CN1201735C - 分枝杆菌抑制剂 - Google Patents
分枝杆菌抑制剂 Download PDFInfo
- Publication number
- CN1201735C CN1201735C CNB99808283XA CN99808283A CN1201735C CN 1201735 C CN1201735 C CN 1201735C CN B99808283X A CNB99808283X A CN B99808283XA CN 99808283 A CN99808283 A CN 99808283A CN 1201735 C CN1201735 C CN 1201735C
- Authority
- CN
- China
- Prior art keywords
- pyrrolidine
- diketone
- nonyl
- amino
- alkyl
- 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.)
- Expired - Fee Related
Links
- 239000003112 inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000012453 solvate Substances 0.000 claims abstract description 7
- -1 nitro, hydroxyl Chemical group 0.000 claims description 70
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 36
- 229910052717 sulfur Inorganic materials 0.000 claims description 36
- 239000011593 sulfur Substances 0.000 claims description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000002757 morpholinyl group Chemical group 0.000 claims description 11
- 125000004193 piperazinyl group Chemical group 0.000 claims description 11
- 125000005936 piperidyl group Chemical group 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 9
- 235000019260 propionic acid Nutrition 0.000 claims description 9
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 7
- 201000008827 tuberculosis Diseases 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- BNGRZGXAWRFVAW-UHFFFAOYSA-N 2-(2,5-dioxopyrrolidin-1-yl)-n-(2-piperidin-4-ylphenyl)propanamide Chemical compound C=1C=CC=C(C2CCNCC2)C=1NC(=O)C(C)N1C(=O)CCC1=O BNGRZGXAWRFVAW-UHFFFAOYSA-N 0.000 claims description 3
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 3
- 229960004194 lidocaine Drugs 0.000 claims description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- ALBYIUDWACNRRB-UHFFFAOYSA-N hexanamide Chemical compound CCCCCC(N)=O ALBYIUDWACNRRB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 208000027531 mycobacterial infectious disease Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
- 239000000243 solution Substances 0.000 description 45
- 239000000203 mixture Substances 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 239000002585 base Substances 0.000 description 35
- 239000000376 reactant Substances 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 238000000034 method Methods 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 229910052938 sodium sulfate Inorganic materials 0.000 description 16
- 235000011152 sodium sulphate Nutrition 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 238000003810 ethyl acetate extraction Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 238000005406 washing Methods 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 8
- 229960003350 isoniazid Drugs 0.000 description 8
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 description 8
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 7
- 206010059866 Drug resistance Diseases 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 229960002317 succinimide Drugs 0.000 description 6
- UNJAMUMWPRRGHF-UHFFFAOYSA-N 1-nonylpyrrole-2,5-dione Chemical compound CCCCCCCCCN1C(=O)C=CC1=O UNJAMUMWPRRGHF-UHFFFAOYSA-N 0.000 description 5
- JQXXHWHPUNPDRT-YOPQJBRCSA-N chembl1332716 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CCN(C)CC1 JQXXHWHPUNPDRT-YOPQJBRCSA-N 0.000 description 5
- 230000036541 health Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 229960001225 rifampicin Drugs 0.000 description 5
- OFNISBHGPNMTMS-UHFFFAOYSA-N 3-methylideneoxolane-2,5-dione Chemical compound C=C1CC(=O)OC1=O OFNISBHGPNMTMS-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 229960000285 ethambutol Drugs 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 4
