CN1315859C - 具有抗菌活性的林可霉素衍生物 - Google Patents
具有抗菌活性的林可霉素衍生物 Download PDFInfo
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- CN1315859C CN1315859C CNB038212935A CN03821293A CN1315859C CN 1315859 C CN1315859 C CN 1315859C CN B038212935 A CNB038212935 A CN B038212935A CN 03821293 A CN03821293 A CN 03821293A CN 1315859 C CN1315859 C CN 1315859C
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- Prior art keywords
- methyl
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- reaction mixture
- alkyl
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- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical class CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 title abstract description 6
- 230000000844 anti-bacterial effect Effects 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 198
- -1 phenyloxycarbonyl Chemical group 0.000 claims description 124
- 229910052799 carbon Inorganic materials 0.000 claims description 55
- 150000003839 salts Chemical class 0.000 claims description 51
- 229910052731 fluorine Inorganic materials 0.000 claims description 40
- 239000011737 fluorine Substances 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 18
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 claims description 10
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 claims description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 2
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 103
- 241000894006 Bacteria Species 0.000 abstract description 23
- 230000000694 effects Effects 0.000 abstract description 17
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000004599 antimicrobial Substances 0.000 abstract description 2
- 230000003389 potentiating effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 515
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 371
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 245
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 225
- 239000000203 mixture Substances 0.000 description 187
- 239000011541 reaction mixture Substances 0.000 description 182
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 164
- 238000002360 preparation method Methods 0.000 description 142
- 238000005160 1H NMR spectroscopy Methods 0.000 description 140
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 129
- 239000000047 product Substances 0.000 description 126
- 239000000243 solution Substances 0.000 description 125
- 238000003756 stirring Methods 0.000 description 121
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 114
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 99
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 98
- 235000019439 ethyl acetate Nutrition 0.000 description 92
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 78
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 78
- 125000000217 alkyl group Chemical group 0.000 description 76
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 75
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 72
- 238000005406 washing Methods 0.000 description 69
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 65
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 57
- 239000012043 crude product Substances 0.000 description 55
- 238000006243 chemical reaction Methods 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 46
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 46
- 238000011097 chromatography purification Methods 0.000 description 46
- 239000011734 sodium Substances 0.000 description 46
- 238000001704 evaporation Methods 0.000 description 45
- 150000001412 amines Chemical class 0.000 description 44
- 239000002585 base Substances 0.000 description 43
- 238000010898 silica gel chromatography Methods 0.000 description 43
- 239000007787 solid Substances 0.000 description 42
- 230000008020 evaporation Effects 0.000 description 41
- 229920006395 saturated elastomer Polymers 0.000 description 39
- 239000003153 chemical reaction reagent Substances 0.000 description 38
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 37
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 37
- 239000003480 eluent Substances 0.000 description 37
- 239000012044 organic layer Substances 0.000 description 37
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 37
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 35
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
- 239000013067 intermediate product Substances 0.000 description 35
- 239000007821 HATU Substances 0.000 description 33
- 239000000706 filtrate Substances 0.000 description 33
- 239000011347 resin Substances 0.000 description 33
