8.64(1H,s),7.29(1H,d,J=3.9Hz),7.27(1H,d,J=3.8Hz),5.87(1H,dd,J=5.2,12.6Hz),2.82-2.95(1H,m),2.60-2.76(2H,m),2.31-2.42(1H,m)。
实施例13(化合物13)
3-[4-(2,5-二溴噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(13-1)向2,5-二溴噻吩-3-羧醛(0.34g,1.26mmol)和(1-重氮-2-氧丙基)膦酸二甲酯(0.32g,1.67mmol)的甲醇(13mL)溶液中加入碳酸钾(0.35g,2.53mmol),将混合物在氩气气氛下于室温搅拌20小时。将反应混合物浓缩,将浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到2,5-二溴-3-乙炔基噻吩(0.30g,90%),为浅棕色固体。
1H-NMR(CDCl3)δ6.97(1H,s),3.30(1H,s)。
(13-2)通过类似于实施例1(1-2)的方法,由2,5-二溴-3-乙炔基噻吩(297.5mg,1.12mmol)得到3-[4-(2,5-二溴噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(241.4mg,51%),为浅棕色固体。
1H-NMR(DMSO-d6)δ11.28(1H,s),8.79(1H,s),7.64(1H,s),5.92(1H,dd,J=5.4,12.8Hz),2.83-2.96(1H,m),2.64-2.83(2H,m),2.30-2.40(1H,m)。
实施例14(化合物14)
3-[4-(4-氯噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
通过类似于实施例1(1-2)的方法,由3-氯-4-乙炔基噻吩(64.1mg,0.45mmol)得到3-[4-(4-氯噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(67.8mg,51%),为白色固体。
1H-NMR(DMSO-d6)δ11.26(1H,s)8.65(1H,s),8.10(1H,d,J=3.6Hz),7.77(1H,d,J=3.6Hz),5.90(1H,dd,J=5.1,12.5Hz),2.65-2.95(3H,m),2.30-2.40(1H,m)。
实施例15(化合物15)
3-[4-(4-甲氧基-5-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(15-1)在氩气气氛下,在不高于5℃下,向氢化铝锂(0.36g,9.49mmol)在乙醚(80mL)中的悬浮液中滴加4-溴-3-甲氧基噻吩-2-羧酸甲酯(2.01g,8.00mmol)的乙醚(14mL)溶液,将混合物在0℃搅拌2小时。向反应混合物中加入水,将混合物通过硅藻土过滤。将水加入滤液中,将混合物用二乙醚萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。将浓缩的残余物通过柱色谱法(二氯甲烷/甲醇)纯化,得到(4-溴-3-甲氧基噻吩-2-基)甲醇(1.29g,72%),为棕色油。
1H-NMR(CDCl3)δ7.15(1H,s),4.77(2H,d,J=5.8Hz),3.90(3H,s),1.92(1H,t,J=5.9Hz)。
(15-2)在0℃下向(4-溴-3-甲氧基噻吩-2-基)甲醇(1.29g,5.78mmol)的二氯甲烷(12mL)溶液中加入亚硫酰氯(0.50mL,6.89mmol),将混合物在氩气气氛下于室温搅拌4.5小时。2小时和3小时后,在0℃下加入亚硫酰氯(0.25mL,3.45mmol)。向反应混合物中加入0℃的水,混合物用二氯甲烷萃取。将有机层用饱和盐水洗涤,用无水硫酸镁干燥,用活性炭处理,浓缩,得到4-溴-2-(氯甲基)-3-甲氧基噻吩(1.32g,95%),为黄色油。所得4-溴-2-(氯甲基)-3-甲氧基噻吩不进行纯化即用于下一步反应。
1H-NMR(CDCl3)δ7.20(1H,s),4.74(2H,s),3.94(3H,s)。
(15-3)在氩气气氛下,在不高于5℃下,向氢化铝锂(0.24g,6.32mmol)在四氢呋喃(55mL)中的悬浮液中滴加4-溴-2-(氯甲基)-3-甲氧基噻吩(1.32g,5.47mmol)的四氢呋喃(10mL)溶液,将混合物在0℃搅拌5小时。向反应混合物中加入水,将混合物通过硅藻土过滤。将水加入滤液中,将混合物用乙酸乙酯萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷/二氯甲烷)纯化,得到4-溴-3-甲氧基-2-甲基噻吩(0.72g,64%),为无色油。
1H-NMR(CDCl3)δ6.95(1H,s),3.81(3H,s),2.37(3H,s)。
(15-4)通过类似于实施例11的方法,由4-溴-3-甲氧基-2-甲基噻吩得到3-[4-(4-甲氧基-5-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(产率34%),为灰色固体。
[(4-甲氧基-5-甲基噻吩-3-基)乙炔基]三甲基硅烷
1H-NMR(CDCl3)δ7.13(1H,s),3.90(3H,s),2.28(3H,s),0.24(9H,s)。
4-乙炔基-3-甲氧基-2-甲基噻吩
1H-NMR(CDCl3)δ7.18(1H,s),3.90(3H,s),3.16(1H,s),2.31(3H,s)。
3-[4-(4-甲氧基-5-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,brs),8.35(1H,s),7.60(1H,s),5.86(1H,dd,J=5.1,12.4Hz),3.73(3H,s),2.63-2.96(3H,m),2.25-2.41(4H,m)。
实施例16(化合物16)
4-[1-(2,6-二氧代哌啶-3-基)-1H-1,2,3-三唑-4-基]-3-甲氧基噻吩-2-羧酸甲酯
通过类似于实施例11的方法,由4-溴-3-甲氧基噻吩-2-羧酸甲酯得到4-[1-(2,6-二氧代哌啶-3-基)-1H-1,2,3-三唑-4-基]-3-甲氧基噻吩-2-羧酸甲酯(产率36%),为灰色固体。
3-甲氧基-4-[(三甲基甲硅烷基)乙炔基]噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.50(1H,s),4.13(3H,s),3.86(3H,s),0.24(9H,s)。
4-乙炔基-3-甲氧基噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.56(1H,s),4.13(3H,s),3.87(3H,s),3.21(1H,s)。
4-[1-(2,6-二氧代哌啶-3-基)-1H-1,2,3-三唑-4-基]-3-甲氧基噻吩-2-羧酸甲酯
1H-NMR(DMSO-d6)δ11.26(1H,s),8.48(1H,s),8.23(1H,s),5.89(1H,dd,J=5.0,12.4Hz),3.98(3H,s),3.83(3H,s),2.64-2.97(3H,m),2.27-2.38(1H,m)。
实施例17(化合物17)
3-[4-(4-乙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
通过类似于实施例11的方法,由3-溴-4-乙氧基噻吩得到3-[4-(4-乙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(产率30%),为浅棕色固体。
[(4-乙氧基噻吩-3-基)乙炔基]三甲基硅烷
1H-NMR(CDCl3)δ7.36(1H,d,J=3.3Hz),6.15(1H,d,J=3.3Hz),4.04(2H,q,J=7.0Hz),1.45(3H,t,J=7.0Hz),0.25(9H,s)。
3-乙氧基-4-乙炔基噻吩
1H-NMR(CDCl3)δ7.41(1H,d,J=3.3Hz),6.18(1H,d,J=3.3Hz),4.07(2H,q,J=7.0Hz),3.17(1H,s),1.46(3H,t,J=7.0Hz)。
3-[4-(4-乙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,s),8.27(1H,s),7.88(1H,d,J=3.4Hz),6.73(1H,d,J=3.4Hz),5.88(1H,dd,J=5.0,12.3Hz),4.11(2H,q,J=7.0Hz),2.64-2.92(3H,m),2.26-2.36(1H,m),1.42(3H,t,J=7.0Hz)。
实施例18(化合物18)
3-[4-(2-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
通过类似于实施例13的方法,由2-甲氧基噻吩-3-羧醛得到3-[4-(2-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(产率25%),为灰色固体。
3-乙炔基-2-甲氧基噻吩
1H-NMR(CDCl3)δ6.82(1H,d,J=5.8Hz),6.50(1H,d,J=5.8Hz),4.02(3H,s),3.21(1H,s)。
3-[4-(2-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,s),8.33(1H,s),7.35(1H,d,J=5.8Hz),6.94(1H,d,J=5.8Hz),5.85(1H,dd,J=5.1,12.5Hz),4.00(3H,s),2.63-2.94(3H,m),2.25-2.35(1H,m)。
实施例19(化合物19)
3-[4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
通过类似于实施例13的方法,由4-甲氧基噻吩-3-羧醛得到3-[4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(产率64%),为灰色固体。
3-乙炔基-4-甲氧基噻吩
1H-NMR(CDCl3)δ7.42(1H,d,J=3.3Hz),6.21(1H,d,J=3.3Hz),3.88(3H,s),3.19(1H,s)。
3-[4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,s),8.35(1H,s),7.88(1H,d,J=3.4Hz),6.75(1H,d,J=3.4Hz),5.86(1H,dd,J=5.1,12.5Hz),3.88(3H,s),2.63-2.94(3H,m),2.27-2.35(1H,m)。
实施例20(化合物20)
3-[4-(5-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
通过类似于实施例1(1-2)的方法,由4-乙炔基-2-甲氧基噻吩(0.64g,4.63mmol)得到3-[4-(5-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(0.80g,59%),为浅棕色固体。
1H-NMR(DMSO-d6)δ11.26(1H,s),8.47(1H,s),7.07(1H,d,J=1.7Hz),6.71(1H,d,J=1.7Hz),5.83(1H,dd,J=5.2,12.7Hz),3.91(3H,s),2.82-2.95(1H,m),2.59-2.75(2H,m),2.30-2.40(1H,m)。
实施例21(化合物21)
3-[4-(4-丙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
通过类似于实施例13的方法,由4-丙氧基噻吩-3-羧醛得到3-[4-(4-丙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(产率50%),为浅棕色固体。
3-乙炔基-4-丙氧基噻吩
1H-NMR(CDCl3)δ7.40(1H,d,J=3.3Hz),6.17(1H,d,J=3.3Hz),3.95(2H,t,J=6.6Hz),3.16(1H,s),1.80-1.91(2H,m),1.04(3H,t,J=7.4Hz)。
3-[4-(4-丙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,s),8.22(1H,s),7.88(1H,d,J=3.3Hz),6.73(1H,d,J=3.4Hz),5.88(1H,dd,J=5.0,12.4Hz),3.97-4.06(2H,m),2.65-2.93(3H,m),2.28-2.38(1H,m),1.77-1.89(2H,m),1.01(3H,t,J=7.4Hz)。
实施例22(化合物22)
3-[4-(5-氯-4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(22-1)向4-甲氧基噻吩-3-羧醛(200mg,1.41mmol)的氯仿(1.4mL)溶液中加入2-氯-1,3-双(甲氧羰基)胍(354.3mg,1.69mmol),将混合物在氩气气氛下在室温搅拌30小时。将反应混合物浓缩,将浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到黄色油状的5-氯-4-甲氧基噻吩-3-羧醛(151mg,60%)。
1H NMR(CDCl3)δ9.80(1H,s),7.83(1H,s),4.03(3H,s)。
(22-2)通过类似于实施例13的方法,由5-氯-4-甲氧基噻吩-3-羧醛得到3-[4-(5-氯-4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(产率49%),为白色固体。
2-氯-4-乙炔基-3-甲氧基噻吩
1H NMR(CDCl3)δ7.21(1H,s),4.01(3H,s),3.19(1H,s)。
3-[4-(5-氯-4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.25(1H,s),8.44(1H,s),7.81(1H,s),5.88(1H,dd,J=5.1,12.5Hz),3.90(3H,s),2.65-2.95(3H,m),2.27-2.37(1H,m)。
实施例23(化合物23)
3-[4-(5-溴-4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(23-1)在0℃下,向4-甲氧基噻吩-3-羧醛(0.10g,0.70mmol)的二氯甲烷(1mL)溶液中少量地加入N-溴琥珀酰亚胺(131.6mg,0.74mmol),将混合物在0℃下搅拌1小时。浓缩反应混合物,将浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到5-溴-4-甲氧基噻吩-3-羧醛(0.16g),为浅棕色油。所得5-溴-4-甲氧基噻吩-3-羧醛不进行纯化即用于下一步反应。
1H-NMR(CDCl3)δ9.81(1H,s),8.00(1H,s),4.01(3H,s)。
(23-2)通过类似于实施例13的方法,由5-溴-4-甲氧基噻吩-3-羧醛得到3-[4-(5-溴-4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(产率46%),为白色固体。
2-溴-4-乙炔基-3-甲氧基噻吩
1H-NMR(CDCl3)δ7.39(1H,s),4.00(3H,s),3.20(1H,s)。
3-[4-(5-溴-4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.24(1H,s),8.44(1H,s),7.96(1H,s),5.88(1H,dd,J=5.1,12.5Hz),3.86(3H,s),2.65-2.96(3H,m),2.27-2.38(1H,m)。
实施例24(化合物24)
3-[4-(5-乙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(24-1)向5-溴噻吩-3-羧醛(9.96g,52.13mmol)的甲醇(78mL)溶液中加入原甲酸甲酯(8.56mL,78.24mmol)和氯化铵(0.39g,7.29mmol)。将混合物在氩气气氛下于60℃搅拌3.5小时。将反应混合物浓缩,将乙醚加入到浓缩的残余物中,将混合物过滤。浓缩滤液,将浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到2-溴-4-(二甲氧基甲基)噻吩(11.80g,95%),为黄色油。
1H-NMR(CDCl3)δ7.23(1H,dd,J=1.0,1.5Hz),7.05(1H,d,J=1.5Hz),5.37(1H,d,J=0.7Hz),3.31(6H,s)。
(24-2)向氢化钠(60%)(0.38g,9.50mmol)在N,N-二甲基甲酰胺(1.27mL)中的悬浮液中缓慢加入乙醇(2.53mL),将混合物在室温下搅拌直至发泡停止。向该溶液中加入2-溴-4-(二甲氧基甲基)噻吩(0.50g,2.11mmol)和溴化铜(I)(15.1mg,0.11mmol),在氩气气氛下使用微波反应器使混合物在160℃下反应15分钟。通过硅藻土过滤反应混合物,浓缩滤液。浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到4-(二甲氧基甲基)-2-乙氧基噻吩(0.19g,48%),为黄色油。
1H-NMR(CDCl3)δ6.56(1H,dd,J=1.0,1.6Hz),6.19(1H,d,J=1.6Hz),5.28(1H,d,J=0.7Hz),4.08(2H,q,J=7.0Hz),3.32(6H,s),1.40(3H,t,J=7.0Hz)。
(24-3)向4-(二甲氧基甲基)-2-乙氧基噻吩(0.58g,3.11mmol)的甲醇(10mL)溶液中加入4.0M盐酸(10mL),将混合物在室温下搅拌20分钟。向反应混合物中加入饱和盐水,将混合物用乙醚萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到5-乙氧基噻吩-3-羧醛(0.32g,66%),为黄色油。