- FJDUDHYHRVPMJZ-UHFFFAOYSA-N nonan-1-amine Chemical compound CCCCCCCCCN FJDUDHYHRVPMJZ-UHFFFAOYSA-N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229960005322 streptomycin Drugs 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- TVOSOIXYPHKEAR-UHFFFAOYSA-N 4-piperidin-1-ylaniline Chemical compound C1=CC(N)=CC=C1N1CCCCC1 TVOSOIXYPHKEAR-UHFFFAOYSA-N 0.000 description 3
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 3
- KGTSLTYUUFWZNW-PPJQWWMSSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-[(E)-(4-methylpiperazin-1-yl)iminomethyl]-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(29),2,4,9,19,21,25,27-octaen-13-yl] acetate pyridine-4-carbohydrazide Chemical compound NNC(=O)c1ccncc1.CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c(O)c(\C=N\N4CCN(C)CC4)c(NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C KGTSLTYUUFWZNW-PPJQWWMSSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 150000003949 imides Chemical class 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- AYMUQTNXKPEMLM-UHFFFAOYSA-N 1-bromononane Chemical compound CCCCCCCCCBr AYMUQTNXKPEMLM-UHFFFAOYSA-N 0.000 description 2
- HDQFSORQWDQSJZ-UHFFFAOYSA-N 3-methyl-1-(4-piperidin-1-ylphenyl)pyrrole-2,5-dione Chemical class O=C1C(C)=CC(=O)N1C1=CC=C(N2CCCCC2)C=C1 HDQFSORQWDQSJZ-UHFFFAOYSA-N 0.000 description 2
- AYKYXWQEBUNJCN-UHFFFAOYSA-N 3-methylfuran-2,5-dione Chemical compound CC1=CC(=O)OC1=O AYKYXWQEBUNJCN-UHFFFAOYSA-N 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N Cysteine Chemical compound SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241000186359 Mycobacterium Species 0.000 description 2
- 241000186367 Mycobacterium avium Species 0.000 description 2
- 241000186366 Mycobacterium bovis Species 0.000 description 2
- 241000187492 Mycobacterium marinum Species 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 235000019270 ammonium chloride Nutrition 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
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000007918 pathogenicity Effects 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
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- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- PZQWVKKXPIZFHC-UHFFFAOYSA-N 1-decylpyrrole-2,5-dione Chemical compound CCCCCCCCCCN1C(=O)C=CC1=O PZQWVKKXPIZFHC-UHFFFAOYSA-N 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- PSIWJOHYNXFGLO-UHFFFAOYSA-N 3-(ethylamino)-4-sulfanylpyrrole-2,5-dione Chemical compound CCNC1=C(S)C(=O)NC1=O PSIWJOHYNXFGLO-UHFFFAOYSA-N 0.000 description 1
- VFSPFAZQYIAAAH-UHFFFAOYSA-N 3-methyl-1-nonylpyrrole-2,5-dione Chemical compound CCCCCCCCCN1C(=O)C=C(C)C1=O VFSPFAZQYIAAAH-UHFFFAOYSA-N 0.000 description 1
- DQQOONVCLQZWOY-UHFFFAOYSA-N 4-hexoxybenzoyl chloride Chemical compound CCCCCCOC1=CC=C(C(Cl)=O)C=C1 DQQOONVCLQZWOY-UHFFFAOYSA-N 0.000 description 1
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 1
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- GJXWDTDPUKVAOQ-UHFFFAOYSA-N C(=O)Cl.C(C)(C)(C)C1=CC=CC=C1 Chemical compound C(=O)Cl.C(C)(C)(C)C1=CC=CC=C1 GJXWDTDPUKVAOQ-UHFFFAOYSA-N 0.000 description 1
- YHSNUGDHZRHVTI-UHFFFAOYSA-N C(=O)Cl.C(CCC)C1=CC=CC=C1 Chemical compound C(=O)Cl.C(CCC)C1=CC=CC=C1 YHSNUGDHZRHVTI-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-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
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- VLQHNAMRWPQWNK-UHFFFAOYSA-N benzyl 2-aminoacetate;hydron;chloride Chemical compound Cl.NCC(=O)OCC1=CC=CC=C1 VLQHNAMRWPQWNK-UHFFFAOYSA-N 0.000 description 1