- 229920005989 resin Polymers 0.000 description 33
- 239000003921 oil Substances 0.000 description 32
- 235000019198 oils Nutrition 0.000 description 32
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 32
- 239000003960 organic solvent Substances 0.000 description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- 238000001914 filtration Methods 0.000 description 30
- XCOBLONWWXQEBS-KPKJPENVSA-N N,O-bis(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)O\C(C(F)(F)F)=N\[Si](C)(C)C XCOBLONWWXQEBS-KPKJPENVSA-N 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
- 241000191967 Staphylococcus aureus Species 0.000 description 28
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000007864 aqueous solution Substances 0.000 description 26
- 238000001035 drying Methods 0.000 description 26
- 239000012266 salt solution Substances 0.000 description 26
- 239000006188 syrup Substances 0.000 description 26
- 235000020357 syrup Nutrition 0.000 description 26
- 238000007429 general method Methods 0.000 description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 24
- 229960002429 proline Drugs 0.000 description 24
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 23
- 238000005984 hydrogenation reaction Methods 0.000 description 23
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 229960001866 silicon dioxide Drugs 0.000 description 23
- 125000003545 alkoxy group Chemical group 0.000 description 22
- 239000003814 drug Substances 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- 229910052763 palladium Inorganic materials 0.000 description 21
- 238000009472 formulation Methods 0.000 description 20
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 20
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 20
- 238000010926 purge Methods 0.000 description 20
- 125000003118 aryl group Chemical group 0.000 description 19
- 239000001257 hydrogen Substances 0.000 description 19
- 239000012299 nitrogen atmosphere Substances 0.000 description 19
- 241000193998 Streptococcus pneumoniae Species 0.000 description 18
- 239000002253 acid Substances 0.000 description 17
- 125000000753 cycloalkyl group Chemical group 0.000 description 17
- 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 17
- 241000606768 Haemophilus influenzae Species 0.000 description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 16
- 239000008194 pharmaceutical composition Substances 0.000 description 16
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 15
- 238000010790 dilution Methods 0.000 description 15
- 239000012895 dilution Substances 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 239000000463 material Substances 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 229910003446 platinum oxide Inorganic materials 0.000 description 15
- 239000000651 prodrug Substances 0.000 description 15
- 229940002612 prodrug Drugs 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 14
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 125000001072 heteroaryl group Chemical group 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 14
- 150000001299 aldehydes Chemical class 0.000 description 13
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 13
- 150000001721 carbon Chemical group 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 229940047650 haemophilus influenzae Drugs 0.000 description 13
- 229910052736 halogen Inorganic materials 0.000 description 13
- 150000002367 halogens Chemical class 0.000 description 13
- 229910052760 oxygen Inorganic materials 0.000 description 13
- 239000003495 polar organic solvent Substances 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- 241000606124 Bacteroides fragilis Species 0.000 description 12
- 241000606123 Bacteroides thetaiotaomicron Species 0.000 description 12
- 241000193163 Clostridioides difficile Species 0.000 description 12
- 241000194032 Enterococcus faecalis Species 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 241000191963 Staphylococcus epidermidis Species 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 12
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 12
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 12
- 238000004108 freeze drying Methods 0.000 description 12
- 150000007530 organic bases Chemical class 0.000 description 12
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- 229910052698 phosphorus Inorganic materials 0.000 description 12
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- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 11
- 150000001335 aliphatic alkanes Chemical class 0.000 description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- 229940032049 enterococcus faecalis Drugs 0.000 description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 10