1H-NMR(CDCl3)δ9.67(1H,s),7.39(1H,d,J=1.6Hz),6.57(1H,d,J=1.6Hz),4.13(2H,q,J=7.0Hz),1.43(3H,t,J=7.0Hz)。
(24-4)通过类似于实施例13的方法,由5-乙氧基噻吩-3-羧醛得到3-[4-(5-乙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(产率46%),为浅棕色固体。
2-乙氧基-4-乙炔基噻吩
1H-NMR(CDCl3)δ6.77(1H,d,J=1.6Hz),6.22(1H,d,J=1.6Hz),4.08(2H,q,J=7.0Hz),2.96(1H,s),1.41(3H,t,J=7.0Hz)。
3-[4-(5-乙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.26(1H,s),8.46(1H,s),7.07(1H,d,J=1.6Hz),6.70(1H,d,J=1.6Hz),5.83(1H,dd,J=5.0,12.7Hz),4.15(2H,q,J=7.0Hz),2.89(1H,ddd,J=5.0,13.1,18.1Hz),2.58-2.75(2H,m),2.30-2.40(1H,m),1.36(3H,t,J=7.0Hz)。
实施例25(化合物25)
3-[4-(4-丁氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(25-1)向3-溴-4-(二乙氧基甲基)噻吩(0.66g,2.49mmol)的1-甲基-2-吡咯烷酮(0.62mL)溶液中加入溴化铜(I)(0.36g,2.51mmol)和1-丁醇钠(22.4w/w%,在1-BuOH中)(3.74g,8.72mmol),使用微波反应器使该混合物在氩气气氛下在160℃下反应15分钟。对2个批次进行相同反应,将2个批次的反应混合物合并,通过硅藻土过滤。将饱和盐水加入到滤液中,将混合物用二乙醚萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到3-丁氧基-4-(二乙氧基甲基)噻吩(0.95g,74%),为浅黄色油。
1H-NMR(CDCl3)δ7.32(1H,dd,J=0.6,3.4Hz),6.17(1H,d,J=3.4Hz),5.48(1H,d,J=0.6Hz),3.96(2H,t,J=6.4Hz),3.51-3.69(4H,m),1.71-1.81(2H,m),1.42-1.54(2H,m),1.22(6H,t,J=7.1Hz),0.96(3H,t,J=7.4Hz)。
(25-2)通过类似于实施例24(24-3、24-4)的方法,由3-丁氧基-4-(二乙氧基甲基)噻吩得带3-[4-(4-丁氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(产率54%),为浅棕色固体。
4-丁氧基噻吩-3-羧醛
1H-NMR(CDCl3)δ9.91(1H,s),8.01(1H,d,J=3.4Hz),6.27(1H,d,J=3.4Hz),4.03(2H,t,J=6.4Hz),1.77-1.87(2H,m),1.45-1.57(2H,m),0.99(3H,t,J=7.4Hz)。
3-丁氧基-4-乙炔基噻吩
1H-NMR(CDCl3)δ7.40(1H,d,J=3.4Hz),6.17(1H,d,J=3.3Hz),3.99(2H,t,J=6.6Hz),3.15(1H,s),1.76-1.86(2H,m),1.44-1.57(2H,m),0.98(3H,t,J=7.4Hz)。
3-[4-(4-丁氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,s),8.21(1H,s),7.88(1H,d,J=3.4Hz),6.73(1H,d,J=3.4Hz),5.88(1H,dd,J=5.3,12.6Hz),4.01-4.11(2H,m),2.64-2.93(3H,m),2.27-2.38(1H,m),1.75-1.85(2H,m),1.40-1.51(2H,m),0.95(3H,t,J=7.4Hz)。
实施例26(化合物26)
3-[4-(4-异丙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(26-1)向氢化钠(60%)(0.38g,9.50mmol)在N,N-二甲基甲酰胺(1.27mL)的悬浮液中缓慢加入2-丙醇(2.53mL),将混合物在室温下搅拌直到发泡停止。向该溶液中加入3-溴-4-(二甲氧基甲基)噻吩(0.50g,2.11mmol)和溴化铜(I)(0.30g,2.09mmol),使用微波反应器在氩气气氛下使混合物在160℃下反应15分钟。向反应混合物中加入乙醚(2mL),将混合物通过硅藻土过滤。对2个批次进行相同的反应,将2个批次的滤液合并。向溶液中加入饱和盐水,将混合物用乙醚萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,用活性炭处理,浓缩,得到黄棕色油状物(1.49g)。向所得黄棕色油状物(1.49g)的甲醇(10mL)溶液中加入4.0M盐酸(10mL),将混合物在氩气气氛下于室温搅拌20分钟。向反应混合物中加入饱和盐水,将混合物用乙醚萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到4-异丙氧基噻吩-3-羧醛混合物(0.65g),为黄色油。所得4-异丙氧基噻吩-3-羧醛混合物不进行纯化即用于下一步反应。
1H-NMR(CDCl3)δ9.88(1H,s),8.00(1H,d,J=3.3Hz),6.26(1H,d,J=3.3Hz),4.47(1H,sep,J=6.1Hz),1.40(6H,d,J=6.1Hz)。
(26-2)通过类似于实施例13的方法,由4-异丙氧基噻吩-3-羧醛混合物(来自3-溴-4-(二甲氧基甲基)噻吩,4步16%)得到3-[4-(4-异丙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮,为灰色固体。
3-乙炔基-4-异丙氧基噻吩
1H-NMR(CDCl3)δ7.39(1H,d,J=3.3Hz),6.20(1H,d,J=3.3Hz),4.42(1H,sep,J=6.1Hz),3.15(1H,s),1.38(6H,d,J=6.1Hz)。
3-[4-(4-异丙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,s),8.24(1H,s),7.86(1H,d,J=3.3Hz),6.74(1H,d,J=3.3Hz),5.87(1H,dd,J=4.9,12.2Hz),4.56(1H,sep,J=6.0Hz),2.65-2.93(3H,m),2.28-2.36(1H,m),1.36(6H,d,J=6.0Hz)。
实施例27(化合物27)
3-{4-[4-(环戊氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
(27-1)向4-溴-3-羟基噻吩-2-羧酸甲酯(1.00g,4.22mmol)的N,N-二甲基甲酰胺(14mL)溶液中加入溴代环戊烷(1.13mL,10.54mmol)和碳酸铯(3.44g,10.56mmol),将混合物在氩气气氛下在100℃至110℃下搅拌48小时。向反应混合物中加入水,将混合物用乙醚萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到4-溴-3-(环戊氧基)噻吩-2-羧酸甲酯(1.20g,93%),为无色油。
1H-NMR(CDCl3)δ7.38(1H,s),5.10-5.17(1H,m),3.87(3H,s),1.85-2.04(4H,m),1.69-1.82(2H,m),1.55-1.69(2H,m)。
(27-2)向4-溴-3-(环戊氧基)噻吩-2-甲酸甲酯(1.20g,3.93mmol)的甲醇(6.7mL)溶液中加入水(2.8mL)和氢氧化钾(85%)(0.31g,4.70mmol),将混合物回流3小时。将反应混合物浓缩,将水加入浓缩的残余物中,将混合物用二乙醚洗涤。向水层中加入2.0M盐酸(2.5mL),将混合物用乙醚萃取。有机层用饱和盐水洗涤,经无水硫酸镁干燥,浓缩,得到4-溴-3-(环戊氧基)噻吩-2-羧酸(1.05g,92%),为白色固体。所得4-溴-3-(环戊氧基)噻吩-2-羧酸不进行纯化即用于下一步反应。
1H-NMR(CDCl3)δ7.51(1H,s),5.30-5.36(1H,m),1.78-2.05(6H,m),1.63-1.73(2H,m)。
(27-3)向4-溴-3-(环戊氧基)噻吩-2-羧酸(1.05g,3.61mmol)的喹啉(15mL)溶液中加入铜粉(0.26g,4.09mmol),将混合物在氩气气氛下在150℃下搅拌15分钟。向反应混合物中加入2.0M盐酸(65mL),将混合物通过硅藻土过滤,将滤液用乙醚萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到3-溴-4-(环戊氧基)噻吩(0.81g,91%),为无色油。
1H-NMR(CDCl3)δ7.16(1H,d,J=3.5Hz),6.18(1H,d,J=3.5Hz),4.64-4.70(1H,m),1.76-1.98(6H,m),1.56-1.68(2H,m)。
(27-4)通过类似于实施例11的方法,由3-溴-4-(环戊氧基)噻吩得到3-{4-[4-(环戊氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(产率8%),为浅蓝色固体。
{[4-(环戊氧基)噻吩-3-基]乙炔基}三甲基硅烷
1H-NMR(CDCl3)δ7.33(1H,d,J=3.3Hz),6.14(1H,d,J=3.3Hz),4.67(1H,sep,J=2.7Hz),1.76-2.06(6H,m),1.56-1.70(2H,m),0.24(9H,s)。
3-(环戊氧基)-4-乙炔基噻吩
1H-NMR(CDCl3)δ7.38(1H,d,J=3.3Hz),6.14(1H,d,J=3.4Hz),4.63-4.70(1H,m),3.12(1H,s),1.75-1.98(6H,m),1.54-1.69(2H,m)。
3-{4-[4-(环戊氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.22(1H,s),8.17(1H,s),7.87(1H,d,J=3.3Hz),6.68(1H,d,J=3.3Hz),5.88(1H,dd,J=5.2,12.5Hz),4.76-4.84(1H,m),2.65-2.92(3H,m),2.27-2.37(1H,m),1.91-2.02(2H,m),1.80-1.91(2H,m),1.67-1.80(2H,m),1.53-1.67(2H,m)。
实施例28(化合物28)
3-{4-[4-(环丙基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
通过类似于实施例27的方法,由4-溴-3-羟基噻吩-2-羧酸甲酯和(溴甲基)环丙烷得到3-{4-[4-(环丙基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(产率14%),为灰色固体。
4-溴-3-(环丙基甲氧基)噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.38(1H,s),4.02(2H,d,J=7.2Hz),3.87(3H,s),1.29-1.41(1H,m),0.58-0.65(2H,m),0.31-0.38(2H,m)。
4-溴-3-(环丙基甲氧基)噻吩-2-羧酸
1H-NMR(CDCl3)δ7.51(1H,s),4.16(2H,d,J=7.4Hz),1.27-1.39(1H,m),0.64-0.71(2H,m),0.33-0.40(2H,m)。
3-溴-4-(环丙基甲氧基)噻吩
1H-NMR(CDCl3)δ7.18(1H,d,J=3.5Hz),6.21(1H,d,J=3.5Hz),3.83(2H,d,J=6.8Hz),1.25-1.38(1H,m),0.61-0.69(2H,m),0.34-0.41(2H,m)。
{[4-(环丙基甲氧基)噻吩-3-基]乙炔基}三甲基硅烷
1H-NMR(CDCl3)δ7.35(1H,d,J=3.3Hz),6.15(1H,d,J=3.4Hz),3.84(2H,d,J=6.7Hz),1.23-1.37(1H,m),0.56-0.73(2H,m),0.35-0.42(2H,m),0.25(9H,s)。
3-(环丙基甲氧基)-4-乙炔基噻吩
1H-NMR(CDCl3)δ7.41(1H,d,J=3.4Hz),6.17(1H,d,J=3.4Hz),3.83(2H,d,J=6.9Hz),3.18(1H,s),1.20-1.47(1H,m),0.56-0.74(2H,m),0.34-0.41(2H,m)。
3-{4-[4-(环丙基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,s),8.24(1H,s),7.87(1H,d,J=3.3Hz),6.72(1H,d,J=3.4Hz),5.89(1H,dd,J=5.3,12.6Hz),3.87-3.97(2H,m),2.65-2.94(3H,m),2.30-2.40(1H,m),1.28-1.40(1H,m),0.59(2H,ddd,J=4.2,6.0,8.0Hz),0.34-0.41(2H,m)。
实施例29(化合物29)
3-{4-[4-(环戊基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
通过类似于实施例27的方法,由4-溴-3-羟基噻吩-2-羧酸甲酯和(碘甲基)环戊烷得到3-{4-[4-(环戊基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(产率17%),为白色固体。
4-溴-3-(环戊基甲氧基)噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.38(1H,s),4.05(2H,d,J=6.9Hz),3.87(3H,s),2.43(1H,sep,J=7.4Hz),1.80-1.91(2H,m),1.53-1.71(4H,m),1.41-1.51(2H,m)。
4-溴-3-(环戊基甲氧基)噻吩-2-羧酸
1H-NMR(CDCl3)δ7.49(1H,s),4.14(2H,d,J=7.0Hz),2.44(1H,sep,J=7.5Hz),1.79-1.94(2H,m),1.53-1.73(4H,m),1.36-1.51(2H,m)。
3-溴-4-(环戊基甲氧基)噻吩
1H-NMR(CDCl3)δ7.17(1H,d,J=3.5Hz),6.20(1H,d,J=3.5Hz),3.86(2H,d,J=6.8Hz),2.41(1H,sep,J=7.5Hz),1.78-1.90(2H,m),1.53-1.72(4H,m),1.33-1.44(2H,m)。
{[4-(环戊基甲氧基)噻吩-3-基]乙炔基}三甲基硅烷
1H-NMR(CDCl3)δ7.34(1H,d,J=3.3Hz),6.14(1H,d,J=3.3Hz),3.85(2H,d,J=6.6Hz),2.40(1H,sep,J=7.3Hz),1.77-1.88(2H,m),1.52-1.73(4H,m),1.37-1.48(2H,m),0.24(9H,s)。
3-(环戊基甲氧基)-4-乙炔基噻吩
1H-NMR(CDCl3)δ7.39(1H,d,J=3.4Hz),6.17(1H,d,J=3.4Hz),3.85(2H,d,J=6.9Hz),3.14(1H,s),2.42(1H,sep,J=7.4Hz),1.79-1.89(2H,m),1.52-1.71(4H,m),1.32-1.43(2H,m)。
3-{4-[4-(环戊基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,s),8.16(1H,s),7.88(1H,d,J=3.4Hz),6.73(1H,d,J=3.4Hz),5.89(1H,dd,J=5.2,12.6Hz),3.89-3.99(2H,m),2.65-2.93(3H,m),2.29-2.48(2H,m),1.78-1.90(2H,m),1.49-1.69(4H,m),1.27-1.40(2H,m)。
实施例30(化合物30)
3-{4-[4-(环己基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
通过类似于实施例27的方法,由4-溴-3-羟基噻吩-2-羧酸甲酯和(溴甲基)环己烷得到3-{4-[4-(环己基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(产率15%),为红棕色固体。
4-溴-3-(环己基甲氧基)噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.37(1H,s),3.96(2H,d,J=6.2Hz),3.87(3H,s),1.65-1.98(6H,m),1.06-1.38(5H,m)。
4-溴-3-(环己基甲氧基)噻吩-2-羧酸
1H-NMR(CDCl3)δ7.49(1H,s),4.05(2H,d,J=6.0Hz),1.66-1.97(6H,m),1.06-1.39(5H,m)。
3-溴-4-(环己基甲氧基)噻吩
1H-NMR(CDCl3)δ7.17(1H,d,J=3.5Hz),6.19(1H,d,J=3.4Hz),3.77(2H,d,J=6.1Hz),1.65-1.93(6H,m),1.14-1.38(3H,m),0.99-1.14(2H,m)。
{[4-(环己基甲氧基)噻吩-3-基]乙炔基}三甲基硅烷
1H-NMR(CDCl3)δ7.33(1H,d,J=3.3Hz),6.13(1H,d,J=3.3Hz),3.76(2H,d,J=6.0Hz),1.65-1.92(6H,m),1.03-1.37(5H,m),0.24(9H,s)。
3-(环己基甲氧基)-4-乙炔基噻吩