- CANCPUBPPUIWPX-UHFFFAOYSA-N benzyl 3-aminopropanoate Chemical compound NCCC(=O)OCC1=CC=CC=C1 CANCPUBPPUIWPX-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940018557 citraconic acid Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940078469 dl- cysteine Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- LKRMTUUCKBQGFO-UHFFFAOYSA-N n-phenylpiperidin-4-amine Chemical compound C1CNCCC1NC1=CC=CC=C1 LKRMTUUCKBQGFO-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical class O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- 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
- A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
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- 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
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
通式(I)的化合物或者其可药用盐或溶剂化物在制备治疗分枝杆菌性疾病的药物中的应用,其中x是0或1;R1、R2、R3和R4具有说明书中给出的含义。
Description
本发明涉及用于治疗分枝杆菌性疾病,尤其是由病原性分支杆菌,例如结核分枝杆菌、牛分枝杆菌、鸟分枝杆菌和海分枝杆菌引起的疾病的化合物。
肺结核仍是一个影响世界各地区的主要公共卫生问题。根据皮试反应,估计有约占世界人口三分之一的人,即17亿人被结核分枝杆菌感染。虽然可利用有效的化疗,但每年仍有三百万人死亡,并有八百万至一千万万人被感染,因此在世界范围内,由于单纯性感染而导致的死亡人数占可避免的死亡人数的26%,占所有死亡人数的7%。据世界卫生组织的报告,发展中国家中,年龄在十五岁以下儿童中每年由于结核而死亡的人数为450000,而且该疾病主要影响较年轻的、更有劳动力的成年人。
众所周知,有五种对结核分枝杆菌特别有效的的一线药物,以及当检测出对一种或多种一线药物耐药时可使用的五种二线药物。结核的优选治疗方式是分两个阶段的短期化疗。第一阶段包括每日服用异烟肼(300mg)、利福平(600mg)、吡嗪酰胺(3g)和乙胺丁醇(1.5g)的两个月方案。第二阶段或后续阶段包括每日服用异烟肼和利福平的接着的四个月方案。虽然在大多数国家采用短期化疗可有效地治愈药物敏感性结核分枝杆菌感染,但由于顺应性差(这是长期化疗反映出来的),治愈率很低。
由于耐受多种药物的结核(MDR-TB)菌株的快速出现而使情况变得更加复杂。例如,在某些患者中,对异烟肼耐药的发生率高达26%,对利福平耐药的发生率高达约15%。在1984年前,从美国患者中分离的结核杆菌的约10%对至少一种分枝杆菌药物耐药。到1984年,该数据已上升为52%,其中超过半数(32%)的菌株对一种以上的药物耐药(MDR-TB)。所记录的MDR-TB的10%发生于以前健康的人中,他们的死亡率(70-90%)已接近感染MDR-TB的免疫抑制性患者的死亡率。自1984年以来,MDR-TB的数量已翻了一番,其中许多结核杆菌对异烟肼和利福平都耐药。诊断MDR-TB存在和死亡的平均间隔仅为四周,因此MDR-TB要求缩短诊断和开始适宜治疗之间的时间。但是,MDR-TB难以治疗,因为大多数患者对二线药物不产生很好的反应,而且改变治疗方法(包括住院和可能的手术),其成本将增至传统治疗的十倍。
因此,仍然迫切需要对一种药物或多种药物耐药的结核分枝杆菌具有明显治疗活性的并且具有许可剂量减少的药代动力学性质的新药,剂量的减少将有助于激励较好的顺应性。
本发明提供一种通式(I)的化合物或者其可药用盐或溶剂化物在制备治疗分枝杆菌性疾病,尤其是结核的药物中的应用,
其中x是0或1;
R1表示氢原子;或C1-C20烷基或桃金娘烷基;或苯基或苄基,它们的芳环上可任选地被一个或多个选自下述的取代基取代:氨基、硝基、羟基、羧基、卤素、三氟甲基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氧羰基、哌啶基、哌嗪基和吗啉基;或(CH2)yCONH-R5基,其中y是1-6的整数,R5表示苯基,它可任选地被一个或多个选自下述的取代基取代:氨基、硝基、羟基、羧基、卤素、三氟甲基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氧羰基、哌啶基、哌嗪基和吗啉基;和
R2表示氢原子或C1-C6烷基;或者R2与R3一起表示一个碳-碳单键,条件是x是0;或者R2与R4一起表示=CH2基,
R3表示氢原子或与R2相连(如上所定义),和
R4表示氢原子或C1-C6烷基;或可任选地被二(C1-C6烷基)氨基取代基取代的C1-C10烷基氨基;或者苯胺基,该基团的芳环上可任选被一个或多个选自下述的取代基取代:氨基、硝基、羟基、羧基、卤素、三氟甲基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氧羰基、哌啶基、哌嗪基和吗啉基;或者-SCH2CH2OH、-SCH2CH2NH2、-SCH2CH2(NH2)CO2H或-SCH2CH2NHCO-R6基,其中R6表示C1-C10烷基或C3-C6环烷基,或者苯基,该苯基可任选地被一个或多个选自下述的取代基取代:氨基、硝基、羟基、羧基、卤素、三氟甲基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氧羰基、哌啶基、哌嗪基和吗啉基;
或者R4与R2相连(如上所定义);
或者
R2、R3和R4一起表示苯基;
条件是:
(i)R1、R2、R3和R4每个不同时表示氢原子,
(ii)当x是0,R1表示4-氟苯基并且R4表示氢原子时,则R2和R3不一起表示碳-碳单键,并且
(iii)当x是0,R1表示4-氟苯基并且R2和R3都表示氢原子时,则R4不表示苯胺基、4-氯苯胺基、2,6-二氯苯胺基、3,4-二氯苯胺基、2,5-二氯苯胺基、3-氯-4-氟苯胺基或4-氟苯胺基。
在本说明书中,除非另有说明,烷基(取代基)或者烷氧基或烷氧羰基取代基中的烷基部分可以是直链或支链的。
式(I)中R1优选表示氢原子;或C1-C15,更优选C1-C10烷基或桃金娘烷基;或苯基或苄基,它们的芳环上可任选地被一个至四个,优选一或两个选自下述的取代基取代:氨基、硝基、羟基、羧基、卤素(如氟、氯或溴)、三氟甲基、C1-C4烷基(如甲基、乙基、丙基、异丙基或丁基)、C1-C4烷氧基(如甲氧基、乙氧基、丙氧基或丁氧基)、C1-C4烷氧羰基(如甲氧羰基、乙氧羰基、丙氧羰基或丁氧羰基)、哌啶基、哌嗪基和吗啉基;或(CH2)yCONH-R5基,其中y是1、2、3或4的整数,R5表示苯基,它可任选地被一至四个,优选一或两个选自下述的取代基取代:氨基、硝基、羟基、羧基、卤素(如氟、氯或溴)、三氟甲基、C1-C4烷基(如甲基、乙基、丙基、异丙基或丁基)、C1-C4烷氧基(如甲氧基、乙氧基、丙氧基或丁氧基)、C1-C4烷氧羰基(如甲氧羰基、乙氧羰基、丙氧羰基或丁氧羰基)、哌啶基、哌嗪基和吗啉基。
R1优选表示氢原子;或C4-C10烷基(如丁基、戊基、己基、庚基、辛基、壬基或癸基)或桃金娘烷基;或被哌啶取代基取代的苯基;或(CH2)yCONH-R5基,其中y是1或2,R5表示被哌啶取代基取代的苯基。
R2优选表示氢原子或C1-C4烷基,尤其是甲基;或者R2与R3一起表示一个碳-碳单键,条件是x是0;或者R2与R4一起表示=CH2基。