- 235000008504 concentrate Nutrition 0.000 description 10
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- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 241000588724 Escherichia coli Species 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 230000002152 alkylating effect Effects 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 229940023064 escherichia coli Drugs 0.000 description 9
- 230000000968 intestinal effect Effects 0.000 description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 9
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 8
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 8
- 241000192125 Firmicutes Species 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 229920002472 Starch Polymers 0.000 description 8
- 125000004414 alkyl thio group Chemical group 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 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 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 239000008107 starch Substances 0.000 description 8
- 229940032147 starch Drugs 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
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- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 7
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 7
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
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- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 7
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 7
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 7
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- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 6
- JVYSADGFOWESAS-UHFFFAOYSA-N 4-pentylpyridine-2-carboxylic acid Chemical compound CCCCCC1=CC=NC(C(O)=O)=C1 JVYSADGFOWESAS-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 125000005817 fluorobutyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 150000003840 hydrochlorides Chemical class 0.000 description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
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- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
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- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
- C07H15/16—Lincomycin; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Crystallography & Structural Chemistry (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (2)
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|---|---|---|---|
| US40377002P | 2002-08-15 | 2002-08-15 | |
| US60/403,770 | 2002-08-15 |
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|---|---|
| CN1681832A CN1681832A (zh) | 2005-10-12 |
| CN1315859C true CN1315859C (zh) | 2007-05-16 |
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| CNB038212935A Expired - Fee Related CN1315859C (zh) | 2002-08-15 | 2003-08-15 | 具有抗菌活性的林可霉素衍生物 |
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|---|---|
| US (1) | US7164011B2 (enExample) |
| EP (1) | EP1529052A2 (enExample) |
| JP (1) | JP2006504673A (enExample) |
| KR (1) | KR20050056195A (enExample) |
| CN (1) | CN1315859C (enExample) |
| AU (1) | AU2003265475B2 (enExample) |
| BR (1) | BR0313725A (enExample) |
| CA (1) | CA2493799A1 (enExample) |
| EA (1) | EA200500353A1 (enExample) |
| IL (1) | IL166476A (enExample) |
| MX (1) | MXPA05001689A (enExample) |
| NO (1) | NO20051289L (enExample) |
| NZ (1) | NZ538141A (enExample) |
| WO (1) | WO2004016632A2 (enExample) |
| ZA (1) | ZA200501012B (enExample) |
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| US7199105B2 (en) | 2002-08-15 | 2007-04-03 | Vicuron Pharmaceuticals, Inc. | Lincomycin derivatives possessing antibacterial activity |
| WO2004016632A2 (en) | 2002-08-15 | 2004-02-26 | Vicuron Pharmaceuticals, Inc. | Lincomycin derivatives possessing antibacterial activity |
| US7256177B2 (en) | 2003-06-17 | 2007-08-14 | Vicuron Pharmaceuticals, Inc. | Lincomycin derivatives possessing antibacterial activity |
| CA2528596A1 (en) * | 2003-06-17 | 2005-01-27 | Vicuron Pharmaceuticals Inc. | Lincomycin derivatives possessing antibacterial activity |
| US7199106B2 (en) | 2003-06-17 | 2007-04-03 | Vicuron Pharmaceuticals, Inc. | Lincomycin derivatives possessing antimicrobial activity |
| AU2004261550A1 (en) * | 2003-06-17 | 2005-02-10 | Vicuron Pharmaceuticals, Inc. | Novel lincomycin derivatives possessing antimicrobial activity |
| US7361743B2 (en) | 2004-02-11 | 2008-04-22 | Pfizer Inc | Lincomycin derivatives possessing antibacterial activity |