1H-NMR(CDCl3)δ7.39(1H,d,J=3.4Hz),6.15(1H,d,J=3.3Hz),3.77(2H,d,J=6.1Hz),3.14(1H,s),1.80-1.93(3H,m),1.65-1.80(3H,m),1.13-1.36(3H,m),0.99-1.13(2H,m)。
3-{4-[4-(环己基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,s),8.17(1H,s),7.87(1H,d,J=3.4Hz),6.72(1H,d,J=3.4Hz),5.88(1H,dd,J=5.1,12.4Hz),3.83-3.93(2H,m),2.65-2.93(3H,m),2.31-2.40(1H,m),1.61-1.92(6H,m),1.01-1.35(5H,m)。
实施例31(化合物31)
3-{4-[4-(4-甲氧基苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
通过类似于实施例27的方法,由4-溴-3-羟基噻吩-2-羧酸甲酯和4-甲氧基氯苄得到3-{4-[4-(4-甲氧基苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(产率4%),为白色固体。
4-溴-3-(4-甲氧基苄氧基)噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.42-7.50(2H,m),7.39(1H,s),6.87-6.94(2H,m),5.14(2H,s),3.88(3H,s),3.82(3H,s)。
4-溴-3-(4-甲氧基苄氧基)噻吩-2-羧酸
1H-NMR(DMSO-d6)δ13.10-13.64(1H,br),7.97(1H,s),7.36-7.43(2H,m),6.91-6.98(2H,m),5.10(2H,s),3.76(3H,s)。
3-溴-4-(4-甲氧基苄氧基)噻吩
1H-NMR(CDCl3)δ7.32-7.42(2H,m).7.18(1H,d,J=3.5Hz),6.88-6.97(2H,m),6.28(1H,d,J=3.5Hz),5.02(2H,s),3.82(3H,s)。
{[4-(4-甲氧基苄氧基)噻吩-3-基]乙炔基}三甲基硅烷
1H-NMR(CDCl3)δ7.35-7.41(3H,m),6.87-6.95(2H,m),6.22(1H,d,J=3.3Hz),5.02(2H,s),3.82(3H,s),0.24(9H,s)。
3-乙炔基-4-(4-甲氧基苄氧基)噻吩
1H-NMR(CDCl3)δ7.41(1H,d,J=3.4Hz),7.34-7.40(2H,m),6.88-6.94(2H,m),6.22(1H,d,J=3.3Hz),5.03(2H,s),3.81(3H,s),3.16(1H,s)。
3-{4-[4-(4-甲氧基苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.22(1H,s),8.21(1H,s),7.87(1H,d,J=3.4Hz),7.40-7.47(2H,m),6.92-6.99(2H,m),6.82(1H,d,J=3.4Hz),5.84(1H,dd,J=5.0,12.4Hz),5.12(2H,s),3.75(3H,s),2.63-2.92(3H,m),2.28-2.38(1H,m)。
实施例32(化合物32)
3-{4-[4-(苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
通过类似于实施例27(27-3、27-4)的方法,由3-(苄氧基)-4-溴噻吩-2-羧酸得到3-{4-[4-(苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(产率29%),为灰色固体。
3-(苄氧基)-4-溴噻吩
1H-NMR(CDCl3)δ7.42-7.48(2H,m),7.36-7.42(2H,m),7.30-7.36(1H,m),7.19(1H,d,J=3.5Hz),6.27(1H,d,J=3.5Hz),5.09(2H,s)。
{[4-(苄氧基)噻吩-3-基]乙炔基}三甲基硅烷
1H-NMR(CDCl3)δ7.28-7.49(6H,m),6.22(1H,d,J=3.3Hz),5.09(2H,s),0.25(9H,s)。
3-(苄氧基)-4-乙炔基噻吩
1H-NMR(CDCl3)δ7.29-7.47(6H,m),6.22(1H,d,J=3.3Hz),5.11(2H,s),3.18(1H,s)。
3-{4-[4-(苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,s),8.28(1H,s),7.89(1H,d,J=3.4Hz),7.47-7.53(2H,m),7.37-7.44(2H,m),7.30-7.37(1H,m),6.82(1H,d,J=3.4Hz),5.86(1H,dd,J=5.1,12.4Hz),5.22(2H,s),2.64-2.93(3H,m),2.29-2.39(1H,m)。
实施例33(化合物33)
3-{4-[4-(吡啶-4-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
(33-1)向4-溴-3-羟基噻吩-2-羧酸甲酯(0.75g,3.16mmol)的N,N-二甲基甲酰胺(11mL)溶液中加入4-(溴甲基)吡啶氢溴酸盐(2.00g,7.91mmol)、三乙胺(1.10mL,7.89mmol)和碳酸铯(2.58g,7.92mmol),将混合物在氩气气氛下于50℃搅拌20小时。过滤反应混合物,将水加入滤液中,将混合物用乙酸乙酯萃取。有机层用水和饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(二氯甲烷/甲醇)纯化,得到4-溴-3-(吡啶-4-基甲氧基)噻吩-2-羧酸甲酯(0.27g,26%),为棕色固体。
1H-NMR(CDCl3)δ8.55-8.75(2H,m),7.46-7.50(2H,m),7.44(1H,s),5.24(2H,s),3.87(3H,s)。
(33-2)向4-溴-3-(吡啶-4-基甲氧基)噻吩-2-羧酸甲酯(0.95g,2.89mmol)的甲醇(4.9mL)溶液加入氢氧化钾(85%)(0.23g,3.48mmol)和水(2.0mL),将混合物回流15小时。浓缩反应混合物,将水(6mL)和1.0M盐酸(3.52mL)加入到浓缩的残余物中,将混合物在室温搅拌10分钟。通过过滤收集沉淀物,用水洗涤以得到4-溴-3-(吡啶-4-基甲氧基)噻吩-2-羧酸(0.89g,98%),为浅棕色固体。所得4-溴-3-(吡啶-4-基甲氧基)噻吩-2-羧酸不进行纯化即用于下一步反应。
1H-NMR(DMSO-d6)δ12.75-14.10(1H,br),8.52-8.69(2H,br),8.03(1H,s),7.51(2H,d,J=5.1Hz),5.24(2H,s)。
(33-3)向4-溴-3-(吡啶-4-基甲氧基)噻吩-2-羧酸(0.89g,2.83mmol)的喹啉(11mL)溶液中加入铜粉(0.21g,3.30),将该混合物在氩气气氛下在150℃下搅拌15分钟。通过硅藻土过滤反应混合物,浓缩滤液。通过柱色谱法(己烷/乙酸乙酯)纯化浓缩的残余物,得到4-[(4-溴噻吩-3-基氧基)甲基]吡啶(0.69g,90%),为棕色固体。
1H-NMR(CDCl3)δ8.50-8.75(2H,br),7.39(2H,brd,J=5.0Hz),7.24(1H,d,J=3.4Hz),6.27(1H,d,J=3.5Hz),5.11(2H,s)。
(33-4)通过类似于实施例11的方法,由4-[(4-溴噻吩-3-基氧基)甲基]吡啶得到3-{4-[4-(吡啶-4-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(产率10%),为灰色固体。
4-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)吡啶
1H-NMR(CDCl3)δ8.50-8.75(2H,br),7.37-7.43(2H,br),7.40(1H,d,J=3.3Hz),6.22(1H,d,J=3.3Hz),5.10(2H,s),0.27(9H,s)。
4-[(4-乙炔基噻吩-3-基氧基)甲基]吡啶
1H-NMR(CDCl3)δ8.58-8.68(2H,m),7.45(1H,d,J=3.4Hz),7.35-7.40(2H,m),6.21(1H,d,J=3.3Hz),5.12(2H,s),3.21(1H,s)。
3-{4-[4-(吡啶-4-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.24(1H,s),8.20-9.55(2H,br),8.36(1H,s),7.90(1H,d,J=3.4Hz),7.23-7.86(2H,br),6.81(1H,d,J=3.4Hz),5.88(1H,dd,J=5.3,12.6Hz),5.25(2H,brs),2.65-2.94(3H,m),2.29-2.40(1H,m)。
实施例34(化合物34)
3-{4-[4-(吡啶-2-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
通过类似于实施例33的方法,由4-溴-3-羟基噻吩-2-羧酸甲酯和2-(溴甲基)吡啶氢溴酸盐得到3-{4-[4-(吡啶-2-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(产率23%),为灰色固体。
4-溴-3-(吡啶-2-基甲氧基)噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ8.55-8.63(1H,m),7.74-7.87(2H,m),7.43(1H,s),7.22-7.28(1H,m),5.33(2H,s),3.85(3H,s)。
4-溴-3-(吡啶-2-基甲氧基)噻吩-2-羧酸
1H-NMR(DMSO-d6)δ12.96-13.89(1H,br),8.51-8.57(1H,m),8.01(1H,s),7.88(1H,dt,J=1.8,7.7Hz),7.69-7.74(1H,m),7.34-7.40(1H,m),5.27(2H,s)。
2-[(4-溴噻吩-3-基氧基)甲基]吡啶
1H-NMR(CDCl3)δ8.55-8.62(1H,m),7.75(1H,dt,J=1.7,7.7Hz),7.58-7.64(1H,m),7.20-7.27(2H,m),6.32(1H,d,J=3.5Hz),5.23(2H,s)。
2-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)吡啶
1H-NMR(CDCl3)δ8.54-8.62(1H,m),7.73(1H,dt,J=1.7,7.7Hz),7.63-7.68(1H,m),7.39(1H,d,J=3.3Hz),7.20-7.25(1H,m),6.26(1H,d,J=3.3Hz),5.21(2H,s),0.27(9H,s)。
2-[(4-乙炔基噻吩-3-基氧基)甲基]吡啶
1H-NMR(CDCl3)δ8.54-8.64(1H,m),7.73(1H,dt,J=1.7,7.7Hz),7.56-7.64(1H,m),7.43(1H,d,J=3.4Hz),7.20-7.25(1H,m),6.26(1H,d,J=3.4Hz),5.24(2H,s),3.22(1H,s)。
3-{4-[4-(吡啶-2-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.24(1H,brs),8.60(1H,d,J=4.4Hz),8.41(1H,s),7.90(1H,d,J=3.4Hz),7.84(1H,dt,J=1.7,7.7Hz),7.54(1H,d,J=7.8Hz),7.36(1H,dd,J=5.0,6.8Hz),6.82(1H,d,J=3.4Hz),5.88(1H,dd,J=5.2,12.5Hz),5.29(2H,s),2.81-2.94(1H,m),2.64-2.81(2H,m),2.30-2.40(1H,m)。
实施例35(化合物35)
3-{4-[4-(吡啶-3-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
通过类似于实施例33的方法,由4-溴-3-羟基噻吩-2-羧酸甲酯和3-(溴甲基)吡啶氢溴酸盐得到3-{4-[4-(吡啶-3-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(产率5%),为灰色固体。
4-溴-3-(吡啶-3-基甲氧基)噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ8.70-8.78(1H,br),8.57-8.64(1H,m),7.91-7.97(1H,m),7.42(1H,s),7.31-7.38(1H,m),5.24(2H,s),3.89(3H,s)。
4-溴-3-(吡啶-3-基甲氧基)噻吩-2-羧酸
1H-NMR(DMSO-d6)δ13.15-13.76(1H,br),8.67(1H,brs),8.53-8.61(1H,m),8.00(1H,s),7.87-7.93(1H,m),7.44(1H,ddd,J=0.4,4.8,7.8Hz),5.23(2H,s)。
3-[(4-溴噻吩-3-基氧基)甲基]吡啶
1H-NMR(CDCl3)δ8.66-8.75(1H,m),8.56-8.64(1H,m),7.79-7.87(1H,m),7.35(1H,ddd,J=0.4,4.9,7.8Hz),7.22(1H,d,J=3.4Hz),6.33(1H,d,J=3.5Hz),5.11(2H,s)。
3-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)吡啶
1H-NMR(CDCl3)δ8.66-8.74(1H,br),8.54-8.63(1H,m),7.80-7.87(1H,m),7.39(1H,d,J=3.3Hz),7.33(1H,dd,J=4.9,7.7Hz),6.28(1H,d,J=3.3Hz),5.11(2H,s),0.24(9H,s)。
3-[(4-乙炔基噻吩-3-基氧基)甲基]吡啶
1H-NMR(CDCl3)δ8.67-8.73(1H,m),8.59(1H,dd,J=1.6,4.8Hz),7.78-7.83(1H,m),7.44(1H,d,J=3.3Hz),7.33(1H,ddd,J=0.6,4.8,7.8Hz),6.28(1H,d,J=3.3Hz),5.12(2H,s),3.17(1H,s)。
3-{4-[4-(吡啶-3-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,s,),8.73(1H,d,J=1.7Hz),8.55(1H,dd,J=1.6,4.8Hz),8.27(1H,s),7.90-7.94(1H,m),7.89(1H,d,J=3.4Hz),7.43(1H,ddd,J=0.7,4.8,7.8Hz),6.89(1H,d,J=3.4Hz),5.85(1H,dd,J=5.2,12.5Hz),5.26(2H,s),2.79-2.92(1H,m),2.63-2.79(2H,m),2.26-2.39(1H,m)。
实施例36(化合物36)
3-(4-{4-[4-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基哌啶-2,6-二酮
(36-1)向4-溴-3-羟基噻吩-2-羧酸甲酯(1.00g,4.22mmol)的乙腈(50mL)溶液加入α,α'-二溴-对二甲苯(3.34g,12.65mmol)和碳酸钾(0.58g,4.20mmol),将混合物在氩气气氛下在50℃下搅拌15小时。将反应混合物浓缩,将饱和盐水加入到浓缩的残余物中,将混合物用乙醚萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到4-溴-3-[4-(溴甲基)苄氧基]噻吩-2-羧酸甲酯(1.30g,73%),为浅棕色固体。
1H-NMR(CDCl3)δ7.50-7.56(2H,m),7.39-7.45(3H,m),5.20(2H,s),4.51(2H,s),3.87(3H,s)。
(36-2)向4-溴-3-[4-(溴甲基)苄氧基]噻吩-2-羧酸甲酯(1.95g,4.64mmol)的二氯甲烷(46mL)溶液中加入吗啉(0.89mL,10.17mmol),在室温下在氩气气氛下搅拌混合物20小时。将反应混合物过滤,浓缩滤液。将浓缩的残余物溶于乙酸乙酯,用水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到4-溴-3-[4-(吗啉代甲基)苄氧基]噻吩-2-羧酸甲酯混合物(2.15g),为浅黄色油。所得4-溴-3-[4-(吗啉代甲基)苄氧基]噻吩-2-甲酸甲酯混合物不进行进一步纯化即用于下一步反应。
1H-NMR(CDCl3)δ7.50(2H,d,J=8.0Hz),7.40(1H,s),7.35(2H,d,J=8.0Hz),5.18(2H,s),3.88(3H,s),3.66-3.78(4H,m),3.51(2H,s),2.41-2.48(4H,m)。
(36-3)通过类似于实施例33(33-2、33-3)的方法,由4-溴-3-[4-(吗啉代甲基)苄氧基]噻吩-2-羧酸甲酯混合物得到4-{4-[(4-溴噻吩-3-基氧基)甲基]苄基}吗啉(产率89%),为红棕色油。
4-溴-3-[4-(吗啉代甲基)苄氧基]噻吩-2-羧酸
1H-NMR(DMSO-d6)δ7.97(1H,s),7.44(2H,d,J=8.0Hz),7.33(2H,d,J=8.0Hz),5.15(2H,s),3.54-3.62(4H,m),3.50(2H,s),2.34-2.42(4H,m)。
4-{4-[(4-溴噻吩-3-基氧基)甲基]苄基}吗啉
1H-NMR(CDCl3)δ7.40(2H,d,J=8.2Hz),7.35(2H,d,J=8.2Hz),7.20(1H,d,J=3.5Hz),6.28(1H,d,J=3.5Hz),5.07(2H,s),3.68-3.73(4H,m),3.50(2H,s),2.42-2.48(4H,m)。