R4优选表示氢原子或C1-C4烷基(如甲基、乙基、丙基或丁基);或可任选地被二(C1-C6烷基)氨基,尤其是二(C1-C4烷基)氨基取代基取代的C2-C10烷基氨基;或者苯胺基,该基团的芳环上可任选被一个至四个,尤其是1或2个选自下述的取代基取代:氨基、硝基、羟基、羧基、卤素(如氟、氯或溴)、三氟甲基、C1-C4烷基(如甲基、乙基、丙基、异丙基或丁基)、C1-C4烷氧基(如甲氧基、乙氧基、丙氧基或丁氧基)、C1-C4烷氧羰基(如甲氧羰基、乙氧羰基、丙氧羰基或丁氧羰基)、哌啶基、哌嗪基和吗啉基;或者-SCH2CH2OH、-SCH2CH2NH2、-SCH2CH2(NH2)CO2H或-SCH2CH2NHCO-R6基,其中R6表示C5-C10烷基或C3-C6环烷基,或者苯基,该苯基可任选地被一个或多个选自下述取代基取代:氨基、硝基、羟基、羧基、卤素(如氟、氯或溴)、三氟甲基、C1-C4烷基(如甲基、乙基、丙基、异丙基或丁基)、C3-C6烷氧基(如丙氧基、丁氧基、戊氧基或己氧基)、C1-C4烷氧羰基(如甲氧羰基、乙氧羰基、丙氧羰基或丁氧羰基)、哌啶基、哌嗪基和吗啉基;或者R4与R2相连(如上所定义)。
R4优选表示氢原子、甲基或乙基;或可任选地被二(C2-C4烷基)氨基取代基取代的C2-C10烷基氨基;或者被哌啶取代基取代的苯胺基;或者-SCH2CH2OH、-SCH2CH2NH2、-SCH2CH2(NH2)CO2H或-SCH2CH2NHCO-R6基,其中R6表示C7烷基、环丙基、环戊基或环己基,或者被硝基、C1-C4烷基或C3-C6烷氧基取代基取代的苯基;或者R4与R2相连(如上所定义)。
特别优选的式(I)化合物包括:
1-癸基吡咯烷-2,5-二酮,
1-壬基哌啶-2,6-二酮,
2-((6,6-二甲基双环[3.1.1]庚-2-基)甲基)异吲哚-1,3-二酮,
1-((6,6-二甲基双环[3.1.1]庚-3-基)甲基)-3-甲基-3-吡咯啉-2,5-二酮,
3-甲基-1-壬基-3-吡咯啉-2,5-二酮,
3-亚甲基-1-壬基吡咯烷-2,5-二酮,
3-甲基-1-辛基-3-吡咯啉-2,5-二酮,
3-亚甲基-1-辛基吡咯烷-2,5-二酮,
(4-(3-甲基-2,5-二氧代-3-吡咯啉基)苯基)哌啶,
1-辛基-3-吡咯啉-2,5-二酮,
1-癸基-3-吡咯啉-2,5-二酮,
1-壬基-3-吡咯啉-2,5-二酮,
1-丁基-3-吡咯啉-2,5-二酮,
1-己基-3-吡咯啉-2,5-二酮,
1-(4-哌啶基苯基)-3-吡咯啉-2,5-二酮,
1-辛基-3-(辛基氨基)-吡咯烷-2,5-二酮,
1-癸基-3-(癸基氨基)-吡咯烷-2,5-二酮,
3-(辛基氨基)-3-吡咯烷-2,5-二酮,
3-(庚基氨基)-1-壬基吡咯烷-2,5-二酮,
1-壬基-3-(壬基氨基)吡咯烷-2,5-二酮,
1-壬基-3-(辛基氨基)吡咯烷-2,5-二酮,
2-氨基-3-(3-甲基-1-壬基-2,5-二氧代-吡咯烷-3-基硫)丙酸,
2-氨基-3-(3-甲基-1-辛基-2,5-二氧代-吡咯烷-3-基硫)丙酸,
2-氨基-3-(1-辛基-2,5-二氧代-吡咯烷-3-基硫)丙酸,
3-甲基-1-辛基吡咯烷-2,5-二酮,
3-甲基-1-壬基吡咯烷-2,5-二酮,
2-(2,5-二氧代吡咯烷基)-N-(4-哌啶基苯基)乙酰胺,
2-(2,5-二氧代吡咯烷基)-N-(4-哌啶基苯基)丙酰胺,
3-乙基-1-壬基吡咯烷-2,5-二酮,
3-(2-氨基乙硫基)-1-壬基吡咯烷-2,5-二酮,
2-乙基-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)己酰胺,
环丙基-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
(4-丁基苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
(4-己氧基苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
(4-甲苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
(4-(叔丁基)苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
环戊基-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,乙烷,
环己基-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
(4-硝基苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
3-((2-(二丁基氨基)乙基)氨基)-1-壬基吡咯烷-2,5-二酮,
3-((2-(二乙氨基)乙基)氨基)-1-壬基吡咯烷-2,5-二酮,
1-壬基-3-((4-哌啶基苯基)氨基)吡咯烷-2,5-二酮,
3-(羟基乙硫基)-3-甲基-1-壬基吡咯烷-2,5-二酮,
3-(2-氨基乙硫基)-3-甲基-1-壬基吡咯烷-2,5-二酮,和
3-甲基-1-辛基-3-(辛基氨基)吡咯烷-2,5-二酮。
式(I)化合物是已知化合物,或可采用本领域的常规技术制备。如果需要,可将式(I)化合物转化为其可药用盐或溶剂化物,优选酸加成盐,例如盐酸盐、氢溴酸盐、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、草酸盐、甲磺酸盐或对甲苯磺酸盐,或者碱金属盐,如钠或钾盐。
某些式(I)化合物可以立体异构体形式存在。应该理解本发明包括式(I)化合物的所有几何和光学异构体及它们的混合物,包括外消旋体。式(I)化合物的互变异构体和它们的混合物也构成了本发明的一部分。
式(I)化合物对分枝杆菌,尤其是病原性分支杆菌,例如结核分枝杆菌、牛分枝杆菌、鸟分枝杆菌和海分枝杆菌具有杀菌活性。
因此,另一方面,本发明提供一种患有分枝杆菌性疾病或有患分枝杆菌性疾病危险的患者的治疗方法,该方法包括给予所述患者治疗有效量的如上定义的式(I)化合物或者其可药用盐或溶剂化物。
式(I)化合物及其可药用盐和溶剂化物可以它们自身的形式使用,但通常是以其中式(I)化合物/盐/溶剂化物(活性成分)与可药用辅剂、稀释剂或载体结合的药物组合物形式施用。根据给药方式的不同,药物组合物优选含有0.05-99%w(重量百分数),更优选含有0.10-70%w的活性成分,以及优选含有1-99.95%w,更优选含有30-99.90%w的可药用辅剂、稀释剂或载体,所有的重量百分数均基于组合物的总重。药物组合物还可含有另一种抗结核药物和/或本领域已知的各种其它成分,例如润滑剂、稳定剂、缓冲剂、乳化剂、粘度调节剂、表面活性剂、防腐剂、芳香剂或着色剂。
当然,式(I)化合物的每日给药剂量将随使用的化合物、给药方式、需要的治疗和所示的分枝杆菌疾病而变化。但当以不超过1g,例如10-50mg/kg体重的每日剂量施用式(I)化合物时,通常可获得令人满意的结果。
式(I)化合物可***性地给药,例如以片剂、胶囊、糖浆、粉末或颗粒形式通过口服或以溶液或悬浮液形式通过非胃肠给药。
本发明将用下列说明性实施例来作进一步说明。
实施例1
1-癸基吡咯烷-2,5-二酮
在0℃下,将溶于无水二甲基甲酰胺的琥珀酰亚胺(0.1M)用氢化钠(0.1M)处理。然后加入壬基溴(0.1M)并将该反应混合物在室温下搅拌3小时。该反应混合物真空浓缩,残余物用乙酸乙酯萃取。该乙酸乙酯层用水洗涤,经硫酸钠干燥并真空浓缩。所得的残余物经硅胶色谱,得到目的产物。
1HNMR:δ0.75(3H,t),1.10-1.20(12H,m),1.35-1.45(2H,m),2.55(4H,s),3.35(2H,dd)
实施例2
1-壬基哌啶-2,6-二酮
重复实施例1的方法,不同的是用戊二酰亚胺代替琥珀酰亚胺。
1HNMR:δ0.9(3H,t),1.2-1.3(12H,m),1.4-1.5(2H,m),1.9(2H,p),2.6(4H,t),
3.7(2H,dd)
实施例3
2-((6,6-二甲基双环[3.1.1]庚-2-基)甲基)异吲哚-1,3-二酮
将邻苯二甲酸酐(0.1M)的吡啶(20ml)溶液用(-)-顺桃金娘烷胺(0.1M)处理。将该反应混合物在90℃加热6小时。然后将该反应混合物真空浓缩,残余物用乙酸乙酯萃取。乙酸乙酯层用水和冷的盐酸水溶液洗涤,然后经硫酸钠干燥并最后真空干燥。如此获得的残余物经硅胶色谱,得到目的化合物。