| JP5064237B2 (ja) * | 2005-12-09 | 2012-10-31 | Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 | リンコマイシン誘導体およびこれを有効成分とする抗菌剤 |
| JP5356223B2 (ja) * | 2007-05-31 | 2013-12-04 | Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 | リンコマイシン誘導体及びこれを有効成分とする抗菌剤 |
| US7867980B2 (en) * | 2007-05-31 | 2011-01-11 | Meiji Seika Kaisha, Ltd. | Lincosamide derivatives and antimicrobial agents comprising the same as active ingredient |
| CN101555223B (zh) * | 2009-04-17 | 2011-06-01 | 北京化工大学 | 一种吡利霉素中间体及其制备方法 |
| US9533973B2 (en) | 2011-12-08 | 2017-01-03 | The Board Of Regents Of The University Of Texas System | Allosteric modulators of 5-hydroxytryptamine 2C receptor (5-HT2CR) |
| CN105566411B (zh) * | 2014-11-07 | 2020-11-13 | 中国科学院上海有机化学研究所 | 林可霉素生物合成中间产物及其制法和用途 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3549615A (en) * | 1968-10-17 | 1970-12-22 | Upjohn Co | Lincomycin derivatives and process for producing the same |
| US3702322A (en) * | 1970-04-06 | 1972-11-07 | Upjohn Co | Derivatives of lincomycin and its analogs and process |
Family Cites Families (53)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US29558A (en) * | 1860-08-14 | Bread-slicer | ||
| US2851463A (en) | 1956-04-09 | 1958-09-09 | Upjohn Co | Desalicetin and salts, and hydrocarbon carboxylic acid esters |
| US2928844A (en) | 1958-02-24 | 1960-03-15 | Upjohn Co | Celesticetin, its salts and method of preparation |
| US3086912A (en) | 1961-07-03 | 1963-04-23 | Upjohn Co | Antibiotic lincolnensin and method of production |
| US3268556A (en) | 1964-04-13 | 1966-08-23 | Upjohn Co | Novel lincomycin derivatives |
| US3255174A (en) | 1964-04-13 | 1966-06-07 | Upjohn Co | 7-0-methyl-n-acyl-3, 4-o-isopropylidene-1-deoxy-lincosamines |
| NL128232C (enExample) | 1964-04-13 | |||
| NL146501C (enExample) | 1964-07-01 | |||
| US3764672A (en) | 1964-08-05 | 1973-10-09 | Upjohn Co | Composition and process of treatment using lincomycin derivatives |
| US3380992A (en) | 1965-06-14 | 1968-04-30 | Upjohn Co | Lincomycin derivatives and process for preparing same |
| US3282917A (en) | 1964-08-17 | 1966-11-01 | Upjohn Co | Methyl n-(1-alkyl-4-alkoxy-prolyl)-alpha-thiolincosaminide compounds and process therefor |
| US3502648A (en) | 1965-02-08 | 1970-03-24 | Upjohn Co | 7-halo-7-deoxythiolincosaminides and process for preparing the same |
| NL140527B (nl) | 1965-02-08 | 1973-12-17 | Upjohn Co | Werkwijze ter bereiding van aan lincomycine verwante verbindingen. |
| US3496163A (en) | 1965-02-08 | 1970-02-17 | Upjohn Co | 7-halo-7-deoxylincomycins and process for preparing the same |
| US3435025A (en) | 1966-03-18 | 1969-03-25 | Upjohn Co | 7-deoxylincomycin and analogs and isomers thereof and process for making the same |
| US3475407A (en) | 1967-12-22 | 1969-10-28 | Upjohn Co | Process for preparing 7(r)- and 7(s)-halolincomycins |
| US3509127A (en) | 1968-04-30 | 1970-04-28 | Upjohn Co | Isologs of lincomycins and process for preparing the same |
| US3544551A (en) | 1968-04-30 | 1970-12-01 | Upjohn Co | 7-mercapto-7-deoxylincomycins and process for preparing the same |
| US3555007A (en) | 1968-07-22 | 1971-01-12 | Upjohn Co | 7-deoxy-7-halo lincomycin d derivatives |
| DE2118636A1 (de) | 1970-04-20 | 1971-11-04 | The Upjohn Co., Kalamazoo, Mich. (V.StA.) | 3-Nucleotide von Lincomycin und deren Analogen, Verfahren zu ihrer Herstellung und ihre Verwendung in therapeutischen Präparaten |
| US3692767A (en) | 1970-05-06 | 1972-09-19 | Upjohn Co | Process for making lincomycin and analogs thereof and novel compounds obtained thereby |
| US3714141A (en) | 1970-05-26 | 1973-01-30 | Upjohn Co | Process for making 7-halolincomycins |
| US3674647A (en) | 1970-10-07 | 1972-07-04 | Upjohn Co | Preparation of lincomycin analogues |
| US3715346A (en) | 1970-11-18 | 1973-02-06 | Upjohn Co | Process for the preparation of lincomycin compounds |
| US3671647A (en) | 1971-03-24 | 1972-06-20 | Upjohn Co | Lincomycin 3-nucleotides and the salts thereof |
| US3892730A (en) | 1971-06-23 | 1975-07-01 | Upjohn Co | 1{40 -({62 -hydroxyethyl)-1{40 -demethyl clindamycin 2-acylates |
| US3892729A (en) | 1971-06-23 | 1975-07-01 | Upjohn Co | 1{40 (Beta-hydroxyethyl)-1{40 -demethyl clindamycin 2-phosphates |
| US3856943A (en) | 1971-06-23 | 1974-12-24 | Upjohn Co | Compositions and process |
| US3787390A (en) | 1971-06-23 | 1974-01-22 | Upjohn Co | Analogs of lincomycin and process |
| US3915954A (en) | 1971-11-15 | 1975-10-28 | Upjohn Co | Derivatives of lincomycin and its analogs and process |
| BE793630A (fr) | 1972-01-03 | 1973-07-03 | Upjohn Co | Nouvel antibiotique de la classe des celesticetines et son procede de preparation |