(36-4)向4-{4-[(4-溴噻吩-3-基氧基)甲基]苄基}吗啉(1.56g,4.24mmol)的乙腈(8.5mL)溶液中加入三乙胺(0.89mL,6.39mmol)、四(三苯基膦)钯(0)(0.24g,0.21mmol)、碘化铜(I)(0.12g,0.63mmol)和三甲基硅基乙炔(0.64mL,4.63mmol),将混合物在氩气气氛下密封在管中,在60℃搅拌4天。向反应混合物中加入水,将混合物用二氯甲烷萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到4-[4-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)苄基]吗啉(0.63g,38%),为棕色油。
1H-NMR(CDCl3)δ7.41(2H,d,J=8.1Hz),7.37(1H,d,J=3.3Hz),7.33(2H,d,J=8.1Hz),6.23(1H,d,J=3.3Hz),5.07(2H,s),3.68-3.74(4H,m),3.51(2H,s),2.41-2.48(4H,m),0.24(9H,s)。
(36-5)通过类似于实施例8(8-2、8-3)的方法,由4-[4-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)苄基]吗啉得到3-(4-{4-[4-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮(50%产率),为棕色固体。
4-{4-[(4-乙炔基噻吩-3-基氧基)甲基]苄基}吗啉
1H-NMR(CDCl3)δ7.42(1H,d,J=3.4Hz),7.40(2H,d,J=8.3Hz),7.34(2H,d,J=8.2Hz),6.22(1H,d,J=3.3Hz),5.09(2H,s),3.71(4H,brt,J=4.7Hz),3.50(2H,s),3.17(1H,s),2.45(4H,brt,J=4.5Hz)。
3-(4-{4-[4-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,s),8.27(1H,s),7.88(1H,d,J=3.4Hz),7.45(2H,d,J=8.0Hz),7.33(2H,d,J=8.1Hz),6.82(1H,d,J=3.4Hz),5.86(1H,dd,J=5.0,12.3Hz),5.20(2H,s),3.56(4H,brt,J=4.6Hz),3.45(2H,s),2.65-2.92(3H,m),2.29-2.39(5H,m)。
(36-6)向3-(4-{4-[4-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮(0.10g,0.21mmol)在丙酮(5mL)的悬浮液中加入甲磺酸(13.9μL,0.21mmol),将混合物在室温搅拌15.5小时。过滤收集沉淀物,用丙酮洗涤,得到3-(4-{4-[4-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮甲磺酸盐(0.10g,86%),为浅棕色固体。
1H-NMR(DMSO-d6)δ11.25(1H,s),9.70-9.86(1H,br),8.34(1H,s),7.89(1H,d,J=3.4Hz),7.61(2H,d,J=7.8Hz),7.52(2H,d,J=7.8Hz),6.82(1H,d,J=3.4Hz),5.87(1H,dd,J=5.2,12.6Hz),5.27(2H,brs),4.36(2H,brd,J=4.8Hz),3.96(2H,brd,J=11.9Hz),3.61(2H,brt,J=12.0Hz),3.26(2H,brd,J=11.6Hz),3.05-3.18(2H,m),2.81-2.94(1H,m),2.65-2.81(2H,m),2.28-2.39(4H,m)。
实施例37(化合物37)
3-(4-{4-[4-(甲氧基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮
(37-1)向4-溴-3-[4-(溴甲基)苄氧基]噻吩-2-羧酸甲酯(通过实施例36(36-1)的方法合成)(2.71g,6.45mmol)的甲醇(11mL)溶液中加入氢氧化钾(85%)(0.52g,7.88mmol)和水(4.5mL),将混合物回流。2小时后,加入氢氧化钾(85%)(0.74g,11.21mmol),将混合物再回流1小时。浓缩反应混合物,将水(20mL)和2.0M盐酸(10.0mL)加入到浓缩的残余物中,将混合物用乙酸乙酯萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩,得到4-溴-3-[4-(甲氧基甲基)苄氧基]噻吩-2-羧酸混合物(2.26g),为黄棕色固体。所得4-溴-3-[4-(甲氧基甲基)苄氧基]噻吩-2-羧酸混合物不进行纯化即用于下一步反应。
1H-NMR(CDCl3)δ7.52(1H,s),7.49(2H,d,J=7.9Hz),7.37(2H,d,J=8.1Hz),5.27(2H,s),4.48(2H,s),3.39(3H,s)。
(37-2)向4-溴-3-[4-(甲氧基甲基)苄氧基]噻吩-2-羧酸混合物(2.26g)的二甲基亚砜(13mL)溶液中加入碳酸银(0.17g,0.62mmol)和乙酸(0.38mL,6.64mmol),将混合物在氩气气氛下于120℃搅拌30分钟。向反应混合物中加入乙酸乙酯,将混合物过滤。将水加入滤液中,将混合物用乙酸乙酯萃取。有机层用水和饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到3-溴-4-[4-(甲氧基甲基)苄氧基]噻吩(1.39g,2步69%),为浅棕色固体。
1H-NMR(CDCl3)δ7.43(2H,d,J=8.2Hz),7.36(2H,d,J=8.2Hz),7.19(1H,d,J=3.5Hz),6.26(1H,d,J=3.5Hz),5.08(2H,s),4.47(2H,s),3.40(3H,s)。
(37-3)通过类似于实施例11的方法,由3-溴-4-[4-(甲氧基甲基)苄氧基]噻吩得到3-(4-{4-[4-(甲氧基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮(产率47%),为白色固体。
({4-[4-(甲氧基甲基)苄氧基]噻吩-3-基}乙炔基)三甲基硅烷
1H-NMR(CDCl3)δ7.45(2H,d,J=8.2Hz),7.37(1H,d,J=3.3Hz),7.34(2H,d,J=8.2Hz),6.21(1H,d,J=3.3Hz),5.09(2H,s),4.47(2H,s),3.39(3H,s),0.25(9H,s)。
3-乙炔基-4-[4-(甲氧基甲基)苄氧基]噻吩
1H-NMR(CDCl3)δ7.43(2H,d,J=8.3Hz),7.41(1H,d,J=3.4Hz),7.35(2H,d,J=8.2Hz),6.21(1H,d,J=3.3Hz),5.10(2H,s),4.46(2H,s),3.39(3H,s),3.17(1H,s)。
3-(4-{4-[4-(甲氧基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,brs),8.27(1H,s),7.88(1H,d,J=3.4Hz),7.48(2H,d,J=8.1Hz),7.34(2H,d,J=8.1Hz),6.81(1H,d,J=3.4Hz),5.86(1H,dd,J=5.1,12.5Hz),5.21(2H,s),4.41(2H,s),3.29(3H,s),2.63-2.93(3H,m),2.29-2.39(1H,m)。
实施例38(化合物38)
3-{4-[4-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
(38-1)通过类似于实施例36(36-1、36-2)和实施例33(33-2)的方法,由4-溴-3-羟基噻吩-2-羧酸甲酯、α,α′-二溴-对二甲苯和顺式2,6-二甲基吗啉得到4-溴-3-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-2-羧酸(产率71%),为浅黄色固体。
4-溴-3-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.51(2H,d,J=8.0Hz),7.41(1H,s),7.34(2H,d,J=8.0Hz),5.18(2H,s),3.88(3H,s),3.64-3.73(2H,m),3.48(2H,s),2.66-2.74(2H,m),1.74(2H,brt,J=10.8Hz),1.14(6H,d,J=6.3Hz)。
4-溴-3-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-2-羧酸
1H-NMR(CDCl3)δ7.46(2H,d,J=8.1Hz),7.41(2H,d,J=8.1Hz),7.29(1H,s),5.31(2H,s),3.95-4.03(2H,m),3.93(2H,s),3.18(2H,d,J=11.1Hz),2.13(2H,brt,J=11.3Hz),1.16(6H,d,J=6.3Hz)。
(38-2)向4-溴-3-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-2-羧酸(1.44g,3.27mmol)的二甲基亚砜(7.5mL)溶液中加入碳酸银(186mg,0.67mmol)和乙酸(0.22mL,3.84mmol),将混合物在120℃搅拌1.5小时。向反应混合物中加入1.0M盐酸,用饱和碳酸氢钠水溶液中和该混合物。用乙酸乙酯萃取并用饱和盐水洗涤该混合物。有机层经无水硫酸镁干燥、浓缩,得到(2S,6R)-4-{4-[(4-溴噻吩-3-基氧基)甲基]苄基}-2,6-二甲基吗啉(1.29g,99%),为棕色油。所得(2S,6R)-4-{4-[(4-溴噻吩-3-基氧基)甲基]苄基}-2,6-二甲基吗啉不进行纯化即用于下一步反应。
1H-NMR(CDCl3)δ7.40(2H,d,J=8.1Hz),7.34(2H,d,J=8.1Hz),7.19(1H,d,J=3.5Hz),6.28(1H,d,J=3.5Hz),5.07(2H,s),3.64-3.74(2H,m),3.47(2H,s),2.66-2.74(2H,m),1.75(2H,dd,J=10.3,11.2Hz),1.13(6H,d,J=6.3Hz)。
(38-3)通过类似于实施例36(36-4、36-5)的方法,由(2S,6R)-4-{4-[(4-溴噻吩-3-基氧基)甲基]苄基}-2,6-二甲基吗啉得到3-{4-[4-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(产率53%),为白色固体。
(2S,6R)-2,6-二甲基-4-[4-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)苄基]吗啉
1H-NMR(CDCl3)δ7.41(2H,d,J=8.1Hz),7.37(1H,d,J=3.3Hz),7.33(2H,d,J=8.1Hz),6.23(1H,d,J=3.3Hz),5.07(2H,s),3.64-3.74(2H,m),3.49(2H,s),2.70(2H,brd,J=10.6Hz),1.75(2H,t,J=10.7Hz),1.13(6H,d,J=6.3Hz),0.24(9H,s)。
(2S,6R)-4-{4-[(4-乙炔基噻吩-3-基氧基)甲基]苄基}-2,6-二甲基吗啉
1H-NMR(CDCl3)δ7.30-7.42(5H,m),6.23(1H,d,J=3.3Hz),5.08(2H,s),3.64-3.73(2H,m),3.47(2H,s),3.17(1H,s),2.66-2.73(2H,m),1.74(2H,dd,J=10.5,11.1Hz),1.13(6H,d,J=6.3Hz)。
3-{4-[4-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(CDCl3)δ8.84-9.26(1H,br),7.94(1H,s),7.91(1H,d,J=3.4Hz),7.40(2H,d,J=8.1Hz),7.34(2H,d,J=8.1Hz),6.41(1H,d,J=3.4Hz),5.31(1H,dd,J=5.2,10.2Hz),5.09and5.13(2H,ABq,J=11.1Hz),3.62-3.74(2H,m),3.46and 3.57(2H,ABq,J=13.0Hz),2.89-3.01(1H,m),2.54-2.84(5H,m),1.85(1H,t,J=10.8Hz),1.77(1H,t,J=10.8Hz),1.15(3H,d,J=6.4Hz),1.14(3H,d,J=6.4Hz)。
实施例39(化合物39)
3-(4-{4-[3-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮
通过类似于实施例38的方法,由4-溴-3-羟基噻吩-2-羧酸甲酯、α,α′-二溴-间二甲苯和吗啉得到3-(4-{4-[3-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮(产率10%),为蓝白色固体。
4-溴-3-[3-(溴甲基)苄氧基]噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.56-7.59(1H,brs),7.45-7.50(1H,m),7.41(1H,s),7.36-7.40(2H,m),5.20(2H,s),4.52(2H,s),3.88(3H,s)。
4-溴-3-[3-(吗啉代甲基)苄氧基]噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.42-7.48(2H,m),7.39(1H,s),7.29-7.37(2H,m),5.21(2H,s),3.88(3H,s),3.71(4H,brt,J=4.7Hz),3.52(2H,s),2.44(4H,brt,J=4.5Hz)。
4-溴-3-[3-(吗啉代甲基)苄氧基]噻吩-2-羧酸
1H-NMR(CDCl3)δ11.07-11.47(1H,brs),7.54-7.62(1H,brs),7.50(1H,brd,J=6.8Hz),7.22-7.35(3H,m),5.22(2H,s),3.92(2H,s),3.82(4H,brt,J=4.6Hz),2.71-2.95(4H,br)。
4-{3-[(4-溴噻吩-3-基氧基)甲基]苄基}吗啉
1H-NMR(CDCl3)δ7.39-7.42(1H,brs),7.26-7.37(3H,m),7.19(1H,d,J=3.5Hz),6.27(1H,d,J=3.5Hz),5.08(2H,s),3.70(4H,brt,J=4.7Hz),3.51(2H,s),2.44(4H,brt,J=4.5Hz)。
4-[3-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)苄基]吗啉
1H-NMR(CDCl3)δ7.39-7.42(1H,br),7.27-7.39(4H,m),6.22(1H,d,J=3.3Hz),5.08(2H,s),3.70(4H,brt,J=4.6Hz),3.51(2H,s),2.43(4H,brt,J=4.5Hz),0.25(9H,s)。
4-{3-[(4-乙炔基噻吩-3-基氧基)甲基]苄基}吗啉
1H-NMR(CDCl3)δ7.39-7.43(2H,m),7.27-7.37(3H,m),6.21(1H,d,J=3.3Hz),5.10(2H,s),3.70(4H,brt,J=4.6Hz),3.51(2H,s),3.17(1H,s),2.43(4H,brt,J=4.5Hz)。
3-(4-{4-[3-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.16-11.30(1H,br),8.27(1H,s),7.88(1H,d,J=3.4Hz),7.31-7.43(3H,m),7.26(1H,brd,J=7.2Hz),6.80(1H,d,J=3.4Hz),5.85(1H,dd,J=5.1,12.4Hz),5.22(2H,s),3.53(4H,brt,J=4.5Hz),3.46(2H,s),2.63-2.94(3H,m),2.21-2.41(5H,m)。
实施例40(化合物40)
3-(4-{4-[2-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮
(40-1)通过类似于实施例38(38-1、38-2)的方法,由4-溴-3-羟基噻吩-2-羧酸甲酯、α,α′-二溴-邻二甲苯和吗啉得到4-{2-[(4-溴噻吩-3-基氧基)甲基]苄基}吗啉(产率64%),为棕色油。
4-溴-3-[2-(溴甲基)苄氧基]噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.56-7.62(1H,m),7.41-7.46(2H,m),7.34-7.39(2H,m),5.32(2H,s),4.86(2H,s),3.90(3H,s)。
4-溴-3-[2-(吗啉代甲基)苄氧基]噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.63-7.69(1H,m),7.41(1H,s),7.24-7.35(3H,m),5.42(2H,s),3.86(3H,s),3.66(2H,s),3.64(4H,brt,J=4.6Hz),2.43(4H,brt,J=4.4Hz)。
4-{2-[(4-溴噻吩-3-基氧基)甲基]苄基}吗啉
1H-NMR(CDCl3)δ7.50(1H,brd,J=6.6Hz),7.22-7.34(3H,m),7.18(1H,d,J=3.5Hz),6.35(1H,d,J=3.5Hz),5.29(2H,s),3.64(4H,brt,J=4.6Hz),3.57(2H,s),2.41(4H,brt,J=4.4Hz)。