1HNMR:δ0.85(1H,d),1.2(6H,d),1.5-1.65(2H,m),1.80-2.05(4H,m),2.27-2.35(1H,m),2.45-2.60(1H,m),3.60-3.75(2H,m),7.65-7.70(2H,m),7.78-7.85(2H,m)
实施例4
1-((6,6-二甲基双环[3.1.1]庚-3-基)甲基)-3-甲基-3-吡咯啉-
2,5-二酮
将柠康酸酐(0.1M)的吡啶(20ml)溶液用(-)-顺桃金娘烷胺(0.1M)处理。将该反应混合物在90℃加热6小时。然后将该反应混合物真空浓缩,残余物用乙酸乙酯萃取。乙酸乙酯层用水和冷的盐酸水溶液洗涤,然后经硫酸钠干燥并最后真空干燥。如此获得的残余物经硅胶色谱,得到目的化合物。
1HNMR:δ0.65(1H,d),1.0(6H,d),1.25-1.37(1H,m),1.55-1.80(5H,m),1.9(3H,s),2.08-2.25(2H,m),3.15-3.40(2H,m),6.1(1H,s)
实施例5
3-甲基-1-壬基-3-吡咯啉-2,5-二酮
将柠康酸酐(0.1M)的吡啶(20ml)溶液用壬胺(0.1M)处理。将该反应混合物在90℃加热6小时。然后将该反应混合物真空浓缩,残余物用乙酸乙酯萃取。乙酸乙酯层用水和冷的盐酸水溶液洗涤,然后经硫酸钠干燥并最后真空干燥。如此获得的残余物经硅胶色谱,得到目的化合物。
1HNMR:δ0.8(3H,t),1.15-1.30(12H,m),1.4-1.55(2H,m),2.05(3H,s),3.4(2H,dd),6.25(1H,s)
实施例6
3-亚甲基-1-壬基吡咯烷-2,5-二酮
将衣康酸酐(0.1M)的吡啶(20ml)溶液用壬胺(0.1M)处理。将该反应混合物在90℃加热6小时。然后将该反应混合物真空浓缩,残余物用乙酸乙酯萃取。乙酸乙酯层用水和冷的盐酸水溶液洗涤,然后经硫酸钠干燥并最后真空干燥。如此获得的残余物经硅胶色谱,得到目的化合物。
实施例7
3-甲基-1-辛基-3-吡咯啉-2,5-二酮
将衣康酸酐(0.1M)的吡啶(20ml)溶液用辛胺(0.1M)处理。将该反应混合物在90℃加热6小时。然后将该反应混合物真空浓缩,残余物用乙酸乙酯萃取。乙酸乙酯层用水和冷的盐酸水溶液洗涤,然后经硫酸钠干燥并最后真空干燥。如此获得的残余物经硅胶色谱,得到目的化合物。
1HNMR:δ0.85(3H,t),1.15-1.30(12H,m),1.45-1.60(2H,m),2.05(2H,s),3.45(2H,dd),6.27(1H,s)
实施例8
3-亚甲基-1-辛基吡咯烷-2,5-二酮
将衣康酸酐(0.1M)的吡啶(20ml)溶液用辛胺(0.1M)处理。将该反应混合物在90℃加热6小时。然后将该反应混合物真空浓缩,残余物用乙酸乙酯萃取。乙酸乙酯层用水和冷的盐酸水溶液洗涤,然后经硫酸钠干燥并最后真空干燥。如此获得的残余物经硅胶色谱,得到目的化合物。
1HNMR:δ 0.85(3H,t),1.20-1.35(10H,m),1.50-1.65(2H,m),3.3(2H,s),3.55(2H,dd),5.6(1H,s),6.35(1H,s)
实施例9
(4-(3-甲基-2,5-二氧代-3-吡咯啉基)苯基)哌啶
将衣康酸酐(0.1M)的吡啶(20ml)溶液用4-(1-哌啶基)苯胺(0.1M)处理。将该反应混合物在90℃加热6小时。然后将该反应混合物真空浓缩,残余物用乙酸乙酯萃取。乙酸乙酯层用水和冷的盐酸水溶液洗涤,然后经硫酸钠干燥并最后真空干燥。如此获得的残余物经硅胶色谱,得到目的化合物。
1HNMR:δ1.5-1.75(6H,m),2.12(3H,s),3.18(4H,t),6.4(1H,br s),6.95(2H,d),7.1(2H,d)
实施例10
1-辛基-3-吡咯啉-2,5-二酮
用15分钟时间,往保持在0℃下的马来酸酐(0.1M)的丙酮(150ml)溶液中滴加辛胺(0.1M)。将该反应混合物再搅拌1小时,将分离出来的白色结晶N-辛基马来酸过滤并干燥。
N-辛基马来酸(0.1M)和乙酸钠(0.1M)在乙酸酐(150ml)中的混合物用蒸汽浴加热2小时。真空除去乙酸酐,将残留的液体产物加到乙酸乙酯中,用水洗涤,经硫酸钠干燥并浓缩,得到粘稠的液体。经快速色谱纯化(10%乙酸乙酯的石油醚溶液),得到目的产物。
1HNMR:δ0.82(3H,t),1.15-1.4(10H,m),1.48-1.6(2H,m),3.45(2H.dd),6.65(2H,s)
实施例11
1-癸基-3-吡咯啉-2,5-二酮
用癸胺代替辛胺,重复实施例10的方法。
1HNMR:δ 0.85(3H,t),1.15-1.30(14H,m),1.50-1.60(2H,m),3.47(2H,dd),6.65(2H,s)
实施例12
1-壬基-3-吡咯啉-2,5-二酮
用壬胺代替辛胺,重复实施例10的方法。
lHNMR:δ0.85(3H,t),1.15-l-35(12H,m),1.5-1.6(2H,m),3.45(2H,c),6.65(1H,s)
实施例13
1-丁基-3-吡咯啉-2,5-二酮
用丁胺代替辛胺,重复实施例10的方法。
1HNMR:δ0.9(3H,t),1.25(2H.m),1.6(2H,m),3.5(2H,dd),6.65(2H,s)
实施例14
1-己基-3-吡咯啉-2,5-二酮
用己胺代替辛胺,重复实施例10的方法。
1HNMR:δ0.85(3H,t),1.2-1.35(6H,m),1.45-1.60(2H,m),3.45(2H,dd),6.65(2H,s)
实施例15
1-(4-哌啶基苯基)-3-吡咯啉-2,5-二酮
用4-(哌啶基)苯胺代替辛胺,重复实施例10的方法。
1HNMR:δ1.5-1.65(6H,m),3.0-3.12(4H,m),6.80(2H,s),6.95(2H,d),7.1(2H,d)
实施例16
1-辛基-3-(辛基氨基)-吡咯烷-2,5-二酮
在室温下,将如上面的实施例10制备的N-辛基马来酰亚胺(0.01M)、辛胺(0.01M)、三乙胺[催化剂,0.1当量]在乙腈(25ml)中的混合物搅拌24小时。真空除去乙腈,残留的液体产物经快速色谱(25%乙酸乙酯的石油醚溶液),得到白色固体的目的产物。
1HNMR:δ0.8(6H,t),1.15-1.35(20H,m),1.45-1.65(4H,m),1.7(1H,s),2.45-2.65(3H,m),2.88(1H,dd),3.25(2H,dd),3.7(1H,dd)
实施例17
1-癸基-3-(癸基氨基)-吡咯烷-2,5-二酮
在室温下,将如上面的实施例11制备的N-癸基马来酰亚胺(0.01M)、癸胺(0.01M)、三乙胺[催化剂,0.1当量]在乙腈(25ml)中的混合物搅拌24小时。真空除去乙腈,残留的液体产物经快速色谱(25%乙酸乙酯的石油醚溶液),得到白色固体的目的产物。
1HNMR:δ0.8(6H,t),1.15-1.35(24H,m),1.45-1.65(4H,m),1.7(1H,s),2.45-2.65(3H,m),2.88(1H,dd),3.25(2H,dd),3.71(1H,dd)
实施例18
3-(辛基氨基)-3-吡咯烷-2,5-二酮
在室温下,将马来酰亚胺(0.01M)、辛胺(0.01M)、三乙胺[催化剂,0.1当量]在乙腈(25ml)中的混合物搅拌24小时。真空除去乙腈,残留的液体产物经快速色谱(25%乙酸乙酯的石油醚溶液),得到白色固体的目的产物。
1HNMR:δ0.85(3H,t),1.15-1.35(10H,m),1.42-1.55(2H,m),2.50-2.70(3H,m),2.90(1H,dd),2.80(1H,dd)
实施例19
3-(庚基氨基)-1-壬基吡咯烷-2,5-二酮
在室温下,将如上面的实施例12制备的N-壬基马来酰亚胺(0.01M)、庚胺(0.01M)、三乙胺[催化剂,0.1当量]在乙腈(25ml)中的混合物搅拌24小时。真空除去乙腈,残留的液体产物经快速色谱(25%乙酸乙酯的石油醚溶液),得到白色固体的目的产物。
实施例20
1-壬基-3-(壬基氨基)吡咯烷-2,5-二酮
在室温下,将如上面的实施例12制备的N-壬基马来酰亚胺(0.01M)、壬胺(0.01M)、三乙胺[催化剂,0.1当量]在乙腈(25ml)中的混合物搅拌24小时。真空除去乙腈,残留的液体产物经快速色谱(25%乙酸乙酯的石油醚溶液),得到白色固体的目的产物。