| US3853843A (en) | 1972-12-13 | 1974-12-10 | Upjohn Co | Derivatives of thiolincosaminide compounds |
| US3849396A (en) | 1973-01-08 | 1974-11-19 | Upjohn Co | Lincomycin and clindamycin 1-o-ethers |
| US3870699A (en) | 1973-03-06 | 1975-03-11 | Upjohn Co | Lincomycin analogs |
| US3833475A (en) | 1973-04-23 | 1974-09-03 | Upjohn Co | Process for preparing lincomycin |
| US4271266A (en) | 1974-06-10 | 1981-06-02 | The Upjohn Manufacturing Company | Process for preparing lincomycin |
| US4031304A (en) | 1976-01-30 | 1977-06-21 | The Upjohn Company | Process for preparing lincomycin derivatives |
| US4278789A (en) | 1979-11-23 | 1981-07-14 | The Upjohn Company | Lincomycin compounds |
| US4309533A (en) | 1980-05-19 | 1982-01-05 | The Upjohn Company | Lincomycin compounds |
| US4310660A (en) | 1980-05-19 | 1982-01-12 | The Upjohn Company | Lincomycin compounds |
| US4293547A (en) | 1980-08-25 | 1981-10-06 | The Upjohn Company | Method of treating malaria |
| US4317903A (en) | 1981-01-26 | 1982-03-02 | The Upjohn Company | Process for the purification of lincomycin |
| US4383109A (en) | 1981-04-20 | 1983-05-10 | The Upjohn Company | Lincomycin nucleotides |
| US4464466A (en) | 1981-04-20 | 1984-08-07 | The Upjohn Company | Process of producing lincomycin nucleotides |
| US4430495A (en) | 1982-09-17 | 1984-02-07 | The Upjohn Company | Process for preparing lincomycin and clindamycin ribonucleotides |
| US4568741A (en) | 1984-05-15 | 1986-02-04 | The Upjohn Company | Synthesis of 7-halo-7-deoxylincomycins |
| CN1004002B (zh) | 1984-11-29 | 1989-04-26 | 厄普约翰公司 | 制备7-卤-7-去氧林可霉素及其类似化合物的改进方法 |
| WO1989004672A1 (en) | 1987-11-20 | 1989-06-01 | The Upjohn Company | Derivatives of lincosaminide antibiotics |
| AU4543899A (en) | 1998-06-08 | 1999-12-30 | Advanced Medicine, Inc. | Multibinding inhibitors of microsomal triglyceride transferase protein |
| WO2004016632A2 (en) | 2002-08-15 | 2004-02-26 | Vicuron Pharmaceuticals, Inc. | Lincomycin derivatives possessing antibacterial activity |
| US7199105B2 (en) | 2002-08-15 | 2007-04-03 | Vicuron Pharmaceuticals, Inc. | Lincomycin derivatives possessing antibacterial activity |
| AU2004261550A1 (en) | 2003-06-17 | 2005-02-10 | Vicuron Pharmaceuticals, Inc. | Novel lincomycin derivatives possessing antimicrobial activity |
| CA2528596A1 (en) | 2003-06-17 | 2005-01-27 | Vicuron Pharmaceuticals Inc. | Lincomycin derivatives possessing antibacterial activity |
-
2003
- 2003-08-15 WO PCT/US2003/025820 patent/WO2004016632A2/en not_active Ceased
- 2003-08-15 US US10/642,807 patent/US7164011B2/en not_active Expired - Fee Related
- 2003-08-15 EA EA200500353A patent/EA200500353A1/ru unknown
- 2003-08-15 CN CNB038212935A patent/CN1315859C/zh not_active Expired - Fee Related
- 2003-08-15 BR BRPI0313725-2A patent/BR0313725A/pt not_active IP Right Cessation
- 2003-08-15 CA CA002493799A patent/CA2493799A1/en not_active Abandoned
- 2003-08-15 NZ NZ538141A patent/NZ538141A/en unknown
- 2003-08-15 JP JP2004529541A patent/JP2006504673A/ja active Pending
- 2003-08-15 ZA ZA200501012A patent/ZA200501012B/en unknown
- 2003-08-15 KR KR1020057002309A patent/KR20050056195A/ko not_active Ceased
- 2003-08-15 EP EP03788609A patent/EP1529052A2/en not_active Withdrawn
- 2003-08-15 MX MXPA05001689A patent/MXPA05001689A/es active IP Right Grant
- 2003-08-15 AU AU2003265475A patent/AU2003265475B2/en not_active Ceased
-
2005
- 2005-01-25 IL IL166476A patent/IL166476A/en not_active IP Right Cessation
- 2005-03-14 NO NO20051289A patent/NO20051289L/no unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3549615A (en) * | 1968-10-17 | 1970-12-22 | Upjohn Co | Lincomycin derivatives and process for producing the same |
| US3702322A (en) * | 1970-04-06 | 1972-11-07 | Upjohn Co | Derivatives of lincomycin and its analogs and process |
Also Published As
| Publication number | Publication date |
|---|---|
| IL166476A (en) | 2010-05-31 |
| AU2003265475A1 (en) | 2004-03-03 |
| WO2004016632A3 (en) | 2004-06-24 |
| EA200500353A1 (ru) | 2006-06-30 |
| WO2004016632A2 (en) | 2004-02-26 |
| NO20051289L (no) | 2005-05-09 |
| US20040116690A1 (en) | 2004-06-17 |
| CA2493799A1 (en) | 2004-02-26 |
| NZ538141A (en) | 2007-06-29 |
| EP1529052A2 (en) | 2005-05-11 |
| CN1681832A (zh) | 2005-10-12 |
| KR20050056195A (ko) | 2005-06-14 |
| US7164011B2 (en) | 2007-01-16 |
| ZA200501012B (en) | 2006-10-25 |
| IL166476A0 (en) | 2006-01-15 |
| BR0313725A (pt) | 2006-06-13 |
| WO2004016632A8 (en) | 2004-09-30 |
| WO2004016632B1 (en) | 2004-08-19 |
| AU2003265475B2 (en) | 2009-08-27 |
| MXPA05001689A (es) | 2005-05-27 |
| JP2006504673A (ja) | 2006-02-09 |
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