(40-2)向4-{2-[(4-溴噻吩-3-基氧基)甲基]苄基}吗啉(680.2mg,1.85mmol)的N,N-二甲基甲酰胺(3.5mL)溶液中加入双(三苯基膦)二氯化钯(II)(128.6mg,0.18mmol)、三乙胺(1.52mL,10.91mmol)和三甲基硅基乙炔(1.25mL,9.04mmol),将混合物在氩气气氛下于70℃搅拌6.5小时。将反应混合物用乙酸乙酯稀释,加入饱和氯化铵水溶液,将混合物用乙酸乙酯萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到4-[2-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)苄基]吗啉(602.8mg,84%),为红棕色油。
1H-NMR(CDCl3)δ7.57(1H,brd,J=7.1Hz),7.37(1H,d,J=3.3Hz),7.22-7.34(3H,m),6.26(1H,d,J=3.3Hz),5.29(2H,s),3.61-3.68(4H,m),3.59(2H,s),2.36-2.47(4H,m),0.23(9H,s)。
(40-3)通过类似于实施例8(8-2、8-3)的方法,由4-[2-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基)甲基]苄基}吗啉得到3-(4-{4-[2-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮(产率40%),为蓝白色固体。
4-{2-[(4-乙炔基噻吩-3-基氧基)甲基]苄基}吗啉
1H-NMR(CDCl3)δ7.48-7.53(1H,m),7.42(1H,d,J=3.3Hz),7.23-7.33(3H,m),6.31(1H,d,J=3.3Hz),5.31(2H,s),3.65(4H,brt,J=4.6Hz),3.58(2H,s),3.16(1H,s),2.42(4H,brt,J=4.4Hz)。
3-(4-{4-[2-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.18-11.26(1H,br),8.25(1H,s),7.89(1H,d,J=3.4Hz),7.45-7.52(1H,m),7.25-7.36(3H,m),6.83(1H,d,J=3.4Hz),5.85(1H,dd,J=5.0,12.4Hz),5.38(2H,s),3.55(2H,s),3.51(4H,brt,J=4.3Hz),2.63-2.91(3H,m),2.24-2.41(5H,m)。
实施例41(化合物41)
3-(4-{4-[4-(吡咯烷-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮盐酸盐
通过类似于实施例38(38-1、38-2)和实施例11的方法,由4-溴-3-羟基噻吩-2-羧酸甲酯、α,α'-二溴-对二甲苯和吡咯烷得到3-(4-{4-[4-(吡咯烷-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮(产率18%),为红棕色油。
在0℃下,向所得3-(4-{4-[4-(吡咯烷-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮(316.9mg,0.70mmol)的乙酸乙酯(2mL)溶液中加入4.0M盐酸/乙酸乙酯溶液(193.0μL),将混合物在0℃下搅拌1小时。过滤收集沉淀物,将残余物从丙酮-甲醇中重结晶,得到3-(4-{4-[4-(4-吡咯烷-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮盐酸盐(159.1mg,47%),为浅棕色固体。
4-溴-3-[4-(吡咯烷-1-基甲基)苄氧基]噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.46-7.58(4H,m),7.41(1H,s),5.20(2H,s),3.88(5H,s),2.69-3.00(4H,br),1.85-2.09(4H,br))。
4-溴-3-[4-(吡咯烷-1-基甲基)苄氧基]噻吩-2-羧酸
MS m/z 398[M+1]+,396[M+1]+
1-{4-[(4-溴噻吩-3-基氧基)甲基]苄基}吡咯烷
1H-NMR(CDCl3)δ7.32-7.45(4H,m),7.19(1H,d,J=3.5Hz),6.27(1H,d,J=3.5Hz),5.07(2H,s),3.62(2H,s),2.47-2.56(4H,m),1.75-1.84(4H,m)。
1-[4-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)苄基]吡咯烷
1H-NMR(CDCl3)δ7.31-7.42(5H,m),6.22(1H,d,J=3.3Hz),5.07(2H,s),3.62(2H,s),2.47-2.54(4H,m),1.74-1.84(4H,m),0.24(9H,s)。
1-{4-[(4-乙炔基噻吩-3-基氧基)甲基]苄基}吡咯烷
1H-NMR(CDCl3)δ7.30-7.44(5H,m),6.22(1H,d,J=3.4Hz),5.09(2H,s),3.61(2H,s),3.17(1H,s),2.45-2.56(4H,m),1.73-1.84(4H,m)。
3-(4-{4-[4-(吡咯烷-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮盐酸盐
1H-NMR(DMSO-d6)δ11.22(1H,s),10.82-10.99(1H,br),8.31(1H,s),7.88(1H,d,J=3.4Hz),7.53-7.66(4H,m),6.83(1H,d,J=3.4Hz),5.89(1H,dd,J=5.0,12.4Hz),5.25(2H,s),4.32(2H,d,J=5.8Hz),3.26-3.39(2H,m),2.96-3.10(2H,m),2.81-2.95(1H,m),2.65-2.81(2H,m),2.29-2.39(1H,m),1.94-2.07(2H,m),1.79-1.94(2H,m)。
实施例42(化合物42)
3-(4-{4-[4-(哌啶-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮盐酸盐(42-1)向4-溴-3-[4-(溴甲基)苄氧基]噻吩-2-羧酸甲酯(通过实施例36(36-1)的方法合成)(1.17g,2.78mmol)在水(7mL)的悬浮液中加入氢氧化钾(85%)(0.53g,8.03mmol)和丙酮(5mL),将混合物回流3小时。将反应混合物浓缩,将水加入浓缩的残余物中,将混合物用二乙醚洗涤。向水层中加入2.0M盐酸(5.0mL),将混合物用乙酸乙酯萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩,得到4-溴-3-[4-(羟甲基)苄氧基]噻吩-2-羧酸(0.94g,99%),为白色固体。
1H-NMR(CD3OD)δ7.66(1H,s),7.46-7.52(2H,m),7.32-7.37(2H,m),5.20(2H,s),4.61(2H,s)。
(42-2)通过类似于实施例37(37-2)的方法,由4-溴-3-[4-(羟甲基)苄氧基]噻吩-2-羧酸(0.94g,2.74mmol)得到{4-[(4-溴噻吩-3-基氧基)甲基]苯基}甲醇(0.67g,82%),为棕色固体。
1H-NMR(CDCl3)δ7.37-7.47(4H,m),7.20(1H,d,J=3.5Hz),6.27(1H,d,J=3.5Hz),5.09(2H,s),4.72(2H,d,J=5.8Hz),1.65(1H,t,J=5.9Hz)。
(42-3)在-20℃下在氩气气氛下,向{4-[(4-溴噻吩-3-基氧基)甲基]苯基}甲醇(0.67g,2.24mmol)和三乙胺(0.62mL,4.45mmol)的二氯甲烷(9mL)溶液中滴加甲磺酰氯(0.26mL,3.36mmol),在-20℃下搅拌该混合物1小时。将反应混合物用二氯甲烷稀释,用水、2.0M盐酸和饱和盐水洗涤。有机层经无水硫酸镁干燥,浓缩,得到4-[(4-溴噻吩-3-基氧基)甲基]苄基甲磺酸盐混合物(0.94g),为浅黄色油。所得4-[(4-溴噻吩-3-基氧基)甲基]苄基甲磺酸盐混合物不进行纯化即用于下一步反应。
1H-NMR(CDCl3)δ7.41-7.53(4H,m),7.21(1H,d,J=3.4Hz),6.28(1H,d,J=3.5H),5.25(2H,s),5.11(2H,s),2.94(3H,s)。
(42-4)在0℃的氩气气氛下,向氢化钠(60%)(0.11g,2.75mmol)在N,N-二甲基甲酰胺(7.5mL)的悬浮液中滴加哌啶(0.27mL,2.73mmol),将混合物在0℃下搅拌20分钟。在0℃下向该悬浮液中滴加4-[(4-溴噻吩-3-基氧基)甲基]苄基甲磺酸盐混合物(0.94g)的N,N-二甲基甲酰胺(4mL)溶液,混合物在0℃至室温下搅拌18小时。向反应混合物中加入饱和氯化铵水溶液,将混合物用乙酸乙酯萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。通过柱色谱法(二氯甲烷/甲醇)纯化浓缩的残余物,得到1-{4-[(4-溴噻吩-3-基氧基)甲基]苄基}哌啶(0.82g,2步99%),为黄色油。
1H-NMR(CDCl3)δ7.30-7.42(4H,m),7.19(1H,d,J=3.4Hz),6.28(1H,d,J=3.5Hz),5.07(2H,s),3.49(2H,s),2.39(4H,brs),1.53-1.63(4H,m),1.38-1.48(2H,m)。
(42-5)通过类似于实施例11的方法,由1-{4-[(4-溴噻吩-3-基氧基)甲基]苄基}哌啶得到3-(4-{4-[4-(4-哌啶-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮(产率10%),为浅棕色无定形物质。
在0℃下,向3-(4-{4-[4-(哌啶-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮(212.9mg,0.46mmol)在乙酸乙酯(2mL)的悬浮液中加入4.0M盐酸/乙酸乙酯溶液(125.7μL),将混合物在0℃下搅拌1小时。过滤收集沉淀物,残余物从乙酸乙酯-甲醇中重结晶,得到3-(4-{4-[4-(4-哌啶丁-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮盐酸盐(133.0mg,57%),为灰色固体。
1-[4-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)苄基]哌啶
1H-NMR(CDCl3)δ7.28-7.45(5H,m),6.23(1H,d,J=3.3Hz),5.07(2H,s),3.48(2H,s),2.28-2.45(4H,br),1.52-1.61(4H,m),1.37-1.47(2H,m),0.24(9H,s)。
1-{4-[(4-乙炔基噻吩-3-基氧基)甲基]苄基}哌啶
1H-NMR(CDCl3)δ7.41(1H,d,J=3.3Hz),7.30-7.40(4H,m),6.23(1H,d,J=3.3Hz),5.08(2H,s),3.47(2H,s),3.17(1H,s),2.27-2.46(4H,br),1.52-1.64(4H,m),1.36-1.48(2H,m)。
3-(4-{4-[4-(哌啶-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮盐酸盐
1H-NMR(DMSO-d6)δ11.22(1H,brs),10.52-10.70(1H,br),8.32(1H,s),7.88(1H,d,J=3.3Hz),7.54-7.66(4H,m),6.84(1H,d,J=3.4Hz),5.89(1H,dd,J=5.0,12.4Hz),5.25(2H,s),4.23(2H,d,J=5.3Hz),3.26(2H,brd,J=11.8Hz),2.65-2.96(5H,m),2.28-2.40(1H,m),1.63-1.87(5H,m),1.24-1.43(1H,m)。
实施例43(化合物43)
3-{4-[4-(4-氯苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
(43-1)向4-溴-3-羟基噻吩-2-羧酸甲酯(1.00g,4.22mmol)的四氢呋喃(85mL)溶液中加入对氯苄醇(0.90g,6.31mmol)和三苯基膦(2.21g,8.43mmol),向该混合物中滴加偶氮二羧酸二异丙酯(1.66mL,8.43mmol)。在氩气气氛下,将混合物在0℃至室温搅拌17小时。将反应混合物浓缩,浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到4-溴-3-(4-氯苄氧基)噻吩-2-羧酸甲酯(1.48g,97%),为白色固体。
1H-NMR(CDCl3)δ7.45-7.52(2H,m),7.41(1H,s),7.33-7.39(2H,m),5.17(2H,s),3.88(3H,s)。
(43-2)通过类似于实施例33(33-2)及实施例38(38-2)的方法,由4-溴-3-(4-氯苄氧基)噻吩-2-羧酸甲酯得到3-溴-4-(4-氯苄氧基)噻吩(产率97%),为白色固体。
4-溴-3-(4-氯苄氧基)噻吩-2-羧酸
1H NMR(CD3OD)δ7.68(1H,s),7.48-7.54(2H,m),7.33-7.40(2H,m),5.18(2H,s)。
3-溴-4-(4-氯苄氧基)噻吩
1H-NMR(CDCl3)δ7.33-7.42(4H,m),7.20(1H,d,J=3.5Hz),6.27(1H,d,J=3.5Hz),5.05(2H,s)。
(43-3)通过类似于实施例11的方法,由3-溴-4-(4-氯苄氧基)噻吩得到3-{4-[4-(4-氯苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(产率19%),为白色固体。
{[4-(4-氯苄氧基)噻吩-3-基]乙炔基}三甲基硅烷
1H-NMR(CDCl3)δ7.32-7.44(5H,m),6.22(1H,d,J=3.3Hz),5.05(2H,s),0.25(9H,s)。
3-(4-氯苄氧基)-4-乙炔基噻吩
1H-NMR(CDCl3)δ7.42(1H,d,J=3.3Hz),7.32-7.41(4H,m),6.21(1H,d,J=3.3Hz),5.07(2H,s),3.18(1H,s)。
3-{4-[4-(4-氯苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.23(1H,brs),8.28(1H,s),7.89(1H,d,J=3.4Hz),7.50-7.55(2H,m),7.44-7.49(2H,m),6.82(1H,d,J=3.4Hz),5.85(1H,dd,J=5.2,12.5Hz),5.21(2H,s),2.64-2.93(3H,m),2.28-2.40(1H,m)。
实施例44(化合物44)
3-{4-[4-(1-苯基乙氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
通过类似于实施例43的方法,由4-溴-3-羟基噻吩-2-羧酸甲酯和(±)-1-苯乙醇得到3-{4-[4-(1-(苯基乙氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮的旋光异构体混合物(产率15%),为白色固体。
4-溴-3-(1-苯基乙氧基)噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.43-7.50(2H,m),7.33(1H,s),7.24-7.38(3H,m),5.75(1H,q,J=6.5Hz),3.83(3H,s),1.68(3H,d,J=6.5Hz)。
4-溴-3-(1-苯基乙氧基)噻吩-2-羧酸
1H-NMR(CDCl3)δ7.45(1H,s),7.42-7.47(2H,m),7.28-7.38(3H,m),5.85(1H,q,J=6.5Hz),1.73(3H,d,J=6.5Hz)。
3-溴-4-(1-苯基乙氧基)噻吩
1H-NMR(CDCl3)δ7.32-7.41(4H,m),7.24-7.30(1H,m),7.12(1H,d,J=3.4Hz),6.02(1H,d,J=3.5Hz),5.18(1H,q,J=6.5Hz),1.67(3H,d,J=6.4Hz)。
三甲基{[4-(1-苯基乙氧基)噻吩-3-基]乙炔基}硅烷
1H-NMR(CDCl3)δ7.23-7.44(6H,m),6.00(1H,d,J=3.3Hz),5.20(1H,q,J=6.4Hz),1.65(3H,d,J=6.4Hz),0.27(9H,s)。
3-乙炔基-4-(1-苯基乙氧基)噻吩
1H-NMR(CDCl3)δ7.24-7.41(6H,m),5.98(1H,d,J=3.3Hz),5.20(1H,q,J=6.5Hz),3.20(1H,s),1.67(3H,d,J=6.5Hz)。
3-{4-[4-(1-苯基乙氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.26(1H,s),8.45(0.8H,s,major),8.43(0.2H,s,minor),7.82(1H,d,J=3.4Hz),7.43-7.48(2H,m),7.31-7.38(2H,m),7.23-7.30(1H,m),6.55(0.2H,d,J=3.4Hz,minor),6.52(0.8H,d,J=3.4Hz,major),5.92(1H,dd,J=4.9,12.2Hz),5.46(1H,q,J=6.3Hz),2.66-2.96(3H,m),2.31-2.41(1H,m),1.64(3H,d,J=6.4Hz)。
实施例45(化合物45)
3-(4-{4-[4-(2-吗啉代乙基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮盐酸盐
(45-1)通过类似于实施例43(43-1)和实施例33(33-2)的方法,由4-溴-3-羟基噻吩-2-羧酸甲酯和[4-(2-吗啉代乙基)苯基]甲醇得到4-溴-3-[4-(2-吗啉代乙基)苄氧基]噻吩-2-羧酸(产率86%),为白色固体。