1HNMR:δ0.85(6H,t),1.15-1.38(24H,m),1.40-1.55(4H,m),1.70(1H,br s),2.45-2.70(3H,m),2.85(1H,dd),3.45(2H,dd),3.70(1H,dd)
实施例21
1-壬基-3-(辛基氨基)吡咯烷-2,5-二酮
在室温下,将如上面的实施例12制备的N-壬基马来酰亚胺(0.01M)、辛胺(0.01M)、三乙胺[催化剂,0.1当量]在乙腈(25ml)中的混合物搅拌24小时。真空除去乙腈,残留的液体产物经快速色谱(25%乙酸乙酯的石油醚溶液),得到白色固体的目的产物。
1HNMR:δ0.8-0.9(6H,m),1.18-1.30(20H,m),1.35-1.60(4H,m),2.5-2.6(3H,m),2.7-3.0(5H,m),3.45(2H,dd)
实施例22
2-氨基-3-(3-甲基-1-壬基-2,5-二氧代-吡咯烷-3-基硫)丙酸
将DL-半胱氨酸(0.0067M)溶于乙酸钾(50mM),将该所得溶液缓慢地加到如上面的实施例6制备的N-壬基衣康酰亚胺(0.004M)中。然后,在轻轻搅拌下,将该反应混合物溶于二甲基甲酰胺并加入三乙胺。在室温下再搅拌4小时。通过反相薄层色谱,用75%甲醇水溶液展开***检测反应进程。通过茚三酮反应检测目的产物的形成。
实施例23
2-氨基-3-(3-甲基-1-辛基-2,5-二氧代-吡咯烷-3-基硫)丙酸
用上面实施例8的亚胺重复实施例22的方法。
1HNMR:δ0.85(3H,t),1.15-1.32(10H,m),1.3(3H,d),1.4-1.52(2H,m).2.65-2.85(2H,m),3.00-3.30(2H,m),3.42(2H,t),3.85(1H,dd)
实施例24
2-氨基-3-(1-辛基-2,5-二氧代-吡咯烷-3-基硫)丙酸
用上面实施例10的亚胺重复实施例22的方法。
实施例25
3-甲基-1-辛基吡咯烷-2,5-二酮
将10%的披钯碳催化剂(5wt%)加到搅拌下的如上面的实施例5制备的N-壬基衣康酰亚胺(0.02M)在甲醇(100ml)中的溶液中。往该溶液中通入3小时氢气。然后将该溶液滤过硅藻土并真空浓缩。经硅胶色谱,得到目的产物。
1HNMR:δ0.85(3H,t),1.15-1.3(10H,m),1.3(3H,d),1.47-1.60(2H,m),2.28(1H,dd),
2.77-2.95(2H,m),3.45(2H,dd)
实施例26
3-甲基-1-壬基吡咯烷-2,5-二酮
用如上面实施例7所述方法制备的N-辛基衣康酰亚胺重复实施例25的方法。
1HNMR:δ0.85(3H,t),1.15-1.3(12H,m),1.3(3H,d),1.47-1.60(2H,m),2.28(1H,dd),2.77-2.95(2H,m),3.45(2H,dd)
实施例27
2-(2,5-二氧代吡咯烷基)-N-(4-哌啶基苯基)乙酰胺
将甘氨酸苄基酯盐酸盐(0.1mM)的***溶液用三乙胺(0.11mM)处理,然后用琥珀酸酐(0.11mM)处理。将该反应混合物在室温下搅拌2小时后,分配到10%盐酸水溶液和乙酸乙酯中。分离乙酸乙酯层,经硫酸钠干燥并真空浓缩,得到黄色油状物。
将该油状物溶于含乙酸钠(0.1mM)的乙酸酐(20ml)中并在90℃加热3小时。将该反应混合物冷却,倾入水中并用乙酸乙酯萃取三次。分离乙酸乙酯层,经硫酸钠干燥并真空浓缩,得到黄色油状物。经硅胶色谱,得到琥珀-酰甘氨酸苄基酯。
将10%披钯碳催化剂(5%wt)加到搅拌下的琥珀-酰苄基酯(0.009M)的甲醇(50mL)溶液中。往该溶液中通入3小时的氢气。然后将该溶液滤过硅藻土并真空浓缩,得到白色固体的相应酸。
将该酸(0.1mM)的无水二氯甲烷溶液冷却到0℃并用二甲基甲酰胺(0.1mM)处理,然后用草酰氯(0.1mM)处理。移走冷却浴,将反应混合物回流1小时。然后将(4-哌啶基)苯胺(0.1mM)加到该反应混合物中,并将该溶液在室温搅拌2小时。用二氯甲烷稀释该反应混合物后,用饱和碳酸氢钠水溶液和水洗涤。有机层经硫酸钠干燥并真空浓缩。所得的残余物经色谱,得到目的产物。
1HNMR:δ1.5-1.7(6H,m),2.8(4H,s),3.10(4H,t),4.3(2H,s),6.85(2H,d),7.30(2H,d),7.42(1H,brs)
实施例28
2-(2,5-二氧代吡咯烷基)-N-(4-哌啶基苯基)丙酰胺
用β-丙氨酸苄基酯盐酸盐替代,重复实施例27的方法。
1HNMR:δ1.50-1.85(6H,m),2.65-2.80(6H,m),3.05(4H,t),3.9(2H,t),6.85(2H,d),7.35(2H,d),7.4-7.5(1H、brs)
实施例29
3-乙基-1-壬基吡咯烷-2,5-二酮
在-78℃下,将含六甲基磷酰三胺的琥珀酰亚胺(15.15mM)的四氢呋喃(15ml)溶液用二异丙基氨基锂(30.30mM)的四氢呋喃(25ml)溶液处理。该溶液在-78℃搅拌1小时后,用碘乙烷(15.90mM)处理。将该反应混合物在-78℃下搅拌30分钟后,温热到室温,然后用饱和氯化铵水溶液使反应停止。分离有机层,水层用乙酸乙酯萃取(3×25ml)。合并的有机层用10%硫代硫酸钠水溶液、盐水洗涤,经硫酸钠干燥并真空浓缩。经硅胶色谱,得到纯净的3-乙基琥珀酰亚胺。
将3-乙基琥珀酰亚胺(4.72mM)的二甲基甲酰胺(10ml)溶液用氢化钠(5.20mM)和壬基溴(5.20mM)处理。将该反应混合物在室温搅拌2小时后,用饱和氯化铵水溶液使反应停止。分离有机层,水层用乙酸乙酯萃取(3×25ml)。合并的有机层用10%硫代硫酸钠水溶液、盐水洗涤,经硫酸钠干燥并真空浓缩。经硅胶色谱,得到目的产物,纯净的3-乙基N-壬基琥珀酰亚胺。
1HNMR:δ0.8(3H,t),0.9(3H,t),1.15-1.35(12H,m),1.45-1.65(3H,m),1.80-1.95(1H,m),2.35(1H,dd),2.6-2.95(2H,m),3.45(2H,dd)
实施例30
3-(2-氨基乙硫基)-1-壬基吡咯烷-2,5-二酮
将如上面的实施例12制备的N-壬基马来酰亚胺(0.01M)、巯基乙胺(0.01M)和三乙胺(0.001M)在乙腈(50ml)中的混合物在室温搅拌24小时。真空蒸发乙腈,获得的残余物用乙酸乙酯(25ml)研制。将所得的悬浮液过滤并用乙酸乙酯洗涤固体。将该固体干燥后,鉴别为目的产物N-壬基,3-巯基乙胺马来酰亚胺。
1HNMR:δ0.85(3H,t),1.15-1.35(12H,m),1.45-1.55(2H,m),2.55(2H,dd),3.1-3.3(2H,m),3.35-3.50(4H,m),4.1(1H,dd),7.5-7.9(2H,broads)
实施例31
2-乙基-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)己酰
胺
将如上面的实施例30制备的N-壬基,3-巯基乙氨基马来酰亚胺(0.5mM)在2ml二氯甲烷中的溶液用一当量三乙胺和一当量2-乙基己酰氯处理。将该反应混合物搅拌5小时。然后蒸发二氯甲烷,得到残余物,往其中加入饱和碳酸氢钠溶液(2ml)并搅拌30分钟,然后加入乙酸乙酯(2ml)并搅拌30分钟。分离乙酸乙酯层并浓缩,得到目的产物。
实施例32
环丙基-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰
胺
用环丙烷甲酰氯替代,重复实施例31的方法。
实施例33
(4-丁基苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙
基)甲酰胺
用4-丁基苯甲酰氯替代,重复实施例31的方法。
实施例34
(4-己氧基苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)
乙基)甲酰胺
用4-己氧基苯甲酰氯替代,重复实施例31的方法。
实施例35
(4-甲苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)
甲酰胺
用4-甲基苯甲酰氯替代,重复实施例31的方法。
实施例36
(4-(叔丁基)装基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基
硫)乙基)甲酰胺
用4-叔丁基苯甲酰氯替代,重复实施例31的方法。
实施例37
环戊基-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰
胺,乙烷
用环戊烷甲酰氯替代,重复实施例31的方法。
实施例38
环己基-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰
胺
用环己烷甲酰氯替代,重复实施例31的方法。
实施例39
(4-硝基苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙
基)甲酰胺
用4-硝基苯甲酰氯替代,重复实施例31的方法。
实施例40
3-((2-(二丁基氨基)乙基)氨基)-1-壬基吡咯烷-2,5-二酮
将如上面实施例12制备的N-壬基马来酰亚胺(0.02mM)在2ml乙腈中的溶液用一当量三乙胺和一当量N,N-二丁基亚乙基二胺处理。将该反应混合物搅拌6小时后,蒸发乙腈。将所得的残余物用冷的稀盐酸水溶液和乙酸乙酯处理并搅拌1小时。然后分离乙酸乙酯层并浓缩,得到目的产物。
实施例41
3-((2-(二乙氨基)乙基)氨基)-1-壬基吡咯烷-2,5-二酮
用3-二乙氨基-1-甲基丙胺替代,重复实施例40的方法。
实施例42
1-壬基-3-((4-哌啶基苯基)氨基)吡咯烷-2,5-二酮
用4-(哌啶基)苯胺替代,重复实施例40的方法。
实施例43
3-(羟基乙硫基)-3-甲基-1-壬基吡咯烷-2,5-二酮
将如上面的实施例5中所述制备的N-壬基柠康酰亚胺(0.5mM)的二甲基甲酰胺(10ml)溶液用三乙胺(0.5mM)处理,然后滴加2-巯基乙醇(0.5mM)。通过薄层色谱检测反应进程,当检测不到原料时,将反应混合物真空浓缩。所得的残余物溶于乙酸乙酯,用水洗涤并经硫酸钠干燥。通过色谱纯化,得到目的产物。
实施例44
3-(2-氨基乙硫基)-3-甲基-1-壬基吡咯烷-2,5-二酮
用2-巯基乙胺替代,重复实施例43的方法。
实施例45
3-甲基-1-辛基-3-(辛基氨基)吡咯烷-2,5-二酮
将如上面实施例7所述制备的N-辛基柠康酸亚胺(0.223g,1mM)的乙腈(2ml)溶液用三乙胺(0.14ml,1mM)处理,然后滴加辛胺(0.165ml,1mM)。通过薄层色谱检测反应进程,当检测不到原料时,将反应混合物真空浓缩。所得的残余物溶于乙酸乙酯,用水洗涤并经硫酸钠干燥。通过色谱纯化,得到目的产物。
1HNMR:δ0.8(6H,t),1.10-1.28(20H,m),1.3(3H,s),1.32-1.58(4H,m),2.25-2.48(2H,m),2.50 & 2.80(2H,ABq),3.42(2H,dd)
实施例46
通过在由Becton-Dickinson Diagnostic Instrument Systems,Sparks,U.S.A开发的“BACTEC”(商标)***中测量其最低抑制浓度(MIC)评价实施例1-45的各种化合物对结核分枝杆菌的杀菌活性,所述***根据放射分析原理,以被认为是生长指数(GI)单位的任意测量单位采用分光光度分析法测定和定量由C14-棕榈酸酯分解代谢释放的二氧化碳。
在“BACTEC”小瓶中接种0.1ml结核分枝杆菌(最终细菌浓度,1×105菌落形成单位/毫升)和一定浓度范围的0.1ml试验化合物。监测GI值直至1∶100稀释对照的GI值≥30。
对于该试验目的,MIC被定义为与未稀释的对照相比,当对照的GI值达到999时,对培养物产生>95%抑制作用的试验化合物的最低抑制浓度。
根据去除1%耐药菌的常规做法(如果观察到生长的细菌的数量高于1%,则认为微生物对特定浓度的试验化合物耐药)决定终点(>99%抑制)。比较在预定浓度的试验化合物的存在下的微生物生长和在没有任何试验化合物的存在下1∶100稀释的同种微生物的生长之间进行。用GI值的变化(ΔGI)决定微生物对试验化合物的终点敏感性。如果1∶100稀释的对照的ΔGI大于试验化合物存在下的ΔGI,则所采用的试验化合物浓度被认为是对微生物杀菌的(抑制作用>99%)。测定了实施例1-46的化合物对下列结核分枝杆菌的MIC:
H37Rv,
H37Ra,
对异烟肼、利福平、乙胺丁醇和链霉素敏感的1个临床分离菌株[E:22/95;Estonia],
对异烟肼耐药的1个临床分离菌株[H:997/94;Honduras],对异烟肼和乙胺丁醇耐药的1个临床分离菌株[E:5/94;Estonia],
对异烟肼和利福平耐药的1个临床分离菌株[H:44/95;Honduras],
对异烟肼和链霉素耐药的1个临床分离菌株[S:150/96;Sweden],对异烟肼/利福平和链霉素耐药的1个临床分离株[AA:063;Ethiopia],
对异烟肼、利福平、链霉素和乙胺丁醇耐药的3个临床分离株[P:24/95;Estonia,S:39/95;Nepal,S:42/95;China,H:1005/94;Honduras],
发现对所有菌株的MIC均小于或等于20μg/ml。因此,实施例1-46的化合物对包括对一种和多种药物耐药在内的上述结核分枝杆菌显示出有效的杀菌活性。
Claims (6)
1.一种通式(I)的化合物或者其可药用盐或溶剂化物在制备治疗分枝杆菌性疾病的药物中的应用,
其中x是0或1;
R1表示氢原子;或C1-C20烷基或桃金娘烷基;或(CH2)yCONH-R5基,其中y是1-6的整数,R5表示苯基,它可任选地被一个或多个选自下述的取代基取代:氨基、硝基、羟基、羧基、卤素、三氟甲基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氧羰基、哌啶基、哌嗪基和吗啉基;和
R2表示氢原子或C1-C6烷基;或者R2与R3一起表示一个碳-碳单键,条件是x是0;或者R2与R4一起表示=CH2基,
R3表示氢原子,或者R3与如上所定义的R2相连,和
R4表示氢原子或C1-C6烷基;或可任选地被二(C1-C6烷基)氨基取代基取代的C1-C10烷基氨基;或者苯胺基,该基团的芳环上可任选被一个或多个选自下述的取代基取代:氨基、硝基、羟基、羧基、卤素、三氟甲基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氧羰基、哌啶基、哌嗪基和吗啉基;或者-SCH2CH2OH、-SCH2CH2NH2、-SCH2CH2(NH2)CO2H或-SCH2CH2NHCO-R6基,其中R6表示C1-C10烷基或C3-C6环烷基,或者苯基,该苯基可任选地被一个或多个选自下述的取代基取代:氨基、硝基、羟基、羧基、卤素、三氟甲基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氧羰基、哌啶基、哌嗪基和吗啉基;
或者R4与如上所定义的R2相连;
或者
R2、R3和R4一起表示苯基;
条件是:
(i)R1、R2、R3和R4每个不同时表示氢原子。
2.权利要求1的应用,其中R1表示氢原子;或C4-C10烷基或桃金娘烷基;或(CH2)yCONH-R5基,其中y是1或2,R5表示被哌啶取代基取代的苯基。
3.权利要求1或2的应用,其中R2表示氢原子或甲基;或者R2与R3一起表示一个碳-碳单键,条件是x是0;或者R2与R4一起表示=CH2基。
4.权利要求1-3任一项的应用,其中R4表示氢原子、甲基或乙基;或可任选地被二(C2-C4烷基)氨基取代基取代的C2-C10烷基氨基;或者被哌啶取代基取代的苯胺基;或者-SCH2CH2OH、-SCH2CH2NH2、-SCH2CH2(NH2)CO2H或-SCH2CH2NHCO-R6基,其中R6表示C7烷基、环丙基、环戊基或环己基,或者被硝基、C1-C4烷基或C3-C6烷氧基取代基取代的苯基;或者R4与如权利要求1中所定义的R2相连。
5.权利要求1的应用,其中的式(I)化合物选自:
1-癸基吡咯烷-2,5-二酮,
1-壬基哌啶-2,6-二酮,
2-((6,6-二甲基双环[3.1.1]庚-2-基)甲基)异吲哚-1,3-二酮,
1-((6,6-二甲基双环[3.1.1]庚-3-基)甲基)-3-甲基-3-吡咯啉-2,5-二酮,
3-甲基-1-壬基-3-吡咯啉-2,5-二酮,
3-亚甲基-1-壬基吡咯烷-2,5-二酮,
3-甲基-1-辛基-3-吡咯啉-2,5-二酮,
3-亚甲基-1-辛基吡咯烷-2,5-二酮,
1-辛基-3-吡咯啉-2,5-二酮,
1-癸基-3-吡咯啉-2,5-二酮,
1-壬基-3-吡咯啉-2,5-二酮,
1-丁基-3-吡咯啉-2,5-二酮,
1-己基-3-吡咯啉-2,5-二酮,
1-辛基-3-(辛基氨基)-吡咯烷-2,5-二酮,