4-溴-3-[4-(2-吗啉代乙基)苄氧基]噻吩-2-羧酸甲酯
1H-NMR(CDCl3)δ7.47(2H,d,J=8.1Hz),7.40(1H,s),7.23(2H,d,J=8.1Hz),5.16(2H,s),3.87(3H,s),3.74(4H,t,J=4.7Hz),2.78-2.86(2H,m),2.56-2.63(2H,m),2.46-2.56(4H,m)。
4-溴-3-[4-(2-吗啉代乙基)苄氧基]噻吩-2-羧酸
1H-NMR(DMSO-d6)δ7.95(1H,s),7.36-7.41(2H,m),7.22-7.27(2H,m),5.13(2H,s),3.54-3.63(4H,m),2.72-2.80(2H,m),2.43-2.59(6H,m)。
(45-2)向4-溴-3-[4-(2-吗啉代乙基)苄氧基]噻吩-2-羧酸(331.0mg,0.78mmol)的二甲基亚砜(3.9mL)溶液中加入碳酸银(24.0mg,0.09mmol)和乙酸(49μL,0.86mmol),将混合物在120℃搅拌15分钟。在5分钟和10分钟后分两次加入碳酸银(48.6mg,0.18mmol)。将反应混合物冷却至室温,加入1.0M盐酸和乙酸乙酯,将混合物搅拌一段时间,用饱和碳酸氢钠水溶液中和。过滤反应混合物,用乙酸乙酯萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。将浓缩的残余物(266.1mg)溶于氯仿(2mL)、4.0M盐酸/乙酸乙酯溶液(0.3mL,1.2mmol),然后加入乙醚(2mL),通过过滤收集沉淀物,得到4-{4-[(4-溴噻吩-3-基氧基)甲基]苯乙基}吗啉盐酸盐(278.4mg,85%),为白色固体。
1H-NMR(DMSO-d6)δ10.73-10.96(1H,br),7.66(1H,d,J=3.5Hz),7.41-7.47(2H,m),7.29-7.35(2H,m),6.84(1H,d,J=3.5Hz),5.08(2H,s),3.94-4.03(2H,m),3.77(2H,brt,J=11.5Hz),3.44-3.53(2H,m),3.28-3.38(2H,m),3.02-3.16(4H,m)。
(45-3)通过类似于实施例40(40-2)的方法,由4-{4-[(4-溴噻吩-3-基氧基)甲基]苯乙基}吗啉盐酸盐(278.4mg,0.66mol)得到4-[4-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)苯乙基]吗啉(192.8mg,73%),为红棕色油。
1H-NMR(CDCl3)δ7.35-7.40(3H,m),7.19-7.24(2H,m),6.22(1H,d,J=3.3Hz),5.06(2H,s),3.72-3.77(4H,m),2.78-2.85(2H,m),2.48-2.63(6H,m),0.25(9H,s)。
(45-4)在0℃下,向4-[4-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)苯乙基]吗啉(164.9mg,0.41mmol)和乙酸(0.24mL,4.19mmol)的四氢呋喃(1.7mL)溶液中加入1M四丁基氟化铵/四氢呋喃溶液(2.1mL,2.10mmol),将混合物在0℃至室温下搅拌6小时。反应混合物用乙酸乙酯稀释,用饱和碳酸氢钠水溶液和饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(乙酸乙酯/甲醇)纯化,得到4-{4-[(4-乙炔基噻吩-3-基氧基)甲基]苯乙基}吗啉(116.1mg,85%),为红棕色油。
1H-NMR(CDCl3)δ7.41(1H,d,J=3.4Hz),7.34-7.39(2H,m),7.19-7.24(2H,m),6.22(1H,d,J=3.4Hz),5.07(2H,s),3.75(4H,brt,J=4.6Hz),3.17(1H,s),2.77-2.87(2H,m),2.49-2.65(6H,m)。
(45-5)向4-{4-[(4-乙炔基噻吩-3-基氧基)甲基]苯乙基}吗啉(101.8mg,0.31mmol)在叔丁醇(1.2mL)和水(1.2mL)中的悬浮液中加入3-叠氮基哌啶-2,6-二酮(通过实施例1(1-1)的方法合成)(53.2mg,0.35mmol)、五水合硫酸铜(II)(7.2mg,0.03mmol)和抗坏血酸钠(12.3mg,0.06mmol),将混合物在氩气气氛下于室温搅拌17小时。向反应混合物中加入乙腈和甲醇,溶解不溶物,用活性炭处理,浓缩。将浓缩的残余物通过柱色谱法(二氯甲烷/甲醇)纯化,将所得化合物溶解于乙酸乙酯(1.5mL)和甲醇(0.5mL)中,在0℃下加入4.0M盐酸/乙酸乙酯溶液(100μL,0.40mmol)。向反应混合物中加入甲醇,将混合物用活性炭处理,将溶剂蒸发。将残余物在丙酮中固化,得到3-(4-{4-[4-(2-吗啉代乙基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮盐酸盐(39.8mg,26%),为浅棕色固体。
1H-NMR(DMSO-d6)δ11.24(1H,brs),11.07-11.30(1H,br),8.29(1H,s),7.88(1H,d,J=3.3Hz),7.48(2H,d,J=8.1Hz),7.30(2H,d,J=8.1Hz),6.81(1H,d,J=3.4Hz),5.88(1H,dd,J=5.0,12.3Hz),5.20(2H,s),3.98(2H,brdd,J=2.3,12.3Hz),3.80(2H,brt,J=11.5Hz),3.47(2H,brd,J=12.3Hz),3.25-3.37(2H,m),2.99-3.15(4H,m),2.63-2.95(3H,m),2.28-2.39(1H,m)。
实施例46(化合物46)
3-[4-(4-{4-[([二甲氨基)甲基]苄氧基}噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮盐酸盐
(46-1)通过类似于实施例36(36-4)的方法,由{4-[(4-溴噻吩-3-基氧基)甲基]苯基}甲醇(通过实施例42(42-1、42-2)的方法合成)(754.3mg,2.52mmol)得到[4-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)苯基]甲醇(468.5mg,59%),为红棕色油。
1H-NMR(CDCl3)δ7.33-7.52(5H,m),6.22(1H,d,J=3.3Hz),5.09(2H,s),4.71(2H,d,J=5.9Hz),1.65(1H,brt,J=6.0Hz),0.25(9H,s)。
(46-2)在-20℃下,向[4-({4-[(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)苯基]甲醇(468.5mg,1.48mmol)的二氯甲烷(5.9mL)溶液中加入三乙胺(0.41mL,2.94mmol)和甲磺酰氯(0.17mL,2.20mmol),将混合物在-20℃至-9℃搅拌1小时。将反应混合物用二氯甲烷稀释,用1.0M盐酸和饱和盐水洗涤,用无水硫酸镁干燥,浓缩。将浓缩的残余物(624.1mg)溶于二氯甲烷(15mL),在0℃下添加2M二甲基胺/甲醇溶液(2.2mL,4.4mmol),将混合物在0℃至室温下搅拌17.5小时。向反应混合物中加入饱和碳酸氢钠水溶液,将混合物用二氯甲烷萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。将浓缩的残余物通过柱色谱法(二氯甲烷/甲醇)纯化,得到1-[4-({[4-(三甲基甲硅烷基)乙炔基]噻吩-3-基氧基}甲基)苯基]-N,N-二甲基甲胺混合物(373.7mg),为棕色油。向所得混合物(373.7mg)的甲醇(2.2mL)溶液中加入碳酸钾(303.9mg,2.20mmol),将混合物在室温搅拌25小时。向反应混合物中加入饱和盐水,将混合物用乙酸乙酯萃取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,浓缩。浓缩的残余物通过柱色谱法(二氯甲烷/甲醇)纯化,得到1-{4-[(4-乙炔基噻吩-3-基氧基)甲基]苯基}-N,N-二甲基甲胺(175.7mg,44%),为红棕色油。
1H-NMR(CDCl3)δ7.38-7.43(3H,m),7.29-7.35(2H,m),6.22(1H,d,J=3.3Hz),5.09(2H,s),3.43(2H,s),3.17(1H,s),2.24(6H,s)。
(46-3)通过类似于实施例1(1-2)的方法,由1-{4-[(4-乙炔基噻吩-3-基氧基)甲基]苯基}-N,N-二甲基甲胺(175.7mg,0.65mmol)得到3-[4-(4-{4-[([二甲氨基)甲基]苄氧基}噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(227.5mg),为绿色油。
将所得绿色油(227.5mg)溶解于乙酸乙酯(2mL)和甲醇(2mL)中,在室温下加入4.0M盐酸/乙酸乙酯溶液(0.3mL,1.20mmol)。蒸发溶剂,将残余物溶于甲醇中,用活性炭处理。蒸发溶剂,将所得残余物悬浮在甲醇(0.5mL)中。通过过滤除去不溶物,浓缩滤液。将浓缩的残余物在40℃溶解于甲醇(0.3mL),在5℃下静置以沉淀出固体。加入甲醇(1.0mL),通过过滤收集沉淀物,用甲醇、乙酸乙酯和乙醚洗涤,得到3-[4-(4-{4-[([二甲氨基)甲基]苄氧基]噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮盐酸盐(87.6mg,29%),为白色固体。
1H-NMR(DMSO-d6)δ11.23(1H,brs),10.07-10.60(1H,br),8.32(1H,s),7.88(1H,d,J=3.4Hz),7.52-7.62(4H,m),6.82(1H,d,J=3.4Hz),5.88(1H,dd,J=5.0,12.4Hz),5.26(2H,s),4.26(2H,brs),2.59-2.95(9H,m),2.28-2.40(1H,m)。
实施例47(化合物47)
3-{4-[4-(苯并[b]噻吩-2-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
(47-1)通过类似于实施例43(43-1)的方法,由苯并[b]噻吩-2-甲醇(0.72g,4.38mmol)和4-溴-3-羟基噻吩-2-羧酸甲酯(0.80g,3.37mmol)得到3-(苯并[b]噻吩-2-基甲氧基)-4-溴噻吩-2-羧酸甲酯(1.20g,93%),为白色固体。
1H-NMR(CDCl3)δ7.80-7.86(1H,m),7.73-7.79(1H,m),7.41(1H,s),7.37(1H,brd,J=0.7Hz),7.31-7.38(2H,m),5.49(2H,d,J=0.7Hz),3.90(3H,s)。
(47-2)将3-(苯并[b]噻吩-2-基甲氧基)-4-溴噻吩-2-羧酸甲酯(1.17g,3.05mmol)溶于四氢呋喃(70mL)-水(9.4mL)混合溶液中,在0℃下加入1.25M氢氧化锂水溶液(18.8mL,23.5mmol),将该混合物在0℃至室温下搅拌17小时。浓缩反应混合物,加入1.0M盐酸(25mL,25mmol),通过过滤收集沉淀物,得到3-(苯并[b]噻吩-2-基甲氧基)-4-溴噻吩-2-羧酸(1.10g,98%),为白色固体。
1H-NMR(DMSO-d6)δ7.90-8.00(2H,m),7.81-7.88(1H,m),7.47(1H,s),7.32-7.42(2H,m),5.53(2H,s)。
(47-3)通过类似于实施例38(38-2)和实施例40(40-2、40-3)的方法,由3-(苯并[b]噻吩-2-基甲氧基)-4-溴噻吩-2-羧酸得到3-{4-[4-(苯并[b]噻吩-2-基甲氧基])噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮(产率14%),为白色固体。
2-[(4-溴噻吩-3-基氧基)甲基]苯并[b]噻吩
1H-NMR(CDCl3)δ7.79-7.86(1H,m),7.72-7.79(1H,m),7.29-7.39(3H,m),7.20(1H,d,J=3.5Hz),6.39(1H,d,J=3.5Hz),5.34(2H,d,J=0.8Hz)。
2-[(4-乙炔基噻吩-3-基氧基)甲基]苯并[b]噻吩
1H-NMR(CDCl3)δ7.79-7.84(1H,m),7.73-7.77(1H,m),7.42(1H,d,J=3.3Hz),7.29-7.39(3H,m),6.34(1H,d,J=3.3Hz),5.35(2H,d,J=0.9Hz),3.19(1H,s)。
3-{4-[4-(苯并[b]噻吩-2-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮
1H-NMR(DMSO-d6)δ11.11-11.30(1H,brs),8.28(1H,s),7.93-7.98(1H,m),7.91(1H,d,J=3.4Hz),7.82-7.88(1H,m),7.58(1H,d,J=0.3Hz),7.33-7.41(2H,m),6.96(1H,d,J=3.4Hz),5.86(1H,dd,J=5.0,12.4Hz),5.52(2H,s),2.64-2.91(3H,m),2.29-2.40(1H,m)。
实施例48(化合物48)
3-[5-溴-4-(噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
向N-溴琥珀酰亚胺(1.19g,6.69mmol)和硝酸银(107.2mg,0.63mmol)在丙酮(30mL)中的悬浮液中加入3-乙炔基噻吩(0.60mL,6.03mmol),将混合物在室温下在黑暗中搅拌16.5小时。将反应混合物用己烷稀释,用饱和盐水和1.0M硫代硫酸钠水溶液洗涤。有机层经无水硫酸镁干燥,浓缩,得到3-(溴乙炔基)噻吩混合物(1.21g),为棕色油。将所得到混合物(1.21g)溶于四氢呋喃(12mL),加入3-叠氮基哌啶-2,6-二酮(通过实施例1(1-1)的方法合成)(0.97g,6.29mmol)、乙酸铜(II))(53.6mg,0.30mmol)和碘化铜(I)(56.1mg,0.29mmol),将该混合物在氩气气氛下于50℃搅拌2天。向反应混合物中加入水(12mL),通过过滤收集沉淀物,用水和乙腈洗涤。将残余物从二甲基亚砜-水中重结晶,得到3-[5-溴-4-(噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(1.14g,55%),为灰色固体。
1H-NMR(DMSO-d6)δ11.33(1H,brs),8.04(1H,dd,J=1.3,2.9Hz),7.75(1H,dd,J=2.9,5.0Hz),7.66(1H,dd,J=1.3,5.0Hz),5.86(1H,dd,J=5.1,12.6Hz),2.96(1H,ddd,J=5.1,13.1,16.6Hz),2.83(1H,dq,J=4.2,12.7Hz),2.65-2.77(1H,m),2.37-2.46(1H,m)。
实施例49(化合物49)
3-[5-碘-4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮
(49-1)向3-乙炔基-4-甲氧基噻吩(通过实施例19的方法合成)(136.5mg,0.99mmol)的四氢呋喃(2.4mL)溶液中加入N-碘吗啉氢碘化物(N-iodomorpholine hydroiodide)(420.2mg,1.23mmol)和碘化铜(I)(10.2mg,0.05mmol),将混合物在室温搅拌26.5小时。向反应混合物中加入己烷,将混合物用饱和盐水和1.0M硫代硫酸钠水溶液洗涤。有机层经无水硫酸镁干燥,浓缩,得到3-(碘乙炔基)-4-甲氧基噻吩(232.2mg,89%),为红棕色油。
1H-NMR(CDCl3)δ7.38(1H,d,J=3.3Hz),6.19(1H,d,J=3.3Hz),3.86(3H,s)。
(49-2)向3-(碘乙炔基)-4-甲氧基噻吩(232.2mg,0.88mmol)的四氢呋喃(1.8mL)溶液中加入3-叠氮基哌啶-2,6-二酮(145.6mg,0.94mmol)、三[(1-苄基-1H-1,2,3-三唑-4-基)甲基]胺(25.4mg,0.05mmol)和碘化铜(I)(9.2mg,0.05mmol),在室温下搅拌混合物4天。将反应混合物浓缩,将浓缩的残余物通过柱色谱法(己烷/乙酸乙酯)纯化,得到浅绿色固体(287.0mg)。将所得浅绿色固体用甲醇和乙酸乙酯洗涤,然后用氯仿和甲醇洗涤,溶解在二甲基亚砜(1mL)中。加入水(0.8mL),通过过滤收集沉淀物。残余物用甲醇和乙酸乙酯洗涤,得到3-[5-碘-4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮(157.5mg,43%),为白色固体。
1H-NMR(DMSO-d6)δ11.15-11.42(1H,brs),7.66(1H,d,J=3.3Hz),6.75(1H,d,J=3.3Hz),5.77(1H,dd,J=5.1,12.4Hz),3.78(3H,s),2.98(1H,ddd,J=5.3,12.9,16.8Hz),2.74-2.88(1H,m),2.70(1H,ddd,J=2.8,4.0,16.8Hz),2.30-2.43(1H,m)。
实施例50:人TNF-α产生抑制试验
用真空采血管(Terumo,含有EDTA/2Na)收集健康成年人的外周血,然后用等体积的OTSUKA NORMAL SALINE(Otsuka Pharmaceutical Co.,Ltd.)将外周血稀释两倍。将稀释后的血液与Lymphoprep(AXIS-SHIELD)(为稀释后血液体积的一半)混合,加到15mL锥形管中,在室温下离心20分钟(2,100rpm)。将积聚于Lymphoprep与血浆之间界面处的单核细胞转移到50mL锥形管中,用OTSUKA NORMAL SALINE稀释,将单核细胞悬浮液在室温下离心10分钟(1,150rpm),然后除去上清液。将所得单核细胞级分(即沉淀物)悬浮于适量的含10%胎牛血清(Thermo Fisher Scientific)的RPMI1640培养基(Thermo Fisher Scientific,以下简称为培养基A),用0.4%台盼蓝溶液(Sigma-Aldrich Co.LLC.)适当地进行稀释。用血细胞计数器(ERMA INC.)计数活细胞的数目。用培养基A稀释,使得所得值为5×105个细胞/mL。另一方面,75μL培养基A、5μL 0.4mg/mL的测试化合物溶液(用培养基A稀释10倍的DMSO溶液)和20μL 10μg/mL的脂多糖(Sigma-Aldrich Co.LLC.)溶液(用培养基A稀释)各自预先添加到Falcon 96孔平底板(Corning Incorporated)的同一孔中,以0.1mL/孔加入上述细胞悬液。将用培养基A稀释10倍的5μL DMSO代替化合物溶液添加到对照孔中。在37℃的5%CO2流中培养24小时后,将培养液在4℃、1,000rpm下离心3分钟,回收上清液。根据常规方法使用ELISA试剂盒(Peprotech)测量上清液中TNF-α的含量。用对照孔中产生的TNF-α的量为100来确定在含有测试化合物的孔中产生的TNF-α的量,计算各个试验的抑制率。如表1所示,本发明化合物在10μg/mL下显示出强的TNF-α产生抑制活性。
[表1]
表1:TNF-α产生抑制率(%)
(在3μg/mL下的抑制率)
实施例51:人骨髓瘤细胞系MM.1S的增殖抑制试验
将MM.1S细胞(ATCC,CRL-2974)悬浮在含10%胎牛血清(Thermo Fisher Scientific)的RPMI1640培养基(ATCC,以下简称为培养基B)中,用0.4%台盼蓝溶液(Sigma-AldrichCo.LLC.)适当地进行稀释。用血细胞计数器(ERMA INC.)计数活细胞的数目。用培养基B稀释,使得所得值为2×105个细胞/mL。另一方面,向Falcon 96孔平底板(CorningIncorporated)的每个孔中加入50μL溶液(用培养基B将4mM待测化合物的DMSO溶液稀释200倍而得到),以50μL/孔(测试化合物的最终浓度为10μM)添加上述细胞悬液。将50μL所得溶液(用培养基B稀释DMSO 200倍而得到)添加到对照孔中。在5%CO2流中于37℃下培养3天后,使用WST-1(DOJINDO LABORATORIES)或WST-8Kit(KISHIDA CHEMICAL Co.,Ltd.)并根据其所附的各个说明手册检测细胞增殖活性。如表2所示,本发明的化合物显示出明显的MM.1S细胞增殖抑制活性。
实施例52:人弥漫性大B细胞淋巴瘤细胞系Pfeiffer增殖抑制试验
将Pfeiffer细胞(ATCC,CRL-2632)悬浮在培养基B中,用0.4%台盼蓝溶液(Sigma-Aldrich Co.LLC.)适当地进行稀释。用血细胞计数器(Funakoshi Co.,Ltd.)计数活细胞的数目。将细胞悬液(通过用培养基B稀释以使所得值为1.3×105个细胞/mL而得到)以75μL/孔添加到Falcon 96孔平底板(Corning Incorporated)中,在37℃、5%CO2流下开始培养。第二天,将25μL溶液(通过用培养基B将4mM测试化合物的DMSO溶液稀释100倍而得到)添加到每个孔中(测试化合物的最终浓度为10μM)。将25μL溶液(通过用培养基B稀释DMSO 100倍而得到)添加至对照孔。在37℃、5%CO2流下培养3天后,用多档位移液器将细胞培养基悬浮均匀,将14μL/孔转移到另一个新的Falcon 96孔平底板中。添加86μL溶液(第一次用培养基B将同一4mM测试化合物的DMSO溶液稀释400倍而得到的溶液)至总量为100μL(测试化合物的最终浓度为10μM)。在37℃、5%CO2流下培养3天后,根据WST-8试剂盒(KISHIDA CHEMICALCo.,Ltd.)所附说明书检测细胞增殖活性。如表2所示,本发明的化合物显示出明显的Pfeiffer细胞增殖抑制活性。
实施例53:人套细胞淋巴瘤细胞系REC-1增殖抑制试验
将REC-1细胞(ATCC,CRL-3004)悬浮在培养基B中,用0.4%台盼蓝溶液(Sigma-AldrichCo.LLC.)适当地进行稀释。用血细胞计数器(Funakoshi Co.,Ltd.)计数活细胞的数目。以75μL/孔将细胞悬液(通过用培养基B稀释以使所得值为1.3×105个细胞/mL而得到)添加到Falcon 96孔平底板(Corning Incorporated)中,在37℃、5%CO2流下开始培养。第二天,将25μL溶液(通过用培养基B将测试化合物的4mM DMSO溶液稀释100倍而得到)添加到每个孔中(测试化合物的最终浓度为10μM)。将25μL溶液(通过用培养基B稀释DMSO 100倍而得到)添加至对照孔中。在37℃、5%CO2流下培养3天后,根据WST-8试剂盒(KISHIDA CHEMICALCo.,Ltd.)所附说明书检测细胞增殖活性。如表2所示,本发明的化合物显示出明显的REC-1细胞增殖抑制活性。
实施例54:人伯基特淋巴瘤细胞系Daudi的增殖抑制试验
将Daudi细胞(国立生物医学创新、健康与营养研究所(NIBIOHN),JCRB9071)悬浮在培养基B中,用0.4%台盼蓝溶液(Sigma-Aldrich Co.LLC.)适当地进行稀释。用血细胞计数器(ERMA INC.)计数活细胞的数目。将细胞悬液(通过用培养基B稀释以使所得值为1.3×105个细胞/mL而得到)以75μL/孔添加到Falcon 96孔平底板(Corning Incorporated)中,在37℃、5%CO2流下开始培养。第二天,将25μL溶液(通过用培养基B将测试化合物的4mM DMSO溶液稀释100倍而得到)添加到每个孔中(测试化合物的最终浓度为10μM)。将25μL溶液(通过用培养基B稀释DMSO 100倍而得到)添加至对照孔中。在37℃、5%CO2流中培养3天后,根据WST-8试剂盒(KISHIDA CHEMICAL Co.,Ltd.)所附说明书检测细胞增殖活性。如表2所示,本发明的化合物显示出明显的Daudi细胞增殖抑制活性。
实施例55:人急性淋巴细胞白血病细胞系Kasumi-7的增殖抑制试验
将Kasumi-7细胞(NIBIOHN,JCRB1401)悬浮在含20%胎牛血清(Thermo FisherScientific,Inc.)的RPMI1640培养基(ATCC,以下简称为培养基C)中,用0.4%台盼蓝溶液(Sigma-Aldrich Co.LLC.)适当地进行稀释。用血细胞计数器(Funakoshi Co.,Ltd.)计数活细胞的数目。将细胞悬液(通过用培养基C稀释以使所得值为1.3×105个细胞/mL而得到)以75μL/孔添加到Falcon 96孔平底板(Corning Incorporated)中,在37℃、5%CO2流下开始培养。第二天,将25μL溶液(通过用培养基C将测试化合物的4mM DMSO溶液稀释100倍而得到)添加至每个孔中(测试化合物的最终浓度为10μM)。将25μL溶液(通过用培养基C稀释DMSO 100倍而得到)添加至对照孔。在37℃、5%CO2流中培养3天后,根据WST-8试剂盒(KISHIDA CHEMICAL Co.,Ltd.)所附说明书检测细胞增殖活性。如表2所示,本发明的化合物显示出明显的Kasumi-7细胞增殖抑制活性。
实施例56:使用人外周血单核细胞(PBMC)的细胞毒性试验
用Venoject II真空采血管(Terumo,含EDTA/2Na)收集健康成人的外周血,然后用等体积的OTSUKA NORMAL SALINE(Otsuka Pharmaceutical Co.,Ltd.)稀释两倍。将稀释后的血液与Lymphoprep(AXIS-SHIELD)(为稀释后的血液体积的一半)混合,添加到15mL锥形管中,在室温下离心20分钟(2,100rpm)。将积聚于Lymphoprep与血浆之间界面处的单核细胞转移到50mL锥形管中,用OTSUKA NORMAL SALINE稀释,将单核细胞悬浮液在室温下离心10分钟(1,150rpm),然后除去上清液。将所得单核细胞级分(即沉淀物)悬浮在适量的培养基A中,用0.4%的台盼蓝溶液(Sigma-Aldrich Co.LLC.)适当地进行稀释。用血细胞计数器(ERMAINC.)计数活细胞的数目。用培养基A稀释,使得得到的值为5×105个细胞/mL。另一方面,37.5μL培养基A、2.5μL 0.4mg/mL测试化合物溶液(用培养基A稀释10倍的DMSO溶液)和10μL10μg/mL脂多糖(Sigma-Aldrich Co.LLC.)溶液(用培养基A稀释)分别预先添加到Falcon96孔平底板(Corning Incorporated)的同一孔中,以50μL/孔添加上述细胞悬液(测试化合物终浓度为10μg/mL)。将2.5μL用培养基A稀释10倍的DMSO代替化合物溶液添加到对照孔中。在37℃、5%CO2流下培养24小时后,使用WST-1(DOJINDO LABORATORIES)或WST-8试剂盒(KISHIDA CHEMICAL Co.,Ltd.)并根据它们各自所附说明手册检测细胞存活率。如表2所示,本发明的化合物未显示出强的细胞毒性。
[表2]
表2:细胞增殖抑制活性
*在10μg/mL化合物下测量的PBMC细胞存活率
**由于化合物在培养基中沉淀而变为3μg/mL
*-:无数据
[工业适用性]
本发明提供了具有TNF-α产生抑制活性和血液癌症细胞增殖抑制活性的新型噻吩衍生物以及包含该噻吩衍生物的药物,该噻吩衍生物可用于治疗类风湿性关节炎、克罗恩氏病、溃疡性结肠炎以及血液癌症。本发明可用于药物产品领域。
本申请基于日本提交的专利申请号2018-010984(申请日:2018年1月25日)和日本提交的专利申请号2018-084202(申请日:2018年4月25日),其全部内容通过引用并入本文。
Claims (26)
2.根据权利要求1所述的化合物或其盐,其中,由式(I)表示的化合物是由下式(IA)或(IB)表示的化合物:
式中:
R1为氢或卤素;
R2为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基;
R3为氢、卤素、C1-6烷基或可选地具有取代基的C1-6烷氧基;
R4为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基;
R5为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基;
R6为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基,或
R5和R6彼此键合并与它们所连接的碳原子一起形成含有1至2个氧原子的5元环或6元环;以及
R7为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷氧羰基或C1-6烷基羰基。
3.根据权利要求2所述的化合物或其盐,其中,
R1为氢或卤素;
R2为氢、卤素或C1-6烷氧基;
R3为氢、卤素、C1-6烷基或可选地具有取代基的C1-6烷氧基;
R4为氢、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基或C1-6烷氧羰基;
R5和R6各自为氢,或
R5和R6彼此键合并与它们所连接的碳原子一起形成含有1至2个氧原子的5元环或6元环;以及
R7为氢、卤素、C1-6烷基或C1-6烷基羰基。
5.根据权利要求4所述的化合物或其盐,其中,X为CH2、CH(CH3)或CH2CH2。
6.根据权利要求2至5中任一项所述的化合物或其酸加成盐,其中,
R1为氢、碘、溴或氯;
R2为氢、溴或甲氧基;
R3为氢、溴、氯、甲基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、环戊氧基、环丙基甲氧基、环戊基甲氧基、环己基甲氧基、苄氧基、1-苯基乙氧基、吡啶-2-基甲氧基、吡啶-3-基甲氧基、吡啶-4-基甲氧基、苯并[b]噻吩-2-基甲氧基、4-甲氧基苄氧基、4-(甲氧基甲基)苄氧基、4-氯苄氧基、4-(吡咯烷-1-基甲基)苄氧基、4-(哌啶-1-基甲基)苄氧基、4-[(二甲氨基)甲基]苄氧基、4-(2-吗啉代乙基)苄氧基、2-(吗啉代甲基)苄氧基、3-(吗啉代甲基)苄氧基、4-(吗啉代甲基)苄氧基或4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基;
R4为氢、溴、氯、甲基、羟甲基、甲氧基、乙氧基或甲氧羰基;
R5和R6各自为氢,或
R5和R6彼此键合并与它们所连接的碳原子一起形成含有2个氧原子的6元环;
R7为氢、氯、溴、甲基或乙酰基。
7.根据权利要求1至6中任一项所述的化合物或其盐,其中,所述化合物或盐选自:
3-[4-(4-溴噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[5-氯-4-(噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-甲基噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-乙酰基噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-{4-[5-(羟甲基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-[4-(2,3-二氢噻吩并[3,4-b][1,4]二恶英-5-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-氯噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-溴噻吩-2-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(2,5-二溴噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-氯噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-甲氧基-5-甲基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
4-[1-(2,6-二氧代哌啶-3-基)-1H-1,2,3-三唑-4-基]-3-甲氧基噻吩-2-羧酸甲酯、
3-[4-(4-乙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(2-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-丙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-氯-4-甲氧基噻吩)-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-溴-4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-乙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-丁氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-异丙氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-{4-[4-(环戊氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(环丙基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(环戊基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(环己基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(4-甲氧基苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(吡啶-4-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(吡啶-2-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(吡啶-3-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-(4-{4-[4-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-(4-{4-[4-(甲氧基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-{4-[4-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-(4-{4-[3-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-(4-{4-[2-(吗啉代甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-(4-{4-[4-(吡咯烷-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-(4-{4-[4-(哌啶-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-{4-[4-(4-氯苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-{4-[4-(1-苯基乙氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-(4-{4-[4-(2-吗啉代乙基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-[4-(4-{4-[(二甲氨基)甲基]苄氧基}噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-{4-[4-(苯并[b]噻吩-2-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-[5-溴-4-(噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮,和