1-癸基-3-(癸基氨基)-吡咯烷-2,5-二酮,
3-(辛基氨基)-3-吡咯烷-2,5-二酮,
3-(庚基氨基)-1-壬基吡咯烷-2,5-二酮,
1-壬基-3-(壬基氨基)吡咯烷-2,5-二酮,
1-壬基-3-(辛基氨基)吡咯烷-2,5-二酮,
2-氨基-3-(3-甲基-1-壬基-2,5-二氧代-吡咯烷-3-基硫)丙酸,
2-氨基-3-(3-甲基-1-辛基-2,5-二氧代-吡咯烷-3-基硫)丙酸,
2-氨基-3-(1-辛基-2,5-二氧代-吡咯烷-3-基硫)丙酸,
3-甲基-1-辛基吡咯烷-2,5-二酮,
3-甲基-1-壬基吡咯烷-2,5-二酮,
2-(2,5-二氧代吡咯烷基)-N-(4-哌啶基苯基)乙酰胺,
2-(2,5-二氧代吡咯烷基)-N-(4-哌啶基苯基)丙酰胺,
3-乙基-1-壬基吡咯烷-2,5-二酮,
3-(2-氨基乙硫基)-1-壬基吡咯烷-2,5-二酮,
2-乙基-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)己酰胺,
环丙基-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
(4-丁基苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
(4-己氧基苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
(4-甲苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
(4-(叔丁基)苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
环戊基-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,乙烷,
环己基-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
(4-硝基苯基)-N-(2-(1-壬基-2,5-二氧代吡咯烷-3-基硫)乙基)甲酰胺,
3-((2-(二丁基氨基)乙基)氨基)-1-壬基吡咯烷-2,5-二酮,
3-((2-(二乙氨基)乙基)氨基)-1-壬基吡咯烷-2,5-二酮,
1-壬基-3-((4-哌啶基苯基)氨基)吡咯烷-2,5-二酮,
3-(羟基乙硫基)-3-甲基-1-壬基吡咯烷-2,5-二酮,
3-(2-氨基乙硫基)-3-甲基-1-壬基吡咯烷-2,5-二酮,和
3-甲基-1-辛基-3-(辛基氨基)吡咯烷-2,5-二酮。
6.前述任一项权利要求的应用,其中的分枝杆菌性疾病是结核。
Applications Claiming Priority (5)
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IN969/MAS/98 | 1998-05-05 | ||
IN969/MAS/1998 | 1998-05-05 | ||
IN969MA1998 | 1998-05-05 | ||
SE98021181 | 1998-06-15 | ||
SE9802118A SE9802118D0 (sv) | 1998-06-15 | 1998-06-15 | Mycobacterial inhibitors |
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CN1308532A CN1308532A (zh) | 2001-08-15 |
CN1201735C true CN1201735C (zh) | 2005-05-18 |
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EP (1) | EP1075261B1 (zh) |
JP (1) | JP2002518324A (zh) |
KR (1) | KR20010043322A (zh) |
CN (1) | CN1201735C (zh) |
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AU (1) | AU739140B2 (zh) |
BR (1) | BR9910185A (zh) |
CA (1) | CA2330667A1 (zh) |
DE (1) | DE69930844T2 (zh) |
IL (1) | IL139144A0 (zh) |
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CN107033060A (zh) * | 2017-05-04 | 2017-08-11 | 浙江工业大学 | 一种n‑取代顺丁烯二酰亚胺类化合物及其制备与抗菌应用 |
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CA2789114C (en) | 2001-11-01 | 2014-03-25 | Spectrum Pharmaceuticals, Inc. | Medical compositions for intravesical treatment of bladder cancer |
CN101291923A (zh) * | 2005-08-19 | 2008-10-22 | 阿斯利康(瑞典)有限公司 | 治疗结核的吡唑啉酮衍生物 |
GB0520368D0 (en) * | 2005-10-06 | 2005-11-16 | Univ Aston | Antibacterial pyrrols |
CN102307854B (zh) * | 2008-12-04 | 2014-11-12 | 巴斯夫欧洲公司 | 用于制备1,3-和1,4-烷基甲基吡咯烷酮的衣康酸或衣康酸衍生物与伯胺的混合物 |
WO2017112362A1 (en) * | 2015-12-23 | 2017-06-29 | Henkel Ag & Co. Kgaa | Metal working fluid |
WO2019108047A2 (ko) * | 2017-12-01 | 2019-06-06 | 주식회사 굳티셀 | 탈모의 예방 또는 치료용 조성물 |
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CN107033060A (zh) * | 2017-05-04 | 2017-08-11 | 浙江工业大学 | 一种n‑取代顺丁烯二酰亚胺类化合物及其制备与抗菌应用 |
CN107033060B (zh) * | 2017-05-04 | 2020-01-14 | 浙江工业大学 | 一种n-取代顺丁烯二酰亚胺类化合物及其制备与抗菌应用 |
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NZ507620A (en) | 2003-05-30 |
JP2002518324A (ja) | 2002-06-25 |
AU4304199A (en) | 2000-01-05 |
KR20010043322A (ko) | 2001-05-25 |
NO20005548L (no) | 2000-12-04 |
IL139144A0 (en) | 2001-11-25 |
DE69930844D1 (de) | 2006-05-24 |
CN1308532A (zh) | 2001-08-15 |
WO1999065483A1 (en) | 1999-12-23 |
US6476053B1 (en) | 2002-11-05 |
AU739140B2 (en) | 2001-10-04 |
BR9910185A (pt) | 2001-01-09 |
ATE322898T1 (de) | 2006-04-15 |
CA2330667A1 (en) | 1999-12-23 |
EP1075261B1 (en) | 2006-04-12 |
DE69930844T2 (de) | 2006-12-28 |
NO20005548D0 (no) | 2000-11-03 |
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