3-[5-碘-4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮,
及它们的酸加成盐。
10.根据权利要求1至9中任一项所述的化合物或其盐,其中,所述化合物或盐选自:
3-[4-(5-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(5-溴-4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-{4-[4-(苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-(4-{4-[4-(甲氧基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-{4-[4-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮、
3-(4-{4-[4-(吡咯烷-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-(4-{4-[4-(哌啶-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-(4-{4-[4-(2-吗啉代乙基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-[4-(4-{4-[(二甲氨基)甲基]苄氧基}噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮,和
3-{4-[4-(苯并[b]噻吩-2-基甲氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮,
及它们的酸加成盐。
11.根据权利要求1所述的化合物或其盐,其中,所述化合物或盐选自:
3-[4-(5-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-[4-(4-甲氧基噻吩-3-基)-1H-1,2,3-三唑-1-基]哌啶-2,6-二酮、
3-(4-{4-[4-(甲氧基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮、
3-{4-[4-(4-{[(2S,6R)-2,6-二甲基吗啉代]甲基}苄氧基)噻吩-3-基]-1H-1,2,3-三唑-1-基}哌啶-2,6-二酮,和
3-(4-{4-[4-(哌啶-1-基甲基)苄氧基]噻吩-3-基}-1H-1,2,3-三唑-1-基)哌啶-2,6-二酮,
及它们的酸加成盐。
12.一种药物,其中,所述药物包含权利要求1所述的化合物或其盐作为活性成分。
13.根据权利要求12所述的药物,其中,所述药物是TNF-α产生抑制剂。
14.根据权利要求12所述的药物,其中,所述药物是炎性疾病、自身免疫性疾病或血液癌症的预防剂或治疗剂。
15.根据权利要求14所述的药物,其中,所述自身免疫性疾病是类风湿性关节炎、克罗恩氏病或溃疡性结肠炎。
16.根据权利要求14所述的药物,其中,所述血液癌症是白血病、恶性淋巴瘤或多发性骨髓瘤。
17.根据权利要求14所述的药物,其中,所述血液癌症是多发性骨髓瘤。
18.根据权利要求14所述的药物,其中,所述血液癌症是恶性淋巴瘤。
19.根据权利要求14所述的药物,其中,所述血液癌症是白血病。
20.根据权利要求16所述的药物,其中,所述恶性淋巴瘤是非霍奇金淋巴瘤。
21.根据权利要求20所述的药物,其中,所述非霍奇金淋巴瘤是前体淋巴样肿瘤或成熟B细胞肿瘤。
22.一种药物组合物,其中,所述药物组合物包含权利要求1所述的化合物或其盐作为活性成分以及药学上可接受的载体。
23.一种抑制哺乳动物中TNF-α产生的方法,其中,所述方法包括向所述哺乳动物施用有效量的权利要求1所述的化合物或其盐。
24.一种预防或治疗炎性疾病、自身免疫性疾病或血液癌症的方法,其中,所述方法包括给有此施用需要的哺乳动物施用预防有效量或治疗有效量的权利要求1所述的化合物或其盐。
25.根据权利要求1所述的化合物或其盐,用于预防或治疗炎性疾病、自身免疫性疾病或血液癌症。
26.权利要求1所述的化合物或其盐在制备药物中的用途。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2018-010984 | 2018-01-25 | ||
JP2018010984 | 2018-01-25 | ||
JP2018084202 | 2018-04-25 | ||
JP2018-084202 | 2018-04-25 | ||
PCT/JP2019/002596 WO2019146773A1 (ja) | 2018-01-25 | 2019-01-25 | チオフェン誘導体およびその用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111655685A true CN111655685A (zh) | 2020-09-11 |
CN111655685B CN111655685B (zh) | 2023-11-17 |
Family
ID=67394982
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980010101.8A Active CN111655685B (zh) | 2018-01-25 | 2019-01-25 | 噻吩衍生物及其用途 |
Country Status (12)
Country | Link |
---|---|
US (1) | US11299485B2 (zh) |
EP (1) | EP3744719B1 (zh) |
JP (1) | JP7241036B2 (zh) |
KR (1) | KR20200112907A (zh) |
CN (1) | CN111655685B (zh) |
AU (1) | AU2019211910B2 (zh) |
BR (1) | BR112020015116A2 (zh) |
CA (1) | CA3089553A1 (zh) |
ES (1) | ES2953704T3 (zh) |
HU (1) | HUE063099T2 (zh) |
IL (1) | IL275935A (zh) |
WO (1) | WO2019146773A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021174024A1 (en) | 2020-02-28 | 2021-09-02 | First Wave Bio, Inc. | Methods of treating iatrogenic autoimmune colitis |
MX2023008296A (es) | 2021-01-13 | 2023-09-29 | Monte Rosa Therapeutics Inc | Compuestos de isoindolinona. |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004528351A (ja) * | 2001-04-30 | 2004-09-16 | ザ プロクター アンド ギャンブル カンパニー | 望ましくないサイトカイン活性に関連する疾患を治療するのに有用なトリアゾール化合物 |
CN1578767A (zh) * | 2001-11-22 | 2005-02-09 | 小野药品工业株式会社 | 哌啶-2-酮衍生化合物及包含其作为活性成分的药学组合物 |
US20080176900A1 (en) * | 2005-09-27 | 2008-07-24 | Hesheng Zhang | 5H-THIOENO(3,4-c)PYRROLE-4,6-DIONE DERIVATIVES AND THEIR USE AS TUMOR NECROSIS FACTOR INHIBITORS |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU4180900A (en) | 1999-04-02 | 2000-10-23 | Du Pont Pharmaceuticals Company | Novel amide derivatives as inhibitors of matrix metalloproteinases, tnf-alpha, and aggrecanase |
US20030045552A1 (en) * | 2000-12-27 | 2003-03-06 | Robarge Michael J. | Isoindole-imide compounds, compositions, and uses thereof |
US20120135005A1 (en) | 2009-04-16 | 2012-05-31 | Harding Fiona A | ANTI-TNF-a ANTIBODIES AND THEIR USES |
EP4289838A3 (en) | 2010-02-11 | 2024-03-13 | Celgene Corporation | Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same |
CN109790143A (zh) | 2016-05-10 | 2019-05-21 | C4医药公司 | 用于靶蛋白降解的胺连接的c3-戊二酰亚胺降解决定子体 |
JP7038099B2 (ja) * | 2016-07-12 | 2022-03-17 | ガレクト バイオテック エービー | ガレクチンのα-D-ガラクトシド阻害剤 |
JP6746208B2 (ja) | 2016-07-14 | 2020-08-26 | 株式会社ディスコ | 切削装置 |
JP6565875B2 (ja) | 2016-11-24 | 2019-08-28 | 株式会社デンソー | 内燃機関の制御装置 |
-
2019
- 2019-01-25 ES ES19743967T patent/ES2953704T3/es active Active
- 2019-01-25 CA CA3089553A patent/CA3089553A1/en active Pending
- 2019-01-25 BR BR112020015116-5A patent/BR112020015116A2/pt unknown
- 2019-01-25 CN CN201980010101.8A patent/CN111655685B/zh active Active
- 2019-01-25 US US16/962,218 patent/US11299485B2/en active Active
- 2019-01-25 AU AU2019211910A patent/AU2019211910B2/en active Active
- 2019-01-25 JP JP2019567196A patent/JP7241036B2/ja active Active
- 2019-01-25 EP EP19743967.2A patent/EP3744719B1/en active Active
- 2019-01-25 KR KR1020207023934A patent/KR20200112907A/ko not_active Application Discontinuation
- 2019-01-25 WO PCT/JP2019/002596 patent/WO2019146773A1/ja unknown
- 2019-01-25 HU HUE19743967A patent/HUE063099T2/hu unknown
-
2020
- 2020-07-09 IL IL275935A patent/IL275935A/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004528351A (ja) * | 2001-04-30 | 2004-09-16 | ザ プロクター アンド ギャンブル カンパニー | 望ましくないサイトカイン活性に関連する疾患を治療するのに有用なトリアゾール化合物 |
CN1578767A (zh) * | 2001-11-22 | 2005-02-09 | 小野药品工业株式会社 | 哌啶-2-酮衍生化合物及包含其作为活性成分的药学组合物 |
US20080176900A1 (en) * | 2005-09-27 | 2008-07-24 | Hesheng Zhang | 5H-THIOENO(3,4-c)PYRROLE-4,6-DIONE DERIVATIVES AND THEIR USE AS TUMOR NECROSIS FACTOR INHIBITORS |
Also Published As
Publication number | Publication date |
---|---|
EP3744719A4 (en) | 2021-10-20 |
EP3744719C0 (en) | 2023-06-07 |
CN111655685B (zh) | 2023-11-17 |
AU2019211910A2 (en) | 2020-09-17 |
JPWO2019146773A1 (ja) | 2021-01-07 |
KR20200112907A (ko) | 2020-10-05 |
EP3744719B1 (en) | 2023-06-07 |
RU2020128040A (ru) | 2022-02-25 |
IL275935A (en) | 2020-08-31 |
US11299485B2 (en) | 2022-04-12 |
ES2953704T3 (es) | 2023-11-15 |
WO2019146773A1 (ja) | 2019-08-01 |
US20210061795A1 (en) | 2021-03-04 |
JP7241036B2 (ja) | 2023-03-16 |
RU2020128040A3 (zh) | 2022-02-25 |
AU2019211910B2 (en) | 2022-09-22 |
AU2019211910A1 (en) | 2020-09-10 |
BR112020015116A2 (pt) | 2021-01-05 |
HUE063099T2 (hu) | 2023-12-28 |
EP3744719A1 (en) | 2020-12-02 |
CA3089553A1 (en) | 2019-08-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102400592B1 (ko) | 페닐레이트 유도체, 그의 제조 방법, 및 그의 약학적 조성물 및 용도 | |
EP3483142A1 (en) | Aromatic acetylene or aromatic ethylene compound, intermediate, preparation method, pharmaceutical composition and use thereof | |
KR20140131955A (ko) | 신규 트리아진 유도체 | |
TWI452044B (zh) | 嗎啉衍生物 | |
TW201524953A (zh) | 治療活性化合物及其使用方法(二) | |
CN112074507B (zh) | 作为抗菌素的化合物 | |
TW202045499A (zh) | 用於治療hbv感染或hbv誘發疾病之醯胺衍生物 | |
JP7241036B2 (ja) | チオフェン誘導体およびその用途 | |
CN113354585A (zh) | 新型ep4拮抗剂的合成及其在癌症和炎症中的用途 | |
KR20060123739A (ko) | 나트륨 채널 차단제로서의 치환된 트리아졸 | |
RU2164226C2 (ru) | Производные 5-(гидроксиметил)-оксазолидин-2-она, способы их получения, лекарство и фармацевтический состав | |
CN111741946B (zh) | 吲哚胺2,3-双加氧酶抑制剂以及它们在医学上的应用 | |
TW202016071A (zh) | 四氫吖唉衍生物及其前藥 | |
RU2781643C2 (ru) | Производное тиофена и его применение | |
CN110759902B (zh) | Set8赖氨酸甲基转移酶抑制剂及其制备方法和用途 | |
CN115466251A (zh) | 一类稠杂环化合物、及其制法和药物组合物与用途 | |
CN114746088A (zh) | 吲哚甲酰胺化合物和其用于治疗分枝杆菌感染的用途 | |
TW201625588A (zh) | 環狀胺衍生物 | |
WO2016019588A1 (en) | Oxacazone compounds to treat clostridium difficile | |
JP2011512382A (ja) | エストロゲン様物質としての置換4−ヒドロキシ−n−(4−ヒドロキシフェニル)インドール | |
WO2024088408A1 (zh) | 一种含氮杂环化合物、其药学上可接受的盐及其制备方法与应用 | |
CN117658885A (zh) | 苄氧芳基类化合物及其制备方法、药物组合物和用途 | |
TW202108576A (zh) | 用於治療hbv感染或hbv誘發的疾病之醯胺衍生物 | |
CN113402414A (zh) | 一种苯甲酸衍生物及其制法和药物用途 | |
CN114105977A (zh) | 雌激素受体调节剂化合物及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |