CN1205211C - 用作抗微生物剂的截短侧耳素衍生物 - Google Patents
用作抗微生物剂的截短侧耳素衍生物 Download PDFInfo
- Publication number
- CN1205211C CN1205211C CNB988127318A CN98812731A CN1205211C CN 1205211 C CN1205211 C CN 1205211C CN B988127318 A CNB988127318 A CN B988127318A CN 98812731 A CN98812731 A CN 98812731A CN 1205211 C CN1205211 C CN 1205211C
- Authority
- CN
- China
- Prior art keywords
- mutilin
- rubane
- acetic ester
- base
- azabicyclic
- 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 - Lifetime
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- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical class C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 title description 14
- 239000004599 antimicrobial Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 263
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 125000003118 aryl group Chemical group 0.000 claims abstract description 19
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 11
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 511
- 229960002771 retapamulin Drugs 0.000 claims description 213
- OBUUFWIMEGVAQS-UHFFFAOYSA-N Pleuromutenol Natural products CC1C(O)C(C)(C=C)CC(O)C2(C)C(C)CCC31C2C(=O)CC3 OBUUFWIMEGVAQS-UHFFFAOYSA-N 0.000 claims description 203
- STZYTFJPGGDRJD-NHUWBDDWSA-N retapamulin Chemical compound C([C@H]([C@@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CS[C@@H]3C[C@H]4CC[C@H](N4C)C3)C)C[C@]32[C@H]1C(=O)CC3 STZYTFJPGGDRJD-NHUWBDDWSA-N 0.000 claims description 199
- 235000019439 ethyl acetate Nutrition 0.000 claims description 185
- 239000000203 mixture Substances 0.000 claims description 147
- 238000000034 method Methods 0.000 claims description 85
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 64
- -1 pyrrolidyl Chemical group 0.000 claims description 63
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 56
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
- 238000002360 preparation method Methods 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 239000007921 spray Substances 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 13
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- 238000005859 coupling reaction Methods 0.000 claims description 10
- 230000000306 recurrent effect Effects 0.000 claims description 10
- 241000894006 Bacteria Species 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 9
- QGZWYBQTXJMHIW-UHFFFAOYSA-N octane-3-thiol Chemical compound CCCCCC(S)CC QGZWYBQTXJMHIW-UHFFFAOYSA-N 0.000 claims description 9
- 201000009890 sinusitis Diseases 0.000 claims description 9
- DDHXWMIWYAKTQY-UHFFFAOYSA-N 3-methylsulfanylheptane Chemical compound CCCCC(CC)SC DDHXWMIWYAKTQY-UHFFFAOYSA-N 0.000 claims description 8
- 206010033078 Otitis media Diseases 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 238000005917 acylation reaction Methods 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 7
- 230000008859 change Effects 0.000 claims description 7
- 230000008878 coupling Effects 0.000 claims description 7
- 238000010168 coupling process Methods 0.000 claims description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 6
- 150000001263 acyl chlorides Chemical class 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 230000000699 topical effect Effects 0.000 claims description 5
- KVBRMLKEFOAMID-UHFFFAOYSA-N 3-methylsulfanyloctane Chemical compound CCCCCC(CC)SC KVBRMLKEFOAMID-UHFFFAOYSA-N 0.000 claims description 4
- ADZAEUFCTQARFM-UHFFFAOYSA-N 4-methylsulfanylheptane Chemical compound CCCC(SC)CCC ADZAEUFCTQARFM-UHFFFAOYSA-N 0.000 claims description 4
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 4
- 206010062255 Soft tissue infection Diseases 0.000 claims description 4
- 206010000496 acne Diseases 0.000 claims description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 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 claims description 4
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 claims description 4
- 206010040872 skin infection Diseases 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 claims description 3
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 230000004048 modification Effects 0.000 claims description 3
- 238000012986 modification Methods 0.000 claims description 3
- 244000052769 pathogen Species 0.000 claims description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- XOCUXOWLYLLJLV-UHFFFAOYSA-N [O].[S] Chemical compound [O].[S] XOCUXOWLYLLJLV-UHFFFAOYSA-N 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 2
- 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 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 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 claims description 2
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 claims description 2
- 125000005936 piperidyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 11
- 239000001257 hydrogen Substances 0.000 abstract description 10
- 125000002619 bicyclic group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 186
- 239000002585 base Substances 0.000 description 165
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 146
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 120
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 104
- 238000005507 spraying Methods 0.000 description 95
- 238000005160 1H NMR spectroscopy Methods 0.000 description 91
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 88
- 239000000243 solution Substances 0.000 description 79
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 74
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 72
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 70
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 58
- 239000000047 product Substances 0.000 description 44
- 239000007787 solid Substances 0.000 description 39
- 229910052786 argon Inorganic materials 0.000 description 37
- 238000003756 stirring Methods 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 238000010898 silica gel chromatography Methods 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 229910021529 ammonia Inorganic materials 0.000 description 29
- 229960004756 ethanol Drugs 0.000 description 29
- 239000006260 foam Substances 0.000 description 27
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 24
- 238000005406 washing Methods 0.000 description 24
- 239000007864 aqueous solution Substances 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 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 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 20
- 239000002253 acid Substances 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 16
- 229910052938 sodium sulfate Inorganic materials 0.000 description 16
- 235000011152 sodium sulphate Nutrition 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 15
- 230000008020 evaporation Effects 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 239000003513 alkali Substances 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- 210000001989 nasopharynx Anatomy 0.000 description 13
- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 239000003242 anti bacterial agent Substances 0.000 description 11
- 229940088710 antibiotic agent Drugs 0.000 description 11
- 229960005215 dichloroacetic acid Drugs 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 11
- 235000015320 potassium carbonate Nutrition 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 238000007738 vacuum evaporation Methods 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000012545 processing Methods 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 229960001866 silicon dioxide Drugs 0.000 description 9
- 239000012453 solvate Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- GKJROTAYDAJLGD-UHFFFAOYSA-N carbonyl dichloride;hydrochloride Chemical compound Cl.ClC(Cl)=O GKJROTAYDAJLGD-UHFFFAOYSA-N 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 230000000845 anti-microbial effect Effects 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical compound CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 description 7
- 238000005984 hydrogenation reaction Methods 0.000 description 7
- 239000012280 lithium aluminium hydride Substances 0.000 description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 7
- 229910052700 potassium Inorganic materials 0.000 description 7
- 239000011591 potassium Substances 0.000 description 7
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
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- 239000000375 suspending agent Substances 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
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- 239000003054 catalyst Substances 0.000 description 6
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- 239000002131 composite material Substances 0.000 description 6
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloro-acetic acid Natural products OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 6
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 6
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
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- 210000001331 nose Anatomy 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
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- 239000002994 raw material Substances 0.000 description 5
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- 241000193998 Streptococcus pneumoniae Species 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
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- 238000001914 filtration Methods 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 4
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- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 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
- 238000002560 therapeutic procedure Methods 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
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- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- 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]
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- 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
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- 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
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- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/32—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C271/36—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/54—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Medicinal Preparation (AREA)
Abstract
其中14位上的乙醇酸酯部分被R2(CH2)mX(CH2)nCH2COO代替的式(IA)或(IB)截短侧耳素衍生物或其可药用盐可用于抗微生物治疗。其中:n和m分别独立地为0、1或2;X选自-O-、-S-、-S(O)-、-SO2-、-COO-、-NH-、-CONH-、-NHCONH-和一个键;R1是乙烯基或乙基;R2是包含1个或2个碱性氮原子并通过环碳原子挂接的非芳香单环或双环基团;R3是H或OH;或者在(IA)或(IB)14位上的R2(CH2)mX(CH2)nCH2COO被RaRbC=CHCOO替代,其中Ra和Rb有一个是氢原子,另一个是R2,或者Ra和Rb一起形成R2。
Description
本发明涉及新化合物、其制备方法、含有它们的药物组合物、和它们在医药治疗、尤其是抗菌治疗中的应用。
式(A)化合物—截短侧耳素是具有抗枝原体活性和适当抗菌活性的天然抗生素。已有人表明,通过用R-X-CH2CO2-替代14位乙醇酸酯部分,可改善其抗微生物活性,其中R是脂族或芳香部分,并且X是O、S、或NR’(H Egger和H Reinshagen,《抗生素杂志》(J Antibiotics),1976,29,923)。用作兽用抗生素的式(B)化合物—硫粘菌素是这类衍生物(G Hogenauer,《抗生素》(Antibiotics),Vol.V.第1部分,ed.F E Hahn,Springer-Verlag,1979,p.344)。
在本申请中,使用的是在该文献(G Hogenauer,上述引文)中常用的非常规编号系统。
WO 97/25309(SmithKline Beecham)描述了对该酰氧基的进一步修饰,公开了mutilin或19,20-dihydromutilin的14-O-氨基甲酰基衍生物,其中该氨基甲酰基上的氮原子未取代、单取代或二取代。
WO 98/05659(SmithKline Beecham)公开了mutilin或19,20-dihydromutilin的14-O-氨基甲酰基衍生物,其中该氨基甲酰基上的氮原子被包含氮杂二环部分的基团酰化。
WO 98/14189(SmithKline Beecham,国际出版日是1998年4月9日)公开了局部用抗菌剂莫匹罗星在治疗与病原生物体在鼻咽内居留有关的细菌感染中的应用,尤其在复发性窦炎和复发性中耳炎的预防性治疗中的应用,特别是采用适于对鼻咽给药的新喷雾剂或霜剂来施用。此外,Nsouli(《变态反应、哮喘和免疫学年报》(Annals of Allergy,Asthmaand Immunology),1996年1月,76(1),117)描述了使用0.2%莫匹罗星水溶液来减轻窦炎发作的临床试验。
我们已经发现,一些新的截短侧耳素衍生物具有改进的抗微生物特性。
因此,本发明提供了通式(IA)或(IB)化合物或它们的可药用盐:
其中:
n和m分别独立地为0、1或2;
X选自-O-、-S-、-S(O)-、-SO2-、-COO-、-NH-、-CONH-、-NHCONH-和一个键;
R1是乙烯基或乙基;
R2是包含1个或2个碱性氮原子并通过环碳原子挂接的非芳香单环或双环基团;
R3是H或OH;
或者在(IA)或(IB)14位上的R2(CH2)mX(CH2)nCH2COO被RaRbC=CHCOO替代,其中Ra和Rb有一个是氢原子,另一个是R2,或者Ra和Rb一起形成R2。
当R2是单环时,其一般包含4-8个环原子,当是双环时,其一般在每个环中包含5-10个环原子,并且R2可选择性地被高达3个取代基取代。合适的取代基包括烷基、烷氧基、链烯基和链烯氧基,所述取代基可通过桥头或非桥头碳原子连接。此外,每一氮原子可被氧取代以形成N-氧化物,或者被一烷基或二烷基取代,应当理解,被烷基取代时可形成季铵阳离子。反离子可以是卤离子,例如氯离子或溴离子,优选为氯离子。该氮杂环系还可包含有一个或多个双键。
代表R2的典型双环和单环基团包括哌啶基、吡咯烷基、奎宁环基、氮杂二环[2.2.1]庚基、氮杂二环[4.3.0]壬基、氮杂二环[3.2.1]辛基、氮杂二环[3.3.0]辛基、氮杂二环[2.2.2]辛基、氮杂二环[3. 2.1]辛烯基、氮杂二环[3.3.1]壬基和氮杂二环[4.4.0]癸基,其中所述基团可被取代或未取代。R2的优选实例包括奎宁环基。
其中R3是羟基的式(IA)化合物在携带该羟基的碳处具有(2S)构型。
n优选为0。m优选为0或1。
优选的化合物是式(IA)化合物。
在本说明书中提及的烷基和链烯基包括具有高达6个碳原子并选择性地被选自下述基团的一个或多个取代基取代的直链和支链烷基和链烯基:芳基、杂环基、(C1-6)烷氧基、(C1-6)烷硫基、芳基(C1-6)烷氧基、芳基(C1-6)烷硫基、氨基、一(C1-6)烷基氨基、二(C1-6)烷基氨基、环烷基、环烯基、羧基及其酯、酰氨基、脲基、脒基、胍基、烷基磺酰基、氨基磺酰基(C1-6)酰氧基、(C1-6)酰氨基、叠氮基、羟基、和卤素。
本说明书所提及的环烷基和环烯基包括具有3-8个环碳原子、并可选择性地被如上所述的烷基和链烯基的取代基取代的基团。
当用于本说明书中时,术语“芳基”表示在每个环中适当地包含4-7个、优选5-6个环原子的单环或稠合环,其中所述环可分别是未取代的、或被例如高达3个取代基取代。稠合环系可包含脂肪环并只需包含一个芳香环。代表性芳基包括苯基和萘基,例如1-萘基或2-萘基。
包括苯基和萘基在内的所有芳基都可选择性地被高达5个、优选高达3个取代基取代。合适的取代基包括卤素、(C1-6)烷基、芳基、芳基(C1-6)烷基、(C1-6)烷氧基、(C1-6)烷氧基(C1-6)烷基、(C1-6)卤代烷基、芳基(C1-6)烷基、羟基、硝基、氰基、叠氮基、氨基、N-一(C1-6)烷基氨基、N-二(C1-6)烷基氨基、酰氨基、芳基羰基氨基、酰氧基、羧基、成盐羧基、成酯羧基、氨基甲酰基、N-一(C1-6)烷基氨基甲酰基、N-二(C1-6)烷基氨基甲酰基、(C1-6)烷氧基羰基、芳氧基羰基、脲基、胍基、磺酰基氨基、氨基磺酰基、(C1-6)烷硫基、(C1-6)烷基亚磺酰基、(C1-6)烷基磺酰基、杂环基、和杂环基(C1-6)烷基。此外,两个相邻的环碳原子可通过(C3-5)亚烷基链连接以形成碳环。
当用于本说明书时,除非另外定义,术语“杂环基”和“杂环”适合包括在每一环中宜含有高达4个杂原子的芳香和非芳香、单环和稠合环,其中所述杂原子分别选自氧、氮和硫,并且所述环可未取代或者被例如高达3个取代基取代。每一杂环宜具有4-7个、优选5个或6个环原子。稠合杂环系可包含碳环并只需包含一个杂环。
杂环基的优选取代基选自卤素、(C1-6)烷基、芳基(C1-6)烷基、(C1-6)烷氧基、(C1-6)烷氧基(C1-6)烷基、(C1-6)卤代烷基、羟基、氨基、N-一(C1-6)烷基氨基、N-二(C1-6)烷基氨基、酰氨基、羧基、成盐羧基、成酯羧基、氨基甲酰基、N-一(C1-6)烷基羰基、N-二(C1-6)烷基羰基、芳氧基羰基、(C1-6)烷氧基羰基(C1-6)烷基、芳基、氧基、脲基、胍基、磺酰基氨基、氨基磺酰基、(C1-6)烷硫基、(C1-6)烷基亚磺酰基、(C1-6)烷基磺酰基、杂环基和杂环基(C1-6)烷基。
根据取代基所连的位置,可能有两个或两个以上的非对映异构体。在这种情况下,本发明包括各非对映异构体和它们的混合物。
优选的本发明化合物实例包括:
Mutilin 14-(奎宁环-4-基硫烷基)乙酸酯;
Mutilin 14-(奎宁环-4-基甲基硫烷基)乙酸酯;
Mutilin 14-(1-甲基哌啶-4-基硫烷基)乙酸酯;和
Mutilin 14-(外-8-甲基-8-氮杂二环[3.2.1]辛-3-基硫烷基)乙酸酯。
本发明化合物可以呈晶体或非晶体形式,并且如果呈晶体形式的话,可选择性地是溶剂化物、尤其是水合物。本发明的范围包括化学计量水合物以及包含不同水量的化合物。
可以以基本上纯的形式适当地提供本发明化合物,例如至少50%纯度、适宜为至少60%纯度、有利的至少75%纯度、优选至少85%纯度、更优选至少95%纯度、尤其是至少98%纯度,其中所述百分比都是重量百分比。
本发明化合物可以是游离碱或酸加成盐形式。携带羧基取代基的化合物可以是两性离子或碱金属盐(该羧基的碱金属盐)形式。可药用盐是优选的。
可药用酸加成盐包括Berge,Bighley,和Monkhouse在《药物科学杂志》(J.Pharm.Sci.),1977,66,1-19中描述的盐。合适的盐包括盐酸盐、马来酸盐和甲磺酸盐,尤其是盐酸盐。
本发明化合物可采用本领域众所周知的合成方法由可用原料容易地制得。
因此,一方面,本发明提供了制备式(I)化合物的方法,包括在成酯条件下,将式(IIA)或(IIB)化合物
其中Y是氢或可除去的羟基保护基,R1A和R3A是如式(IA)和(IB)中所定义的R1和R3,或者是可转化成R1和R3的基团,
与式(III)羧酸的活化衍生物反应,
R2A-(CH2)m-X-(CH2)n-CH2CO2H (III)其中R2A是如式IA和IB中所定义的R2,或者是可转化成R2的基团,
随后可以根据需要或要求,将Y转化成氢,将R1A、R2A或R3A转化成R1、R2或R3,和/或将一个R1、R2或R3转化成另一个R1、R2或R3。
用于形成酯的常规方法描述在文献中,例如《综合有机官能团转化》(Comprehensive Organic Functional Group Transformation),Vol.5,ed.C J Moody,p.123-130,Elsevier Scientific,Oxford,1995。用作酰化剂的活性衍生物可以是例如酰氯、酰溴、混合酸酐、或N-酰基咪唑。优选的酰化剂是酰氯。形成这类酰化剂的常规方法描述在化学文献中(参见I O Sutherland,《综合有机化学》(Comprehensive OrganicChemistry),Vol.2,ed.I O Sutherland,第875-883页(PergamonPress,Oxford,1979),及其引用的文献)。
该酯形成反应可在有机碱、无机碱、或酸存在下进行。有机碱包括吡啶、2,6-二甲基吡啶、三乙胺和N,N-二甲基苯胺。无机碱包括氢化钠、氢化锂、碳酸钾、六甲基二硅氮烷锂和六甲基二硅杂叠氮化钠。酸包括对甲苯磺酸、苯磺酸和硫酸。当反应在碱存在下进行时,也可选择性地将酰化催化剂(G Hofle和W Steglich,《合成》(Synthesis),1972,619)例如4-二甲基氨基吡啶或4-吡咯烷并吡啶加到该反应混合物中。适用于该酯形成反应的溶剂包括四氢呋喃、1,4-二氧杂环己烷、乙腈、N,N-二甲基甲酰胺、乙醚、二氯甲烷和氯仿。优选的溶剂是四氢呋喃。
在本发明中,可用于酰化14-羟基的方法包括采用下述方案:在N,N-二甲基甲酰胺中于高温下(例如100℃-120℃)使用酰氯;在有机碱(例如吡啶、2,6-二甲基吡啶、2,4,6-三甲吡啶、二异丙基乙基胺)或无机碱(例如六甲基二硅杂叠氮化钠、六甲基二硅杂叠氮化锂)存在下使用酰氯;在二环己基碳化二亚胺和酰化催化剂(例如4-二甲基氨基吡啶、4-吡咯烷并吡啶)存在下使用羧酸;mutilin 14-氯甲酸酯衍生物加羧酸、叔碱(例如三乙胺、二异丙基乙胺)和酰化催化剂(例如4-二甲基氨基吡啶、4-吡咯烷并吡啶)。
将R1A、R2A或R3A转化成R1、R2或R3的反应一般在下述情况时进行:即当在上述偶合反应或通过下述方法制备反应物的反应中需要使用保护基时。将一个R1、R2或R3转化成另一个R1、R2或R3的反应一般在下述情况时进行:即当一个式IA/B化合物被用作另一个式IA/B化合物的中间前体时,或者当在合成顺序结束时易于引入更复杂或反应性更强的取代基时。
Y优选为羟基保护基,例如酰基,这样-OY是三氟乙酰氧基或二氯乙酰氧基。当预定的R3也是羟基时,则R3A也优选为酰氧基,例如乙酰氧基或二氯乙酰氧基。可例如在0℃、在四氢呋喃中使用二氯乙酸酐和吡啶或在四氢呋喃中使用N-三氟乙酰基咪唑来将11位和2位羟基(作为OY和R3A)保护。用酸III衍生物进行的反应完全后,可通过水解例如用NaOH在MeOH中进行水解来把羟基保护基除去以恢复羟基。
在与式(IIA)或(IIB)化合物反应之前,可能还需要保护式(III)酸组分上的取代基,例如用烷氧基羰基如叔丁氧基羰基保护N原子。
合适的羟基、羧基和氨基保护基是本领域众所周知的、可在常规条件下除去而不会影响该分子其余部分的保护基。关于可用于将羟基、羧基和氨基保护的方法以及将所得保护衍生物裂开的方法的全面讨论描述在例如“有机化学中的保护基”(T.W.Greene,Wiley-Interscience,New York,第2版,1991)中。特别合适的羟基保护基包括,例如三有机硅基团如三烷基硅烷基,和有机羰基和有机氧羰基如乙酰基、烯丙氧基羰基、4-甲氧基苄氧基羰基和4-硝基苄氧基羰基。特别合适的羧基保护基包括烷基和芳基,例如甲基、乙基和苯基。特别合适的氨基保护基包括烷氧基羰基、4-甲氧基苄氧基羰基和4-硝基苄氧基羰基。
R1A一般是R1乙烯基,通过将该乙烯基氢化成乙基可把R1乙烯基转化成R1乙基,一般是在溶剂例如乙酸乙酯、乙醇、二氧杂环己烷、或四氢呋喃中、在钯催化剂(例如10%披钯碳)存在下进行氢化。
R3A一般是氢或被保护的羟基例如酰氧基。偶合反应后,可通过水解例如用NaOH在MeOH中进行水解除去羟基保护基以恢复羟基。
或者,其中R3是氢的式(IA)化合物可通过在成酯条件下,用式(III)酸的活化衍生物处理式(IIC)化合物来制得:
其中R1A的定义同式(IIA)和(IIB)所述,
随后用酸处理产物,并可根据需要或要求,将R1A或R2A转化成R1或R2,和/或将一个R1或R2转化成另一个R1或R2。
上述酸处理把表-mutilin构型的式(IIC)化合物转化成了常见的式(IIA)mutilin核。该转化一般是通过在二氧杂环己烷中用浓盐酸或Lukas试剂(用ZnCl2饱和的浓盐酸)处理来进行的。
如在式(IIA)和(IIB)中,R2A一般是R2乙烯基,通过将该乙烯基氢化成乙基可把R2乙烯基转化成R2乙基,同样也可能需要在反应前把式(III)酸衍生物上的取代基保护,例如用叔丁氧基羰基保护N原子。
当使用式(IIA)和(IIB)中间体(例如Y=乙酰基)时,可在将基团Y脱保护的同时把对碱不稳定的保护基方便地除去。当使用式(IIC)中间体时,可在将表-mutilin构型转化成所需构型本发明化合物的酸处理的同时把对酸不稳定的保护基方便地除去。
式(IIA)、(IIB)和(IIC)化合物可由式(IV)和(V)化合物制得,
合适的式(IV)化合物包括11-O-酰基mutilin衍生物,例如mutilin11-乙酸酯(A J Birth.C W Holzapfel,R W Richards,《四面体》(Tetrahedron)(Suppl.),1966,8,Part II,359)或mutilin11-二氯乙酸酯或mutilin11-三氟乙酸酯。式(V)化合物是(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表-mutilin(H Berner,G Schulz和Schneider,《四面体》(Tetrahedron),1980,36,1807)。
化合物(IV)和(V)分别有效地为其中R1A是乙烯基且R3A是氢(化合物IIA)的式(IIA)和(IIC)化合物。通过氢化可将它们转化成其中R1A是乙基的相应的化合物,一般是在溶剂例如乙酸乙酯、乙醇、二氧杂环己烷或四氢呋喃中、在钯催化剂(例如10%披钯碳)存在下进行氢化。
其中R3A是羟基的式(IIA)化合物可通过先用化合物(IV)制备2-羟基亚甲基mutilin来获得。采用基于A.J.Birch,C.W.Holzapfel和R.W.Rickards(《四面体》(Tetrahedron)(Suppl.),1996,8,PartIII,359)的方法,用甲醇钠在甲苯中处理式(IV)化合物和甲酸甲酯,并在氩气氛下搅拌。产物是所需2-羟基亚甲基化合物与在11位(如果OY是OH)和/或14位被甲酸酯取代的相应化合物的混合物。需要时,可通过用氢氧化钾在甲醇中处理来除去该甲酸酯基。
然而,采用H Berner,G Schulz,和G Fisher,《化学月刊》(Monatsh.Chem.),1981,112,1441描述的方法,该产物混合物可直接用于制备2-重氮基mutilin衍生物,例如在-10℃和氩气氛下,将2-羟基亚甲基mutilin和该甲酸酯衍生物在二氯甲烷中的溶液与甲苯磺酰基叠氮化物和三乙胺反应。除去上述甲酸酯基以给出2-重氮基mutilin,2-重氮基mutilin可与羧酸反应以生成2-酰氧基mutilin,这是其中R3A是被保护的羟基的式(IIA)化合物。与二氯乙酸进行适当反应以生成2-二氯乙酰氧基mutilin,可将2-二氯乙酰氧基mutilin脱保护以提供2-OH,优选在与式(III)酸衍生物偶合后进行脱保护。该反应生成了(2S)-羟基衍生物。
式(IIB)化合物是1,2-二去氢mutilin,或者可如上所述利用OY和R1A由1,2-二去氢mutilin制得。1,2-二去氢mutilin可用G Schulz和H Berner在《四面体》(Tetrahedron),1984,40,905中描述的方法制得。
上述对mutilin核的修饰也可在将其中R3A是氢的式(IIA)和(IIC)化合物(即基于mutilin和表-mutilin)与式(III)酸的活化衍生物偶合之后进行。
另一方面,本发明提供了制备其中X是O、S、NH、COO或CONH的本发明化合物的方法,包括通过下述步骤中之一,将式VIA或VIB化合物
其中Y是氢或可除去的羟基保护基,R1A和R3A是如式IA和IB中所定义的R1和R3,或者是可转化成R1和R3的基团,n的定义同式IA和IB中所述,并且RL是离去基团或OH或NH2,
与式(VII)化合物反应,
R2A-(CH2)m-XH (VII)其中R2A是如式(IA)和(IB)中所定义的R2,或者是可转化成R2的基团,X和m的定义同式IA和IB中所述,
或者当X是COO时与式(VII)酸的活化衍生物反应,
并且根据需要或要求,将Y转化成氢,将R1A、R2A或R3A转化成R1、R2或R3,和/或将一个R1、R2或R3转化成另一个R1、R2或R3。
如在用化合物(IIA/B/C)作为原料的上述方法中一样,Y优选为羟基保护基例如酰基,这样-OY就是三氟乙酰氧基或二氯乙酰氧基。当预定的R3也是羟基时,则R3A也优选为酰氧基,例如乙酰氧基或二氯乙酰氧基。
在与式(VIA)或(VIB)化合物反应之前,可能还需要保护式(VII)化合物中的取代基,例如用烷氧基羰基如叔丁氧基羰基保护N原子。
合适的羟基、羧基和氨基保护基是本领域众所周知以及上文讨论的保护基。
R1A一般是R1乙烯基,通过将该乙烯基氢化成乙基可把R1乙烯基转化成R1乙基,一般是在溶剂例如乙酸乙酯、乙醇、二氧杂环己烷或四氢呋喃中、在钯催化剂(例如10%披钯碳)存在下进行氢化。
R3A一般是氢或被保护的羟基例如酰氧基。偶合反应后,可通过水解例如用NaOH在MeOH中进行水解除去起保护作用的酰基以恢复羟基。
将RL(CH2)nCH2COO-与R2A(CH2)m-XH偶合的步骤包括下述内容:
(a)当RL是离去基团,例如4-MeC6H4SO2O、MeSO2O、F3CSO2O、Br或Cl,并且X是O、S或NH时;
(i)当X=O时,在与式VIA/B化合物反应之前,通过在非羟基溶剂例如N,N-二甲基甲酰胺或四氢呋喃中与无机碱例如氢化钠、氢化锂、六甲基二硅杂叠氮化钠或六甲基二硅杂叠氮化锂反应,可将醇R2-(CH2)m-OH转化成醇盐;
(ii)当X=S时,可在溶剂例如2-丙醇、乙醇、甲醇、N,N-二甲基甲酰胺、或四氢呋喃中,在无机碱例如甲醇钠、乙醇钠、氢化钠、六甲基二硅杂叠氮化钠、或六甲基二硅杂叠氮化锂存在下,将硫醇R2-(CH2)m-SH与式VIA/B化合物反应;
(iii)当X=NH时,可在溶剂例如N,N-二甲基甲酰胺或四氢呋喃中,选择性地在碱例如碳酸钾、吡啶、N,N-二(异丙基)乙胺、或三乙胺存在下,将胺R2-(CH2)m-NH2与式VIA/B化合物反应;
(b)当X是CONH时,可使用一种在化学文献中描述的用于形成酰胺的常规方法,将其中RL是氨基的式VIA/B化合物与式R2A-(CH2)m-CO2H化合物或由其衍生的酰化剂反应。B C Challis和J A Challis在《综合有机化学》(Comprehensive Organic Chemistry),Vol.2,ed.I OSutherland,第959-964页(Pergamon Press,Oxford,1979)中描述了用于形成酰胺的常规方法。
(c)当X是COO时,可使用一种在化学文献中描述的常规方法,将其中RL是羟基的式VIA/B化合物与衍生自式R2A-(CH2)m-CO2H化合物的酰化剂反应,例如在适当溶剂例如DMF中用草酰氯处理该酸并与RL=羟基反应。
或者,上述反应可这样进行:通过上述步骤(a)、(b)或(c),使用式(VIC)化合物与式(VII)化合物进行反应,
其中Y和R1A的定义同式IIA和IIB中定义,并且RL的定义同式(VIA)和(VIB)定义,
然后用酸处理所得产物,
并根据需要或要求,将R1A或R2A转化成R1或R2,和/或将一个R1或R2转化成另一个R1或R2。
如上所述,上述酸处理将式(VIC)表-mutilin构型转化成了常见的式(VIA)mutilin核。该转化一般是通过在二氧杂环己烷中用浓盐酸或Lukas试剂(用ZnCl2饱和的浓盐酸)处理来进行。
如在式(VIA)和(VIB)中,R1A一般是R1乙烯基,通过将该乙烯基氢化成乙基可把R1乙烯基转化成R1乙基。同样也可能需要在反应前将式(VII)化合物上的取代基保护,例如用烷氧基羰基如叔丁氧基羰基将N原子保护。
采用常规方法,通过将相应的式(IIA)、(IIB)和(IIC)化合物反应以引入被羟基、胺或离去基团取代的酰基,可制得式(VIA)、(VIB)和(VIC)化合物。
参考文献中描述了以截短侧耳素或19,20-截短侧耳素(n=0)作为原料来制备其氯化物和甲苯磺酸酯(K Riedl在《抗生素杂志》(J.Antibiotics),1976,29,132中);和制备其甲苯磺酸酯与甲磺酸酯(H Egger和H Reinshagen在《抗生素杂志》(J.Antibiotics),1976,29,915中)。其中RL是氯或溴的化合物也可通过将Br(CH2)n(CH2)COOCl或Cl(CH2)n(CH2)COOCl与上述化合物IV和V反应来制得。应当理解,当n=0时,其中RL是羟基的化合物是截短侧耳素和19,20-截短侧耳素。其中RL是NH2的化合物可由其中RL是离去基团的化合物制得,例如用叠氮化钠处理甲苯磺酸酯,然后用三苯基膦和碱处理。
其中X是S(O)或SO2的式(IA)化合物可通过制备其中X=S的相应化合物、并用氧化剂处理来制得;例如,在氯仿中用3-氯过氧苯甲酸处理,或在四氢呋喃和叔丁醇中用催化四氧化锇加N-甲基吗啉N-氧化物进行处理。
应当理解,也能进行其取代基颠倒的化合物VIA/B/C与化合物VII的反应,即具有-CH2(CH2)nXH作为14-mutilin取代基并且RL是在R2A-(CH2)m-残基上的化合物VIA/B/C与化合物VII的反应。例如,可在溶剂例如2-丙醇、乙醇、甲醇、或四氢呋喃中,在无机碱例如甲醇钠、乙醇钠或氢化钠存在下,将22-去氧-22-硫烷基截短侧耳素(US 4130709)与式R2A-(CH2)m-RL化合物反应,其中RL是离去基团,例如4-MeC6H4SO2O、MeSO2O、F3CSO2O、或Cl。
式(III)和(VII)化合物可商购获得,或者可通过常规方法由可商购获得的化合物或在文献中描述的化合物制得。
当用于上述方法的中间体是新化合物时,它们也是本发明的一部分。
本发明化合物可包含手性中心,因此上述方法的产物可包括非对映异构体的混合物或单独的非对映异构体。单独的非对映异构体可通过分离由外消旋原料合成的非对映异构体混合物而制得,或者通过用旋光纯的原料合成得到。
本发明方法的产物可以是结晶或非结晶形式,当是结晶形式时,产物可选择性地为水合物或溶剂化物。当使用有机溶剂来结晶或重结晶一些本发明化合物时,在结晶产物中可包含结晶的溶剂。本发明的范围包括这类溶剂。同样,可用含有水的溶剂来结晶或重结晶一些本发明化合物。在这种情况下,结晶产物可包含水合水。本发明的范围包括在化学计量水合物、以及可通过方法例如冷冻干燥制得的含不同水量的化合物。
依据本发明方法制得的化合物经适当处理成为基本上纯的形式,例如至少50%纯度、合适的至少60%纯度、有利的至少75%纯度、优选至少85%纯度、更优选至少95%纯度、尤其是至少98%纯度,其中所述百分比都是重量百分比。不纯或较不纯的本发明化合物可用于例如制备适于药用的更纯的同一化合物或相关化合物(例如相应的衍生物)。
本发明还包括本发明化合物的可药用盐及衍生物。当其中一个取代基携带酸性或碱性基团时,可形成盐。盐可通过以常规方式进行的盐交换来制得。
酸加成盐可以是可药用盐或非可药用盐。当是非可药用盐时,其可用于分离和纯化本发明化合物或其中间体,然后再转化成可药用盐或游离碱。可药用酸加成盐包括Berge,Bighley和Monkhouse在《药物科学杂志》(J.Pharm.Sci.),1977,66,1-19中描述的盐。合适的盐包括盐酸盐、马来酸盐、和甲磺酸盐,尤其是盐酸盐。
应当理解,当本发明化合物包含游离羧基部分时,其可形成两性离子。
本发明化合物及其可药用盐或衍生物具有抗微生物特性,因此可用于治疗,尤其是用于在动物、特别是包括人在内的哺乳动物、尤其是人和驯养动物(包括农场动物)中治疗微生物体感染。本发明化合物可用于治疗由例如下述微生物引起的感染:革兰氏阳性和革兰氏阴性细菌及枝原体,例如金黄色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(Staphylococcus epidermidis)、粪肠球菌(Enterococcusfaecalis)、酿脓链球菌(Streptococcus pyogenes)、无乳链球菌(Streptococcus agalactiae)、肺炎链球菌(Streptococcuspneumoniae)、嗜血菌属(Haemophilius sp.)、奈瑟氏球菌属(Neisseriasp.)、军团菌属(Legionella sp.)、衣原体属(Chlamydia sp.)、粘膜炎莫拉氏菌(Moraxella catarrhalis)、肺炎枝原体(Mycoplasmapneumoniae)、和鸡败血枝原体(Mycoplasma gallisepticum)。
本发明还提供了在动物、尤其是人和驯养的哺乳动物中治疗微生物感染的方法,包括将本发明化合物、或其可药用盐或衍生物或溶剂化物、或本发明组合物对需要治疗的患者给药。
本发明还提供了本发明化合物或其可药用盐或衍生物或溶剂化物在制备用于治疗微生物感染的药物中的应用。
通过局部施用,本发明化合物可用于治疗皮肤和软组织感染和痤疮。因此,另一方面,本发明提供了本发明化合物或其可药用盐或衍生物或溶剂化物在制备适于局部给药以治疗人皮肤和软组织感染以及痤疮的药物中的应用。
通过将本发明化合物对鼻腔给药,本发明化合物还可用于消除或减轻致病细菌例如金黄色葡萄球菌、流感嗜血菌(H.influenzae)、肺炎链球菌和粘膜炎莫拉氏菌的经鼻感染、尤其是这些生物体在鼻咽内居留。因此,另一方面,本发明提供了本发明化合物或其可药用盐或衍生物或溶剂化物在制备适于对鼻腔给药以减轻或消除致病生物体的经鼻感染的药物中的应用。所述药物优选适于集中给到鼻咽内、尤其是前鼻咽。
据信,这种减轻或消除经鼻感染可用于人类预防复发性急性细菌窦炎或复发性中耳炎,尤其是用于减少给定时间内患者经历的发作次数或发作时间间隔。因此,另一方面,本发明提供了本发明化合物或其可药用盐或衍生物或溶剂化物在制备适于对鼻腔给药以预防复发性急性细菌窦炎或复发性中耳炎的药物中的应用。
本发明化合物还可用于治疗慢性窦炎。因此,另一方面,本发明提供了本发明化合物或其可药用盐或衍生物或溶剂化物在制备用于治疗慢性窦炎的药物中的应用。
本发明化合物可适当地以1.0-50mg/kg体重的日剂量对患者给药。对于成年人(体重约为70kg),每天可将50-3000mg、例如约1500mg本发明化合物给药。对于成年人,剂量宜为5-20mg/kg/天。然而,可依据标准临床惯例采用更高或高低的剂量。
在预防复发性中耳炎或复发性急性细菌窦炎期间,为了减小刺激抗药性生物体发展的危险性,优选将药物间歇给药,而不是连续给药。在预防复发性中耳炎或复发性窦炎的合适间歇性治疗方案中,将药物以每日为基础给药少许天数,例如2-10天,适当为3-8天,更适当约为5天,然后一定间隔后再重复给药,例如以每月为基础的数月时间,例如高达6个月。将药物以每日为基础连续给药长时间例如数月是不可取的。对于预防复发性中耳炎或复发性窦炎,药物以每日给药1次或2次为宜。将药物在细菌感染例如复发性中耳炎和复发性窦炎更流行的冬季月份给药是适当的。可将药物以0.05-1.00mg、通常约0.1-0.2mg/鼻孔的剂量给药,每天给药1次或2次。
象其它抗生素一样,更通常将本发明化合物和组合物配制成能以任何方便方式给药以用作人或兽药的制剂。
因此,本发明提供了包含本发明化合物或其可药用盐或衍生物或溶剂化物与可药用载体或赋形剂的药物组合物。
可将本发明化合物和组合物配制成通过任意途径例如口服、局部或非胃肠道给药的剂型。可将本发明组合物制成例如片剂、胶囊剂、粉剂、粒剂、锭剂、霜剂、糖浆剂、喷雾剂或液体制剂如溶液剂或悬浮剂,其中可将所述溶液剂或悬浮剂配制成口服使用的剂型或通过注射或输注进行非胃肠道给药的无菌剂型。
用于口服给药的片剂或胶囊剂可以呈单位剂型,并且可含有常用赋形剂,包括例如粘合剂如糖浆、阿拉伯胶、明胶、山梨醇、黄蓍胶、或聚乙烯吡咯烷酮;填充剂,例如乳糖、糖、玉米淀粉、磷酸钙、山梨醇或甘氨酸;制片润滑剂,例如硬脂酸镁、滑石、聚乙二醇或二氧化硅;崩解剂,例如土豆淀粉;和可药用湿润剂,例如十二烷基硫酸钠。可依据标准制药惯例中众所周知的方法将片剂包衣。
口服液体制剂可以呈例如水悬浮剂或油悬浮剂、溶液剂、乳剂、糖浆剂或酏剂等剂型,或者可以是在使用前用水或其它合适载体重新配制的干燥产品。这类液体制剂可含有常用添加剂,包括例如悬浮剂如山梨醇、甲基纤维素、葡萄糖糖浆、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝聚或氢化食用脂肪;乳化剂,例如卵磷脂、脱水山梨醇油酸酯或阿拉伯胶;非水载体(可包括食用油),例如杏仁油、油性酯(例如甘油)、丙二醇、或乙醇;防腐剂,例如对羟基苯甲酸甲酯、对羟基苯甲酸丙酯或山梨酸;如果需要的话,还可含有调味剂和着色剂。
用于局部给药的本发明组合物可以呈例如软膏剂、霜剂、洗剂、眼药膏、滴眼剂、滴耳剂、滴鼻剂、鼻用喷雾剂、浸渗敷剂、和气雾剂等剂型,并且可包含适当常规添加剂,包括例如防腐剂、促进药物穿透的溶剂、和软膏剂及霜剂用的润肤剂。这类局部制剂还可包含可配伍的常用载体,例如霜剂及软膏剂基质、洗剂用乙醇或油醇、和喷雾剂用水性基质。这类载体可占制剂重量的约1%-98%;更通常占制剂重量的高达约80%。
除了上述组分以外,用于局部给药的本发明组合物还可包含甾族抗炎剂,例如倍他米松。
本发明组合物可配制成栓剂,其可含有常用栓剂基质,例如可可油或其它甘油酯。
用于非胃肠道给药的本发明组合物可方便地用本发明化合物和无菌载体、优选为水制备成液体单位剂型。根据所用载体和浓度,可将本发明化合物悬浮或溶解在载体中。在制备溶液剂时,可将本发明化合物溶于注射用水,过滤灭菌,装入合适的小瓶或安瓿中,然后密封。可将常用添加剂,包括例如局麻剂、防腐剂、和缓冲剂溶于载体中。为了增强该溶液剂的稳定性,可将组合物在装入小瓶以后冷冻,并在真空下除去水;然后可将形成的冷冻干燥粉末密封在小瓶中,并可提供装有注射用水的伴随小瓶以在使用前重新配制该液体。可以以基本上相同的方式制备非胃肠道给药用悬浮剂,只是将化合物悬浮而不是溶解在载体中,并且不能用过滤方法进行灭菌。在悬浮于无菌载体中之前,可将化合物通过露置于环氧乙烷来灭菌。可在这类悬浮剂中加入表面活性剂和润湿剂以促进化合物均匀分布。
本发明化合物或组合物适宜以抗微生物有效量对患者给药。
根据给药方法,本发明组合物可适当地含有0.001%-60%、优选10%(除了喷雾组合物以外的其它组合物)-60%重量的本发明组合物(按组合物的总重量计)。
当本发明组合物是以单位剂型、例如片剂提供时,每一单位剂量可适当地包含25-1000mg、优选50-500mg本发明化合物。
优选的本发明组合物包括适于鼻内给药的组合物,尤其是能到达鼻咽的组合物。这类组合物优选适于集中递送到并停留在鼻咽内。术语“集中递送”是表示将组合物递送到鼻咽内,而不是保留在鼻孔内。术语“停留”在鼻咽内是表示,一旦被递送到鼻咽内,组合物就在鼻咽内停留数小时,而不是或多或少立即洗掉。优选的组合物包括喷雾组合物和霜剂。代表性喷雾组合物包括水性组合物,和含有两亲剂以增强组合物与水分接触时的粘性的油性组合物。也可使用霜剂,尤其是具有能使霜剂在鼻咽内容易铺展的流变学特征的霜剂。
除了水之外,优选的水性喷雾组合物还含有其它赋形剂,包括渗透压调节剂如盐,例如氯化钠;防腐剂,例如苯甲烃铵盐;表面活性剂,例如非离子表面活性剂如聚山梨醇酯;和缓冲剂,例如磷酸二氢钠;这些赋形剂的含量都很低,一般小于1%。可调节组合物的pH,以使药物在贮存期间有最佳稳定性。对于本发明化合物,pH为5-6、优选约5.3-5.8、一般约5.5最佳。
代表性油性喷雾剂和霜剂组合物描述在WO 98/14189(SmithKlineBeecham)中。
药物在经鼻给药组合物中的含量以占该组合物重量的0.001%-5%为宜,优选0.005%-3%。合适的量包括占组合物重量的0.5%-1%(对于油性组合物和霜剂)和0.01%-0.2%(水性组合物)。
优选使用水性喷雾组合物。据发现,与在WO 98/14189中描述的油性组合物相比,在γ闪烁扫描术实验中这类组合物在靶区域(鼻腔和鼻咽)表现出类似保留性,并且在合成膜扩散实验中表现出更好的释放速率。
可通过本领域内众所周知的用于鼻喷雾的喷雾装置,例如气升泵,把本发明喷雾组合物递送到鼻腔内。优选的装置包括能计量提供单位体积组合物、优选约100μl组合物、并且可选择性地通过加上改进喷口而适合经鼻给药的装置。
通过参照本发明范围内的具体化合物的制备,下述实施例举例说明了本发明,尤其是上述制备方案。
截短侧耳素类似物命名注解
在本发明实施例中,在IUPAC体系中系统命名为(1S,2R,3S,4S,6R,7R,8R,14R)-3,6-二羟基-2,4,7,14-四甲基-4-乙烯基-三环[5.4.3.01,8]十四烷-9-酮的化合物(a)的俗名是mutilin,并且mutilin采用的是H Berner,G Schulz和H Schneider在《四面体》(Tetrahedron),1981,37,915-919中描述的编号系统。
(a)IUPAC编号方式 (a)Mutilin编号方式
同样,系统命名为(1R,2R,4S,6R,7R,8S,9R,14R)-6-羟基-9-甲氧基-2,4,7,14-四甲基-4-乙烯基-三环[5.4.3.01,8]十四烷-3-酮的化合物(b)称为(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表-mutilin。
实施例1 Mutilin 14-(奎宁环-4-基硫烷基)乙酸酯
在室温、氩气氛和搅拌下,将奎宁环-4-硫醇氢溴化物(1.9g,0.009mol)(W.Eckhardt和E.A.Grob,《瑞士化学学报》(Helvetica ChimicaActa)(1974),57(8)m 2339-2345)加到乙醇钠(1.72g,().0253mol)的乙醇(50ml)溶液中。将该混合物搅拌10分钟,然后加入mutilin 14-甲苯磺酰氧基乙酸酯(K.Ridel,《抗生素杂志》(J.Antibiotics)(1976),29m,132-139)(6.23g,0.0117mol)的甲基乙基甲酮(20ml)溶液。将该混合物在室温和氩气氛下搅拌过夜,然后真空浓缩。把残余物在二氯甲烷和水之间分配。将有机相用水洗涤,用硫酸镁干燥,并真空浓缩。将粗产物通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液(19∶1∶0.1)洗脱,获得了本标题化合物,为固体,1.8g(40%)。
1H NMR(CDCl3)尤其0.75(3H,d,J 6.7Hz),0.88(3H,d,J 7Hz),1.25(3H,s),1.46(3H,s),1.68(6H,t,J 7.6Hz),2.93(6H,t,J 7.6Hz),3.18(2H,ABq),3.35(1H,m),5.19(1H,dd,J 17.5和),5.33(1H,dd),6.45(1H,dd,J 17.4和11Hz).MS(EI)m/z 504(M+)
实施例2 Mutilin 14-(奎宁环-4-基硫烷基)乙酸酯盐酸盐
将Mutilin 14-(奎宁环-4-硫烷基)乙酸酯(1.0g)溶于最少量的丙酮,加入1M的HCl乙醚溶液。将该非均匀混合物真空浓缩。把残余物用乙醚(20ml)和1M HCl/乙醚(5ml)研制,获得了本标题化合物,为淡棕色固体(0.94g)。
1H NMR(D2O)尤其0.63(3H,d,J 6Hz),0.86(3H,d,J 6.8Hz),1.09(3H,s),1.36(3H,s),2.05(6H,m),3.40(6H,m),3.49(1H,m),5.10(2H,m),5.64(1H,d,J 8.3Hz),6.29(1H,dd,J 17.4和11Hz)。MS(EI)m/z 504(M+)
实施例3 19,20-dihydromutilin 14-(奎宁环-4-基硫烷基)乙酸酯
在室温,用10%Pd-C糊(含水量为50%)将Mutilin 14-(奎宁环-4-基硫烷基)乙酸酯(0.314g,0.00063mol)的乙醇(30ml)溶液氢化1小时。滤出催化剂,将滤液真空浓缩。把该残余物溶于氯仿,用饱和碳酸钠水溶液洗涤,并用硫酸镁干燥。把所得溶液真空蒸发至干,获得了本标题化合物(0.18g)(57%)
1H NMR(CDCl3)尤其0.71(3H,1d,J 6.6Hz),0.78(3H,t,J 7.5Hz),0.94(3H,d,J 7Hz),0.96(3H,s),1.43(3H,s),1.7(6H,t,J 7Hz),2.40(1H,m),2.94(6H,t,J 7.5Hz),3.19(2H,s),3.41(1H,d,J 8.4Hz),5.60(1H,d).MS(EI)m/z 506(M+)
实施例4 Mutilin 14-(奎宁环-3-基氧基)乙酸酯盐酸盐
在氩气氛下,将3-奎宁环醇(0.653g)在无水DMF(4ml)中搅拌,并用氢化钠(0.21g,60%油悬浮液)处理。1小时后,将该混合物冷却至-15℃,并滴加mutilin 14-甲磺酰氧基乙酸酯(2.28g,参见H.Egger和H.Reinshagen,《抗生素杂志》(J.Antibiotics),29(9),915)的无水DMF(4ml)溶液。将该混合物逐渐升至室温,放置1小时,并用水(30ml)和氯仿(30ml)稀释。振摇各层并分离,将有机相用水再洗涤2次,用硫酸镁干燥并蒸发。将残余物通过二氧化硅色谱法纯化,用二氯甲烷/甲醇/35%氨水溶液(19∶1∶0.1)洗脱,以在二氧化硅薄层上于Rf约为0.45处分离到化合物,用同一溶剂混合物洗脱。将该化合物的氯仿(5ml)溶液用1N的HCl乙醚溶液(2ml)处理,蒸发,获得了本标题化合物,为暗黄色泡沫状物(0.339g)。
υmax(CHCl3)3562,3435(宽),2447(宽),1735 cm-1;1H NMR(CDCl3)尤其0.71(3H,d,J 6.7Hz),0.90(3H,d,J 6.7Hz),3.1-3.6(7H,m),3.8-4.13H,m),5.22(1H,d,17.5Hz),5.38(1H,d,J 10.8Hz),5.81(1H,d,J 8.3Hz),6.48(1H,dd,J 14.7和11.0Hz),12.3(1H,宽单峰,用D2O交换后消失);MS(+ve离子电喷雾)m/z488(MH+,90%),186(100%)。
实施例5 Mutilin 14-(奎宁环-3-基硫烷基)乙酸酯
按照专利文献(J.Barriere,C.Cotret和J.Paris的EP 248703[1987])制备奎宁环-3-硫醇。在氩气氛下,将三苯基膦(12g)的THF(85ml)溶液用冰冷却,并滴加偶氮二甲酸二异丙酯(9ml)。30分钟后,用1小时滴加3-奎宁环醇(2.9g)和硫羟乙酸(3.24ml)的THF(170ml)溶液。将该混合物在室温搅拌过夜,蒸发,把残余物置于乙醚(250ml)中。用1M盐酸(2×40ml)萃取该溶液,合并水萃取液,用乙醚(100ml)洗涤,并蒸发至干。在真空下用P2O5将该残余物干燥4天,获得了浅黄色固体。把一部分该固体(0.443g)溶于乙醇(10ml),并用甲醇钠(0.216g)处理。1小时后,加入mutilin 14-甲磺酰氧基乙酸酯(0.912g),将该混合物再搅拌1小时,用氯仿(30ml)和水(30ml)稀释,振摇并分离。将有机相用水(30ml)洗涤,用硫酸镁干燥,并蒸发。将残余物通过二氧化硅色谱法纯化,用氯仿/甲醇/35%氨水溶液(19∶1∶0.1)洗脱,获得了本标题化合物,为浅黄色泡沫状物,0.62g(62%);
υmax(CHCl3)3563,1730cm-1;lHNMR(CDCl3)尤其0.74(3H,d,J 6Hz),0.88(3H,d,J 7Hz).5.1-5.4(2H,m),5.76和5.77(1H,2d,J 8.3Hz),6.49(1H,dd,J 17和11Hz);MS(+ve离子电喷雾)m/z 504(MH+,100%),202(55%)。
实施例6 Mutilin 14-(奎宁环-4-基硫烷基)乙酸酯
步骤1.奎宁环-4-基硫醇盐酸盐
将奎宁环-4-基硫醇盐酸盐粗产物(Eckharat等人,《瑞士化学学报》(Helv.Chem.Acta),57(4),(1974)2339-2345)(15.1g,0.057mol)溶于水(200ml)。加入碳酸钠(2l.0g,0.2mol)。用氯仿(200ml×7)萃取该混合物。合并有机萃取液,用硫酸镁干燥,并真空浓缩。将1M的HCl乙醚(100ml)溶液加到该浓缩物中。把该混合物真空蒸发至干,获得了本标题化合物,为白色固体,7.135g(71%);
1H NMR(D2O)2.18(6H,t,J 8Hz),3.40(6H,t,J 8Hz),MS(EI)m/z 144([(M-HCl)H]+,100%)。
步骤2.Mutilin 14-(奎宁环-4-基硫烷基)乙酸酯
在氩气氛下,将奎宁环-4-基硫醇盐酸盐(5g)与乙醇(110ml)一起搅拌,并加入甲醇钠固体(3.15g)。30分钟后,加入mutilin 14-甲磺酰氧基乙酸酯(12.7g),然后加入乙醇(30ml)。又过了30分钟后,将该混合物用氯仿(250ml)和水(250ml)稀释,振摇并分离。将有机相用水(200ml)洗涤,用硫酸镁干燥,并蒸发。将残余物通过二氧化硅色谱法纯化,用氯仿/甲醇/35%氨水溶液(19∶1∶0.1)洗脱,获得了本标题化合物,为灰白色泡沫状物,(12.24g),其NMR光谱与实施例l产物完全相同。
实施例7 Mutilin 14-[N-(2,2-二甲基氮杂二环[4.3.0]壬-4-基甲基)]-氨基乙酸酯
步骤1(±)平伏4-氰基-2,2-二甲基氮杂二环[4.3.0]壬烷
在-10℃,依次将乙醇(3.4ml)和叔丁醇钾(7.21g,0.064mol)加到(±)2,2-二甲基氮杂二环[4.3.0]壬-4-酮(4.7g,0.028mol)(F.D.King,《英国化学会杂志,柏尔金学会论文集)》(J.Chem.Soc.Prekins.Trans)1,447,1986)和甲苯磺酰基甲基异氰化物(6.47g,0.033mol)在无水二甲氧基乙烷(100ml)中的混合物中。将该混合物在-10℃搅拌1小时,然后升温至50℃并搅拌2小时。将该混合物冷却,加入乙醚(500ml)。过滤,将滤液真空浓缩,获得了油状物。将残余物进行硅胶柱色谱纯化,用乙酸乙酯洗脱,获得了本标题化合物,为油状物,3.0g(60%);
1H NMR(CDCl3)0.95(3H,s),1.21(3H,s),1.35-1.51(2H,m),1.61-1.91(4H,m),2.15-2.19(1H,m),2.28-2.39(2H,m),2.57-2.71(1H,m),2.89-2.98(1H,m)。
步骤2(±)平伏氨基甲基-2,2-二甲基氮杂二环[4.3.0]壬烷
在四氢呋喃(50ml)中用氢化锂铝(1.07g,0.028mol)处理(±)平伏4-氰基-2,2-二甲基氮杂二环[4.3.0]壬烷(1.0g,0.0056mole),并在室温搅拌18小时。加入乙醚(50ml),之后加入水(4ml)和10%氢氧化钠水溶液(1.5ml)的混合物。过滤,将滤液真空浓缩,获得了0.97g(95%)本标题化合物,为油状物。
1H NMR(CDCl3)0.95(3H,s),1.20(3H,s),1.25-1.95(9H,m),2.25-2.40(2H,m),2.55(2H,d,J 6Hz),2.89-2.97(1H,m)。
步骤3 Mutilin 14-[N-(2,2-二甲基氮杂二环[4.3.0]壬-4-基甲基)]-氨基乙酸酯
在乙醇(20ml)中用mutilin 14-甲苯磺酰氧基乙酸酯(0.25g,0.0005mol)(K.Ridel,《抗生素杂志》(J.Antibiotics)29(2),133,1976)和N,N-二异丙基乙胺(0.1ml,0.0006mol)处理(±)平伏氨基甲基-2,2-二甲基氮杂二环[4.3.0]壬烷(0.1g,0.0006mol),并加热回流6小时。然后将该混合物真空浓缩,把残余物在饱和碳酸氢钠水溶液和二氯甲烷之间分配。分离有机相并干燥(Na2SO4)。通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液(90∶9∶1)洗脱,获得了本标题化合物,0.08g(31%);
1H NMR(CDCl3)0.71(3H,d,J 6.5Hz)0.90(3H,d,J 6.5Hz),0.95(3H,s),1.25-2.55(38H,m),2.85-2.97(1H,m),3.19-3.39(2H,m),5.15(1H,d,J16.5Hz),5.31(1H,d,J 11.1Hz),5.78(1H,d,J 8.6Hz),6.50(1H,dd,J 15.0和11.1Hz).MS(+ve离子电喷雾)m/z 543(MH+,100%)。
实施例8 Mutilin 14-(奎宁环-4-基羰基氨基)乙酸酯
步骤1.Mutilin 14-叠氮基乙酸酯
在搅拌下,将叠氮化钠(0.7g,0.011mol)的水(6.5ml)溶液加到mutilin 14-甲苯磺酰氧基乙酸酯(5.33g,0.01mol)的丙酮(50ml)溶液中。短暂沉淀出的固体又重新溶解了。将该均匀混合物在室温搅拌2小时,然后加热回流3小时。将该混合物真空浓缩至小体积,然后用氯仿稀释。把所得溶液用水洗涤3次,然后用硫酸镁干燥。真空浓缩,获得了浅黄色泡沫状物,将其用硅胶色谱法纯化,用乙酸乙酯/己烷混合物洗脱,获得了本标题化合物,为白色泡沫状物,3.3g(82%);
1H NMR(CDCl3)尤其0.73(3H,d,J 6.8Hz),0.89(3H,d,J 7.1Hz),1.23(3H,s),1.47(3H,s),3.37(1H,dd,J 10.7和6.6Hz),3.77(2H,s),5.22(1H,dd,J17.4和1.3Hz),5.38(1H,dd,J 11和1.3Hz),5.86(1H,d,J 8.5Hz),6.49(1H,dd,J17.4和11Hz)。
步骤2.Mutilin 14-(三苯基膦亚氨基)乙酸酯
在氩气氛和搅拌下,将三苯基膦(0.275g,0.00105mol)加到mutilin 14-叠氮基乙酸酯(0.040g,0.001mol)的二氯甲烷溶液中。该溶液迅速地变均匀,并且释放出气体。继续搅拌17小时,然后真空浓缩,将残余物用石油醚研制,过滤,获得了本标题化合物,为白色固体,0.638g(100%);MS(+ve离子电喷雾)m/z 638(MH+,100%)。
步骤3.Mutilin 14-氨基乙酸酯
将Mutilin 14-(三苯基膦亚氨基)乙酸酯(1g,0.00157mol)悬浮在乙醇(25ml)中,加入氢氧化钾(0.175g,0.00314mol)。将该混合物搅拌17小时,在此期间混合物变均匀。然后加入2M盐酸(1.7ml),继续搅拌10分钟,然后将该混合物真空浓缩。把残余物置于2M盐酸中,将该溶液用二氯甲烷洗涤3次。用二氯甲烷将该水相分层,并通过在剧烈搅拌下加入碳酸钾固体将pH调节至11。然后分离有机相,用二氯甲烷萃取水相,合并有机萃取液,用盐水洗涤,用硫酸镁干燥,真空浓缩。获得了本标题化合物,为白色泡沫状物,0.505g(85%);
1H NMR(CDCl3)尤其0.71(3H,d,J 6.5Hz),0.89(3H,d,J 6.9Hz),1.17(3H,s),1.45(3H,s),3.33(3H,m),5.21(1H,d,J 17.4Hz),5.36(1H,d,J 11Hz),5.78(1H, d,J 8.4Hz),6.52(1H,dd,J 17.4和11Hz)。
步骤4.奎宁环-4-基碳酰氯盐酸盐
将奎宁环-4-甲酸盐酸盐(0.192g,0.001mol)悬浮在二氯甲烷(5ml)中,加入二甲基甲酰胺(1滴)和草酰氯(0.436ml,0.635g,0.005mol)。在氩气氛下将所得悬浮液加热回流6小时。将该悬浮液真空浓缩,把残余物悬浮在二氯甲烷中,真空浓缩,最后真空干燥,获得了本标题化合物,为浅棕色固体。
步骤5.Mutilin 14-(奎宁环-4-基羰基氨基)乙酸酯
将奎宁环-4-基碳酰氯盐酸盐(理论上为0.001mol,步骤4)悬浮在二氯甲烷(6ml)中,加入mutilin 14-氨基乙酸酯(0.126g,0.00033mol)。在氩气氛下,将三乙胺(0.278ml,0.202g,0.002mol)加到该搅拌的悬浮液中,并继续搅拌18小时。加入氯仿和水,通过加入固体碳酸钾将水相pH调节至11。振摇后,分离各相,将有机相依次用饱和碳酸氢钠水溶液和盐水各洗涤1次,用硫酸镁干燥,真空浓缩,获得了粗产物,为灰白色泡沫状物。通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液洗脱,获得了浅黄色玻璃状物。将产物溶于2M盐酸,把该溶液用二氯甲烷洗涤2次,然后用二氯甲烷分层。通过加入碳酸钾固体将水相pH调节至11。振摇后,分离有机相,用硫酸镁干燥,并真空浓缩。将残余物重新溶于氯仿并真空浓缩。最后将残余物用乙醚研制,获得了本标题化合物,为暗黄色固体,0.0019g(11%);
1H NMR(CDCl3)尤其0.71(3H,d,J 6.9Hz),0.88(3H,d,J 7Hz),1.18(3H,s),1.45(3H,s),2.96(6H,m),3.37(1H,m),3.93(2H,d,J 4.9Hz),5.23(1H,d,J 17.4Hz),5.36 (1H,d,J 11Hz),5.79(1H,d,J 8.5Hz),6.02(1H,m(br)),6.47(1H,dd,J 17.4和11Hz);MS(+ve离子电喷雾)m/z 515(MH+,100%)。
实施例9 Mutilin 14-[(3R,4R)-氮杂二环[2.2.1]庚-3-基羰基氨基]乙酸酯
步骤1.(3R,4R)-氮杂二环[2.2.1]庚-3-基碳酰氯盐酸盐
将3R,4R-氮杂二环[2.2.1]庚-3-甲酸氢溴化物(0.127g,0.0005mol)悬浮在二氯甲烷(2ml)中,加入二甲基甲酰胺(1滴)和草酰氯(0.131ml,0.191g,0.0015mol)。将该混合物在氩气氛下搅拌4小时。把所得均匀溶液真空浓缩,将残余物溶于二氯甲烷,真空浓缩,最后真空干燥,获得了本标题化合物,为灰白色固体。
步骤2.Mutilin 14-[(3R,4R)-氮杂二环[2.2.1]庚-3-基羰基氨基]乙酸酯
将(3R,4R)-氮杂二环[2.2.1]庚-3-基碳酰氯盐酸盐(理论上为0.0005mol,步骤1)溶于二氯甲烷(4ml),加入mutilin 14-氨基乙酸酯(0.126g,0.00033mol)。在氩气氛下将三乙胺(0.134ml,0.101g,0.001mol)加到该搅拌的溶液中。把所得溶液搅拌17小时。加入氯仿和水,通过加入碳酸钾固体将水相pH调节至11。振摇后,分离各相,将有机相依次用饱和碳酸氢钠水溶液和盐水各洗涤1次,用硫酸镁干燥,真空浓缩,获得了粗产物,为灰白色泡沫状物。通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液洗脱,获得了本标题化合物,为白色泡沫状物,0.142g(86%);
1H NMR(CDCl3)尤其0.72(3H,d,J 6.9Hz),0.89(3H,d,J 7Hz),1.18(3H,s),1.46(3H,s),3.37(1H,m(br)),3.96(2H,d,J 5.1Hz),5.22(1H,d,J 17.4Hz),5.36(1H,d,J 11Hz),5.78(1H,d,J 8.4Hz),5.96(1H,m(br)),6.47(1H,dd,J 17.4和11Hz),;MS(+ve离子电喷雾)m/z 501(MH+,40%)。
实施例10 Mutilin 14-(1-甲基哌啶-4-基羰基氨基)乙酸酯
步骤1.1-甲基哌啶-4-基碳酰氯盐酸盐
将1-甲基哌啶-4-甲酸盐酸盐(0.09g,0.0005mol)悬浮在二氯甲烷(5ml)中,加入二甲基甲酰胺(1滴)和草酰氯(0.131ml,0.191g,0.0015mol)。将该混合物在氩气氛下搅拌4小时。把所得均匀溶液真空浓缩,将残余物溶于二氯甲烷,真空浓缩,最后真空干燥,获得了本标题化合物,为灰白色固体。
步骤2.Mutilin 14-(1-甲基哌啶-4-基羰基氨基)乙酸酯
将1-甲基哌啶-4-基碳酰氯盐酸盐(理论上为0.0005mol,步骤1)溶于二氯甲烷(4ml),加入mutilin 14-氨基乙酸酯(0.126g,0.00033mol)。在氩气氛下将三乙胺(0.139ml,0.101g,0.001mol)加到该搅拌的溶液中。2小时后,加入氯仿和水,通过加入碳酸钾固体将水相pH调节至11。振摇后,分离各相,将有机相依次用饱和碳酸氢钠水溶液和盐水各洗涤1次,用硫酸镁干燥,真空浓缩,获得了粗产物,为灰白色泡沫状物。通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液洗脱,获得了本标题化合物,为白色泡沫状物,0.150g(90%);
1H NMR(CDCl3)尤其0.71(3H,d,J 6.8Hz),0.89(3H,d,J 7Hz),1.18(3H,s),1.45(3H,s),3.36(1H,m),3.94(2H,d,J 5Hz),5.22(1H,d,J 18.6Hz),5.35(1H,d,J 12.2Hz),5.78(1H,d,J 8.4Hz),5.99(1H,m(br)),6.47(1H,dd,J 17.4和11Hz);MS(+ve离子电喷雾)m/z 503(MH+,25%)。
实施例11 Mutilin 14-[3-(1-甲基哌啶-4-基)]丙酸酯
步骤1.3-(1-甲基哌啶-4-基)丙酰氯
在氩气氛下,用二甲基甲酰胺(1滴)和草酰氯(0.146ml,0.065g,0.00477mol)处理3-(1-甲基哌啶-4-基)丙酸盐酸盐(WO 9620173 A1,实施例1)(0.33g,0.00159mol)在无水二氯甲烷(10ml)中的悬浮液。搅拌3.5小时后,将该混合物真空浓缩。把残余物溶于无水二氯甲烷,并真空浓缩,获得了本标题化合物,为白色固体。
步骤2.
在氩气氛下,将3-(1-甲基哌啶-4-基)丙酰氯(理论上为0.00159g,步骤1)和(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表-mutilin(H Berner,G Schulz和Schneider,《四面体》(Tetrahedron),1980,36,1807)在无水二甲基甲酰胺中的溶液在110℃加热17小时。然后将该混合物真空浓缩,把残余物通过硅胶色谱法纯化,用二氯甲烷/甲醇/35%氨水溶液混合物洗脱。获得了本标题化合物,为浅黄色油状物,0.284g(49%);
1H NMR(CDCl3)尤其0.79(3H,d,J 6.9Hz),0.99(3H,d,J 6.4Hz),1.18(3H,s),1.24(3H,s),2.37(3H,s),2.97(3H,m),3.23(3H,s),3.48(1H,m),5.01(1H,d,J17.6Hz),5.30(1H,d,J 10.7Hz),5.74(1H,d,J 10Hz),6.67(1H,dd,J 17.5和10.6Hz);MS(+ve离子电喷雾)m/z488(MH+,100%)。
步骤3.Mutilin 14-[3-(1-甲基哌啶-4-基)]丙酸酯
将(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表-mutilin(0.355g,0.000728mol)的二氧杂环己烷(3ml)溶液用浓盐酸(3ml)处理。4小时后,将该混合物用水稀释,用二氯甲烷分层,在剧烈搅拌下加入碳酸钾固体将混合物的pH调节至11。然后分离各相,用二氯甲烷萃取水相。合并有机萃取液,用饱和碳酸氢钠水溶液和盐水洗涤,用硫酸镁干燥,并真空浓缩。将该残余物通过硅胶色谱法纯化,用二氯甲烷/甲醇/35%氨水溶液(90∶9∶1)洗脱,获得了本标题化合物,为白色泡沫状物,0.284g(82%);
1H NMR(CDCl3)尤其0.70(3H,d,J 6.6Hz),0.88(3H,d,J 7Hz),1.17(3H,s),1.45(3H,s),2.44(3H,s),3.05(2H,m),3.36(1H,dd,J 11.4和7.4Hz),5.20(1H,d,J 17.5Hz),5.36(1H,d,J 11Hz),5.74(1H,d,J 8.4Hz),6.51(1H,dd,J 17.5和11Hz);MS(+ve离子电喷雾)m/z 474(MH+,100%)。
实施例12 Mutilin 14-(奎宁环-4-基甲基硫烷基)乙酸酯
将偶氮二甲酸二异丙酯(0.85g,0.0042mol)滴加到三苯基膦(1.19g,0.0042mol)的无水四氢呋喃冰冷溶液中。30分钟后,用10分钟滴加奎宁环-4-基甲醇(0.565g,0.004mol)和硫羟乙酸(0.315ml,0.0042mol)在无水四氢呋喃(20ml)中的溶液。将该混合物在5℃放置72小时,然后真空浓缩,把残余物溶于乙醚(200ml)。用1M盐酸(3×50ml)萃取所得溶液。合并萃取液,真空浓缩,真空干燥,获得了0.65g树胶状残余物。把该残余物溶于乙醇(30ml),并在氩气氛下用叔丁醇钾(0.785g,0.007mol)处理30分钟。然后将Mutilin14-甲磺酰氧基乙酸酯(1.38g,0.003mol)加到该乙醇溶液中,把该混合物在氩气氛下搅拌过夜。滤出不溶的副产物,将滤液蒸发至干。把残余物在氯仿和水之间分配。将有机层用盐水洗涤,用硫酸镁干燥,并蒸发至干。将残余物通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液(19∶1∶0.1)洗脱,获得了本标题化合物,为白色泡沫状物,0.48g(31%);
1H NMR(CDCl3)尤其0.74(3H,d,J 6.6Hz),0.88(3H,d,J 7Hz),1.76(3H,s),1.44(6H,t,J 7.7Hz),2.47(2H,s),2.87(6H,t,J7.5Hz),3.09(2H,s),3.36(1H,m),5.1-5.4(2H,m),5.75(1H,d,J 8.3Hz),6.48(1H,m);MS(+ve离子电喷雾)m/z 518(MH+,100%)。
实施例13 19,20-Dihydromutilin 14-(奎宁环-4-基磺酰基)乙酸酯
在氩气氛下,在无水四氢呋喃(2ml)和叔丁醇(0.2ml)中,用N-甲基吗啉氧化物(0.036g,0.003mol)和催化量的四氧化锇将19,20-Dihydromutilin 14-(奎宁环-4-基硫)乙酸酯(0.05g,0.0001mol)处理4.5小时。用乙酸乙酯萃取该混合物。将该有机溶液过滤以除去无机残余物。把滤液真空浓缩。将残余物通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液洗脱,获得了本标题化合物,为泡沫状物,0.043g(80%);
1H NMR(CDCl3)尤其0.70(3H,d,J 7Hz),0.82(3H,t,J 7Hz),0.93(3H,d,J 7Hz),0.96(3H,s),1.92(6H,t,J 7.5Hz),3.01(6H,t,J 7.5Hz),3.41(1H,m),3.73(1H,d,J 13.3Hz),3.87(1H,d,J 13.3Hz),5.68(1H,d,J 8Hz);MS(+ve离子电喷雾)m/z 538(MH+,60%)。
实施例14 19,20-Dihydromutilin 14-(奎宁环-4-基硫氧基)乙酸酯
在0℃,用80%3-氯过苯甲酸(0.069g,0.0032mol)处理19,20-Dihydromutilin 14-(奎宁环-4-基硫)乙酸酯(0.152g,0.0003mol)和冰醋酸(0.06g,0.001mol)在氯仿(5ml)中的冰冷溶液,将该混合物升至室温并搅拌72小时。将溶剂真空除去。把残余物通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液(20∶1∶0.1)洗脱,获得了本标题化合物,为白色固体,0.064g(41%);
1H NMR(CDCl3)尤其0.72-0.95(12H,m),1.45(6H,t,J 8.5Hz),1.74(6H,t,J 8Hz),2.13-2.25(3H,m),2.39(1H,m),3.02(6H,t,J 7.6Hz),3.35-3.42(3H,m),5.71(1H,d,J 8.4Hz);MS(+ve离子电喷雾)m/z 522(MH+,100%)。
实施例15 Mutilin 14-(1-甲基哌啶-4-基硫烷基)乙酸酯
在氩气氛下将三苯基膦(5.51g,0.021mol)在无水四氢呋喃(100ml)中的溶液用冰冷却,并用偶氮二甲酸二异丙酯(4.25g,0.021mol)处理。30分钟后,用30分钟加入4-羟基-1-甲基哌啶(2.3g,0.02mol)和硫羟乙酸(1.54g,0.02mol)在无水四氢呋喃(50ml)中的溶液。将该混合物在室温搅拌过夜,真空蒸发,把残余物置于乙醚(200ml)中。用1M盐酸(50ml×4)萃取该乙醚溶液。合并水萃取液,用乙醚洗涤,蒸发至干并真空干燥,获得了黄色树胶状物(2.4g)。将一部分该树胶状物(0.517g)溶于乙醇,并在氩气氛下用叔丁醇钾(0.785g)处理30分钟。加入Mutilin 14-甲磺酰氧基乙酸酯(0.92g,0.002mol),将该混合物搅拌过夜,然后真空浓缩。将残余物在氯仿和水之间分配。将有机层用盐水洗涤,用硫酸镁干燥,并真空浓缩。通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液洗脱,获得了本标题化合物,为泡沫状物,0.557g(57%);
1H NMR(CDCl3)尤其0.73(3H,d,J 6.5Hz),0.87(3H,d,J 7Hz),1.30(3H,s),1.67(3H,s),2.25(3H,s),3.16(2H,s),3.36(1H,m),5.28(2H,m),5.77(1H,d,J 8.5Hz),6.47(1H,m);MS(+ve离子电喷雾)m/z 492(MH+,100%)。
实施例16 Mutilin 14-{(3RS,4SR)-1-氮杂二环[2.2.1]庚-3-基硫烷基}乙酸酯
采用实施例5中描述的方法,由内-3-羟基氮杂二环[2.2.1]庚烷(S.M.Jenkins等人《药物化学杂志》(J.Med.Chem.);1992,35,2392-2406)制得了本标题化合物,总产率为32%。分离出的本标题化合物为无色固体,在1H NMR波谱中,在d 3.05-3.40和6.43-6.56的8线多重峰表明产物是1∶1的非对映并构体混合物。
1H NMR(CDCl3)尤其0.74(3H,d,J 6.4Hz),0.88(3H,d,J 7.0Hz),3.05-3.40(2H,m),5.21(1H,d,J 17.5Hz),5.35(1H,d,J 11.0Hz),5.75-5.80(1H,m).6.43-6.56(1H,m);MS(+ve电喷雾)m/z 490(MH+)。
实施例17 Mutilin 14-{(3RS,4SR)-1-氮杂二环[2.2.1]庚-3-基硫烷基}乙酸酯盐酸盐
按照实施例2中描述的方法,用Mutilin 14-{(3RS,4SR)-1-氮杂二环[2.2.1]庚-3-基硫烷基}乙酸酯制得了本标题化合物。分离出的本标题化合物为无色固体,是1∶1的非对映异构体混合物。
1H NMR(DMSO-d6)尤其0.65(3H,d,J 6.4Hz),0.84(3H,d,J 6.8Hz),1.09(3H,s),1.39(1H,s),4.61(1H,d,J5.2Hz.用D2O交换),5.05-5.12(2H,m),5.60(1H,d,J 7.9Hz),6.14(1H,dd,J 18和10.7Hz),10.4-10.6(1H,br,用D2O交换);MS(+ve电喷雾)m/z 490(MH+游离碱)。
实施倒18 Mutilin 14-(亚奎宁环-3-基)乙酸酯盐酸盐(都是几何异构体)
步骤1.亚奎宁环-3-基乙酸甲酯盐酸盐
将奎宁环-3-酮盐酸盐(3.23g)在DMF(20ml)中的悬浮液用甲醇钠(1.08g)处理,并剧烈搅拌30分钟。用15分钟滴加膦酰基乙酸三甲酯(4.05ml)和甲醇钠(1.35g)在DMF(20ml)中的溶液,并再搅拌2.5小时。将DMF蒸发,把残余物用无水乙醚(100ml)处理,研制并过滤。将滤液用1N的HCl乙醚溶液(30ml)处理,把所得固体研制,并弃去乙醚。加入乙醚(200ml),将该悬浮液剧烈搅拌30分钟,滤出固体,并在真空下于60℃加热2天。所得亚奎宁环-3-基乙酸甲酯盐酸盐(3.93g)是大约1∶1的几何异构体混合物;1H NMR(D2O)5.84(宽s)和5.94(t,J 2.5Hz)(两个几何异构体的乙烯基质子)。
步骤2.亚奎宁环-3-基乙酸盐酸盐
将亚奎宁环-3-基乙酸甲酯盐酸盐(1g)在浓盐酸(10ml)中于60℃加热18小时,将该溶液蒸发至干。将该残余物在真空下用P2O5干燥3天,获得了0.91g(97%)亚奎宁环-3-基乙酸盐酸盐,为白色固体;1H NMR(D2O)5.77(宽s)和5.86(宽s)(约1∶1,两个几何异构体的乙烯基质子)。
步骤3.(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin 14-(亚奎宁环-3-基)乙酸酯
将亚奎宁环-3-基乙酸盐酸盐(0.204g)悬浮在氯仿(5ml)中,在氩气氛下搅拌,并用1滴DMF和草酰氯(0.87ml)处理。2小时后,将溶剂蒸发,将甲苯(10ml)加到该残余物中并蒸发。将残余物置于DMF(2ml)中,用(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin(0.344g,依据H Berner,G Schulz和Schneider,《四面体》(Tetrahedron),1980,36,1807的方法制得的)处理,在氩气氛下于100℃加热3小时。在室温放置过夜后,将该混合物用氯仿(20ml)稀释,用饱和碳酸氢钠水溶液和水洗涤,干燥并蒸发至干。通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液(19∶1∶0.1)洗脱,分离到了本标题化合物的2种几何异构体。
较小极性异构体,0.1g(20%);1H NMR(CDCl3)尤其3.23(3H,s),3.4-3.6(1H,m),3.96(2H,ABq,J 20Hz),5.02(1H,d,J 17.5Hz),5.34(1H,d,J 10.5Hz),5.64(1H,t,J 2.5Hz),5.81(1H,d,J 10Hz),6.74(1H,dd,J 17.5和10.5Hz);MS(+ve离子电喷雾)m/z484(MH+,100%)。
较大极性异构体,0.234g(48%);1H NMR(CDCl3)尤其3.12(2H,s),3.23(3H,s),3.4-3.5(1H,m),5.01(1H,d,J 17.5Hz),5.30(1H,d,J 10.5Hz),5.78(1H,d,J 10Hz),6.37(1H,d,J 0.95Hz),6.65(1H,dd,J 17.5和10.5Hz);MS(+ve离子电喷雾)m/z484(MH+,100%)。
步骤4.Mutilin 14-(亚奎宁环-3-基)乙酸酯盐酸盐
将(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin 14-(亚奎宁环-3-基)乙酸酯极性较小的几何异构体(0.1g)溶于二氧杂环己烷(3ml),在冰水中短暂冷却,用浓盐酸(2ml)处理。在室温放置5小时后,加入氯仿(10ml)和水(20ml),然后加入固体碳酸氢钠直至呈碱性。分离各层,将水相再用氯仿萃取,合并有机相,干燥并蒸发。将残余物进行色谱法纯化,用氯仿/甲醇/35%氨水溶液(97∶3∶0.3)洗脱,把产物在氯仿中的溶液用1M的HCl乙醚溶液(1ml)处理。蒸发,获得了本标题化合物极性较小的几何异构体,为白色泡沫状物,0.105g;
1H NMR(CD3SOCD3)尤其2.85(1H,s),4.38(2H,ABq,J 19Hz),4.59(1H,d,J 6Hz,用D2O交换后消失),5.0-5.2(2H,m),5.64(1H,d,J 8Hz),5.92(1H,s),6.27(1H,dd,J 17.5和11Hz),10.7(1H,宽,用D2O交换后消失);MS(+ve离子电喷雾)m.z 470(MH+-HCl,100%)。
以相同方式,将(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin 14-(亚奎宁环-3-基)乙酸酯极性较大的几何异构体(0.116g)转化成本标题化合物极性较大的几何异构体(0.096g),为白色泡沫状物;
1H NMR(CD3SOCD3)尤其4.62(1H,d,J 6Hz,用D2O交换后消失),5.0-5.2(2H,m),5.65(1H,d,J 8Hz),6.18(1H,dd,J 17.5和11Hz),6.64(1H,s),11.42(1H,宽s,用D2O交换后消失);MS(+ve离子电喷雾)m/z 470(MH+-HCl,100%)。
实施例19 Mutilin 14-[(±)-奎宁环-3-基]乙酸酯盐酸盐
步骤1.(±)-奎宁环-3-乙酸盐酸盐
将亚奎宁环-3-基乙酸甲酯盐酸盐(实施例18,步骤1)(2g)、乙醇(50ml)、2M盐酸(5ml)和10%Pd/C(1g)的混合物在氢气氛和大气压力下搅拌24小时,通过硅藻土过滤并蒸发至干。将残余物溶于浓盐酸(10ml),在60℃加热18小时,再用10ml浓盐酸处理,在80℃加热6小时,并蒸发至干。将残余物在真空下用P2O5干燥3天,获得了本标题化合物,为白色固体(1.8g);MS(+ve离子电喷雾)m/z 170(MH+,100%)。
步骤2.(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin 14-[(±)-奎宁环-3-基]乙酸酯
按照实施例18、步骤3中的方式,将(±)-奎宁环-3-乙酸盐酸盐转化成酰氯,并与(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin反应。将产物进行色谱法纯化,获得了本标题化合物,为白色泡沫状物(68%);
1H NMR(CDCl3)尤其3.23(3H,s),3.3-3.5(1H,m),5.01(1H,d,J 17.5Hz),5.32(1H,d,J 10.5Hz),5.75(1H,d,J 9.8Hz),6.68和6.69(1H,2dd.J 17.5和10.5Hz);MS(+ve离子电喷雾)m/z 486(MH+,100%)。
步骤3.Mutilin 14-[(±)-奎宁环-3-基]乙酸酯盐酸盐
(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin 14-[(±)-奎宁环-3-基]乙酸酯以实施例18步骤4的方式重排,生成了本标题化合物,为白色泡沫状物(95%);
1H NMR(CDCl3)尤其5.1-5.4(2H,m),5.74(1H,d,J 8.3Hz),6.43和6.47(1H,2 dd,J 17.5和10.5Hz);MS(+ve离子电喷雾)m/z472(MH+,100%)。
实施例20 Mutilin 14-[(±)-奎宁环-3-基乙酰氧基]乙酸酯盐酸盐
在氩气氛下将(±)-奎宁环-3-乙酸盐酸盐(0.206g)悬浮在氯仿(5ml)中,用DMF(1滴)和草酰氯(0.87ml)处理,并搅拌1小时。将该溶液蒸发,加入甲苯并蒸发,将残余物置于DMF(2ml)中。加入截短侧耳素(0.378g),将该混合物在氩气氛下搅拌18小时,然后在110℃加热30分钟。将该混合物用氯仿(10ml)稀释,用碳酸氢钠水溶液(2次)和水洗涤,干燥并蒸发。将残余物通过色谱法纯化,用氯仿/甲醇/35%氨水溶液(9∶1∶0.1)洗脱。把所得产物的氯仿溶液用1M的HCl乙醚溶液(2ml)处理,并蒸发。用乙醚研制,过滤,获得了本标题化合物,为灰白色固体,0.22g(42%);
1H NMR(CD3SOCD3)尤其4.5-4.7(3H,m,还原2H,mD20交换);5.0-5.2(2H,m),5.59(1H,d,J 8Hz),6.10(1H,dd,J17.5和10.5Hz),10.06(1H,宽s,用D2O交换后消失);MS(+ve离子电喷雾)m/z 530(MH+,100%)。
实施例21 Mutilin 14-(奎宁环-3-基甲基硫烷基)乙酸酯
步骤1.(±)-奎宁环-3-基甲基硫烷基乙酸酯盐酸盐和(±)-奎宁环-3-基甲硫醇盐酸盐的混合物
按照实施例5的方法,将(±)-奎宁环-3-甲醇(L.I.Mastafonova,L.N Yakhontov,M.V.Rubtsov,《杂环化合物化学》(Khim.Geterotsikl.Soedin.),Akad.Nauk Latv.SSR.1965(6),858-863)转化成本标题混合物。MS(+ve离子电喷雾)m/z 200(MH+,硫代乙酸酯,100%)、158(MH+,硫醇,40%)。
步骤2.Mutilin 14-(奎宁环-3-基甲基硫烷基)乙酸酯
按照实施例5所述方法,将步骤1混合物与mutilin 14-甲磺酰氧基乙酸酯反应,获得了本标题化合物,为灰白色泡沫状物(28%);
1H NMR(CDCl3)尤其0.75(3H,d,J 6.7Hz),0.89(3H,d,J 7.0Hz),3.12(2H,s),3.37(1H,宽,D2O交换后变成 d,J 6.3Hz),5.21(1H,d,J 17.5Hz),5.36(1H,d,J 11Hz),5.75(1H,d,J 8.4Hz),6.51(1H,dd,J 17.5和11Hz);MS(正离子电喷雾)m/z 518(MH+,100%)。
实施例22 1,2-Didehydromutilin 14-(奎宁环-4-基硫烷基)乙酸酯
步骤1.1,2-Didehydromutilin 14-甲磺酰氧基乙酸酯
按照现有技术中描述的关于截短侧耳素的方法(H Egger和HReinshagen,《抗生素杂志》(J Antibiotics),(1976),29,915-22),将1,2-二去氢截短侧耳素(0.2g,0.00053mol)(G Schulz和H.Berner,《四面体》(Tetrahedron),(1984)40,905-17)转化成1,2-Didehydromutilin 14-甲磺酰氧基乙酸酯,制得了本标题化合物,为黄色泡沫状物(100%);
1H NMR(CDCl3)尤其0.80(3H,d,J 6.7Hz),1.10(3H,d,J 7.0Hz),1.16(3H,s),1.54(3H,s),3.21(3H,s),4.67(2H,s),5.22(1H,dd,J 17.4和1.3Hz),5.38(1H,dd,J 11和1.2Hz),5.8(1H,d,J 8.9Hz),6.05(1H,d,J 6.1Hz),6.44(1H,dd,17.3和11Hz),7.74(1H,d,J6.1Hz)。
步骤2.1,2-Didehydromutilin 14-(奎宁环-4-基硫烷基)乙酸酯
将1,2-Didehydromutilin 14-甲磺酰氧基乙酸酯(0.00053)的乙醇溶液用奎宁环-4-基硫醇盐酸盐(0.105g,0.000583mol)处理。15分钟后,将甲醇钠(0.057g,0.00106mol)加到该搅拌的溶液中。1小时后,将该混合物浓缩成浆状物。然后加入氯仿和水。通过加入固体碳酸钾将水相的pH调节至11-12。分离各相,将水相再用氯仿萃取。合并有机萃取液,用硫酸镁干燥,真空浓缩。通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液洗脱,获得了本标题化合物,为灰白色泡沫状物,0.19g(72%);
1H NMR(CDCl3)尤其0.80(3H,d,J 6.4Hz),1.08(3H,d,J 7Hz),1.15(3H,s),1.55(3H,s),3.20(2H,ABq),5.20(1H,dd,J 17.4和1.4Hz),5.35(1H,dd,J 11和1.4Hz),5.74(1H,d,J 8.7Hz),6.04(1H,d,J 6.1Hz),6.47(1H,dd,J 17.3和11Hz),7.74(1H,d,J 6.1Hz);MS(-ve离子电喷雾)m/z 500([M-H]-,50%)。
实施例23 2α-Hydroxymutilin 14-(奎宁环-4-硫烷基)乙酸酯
步骤1.2-Diazomutilin 14-甲磺酰氧基乙酸酯
按照现有技术中描述的关于截短侧耳素的方法(H Egger和HReinshagen,《抗生素杂志》(J Antibiotics),(1976),29,915-22),将2-重氮基截短侧耳素(0.809g,0.002mol)(G Schulz和H.Berner,《四面体》(Tetrahedron),(1984)40,905-17)转化成2-Diazomutilin14-甲磺酰氧基乙酸酯,制得了本标题化合物,为嫩黄色树胶状物(100%);
1H NMR(CDCl3)尤其0.75(3H,d,J 6.9Hz),0.93(3H,d,J 6.9Hz),1.18(3H,s),1.50(3H,s),3.20(3H,s),4.65(2H,s),5.24(1H,d,J 17.5Hz),5.37(1H,d,J 11Hz),5.84(1H,d,J 8.5Hz),6.43(1H,dd,J 17.4和11Hz)。
步骤2.2α-Dichloroacetoxymutilin 14-甲磺酰氧基乙酸酯
在氩气氛下,将步骤1所得2-Diazomutilin 14-甲磺酰氧基乙酸酯(理论上为0.0002mol)在冰浴中冷却。用2分钟将二氯乙酸(0.309g,0.0024mol)滴加到该搅拌的溶液中。继续搅拌2.5小时。将该混合物用二氯甲烷稀释,依次用饱和碳酸氢钠水溶液洗涤2次,用盐水洗涤1次。用硫酸镁干燥后,真空浓缩,获得了本标题化合物,为浅黄色泡沫状物(100%);
1H NMR(CDCl3)尤其0.76(3H,d,J 6Hz),0.93(3H,d,J 7Hz),1.12(3H,s),1.49(3H,s),3.20(3H,s),4.66(2H,s).5.05(1H,t,J 9Hz),5.25(1H,d,J 17.3Hz),5.38(1H,d,J 11Hz),5.83(1H,d,J 8.5Hz),5.97(1H,s),6.43(1H,dd,J 17.4和11Hz)。
步骤3.2α-Hydroxymutilin 14-(奎宁环-4-基硫烷基)乙酸酯
将步骤2所得2α-Dichloroacetoxymutilin 14-甲磺酰氧基乙酸酯(理论上为0.001mol)的乙醇(2ml)溶液加到奎宁环-4-硫醇盐酸盐(0.27g,0.0015)和甲醇钠(0.162g,0.003mol)在乙醇(8ml)中的预混合溶液内。搅拌1小时后,将该混合物用氯仿稀释,依次用饱和碳酸氢钠水溶液洗涤2次,用盐水洗涤1次,然后用硫酸镁干燥。真空浓缩,然后进行硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液洗脱。获得了产物,为白色泡沫状物,0.2g(3步总产率为38%);
1H NMR(CDCl3)尤其0.75(3H,d,J 6.5Hz),0.92(3H,d,J 7Hz),1.17(3H,s),1.48(3H,s),3.19(2H,ABq),3.99(1H,t,J 8.7Hz),5.20(1H,d,J 17.3Hz),5.33(1H,d,J 11Hz),5.75(1H,d,J 8.4Hz),6.45(1H,dd,J 17.3和11Hz);MS(+ve离子电喷雾)m/z 520(MH+,100%)。
实施例24 Mutilin 14-(奎宁环-4-基)乙酸酯
步骤1.奎宁环-4-基甲醇
在室温,用氢化锂铝(5.0g,0.137mmol)将奎宁环-4-甲酸盐酸盐(6.0g,0.031mmol)在四氢呋喃(300ml)中处理18小时。小心地加入水(20ml)和10%氢氧化钠水溶液(7.5ml),将该混合物过滤,用乙醚洗涤。合并滤液,蒸发至干,获得了本标题化合物,为白色固体,4.04g(91%);MS(+ve离子电喷雾)m/z 142(MH+,100%)。
步骤2.奎宁环-4-基乙腈
通过用三乙胺/甲磺酰氯在氯仿中处理,将奎宁环-4-基甲醇(2.19g,0.015mol)转化成相应的甲磺酸酯。将该有机溶液用饱和碳酸钾水溶液洗涤,用硫酸钠干燥,蒸发至干,获得了3.24g(95%)该甲磺酸酯。将该甲磺酸酯溶于无水二甲基甲酰胺(50ml),用氰化钠(2.26g,0.046mol)处理,并在130℃加热18小时。将该混合物蒸发至干,把残余物在饱和碳酸钠水溶液和氯仿之间分配。将有机相干燥(硫酸钠),通过硅胶色谱法纯化,用0-10%甲醇/氯仿洗脱。获得了1.1g(50%)本标题化合物;
1H NMR(CDCl3)1.45(6H,t,J 9Hz),2.12(2H,s),2.85(6H,t,J 9Hz);MS(+ve离子电喷雾)m/z 151(MH+,100%)。
步骤3.奎宁环-4-基乙酸乙酯
在回流状态下,将氯化氢气体通入奎宁环-4-基乙腈(1.1g,0.007mol)的乙醇(40ml)溶液48小时。将该混合物真空浓缩,并用饱和碳酸钾水溶液处理。用氯仿(4×50ml)萃取,干燥,通过硅胶色谱法纯化,用0-10%甲醇/氯仿洗脱。获得了1.0g(69%)本标题化合物;
1H NMR(CDCl3)1.25(3H,t,J 8Hz),1.45(6H,t,J9Hz),2.08(2H,s),2.85(6H,t,J 9Hz),4.05(2H,q,J 8Hz)。
步骤4.奎宁环-4-基乙酸盐酸盐
将奎宁环-4-基乙酸乙酯(1.0g,0.005mol)在5M盐酸(60ml)中加热回流18小时。蒸发至干,并用丙酮研制,获得了0.93g(89%)本标题化合物;
1H NMR(CD3SOCD3)1.71(6H,t,J 9Hz),2.15(2H,s),3.05(6H,t,J 9Hz),10.35-10.55(1H,br s),12.19-12.29(1H,br s)。
步骤5.奎宁环-4-基乙酰氯盐酸盐
按照实施例8步骤4的方法,将奎宁环-4-乙酸盐酸盐(0.5g,0.0024mol)转化成本标题化合物;
MS(+ve离子电喷雾)m/z 183(甲酯MH+,100%,表明转化完全)。
步骤6.(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin 14-(奎宁环-4-基)乙酸酯
将奎宁环-4-基乙酰氯盐酸盐(0.54g,0.0024mol)与(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin(0.84g,0.0025mol)在无水二甲基甲酰胺(15ml)中在100℃加热6小时。将混合物蒸发至干,把残余物在饱和氢氧化钠水溶液和氯仿之间分配。将有机层干燥,通过硅胶色谱法纯化,用0-6%甲醇/氯仿洗脱。获得了0.4g(39%)本标题化合物,为泡沫状物;
1H NMR(CDCl3)0.87(3H,d,J 7Hz),0.98(3H,d,J 7Hz),1.05-1.70(19H,m),1.95-2.03(2H,m),2.15(2H,d,J 5Hz),2.17-2.21(1H,m),2.35-2.45(1H,m),2.85-2.97(8H,m),3.15(3H,s),3.35-3.45(1H,m),4.95(1H,d,J 17Hz),5.30(1H,d,J 12Hz),5.70(1H,d,J 12Hz),6.67(1H,dd,J 17Hz和J 10Hz);MS(+ve离子电喷雾)m/z 486(MH+,100%)。
步骤7.Mutilin 14-(奎宁环-4-基)乙酸酯
用浓盐酸(5ml)在二氧杂环己烷(5ml)中处理(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin 14-(奎宁环-4-基)乙酸酯,并在室温搅拌4小时。加入水(20ml),将该混合物用碳酸氢钠碱化。将产物萃取到氯仿(2×25ml)中,干燥(硫酸钠),过滤并蒸发至干,获得了0.33g(92%)本标题化合物,为白色泡沫状物;
1H NMR(CDCl3)尤其0.7(1H,d,J 7Hz),0.85(1H,d,J 7Hz),1.1(3H,s),1.4(3H,s),2.85(6H,t,J 9Hz),3.30-3.45(1H,br s),5.18(1H,d,J 17Hz),5.31(1H,d,J 10Hz),5.75(1H,J,10Hz),6.50(1H,dd,J 17和10Hz).MS(+ve离子电喷雾)m/z 472(MH+,100%)。
实施例25 Mutilin 14-(奎宁环-4-基甲基)氨基乙酸酯
步骤1.4-氰基奎宁环
将奎宁环-4-基碳酰氯盐酸盐(实施例8,步骤4)(3.4g,0.016mol)溶于乙腈(150ml),并用35%氨水溶液(50ml)处理。将该混合物在室温搅拌18小时,并真空浓缩至干。然后将1g残余物在三氯氧化磷(8ml)中回流5小时。将该混合物真空浓缩,把残余物在饱和碳酸钾水溶液和乙醚(4×50ml)之间分配。合并有机萃取液,干燥(硫酸钠),过滤并浓缩。进行硅胶柱色谱法纯化,用0-5%甲醇/氯仿洗脱,获得了0.34g(75%)本标题化合物;
1H NMR(CDCl3)1.85(6H,t,J 10Hz),2.91(6H,t,J 10Hz)
步骤2.4-氨基甲基奎宁环
在室温用氢化锂铝(0.45g,0.012mol)将4-氰基奎宁环(0.31g,0.0028mol)在四氢呋喃(20ml)中还原18小时。加入乙醚(20ml),然后加入水(1.8ml)和10%(w/v)氢氧化钠水溶液(0.68ml),将该混合物搅拌30分钟。然后把该混合物过滤,将滤液真空浓缩,获得了0.3g(94%)本标题化合物。
步骤3.Mutilin 14-(奎宁环-4-基甲基)氨基乙酸酯
用二异丙基乙胺(0.54g,0.0042mol)和mutilin 14-甲磺酰氧基乙酸酯(0.65g,0.0014mol)在氯仿(20ml)中处理4-氨基甲基奎宁环(0.2g,0.0014mol)。将该混合物加热回流4小时,然后冷却。将该溶液用饱和碳酸氢钠水溶液(2×20ml)洗涤。分离有机相,干燥(硫酸钠)并浓缩。通过Sep-Pak硅胶(10g)柱进行色谱纯化,用其中9∶1甲醇/35%氨水溶液含量为0-10%的氯仿洗脱,获得了0.0065g(1%)本标题化合物;
1H NMR(CDCl3)尤其0.71(3H,d,J 7Hz),0.89(3H,d,J 7Hz),1.1(3H,s),1.41(3H,s),2.80(6H,t,J 10Hz),3.28(2H,q,J 21Hz),5.20(1H,d,J 17Hz),5.35(1H,d,J 11Hz),5.75(1H,d,J 8Hz),6.52(1H,dd,J 17和11Hz).MS(+ve离子电喷雾)m/z501(MH+,30%)。
实施例26 Mutilin 14-[3-(奎宁环-4-基)丙烯酸酯]
步骤1.N’,O-二甲基奎宁环-4-基甲酰胺
在0℃,用N,O-二甲基羟基胺盐酸盐(8.8g,0.09mol)和吡啶(20ml,0.24mol)在乙腈(600ml)中处理奎宁环-4-基碳酰氯盐酸盐(实施例8,步骤4)(16.5g,0.079mol),并在室温搅拌18小时。将混合物真空浓缩,把残余物在饱和碳酸钾水溶液和乙醚之间分配。将有机相干燥(硫酸钠),过滤,并蒸发至干,获得了8.8g(57%)本标题化合物;
1H NMR(CDCl3)1.88(6H,t,J 10Hz),2.91(6H,t,J 10Hz),3.13(3H,s),3.65(3H,s)。
步骤2.奎宁环-4-甲醛
在-70℃,用1.5摩尔氢化二异丁基铝(45ml,0.067mol)在无水甲苯中处理N’,O-二甲基奎宁环-4-基甲酰胺(8.77g,0.044mol),然后用2小时升至室温。用过量5M盐酸将反应中止,用碳酸钾碱化,并萃取到乙醚中。将有机相干燥(硫酸钠),过滤并浓缩。通过硅胶色谱法纯化,用其中9∶1甲醇/880氨水含量为0-10%的氯仿洗脱,获得了1.3g(21%)本标题化合物;
1H NMR(CDCl3)1.59(6H,t,J 10Hz),2.90(6H,t,J 10Hz),9.40(1H,s)。
步骤3.3-(奎宁环-4-基)丙烯酸乙酯
在室温,用60%氢化钠油悬浮液(0.35g,0.0088mol)在二甲氧基乙烷(50ml)中将三乙基膦酰基乙酸酯(1.6ml,0.0077mol)处理1小时。然后加入奎宁环-4-甲醛(1.0g,0.0072mol),将该混合物加热回流2小时,冷却,真空浓缩。将残余物进行硅胶色谱法纯化,如步骤2所述进行洗脱,获得了0.71g(47%)本标题化合物;
1H NMR(CDCl3)1.29(3H,t,J 10Hz),1.55(6H,t,J 10Hz),2.99(6H,t,J10Hz),4.18(2H,q,J 10Hz),5.65(1H,d,J 19Hz),6.79(1H,d,J 19Hz)。
步骤4.3-(奎宁环-4-基)丙烯酸盐酸盐
将3-(奎宁环-4-基)丙烯酸乙酯(0.7g,0.0033mol)在5摩尔盐酸(30ml)中加热回流18小时,然后冷却,真空浓缩至油状物。用丙酮研制,获得了本标题化合物,为灰白色固体,0.43g(60%)。
MS(+ve离子电喷雾)m/z 182(MH+,100%)。
步骤5.3-(奎宁环-4-基)丙烯酰氯盐酸盐
按照实施例8步骤4的方法,由3-(奎宁环-4-基)丙烯酸制得了本标题化合物(0.24g,100%)。MS(+ve离子电喷雾)m/z 196(MH+,100%-与甲醇反应所得甲酯)。
步骤6.(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin 14-[3’-(奎宁环-4-基)丙烯酸酯]
将3-(奎宁环-4-基)丙烯酰氯(0.24g,0.001mol)和(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin(0.34g,0.001mol)一起在二甲基甲酰胺(15ml)中于110℃加热18小时。将该混合物冷却,并真空浓缩。把残余物在氯仿和饱和碳酸氢钠水溶液之间分配。将有机层干燥(硫酸钠),过滤并蒸发至干。通过Sep-Pak硅胶(10g)柱进行色谱纯化,用其中9∶1甲醇/35%氨水溶液含量为0-10%的氯仿洗脱,获得了0.035g(6.5%)本标题化合物;MS(+ve离子电喷雾)m/z 498(MH+,100%)。
步骤7.Mutilin 14-[3-(奎宁环-4-基)丙烯酸酯]
按照实施例24步骤7所述方法,用(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin 14-[3’-(奎宁环-4-基)丙烯酸酯](0.035g,0.00007mol)制得了本标题化合物,0.026g(76%);
1H NMR(CDCl3)尤其0.61(3H,d,J 7Hz),0.8(3H,d,J 7Hz),1.1(3H,s),2.80(6H,t,J 10Hz),5.12(1H,d,J 17Hz),5.28(1H,d,J 11Hz),5.49(1H,d,J 15Hz),5.70(1H,d,J 8Hz),6.49(1H,dd,J 17和11Hz),6.64(1H,d,J 15Hz);MS(+ve离子电喷雾)m/z484(MH+,85%)。
实施例27 Mutilin 14-[3-(奎宁环-4-基)]丙酸酯
步骤1.3-(奎宁环-4-基)丙酸盐酸盐
在室温和大气压下,用10%披钯碳(0.05g)将3-(奎宁环-4-基)丙烯酸(实施例26,步骤4)(0.2g,0.0009mol)氢化18小时。滤出催化剂,将滤液蒸发至干,获得了本标题化合物,0.18g(89%);MS(+ve离子电喷雾)m/z 184(MH+,100%)。
步骤2.3-(奎宁环-4-基)丙酰氯盐酸盐
按照实施例8步骤4的方法,由3-(奎宁环-4-基)丙酸盐酸盐(0.18g,0.0008mol)制得了本标题化合物(0.19g,100%);MS(+ve离子电喷雾)m/z 198(MH+,100%-与甲醇反应所得甲酯)。
步骤3.(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin 14-[3’-(奎宁环-4-基)丙酸酯]
按照实施例24步骤6的方法,用3-(奎宁环-4-基)丙酰氯盐酸盐(0.19g,0.0008mol)和(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin(0.27g,0.0008mol)制得了0.19g(48%)本标题化合物;MS(+ve离子电喷雾)m/z 500(MH+,100%)。
步骤4.Mutilin 14-[3-(奎宁环-4-基)丙酸酯]
按照实施例24步骤7所述方法,用(3R)-3-去氧代-11-去氧-3-甲氧基-11-氧代-4-表mutilin 14-[3’-(奎宁环-4-基)丙酸酯](0.18g,0.0004mol)制得了本标题化合物,0.15g(83%);
1H NMR(CDCl3)尤其0.69(3H,d,J 7Hz),0.87(3H,d,J 7Hz),1.15(3H,s),1.45(3H,s),2.85(6H,t,J 10Hz),5.17(1H,d,J 17Hz),5.33(1H,d,J 11Hz),5.69(1H,d,J 8Hz),6.51(1H,dd,J 17和11Hz).MS(+ve离子电喷雾)m/z 486(MH+,100%)。
实施例28 Mutilin 14-(奎宁环-4-基甲氧基)乙酸酯
步骤1.奎宁环-4-基甲醇
在室温,用氢化锂铝(2.5g,0.066mol)在四氢呋喃(150ml)中将奎宁环-4-甲酸盐酸盐(3.0g,0.016mol)处理18小时。按照实施例25步骤1所述方法将反应混合物进行反应后处理,获得了2.24g(100%)本标题化合物;MS(+ve离子电喷雾)m/z 142(MH+,100%)。
步骤2.Mutilin 14-(奎宁环-4-基甲氧基)乙酸酯
在室温,用60%氢化钠油悬浮液(0.095g,0.0022mol)在无水二甲基甲酰胺(5ml)中将奎宁环-4-基甲醇(0.3g,0.002mol)处理1小时。然后将该混合物冷却至-10℃,加入mutilin 14-甲磺酰氧基乙酸酯(1.0g,0.002mol)。将该混合物在室温搅拌4小时,然后真空浓缩。把残余物在饱和碳酸氢钠水溶液和氯仿之间分配。将有机层干燥(硫酸钠),过滤并蒸发至干。通过Sep-Pak硅胶(10g)柱进行色谱纯化,用其中9∶1甲醇/880氨水含量为0-10%的氯仿洗脱,获得了0.012g(12%)本标题化合物;
1H NMR(CDCl3)尤其0.71(3H,d,J 7Hz),0.88(3H,d,J 7Hz),1.15(3H,s),1.40(3H,s),2.85(6H,t,J 10Hz),3.14(2H,dd,J 10和J 2.6Hz),3.93(2H,q,J 17Hz),5.19(1H,d,J 17Hz),5.35(1H,d,J 11Hz),5.82(1H,d,J 8Hz),6.52(1H,dd,J 17和J 11Hz),5.82(1H,d,J 8Hz),6.52(1H,dd,J 17和J 11Hz).MS(+ve离子电喷雾)m/z 502(MH+,100%)。
实施例29 Mutilin 14-[(3R)-奎宁环-3-基氨基]乙酸酯
按照实施例28步骤2的方法,用(R)-(+)-3-氨基奎宁环二盐酸盐和mutilin 14-甲磺酰氧基乙酸酯制得了本标题化合物,0.05g(9%);
1H NMR(CDCl3)尤其0.72(3H,d,J 7Hz),0.88(3H,d,J 7Hz),1.18(3H,s),1.45(3H,s),5.20(1H,d,J 17Hz),5.35(1H,d,J 11Hz),5.78(1H,d,J 8Hz),《6.52(1H,dd,J17和J 11Hz).MS(+ve离子电喷雾)m/z 487(MH+,82%)。
实施例30 Mutilin 14-(奎宁环-4-氨基)乙酸酯
步骤1.4-氨基奎宁环二盐酸盐
在50℃,用叠氮化钠(0.34g,0.005mol)在二甲基甲酰胺(10ml)中将奎宁环基-4-碳酰氯(实施例8,步骤4)(1.0g,0.0048mol)处理18小时。将该混合物真空浓缩,把残余物在饱和碳酸钾水溶液和甲苯之间分配。分离甲苯溶液,干燥(硫酸钠),过滤,将滤液加热回流1小时以生成异氰酸酯。将该混合物冷却,然后用5M盐酸(3×20ml)萃取。合并酸萃取液,然后加热回流1小时,冷却后蒸发至干,用丙酮研制,获得了0.56g(60%)白色固体。MS(+ve离子电喷雾)m/z 127(MH+,100%)。
步骤2.Mutilin 14-(奎宁环-4-基氨基)乙酸酯
按照实施例28步骤2的方法,用4-氨基奎宁环二盐酸盐和mutilin14-甲磺酰氧基乙酸酯制得了本标题化合物,0.023g(3%);
1HNMR(CDCl3)尤其0.7(3H,d,J 7Hz),0.88(3H,d,J 7Hz),1.17(3H,s),1.48(3H,s),2.95(6H,t,J 10Hz),5.20(1H,d,J 17Hz),5.35(1H,d,J 11Hz),5.75(1H,d,J 8Hz),6.49(1H, dd,J 17和J 11Hz).M.S.(+ve离子电喷雾)m/z 487(MH+,100%)。
实施例31 Mutilin 14-[4-(奎宁环-4-基)]丁酸酯
步骤1.奎宁环-4-乙腈
通过用甲磺酰氯和三乙胺在氯仿中处理,将奎宁环-4-基甲醇(1.94g,0.014mol)转化成相应的甲磺酸酯。将该甲磺酸酯溶于二甲基甲酰胺(50ml),在120℃用氰化钠(1.4g,0.028mol)处理18小时。将该混合物冷却,并真空浓缩。把残余物在饱和碳酸钾水溶液和氯仿之间分配。分离有机层,干燥(硫酸钠),过滤,并蒸发至干。通过硅胶色谱法纯化,用0-10%甲醇/氯仿洗脱,获得了1.5g(72%)本标题化合物;MS(+ve离子电喷雾)m/z 151(MH+,100%)。
步骤2.奎宁环-4-乙醛
在室温,用1.5摩尔氢化二异丁基铝(19.7ml,0.03mol)在无水甲苯(100ml)中将奎宁环-4-乙腈(3.0g,0.02mol)处理5小时。通过加入2M盐酸(50ml)将该混合物反应中止,并搅拌30分钟。然后用碳酸钾将该混合物碱化,并用氯仿萃取。分离有机层,干燥(硫酸钠),过滤,并蒸发至干,获得了2.2g(72%)本标题化合物,为油状物;MS(+ve离子电喷雾)m/z 154(MH+,100%)。
步骤3.Mutilin 14-[4-(奎宁环-4-基)]丁酸酯
按照类似于实施例26步骤3-4和实施例27步骤1-4的方法,用奎宁环-4-基乙醛制得了0.08g(6步总产率为3%)本标题化合物;
1H NMR(CDCl3)尤其0.65(3H,d,J 7Hz),0.81(3H,d,J 7Hz),1.10(3H,s),1.39(3H,s),2.95(6H,t,J 10Hz),5.12(1H,d,J 17Hz),5.27(1H,d,J 11Hz),5.65(1H,d,J 8Hz),6.43(1H,dd,J17和J 11Hz).M.S.(+ve电喷雾)m/z 500(MH+,100%)。
实施例32
(±)Mutilin 14-(1-氮杂二环[3.3.0]辛-4-基甲基硫烷基)乙酸酯
按照实施例15的方法,由(±)-1-氮杂二环[3.3.0]辛-4-基甲醇(1.85g,0.007mol)(Pizzorno,M.T.,Albornico S.M.,《有机化学杂志》(J.Org.Chem.)(1974)39,731)制得了本标题化合物。获得了1.3g(71%)产物;
1H NMR(CDCl3)尤其0.75(3H,d,J 7Hz),0.88(3H,d,J 7Hz),1.17(3H,s),1.45(3H,s),5.20(1H,d,J 17Hz),5.35(1H,d,J 11Hz),5.75(1H,d,J 8Hz),6.50(1H,dd,J 17和11Hz).M.S.(+ve离子电喷雾)m/z 518(MH+,100%)。
实施例33(±)Mutilin 14-(1-氮杂二环[3.3.0]辛-3-基硫烷基)乙酸酯
按照实施例15的方法,由(±)-1-氮杂二环[3.3.0]辛-4-醇(0.6g,0.0047mol)(Schnekenburger,J.Pharm.Inst.,Univ.Kiel.Kiel.D-2300,Fed.Rep.Ger.Arch.Pharm.(1988),321(12),925-9)制得了本标题化合物。获得了0.21g(9%)产物;
1H NMR(CDCl3)尤其0.72(3H,d,J 7Hz),0.88(3H,d,J 7Hz),1.18(3H,s),1.45(3H,s),5.20(1H,d,J 17Hz),5.34(1H,d,J 11Hz),5.74(1H,d,J 8Hz),6.46(1H,dd,J 17和J 11Hz),M.S.(+ve离子电喷雾)m/z 504(MH+,35%)。
实施例34 Mutilin 14-(内8-甲基-8-氮杂二环[3.2.1]辛-3-基硫烷基)乙酸酯
按照实施例15的方法,由外8-甲基-8-氮杂二环[3.2.1]辛-3-醇(1.8g,0.0127mol)(Nickon,A.,Fieser,L.F.,《美国化学会杂志》(J.American.Chem.Soc.)(1952)74,5566)制得了本标题化合物。获得了0.1g(1.5%)产物;
1H NMR(CDCl3)尤其0.73(3H,d,J 7Hz),0.88(3H,d,J 7Hz),1.17(3H,s),1.47(3H,s),5.18(1H,d,J 17Hz),5.32(1H,d,J 11Hz),5.75(1H,d,J 8Hz),6.47(1H,dd,J 17和11Hz).M.S.(+ve离子电喷雾)m/z 518(MH+,100%)。
实施例35 (±)Mutilin 14-(1-氮杂二环[4.3.0]壬-4-基硫烷基)乙酸酯
步骤1.(±)1-氮杂二环[4.3.0]壬-4-醇
在室温,用氢化锂铝(0.7g,0.0185mol)在四氢呋喃(50ml)中将1-氮杂二环[4.3.0]壬-4-酮(1.0g,0.0072mol)(King F.D.,《英国化学会杂志,柏尔金学会论文集I》(J.Chem.Soc.Prekins.Trans I)(1986)447)处理18小时。进行常规反应后处理,获得了1.0g(100%)本标题化合物;MS(+ve离子电喷雾)m/z 142(MH+,95%)。
步骤2.(±)Mutilin 14-(1-氮杂二环[4.3.0]壬-4-基硫烷基)乙酸酯
按照实施例15的方法,由(±)1-氮杂二环[4.3.0]壬-4-醇(1.0g,0.0072mol)制得了本标题化合物。获得了1.12g(28%)产物;
1H NMR(CDCl3)尤其0.72(3H,d,J 7Hz),0.88(3H,d,J 7Hz),1.20(3H,s),1.47(3H,s),5.21(1H,d,J 17Hz),5.34(1H,d,J 11Hz),5.77(1H,d,J 8Hz),6.48(1H,dd,J 17和11Hz).M.S.(+ve离子电喷雾)m/z 518(MH+,100%)。
实施例36 (±)19,20-Dihydromutilin 14-(1-氮杂二环[4.3.0]壬-4-基硫烷基)乙酸酯
按照实施例15的方法,由(±)1-氮杂二环[4.3.0]壬-4-醇(0.66g,0.0047mol)和19,20-dihydromutilin 14-甲磺酰氧基乙酸酯(2.43g,0.0047mol)制得了本标题化合物,获得了0.44g(18%)产物;
1H NMR(CDCl3)尤其0.71(3H,d,J 7Hz),0.8(3H,t,J 9Hz),1.45(3H,s),3.15(2H,s),5.65(1H,d,J 8Hz).M.S.(+ve离子电喷雾)m/z 520(MH+,100%)。
实施例37 Mutilin 14-(1-羧甲基哌啶-4-基硫烷基)乙酸酯
步骤1.(哌啶-4-酮-1-基)乙酸叔丁酯
在100℃,用溴乙酸叔丁酯(6.98g,0.037mol)和碳酸钾(13.65g,0.099mol)在二甲基甲酰胺(100ml)中将4-哌啶酮-水合物盐酸盐(5g,0.033mol)处理24小时。将该混合物冷却,并真空浓缩。把残余物在饱和碳酸钾水溶液和乙醚(2×50ml)之间分配。合并有机层,干燥(硫酸钠),过滤,并蒸发至干,获得了7.36g(94%)本标题化合物;
1H NMR(CDCl3)1.45(9H,s),2.45(4H,t,J 7Hz),2.3-2.4(4H,m),3.29(2H,s)。
步骤2.(哌啶-4-醇-1-基)乙酸叔丁酯
在室温,用硼氢化钠(1.13g,0.028mol)在甲醇(150ml)中将(哌啶-4-酮-1-基)乙酸叔丁酯(3g,0.014mol)处理1小时。加入冰醋酸(1.68g,0.028mol),将该混合物搅拌15分钟。将混合物真空浓缩,把残余物在饱和碳酸钠水溶液和乙酸乙酯之间分配。分离有机层,干燥(硫酸钠),过滤并蒸发至于,获得了本标题化合物(2.9g,96%);MS(+ve离子电喷雾)m/z 216(MH+,100%)。
步骤3.Mutilin(1-羧甲基哌啶-4-基硫烷基)乙酸酯
按照实施例15的方法,由(哌啶-4-醇-1-基)乙酸叔丁酯制得了本标题化合物。在后处理中,叔丁酯基被水解。获得了0.3g(8%)产物;
1H NMR(CDCl3)尤其0.7(3H,d,J7Hz),0.88(3H,d,J 7Hz),1.17(3H,s),1.47(3H,s),5.22(1H,d,J 17Hz),5.35(1H,d,J11Hz),5.75(1H,d,J 8Hz),6.45(1H,dd,J 17和11Hz).M.S.(+ve离子电喷雾 )m/z 536(MH+,100%)。
实施例38 Mutilin 14-(哌啶-4-基硫烷基)乙酸酯
步骤1.1-(叔丁氧基羰基)哌啶-4-醇
按照实施例37步骤2的方法,用硼氢化钠(1.89g,0.05mol)处理1-(叔丁氧基羰基)哌啶-4-酮(5g,0.025mol),制得了5.07g(100%)本标题化合物;
1H NMR(CDCl3)尤其1.45(9H,s),1.29-1.41(2H,m),2.42-3.05(2H,m),3.75-3.99(3H,m)。
步骤2.Mutilin 14-(1-叔丁氧基羰基哌啶-4-基硫)乙酸酯
按照实施例15的方法,由1-(叔丁氧基羰基)哌啶-4-醇(2.5g,0.012mol)制得了本标题化合物;MS(-ve离子电喷雾)m/z 576(MH-,100%)。
步骤3.Mutilin 14-(哌啶-4-基硫烷基)乙酸酯
在0℃,用三氟乙酸(10ml)在二氯甲烷(100ml)中将步骤2所得产物处理2小时。将该混合物真空浓缩,把残余物在饱和碳酸氢钠水溶液和氯仿之间分配。分离出有机层,干燥(硫酸钠),过滤,并蒸发至干。进行硅胶色谱纯化,用其中9∶1甲醇/880氨水含量为0-10%的氯仿洗脱,获得了1.01g(26%)本标题化合物;
1H NMR(CDCl3)尤其0.75(3H,d,J 7Hz),0.9(3H,d,J 7Hz),1.18(3H,s),1.45(3H,s),5.20(1H,d,J 17Hz),5.35(1H,d,J 11Hz),5.80(1H,d,J8Hz),6.52(1H,dd,J 17和11Hz).M.S.(+ve离子电喷雾)m/z 478(MH+,65%)。
实施例39 Mutilin 14-(1-甲基哌啶-4-基甲基硫烷基)乙酸酯盐酸盐
步骤1.1-甲基-4-(羟基甲基)哌啶
在0℃和氩气氛下,将1-甲基哌啶-4-甲酸盐酸盐(《药物化学杂志》(J.Med.Chem.);1988,31,812)(1g,0.007mol)滴加到氢化锂铝(1.3g,0.035mol)在无水四氢呋喃(100ml)内的悬浮液中。将该混合物加热回流过夜,然后冷却至0℃,并滴加水(1.3ml)、10%氢氧化钠水溶液(1.95ml)和水(3.25ml),在室温搅拌1小时。将所得浆状物通过硅藻土过滤,把滤液真空蒸发,获得了0.90g(99.7%)本标题化合物,为浅橙色油状物;
1HNMR(CDCl3)1.18-1.53(3H,m),1.67-1.81(2H,m),1.83-2.12(3H,m),2.28(3H,s),2.79-2.94(2H,m),3.50(2H,d,J 7Hz);MS(+ve离子电喷雾)m/z 130(MH+)。
步骤2。(1-甲基哌啶-4-基甲基硫烷基)乙酸酯
在氩气氛下,将三苯基膦(3.67g,0.014mol)溶于无水四氢呋喃(25ml),并冷却至0℃。滴加偶氮二甲酸二异丙酯(2.75ml,0.014mol),并将该混合物在0℃搅拌0.5小时。滴加步骤1产物(0.90g,0.007mol)和硫羟乙酸(1.0ml,0.014mol)在无水四氢呋喃(50ml)中的溶液,将该混合物在室温搅拌过夜。将溶剂真空除去,把残余物在1M盐酸和乙醚之间分配。将水层用乙醚洗涤直至三苯基膦氧化物被除去,用碳酸钾固体碱化,萃取到二氯甲烷中,干燥(硫酸镁),真空蒸发,获得了0.60g(46%)本标题化合物,为浅黄色油状物;
1H NMR(CDCl3)1.22-1.59(3H,m),1.72-1.85(2H,m),1.95(2H,dt,J 13和3Hz),2.28(3H,s),2.35(3H,s),2.80-2.98(4H,m);MS(+ve离子电喷雾)m/z 188(MH+)。
步骤3.Mutilin 14-(1-甲基哌啶-4-甲基硫烷基)乙酸酯盐酸盐
在氩气氛下,将步骤2产物(0.19g,0.001mol)溶于无水乙醇(10ml),并用甲醇钠(0.054g,0.001mol)处理。将该混合物搅拌1小时,加入mutilin 14-甲磺酰氧基乙酸酯(0.456g,0.001mol)。将该混合物在室温搅拌过夜。把溶剂真空除去,将残余物在水和二氯甲烷之间分配。将有机层干燥(硫酸镁),并真空蒸发。将残余物通过柱色谱法纯化,用二氯甲烷-15%甲醇/二氯甲烷洗脱。把所得浆状物转化成其盐酸盐,获得了0.17g(34%)本标题化合物,为白色泡沫状物;
1H NMR(CDCl3)尤其0.73(3H,d,J 7Hz).0.90(3H,d,J 7Hz),5.23(1H,dd,J 17和3Hz),5.35(1H,dd,J 13和3Hz),5.73(1H,d,J 7Hz),6.48(1H,q,J 17和10Hz),12.26-12.69(1H,br s);MS(+ve离子电喷雾)m/z 506(MH+游离碱)。
实施例40 Mutilin 14-{(3S,4R)-1-氮杂二环[2.2.1]庚-3-基甲基硫烷基}乙酸酯
步骤1.(3S,4R)-1-氮杂二环[2.2.1]庚-3-基甲醇
采用实施例1步骤1的方法,用(3S,4R)-1-氮杂二环[2.2.1]庚烷-3-甲酸(WO 98/05659,SmithKline Beecham)制得了0.60g(84%)本标题化合物;
1H NMR(CDCl3)1.38-1.65(1H,m),1.83-2.00(1H,m),2.12-2.66(7H,m),2.78-3.05(2H,m),3.49-3.81(2H,m);MS(+ve离子电喷雾)m/z 128(MH+)。
步骤2.[(3S,4R)-1-氮杂二环[2.2.1]庚-3-基甲基硫烷基]乙酸酯
采用实施例1步骤2的方法,由步骤1产物制得了0。58g(66%)本标题化合物;
1H NMR(CDCl3)1.36-1.63(2H,m),1.90-2.01(1H,m),2.10-2.29(1H,m),2.34(3H,s),2.40-2.58(4H,m),2.78-2.96(2H,m),3.00-3.13(2H,m);MS(+ve离子电喷雾)m/z 186(MH+)。
步骤3.Mutilin 14-{(3S,4R)-1-氮杂二环[2.2.1]庚-3-基甲基硫烷基}乙酸酯
采用实施例1步骤3的方法,由步骤2产物制得了0.21g(42%)本标题化合物。通过快速硅胶柱色谱法纯化该化合物,用10%甲醇/二氯甲烷洗脱;
1H NMR(CDCl3)尤其0.76(3H,d,J 7Hz),0.90(3H,d,J 7Hz),3.13(2H,s),5.20(1H,dd,J18和2Hz),5.34(1H,dd,J 12和2Hz),5.78(1H,d,J 7Hz),6.51(1H,q,J 18和13Hz);MS(+ve离子电喷雾)m/z 504(MH+)。
实施例41 Mutilin 14-(奎宁环-2-基甲基硫烷基)乙酸酯
步骤1.(奎宁环-2-基甲基硫烷基)乙酸酯
采用实施例1步骤2的方法,由奎宁环-2-基甲醇(《美国化学会杂志》(J.Am.Chem.Soc.),1988,116,1278)制得了0.78g(55%)本标题化合物;
1H NMR(CDCl3)1.08-1.22(1H,m),1.40-1.58(4H,m),1.73-1.90(2H,m),2.35(3H,s),2.66-3.28(7H,m);MS(+ve离子电喷雾)m/z 158(MH+硫酸)。
步骤2.Mutilin 14-(奎宁环-2-基甲基硫烷基)乙酸酯
采用实施例1步骤3的方法,由步骤1产物制得了0.20g(39%)本标题化合物;
1H NMR(CDCl3)尤其1.75(3H,d,J 7Hz),0.90(3H,d,J 7Hz),3.18(2H,d,J 7Hz),5.21(1H,dd,J 18和2Hz),5.37(1H,dd,J 12和2Hz),5.75(1H,d,J 7Hz),6.50(1H,q,J 18和12Hz);MS(+ve离子电喷雾)m/z 518(MH+)。
实施例42 Mutilin 14-(1-氮杂二环[2.2.1]庚-4-基甲基硫烷基)乙酸酯
步骤1.(1-氮杂二环[2.2.1]庚-4-基甲基硫烷基)乙酸酯
采用实施例1步骤2的方法,用1-氮杂二环[2.2.1]庚-4-基甲醇(WO 93/15080)制得了0.55g(42%)本标题化合物;
1H NMR(CDCl3)1.21-1.35(2H,m),1.50-1.68(2H,m),2.29(2H,s),2.38(3H,s),2.53-2.70(2H,m),2.99-3.05(2H,m),3.28(2H,s);MS(+ve离子电喷雾)m/z 186(MH+)。
步骤2.Mutilin 14-(1-氮杂二环[2.2.1]庚-4-基甲基硫烷基)乙酸酯
采用实施例1步骤3的方法,由步骤1产物制得了0.14g(28%)本标题化合物;
1H NMR(CDCl3)尤其0.78(3H,d,J 7Hz),0.90(3H,d,J 7Hz),3.16(2H,s),5.22(1H,dd,J 18和2Hz),5.37(1H,dd,J 12和2Hz),5.78(1H,d,J 8Hz),6.50(1H,q,J 18和12Hz);MS(+ve离子电喷雾)m/z 504(MH+)。
实施例43 Mutilin 14-{(3R,4S)-1-氮杂二环[2.2.1]庚-3-基甲基硫烷基}乙酸酯
步骤1.(3R,4S)-1-氮杂二环[2.2.1]庚-3-基甲醇
采用实施例1步骤1的方法,用(3R,4S)-1-氮杂二环[2.2.1]庚烷-3-甲酸制得了0.68g(95%)本标题化合物;
1H NMR(CDCl3)1.37-1.71(2H,m),1.82-2.00(1H,m),2.10-2.72(6H,m),2.77-3.05(2H,m),3.47-3.76(2H,m);MS(+ve离子电喷雾)m/z 128(MH+)。
步骤2.[(3R,4S)-1-氮杂二环[2.2.1]庚-3-基甲基硫烷基]乙酸酯
采用实施例1步骤2的方法,由步骤1产物制得了0.22g(25%)本标题化合物;
1H NMR(CDCl3)1.40-1.70(2H,m),1.93-2.09(1H,m),2.12-2.31(1H,m),2.35(3H,s),2.51-2.70(4H,m),2.78-2.98(2H,m),3.0-3.15(2H,m);MS(+ve离子电喷雾)m/z 186(MH+)。
步骤3.Mutilin 14-{(3R,4S)-1-氮杂二环[2.2.1]庚-3-基甲基硫烷基}乙酸酯
采用实施例1步骤3的方法,由步骤2产物制得了0.12g(20%)本标题化合物;
1H NMR(CDCl3)尤其0.72(3H,d,J 7Hz),0.89(3H,d,J 7Hz),3.13(2H,s),5.21(1H,dd,J 18和2Hz),5.35(1H,dd,J 12和2Hz),5.76(1H,d,J 7Hz),6.50(1H,q,J 18和12Hz);MS(+ve离子电喷雾)m/z 504(MH+)。
实施例44 Mutilin 14-(1-氮杂二环[3.2.1]辛-5-基甲基硫烷基)乙酸酯
步骤1. 1-氮杂二环[3.2.1]辛-5-基甲醇
采用实施例1步骤1的方法,由1-氮杂二环[3.2.1]辛烷-5-甲酸盐酸盐(《药物化学杂志》(J.Med.Chem.);1991,34,2726-2735)制得了2.05g(93%)本标题化合物;
1H NMR(CDCl3)1.39-1.90(5H,m),2.61(2H,s),2.70(4H,m),3.35-3.75(4H,m);MS(+ve离子电喷雾)m/z 142(MH+)。
步骤2.(1-氮杂二环[3.2.1]辛-5-基甲基硫烷基)乙酸酯
采用实施例1步骤2的方法,用步骤1产物制得了1.0g(35%)本标题化合物;
1H NMR(CDCl3)1.45-1.89(6H,m),2.47(3H,s),2.60(2H,s),2.70-2.94(3H,m),3.00-3.17(3H,m);MS(+ve离子电喷雾)m/z 200(MH+)
步骤3.Mutilin 14-(1-氮杂二环[3.2.1]辛-5-基甲基硫烷基)乙酸酯
采用实施例1步骤3的方法,由步骤2产物制得了0.19g(7%)本标题化合物;
1H NMR(CDCl3)尤其0.73(3H,d,J 7Hz),0.90(3H,d,J 7Hz),5.20(1H,dd,J 18和2Hz),5.37(1H,dd,J 12和2Hz),5.76(1H,d,J 7Hz),6.48(1H,q,J18和12Hz);MS(+ve离子电喷雾)m/z 518(MH+)。
实施例45 Mutilin 14-{(R)-1-甲基哌啶-2-基甲基硫烷基}乙酸酯
步骤1.(R)-1-乙基氨基甲酰基哌啶-2-甲酸
在氩气氛下,将L-2-哌啶甲酸(0.50g,0.004mol)在无水二氯甲烷(10ml)中冷却至0℃,用三乙胺(0.65ml,0.0046mol)处理,然后滴加氯甲酸乙酯(0.37ml,0.004mol)的无水二氯甲烷(2ml)溶液。将该混合物在室温搅拌过夜,然后用二氯甲烷稀释,用5M盐酸洗涤,将有机层干燥(硫酸镁),并真空蒸发,获得了0.60g(77%)本标题化合物,为橙色油状物;
1H NMR(CDCl3)1.12-1.84(8H,m),2.15-2.40(1H,m),2.88-3.20(1H,m),3.90-4.28(3H,m),4.77-5.07(1H,m),5.68-6.82(1H,br s)。
步骤2.(R)-1-甲基哌啶-2-基甲醇
将步骤1产物(0.60g,0.003mol)在无水四氢呋喃(10ml)中的溶液滴加到氢化锂铝(0.57g,0.015mol)在无水四氢呋喃(20mol)内的悬浮液中。将该混合物加热回流2小时,并在室温搅拌过夜。将该反应混合物冷却至0℃,滴加水(0.5ml),然后滴加10%氢氧化钠水溶液(0.9ml)和水(1.4ml)。将该混合物搅拌1小时,通过硅藻土过滤,将滤液真空蒸发,获得了0.31g(80%)本标题化合物,为浅黄色油状物;
1H NMR(CDCl3)1.17-2.00(8H,m),2.14(1H,dt,J 13和2Hz),2.30(3H,s),2.76-2.96(1H,m),3.40(1H,dd,J 13和1Hz),3.88(1H,dd,J 12和5Hz);MS(+ve离子电喷雾)m/z 130(MH+)。
步骤3.[(R)-1-甲基哌啶-2-基甲基硫烷基]乙酸酯
采用实施例1步骤2的方法,由步骤2产物制得了0.30g(71%)本标题化合物;
1H NMR(CDCl3)1.16-1.76(6H,m),2.00-2.18(2H,m),2.29(3H,s),2.35(3H,s),2.80-2.92(1H,m),3.00-3.23(2H,m)。
步骤4.Mutilin 14-{(R)-1-甲基哌啶-2-基甲基硫烷基}乙酸酯
采用实施例1步骤3的方法,由步骤3产物制得了0.19g(22%)本标题化合物;
1H NMR(CDCl3)尤其0.75(3H,d,J 7Hz),0.89(3H,d,J 7Hz),3.11(2H,s),3.36(1H,q,J 12和7Hz),5.19(1H,dd,J 18和2Hz),5.35(1H,dd,J 12和2Hz),5.75(1H,d,J 7Hz),6.50(1H,q,J 18和12Hz);MS(+ve离子电喷雾)m/z 506(MH+)。
实施例46 Mutilin 14-{(S)-1-甲基吡咯烷-2-基甲基硫烷基}乙酸酯
步骤1.[(S)-1-甲基吡咯烷-2-基甲基硫烷基]乙酸酯
采用实施例1步骤2的方法,由(S)(-)-1-甲基-2-吡咯烷-2-基甲醇制得了0.64g(85%)本标题化合物;
1H NMR(CDCl3)1.44-1.61(1H,m),1.65-1.85(2H,m),1.87-2.04(1H,m),2.15-2.42(2H,m),2.35(3H,s),2.38(3H,s),2.82-2.94(1H,m),3.05-3.14(1H,m),3.28(1H,dd,J 13和3Hz);MS(-ve离子电喷雾)m/z 130(M-H,硫酸)。
步骤2.Mutilin 14-{(S)-1-甲基吡咯烷-2-基甲基硫烷基}乙酸酯
采用实施例1步骤3的方法,由步骤1产物制得了0.17g(23%)本标题化合物;
1H NMR(CDCl3)尤其0.76(3H,d,J 7Hz),0.90(3H,d,J 7Hz),3.18(2H,s),3.35(1H,q,J 10和7Hz),5.20(1H,dd,J 18和2Hz),5.35(1H,dd,J 12和2Hz),5.75(1H,d,J 7Hz),6.50(1H,q,J 18和12Hz);MS(+ve离子电喷雾)m/z 492(MH+)。
实施例47 Mutilin 14-{(R)-1-甲基哌啶-3-基甲基硫烷基}乙酸酯
步骤1.(R)-1-乙基氨基甲酰基哌啶-3-甲酸乙酯
在氩气氛下,将(R)-3-哌啶甲酸乙酯(《有机化学杂志》(J.Org.Chem.),56,1991,1166-1170)(3.0g,0.019mol)在无水二氯甲烷(50ml)中冷却至0℃。加入三乙胺(3.19ml,0.023mol),然后滴加氯甲酸乙酯(1.83ml,0.019mol)的无水二氯甲烷(6ml)溶液,将该混合物在室温搅拌过夜。将该反应混合物用二氯甲烷稀释,用水洗涤,干燥(硫酸镁),并真空蒸发,获得了3.45g(79%)本标题化合物,为无色油状物;
1H NMR(CDCl3)1.28(6H,t,J 7Hz),1.38-1.82(3H,m),2.00-2.15(1H,m),2.38-2.55(1H,m),2.77-3.13(2H,m),3.91-4.04(1H,m),4.07-4.35(5H,m)
步骤2.(R)-1-甲基哌啶-3-基甲醇
采用实施例7步骤2的方法,由步骤1产物制得了1.8g(92%)本标题化合物;
1H NMR(CDCl3)0.90-1.12(1H,m),1.50-1.90(5H,m),1.94-1.99(1H,m),2.25(3H,s),2.57-2.74(1H,m),2.79-2.92(1H,m),3.14-3.71(3H,m);MS(+ve离子电喷雾)m/z 130(MH+).
步骤3.[(R)-1-甲基哌啶-3-基甲基硫烷基]乙酸酯
采用实施例1步骤2的方法,由步骤2产物制得了0.59g(81%)本标题化合物;
1H NMR(CDCl3)0.87-1.06(1H,m),1.44-1.94(6H,m),2.27(3H,s),2.34(3H,s),2.62-2.92(4H,m);MS(+ve离子电喷雾)m/z 188(MH+)
步骤4.Mutilin 14-{(R)-1-甲基哌啶-3-基甲基硫烷基}乙酸酯
采用实施例1步骤3的方法,由步骤3产物制得了0.26g(34%)本标题化合物;
1H NMR(CDCl3)尤其0.74(3H,d,J 7Hz),0.90(3H,d,J 7Hz),3.12(2H,d,J 2Hz),3.30-3.44(1H,m),5.22(1H,dd,J 18和2Hz),5.38(1H,dd,J 12和2Hz),5.76(1H,d,J 7Hz),6.50(1H,q,J 18和12Hz);MS(+ve离子电喷雾)m/z 506(MH+)。
实施例48 Mutilin 14-(奎宁环-4-基甲基硫烷基)乙酸酯
在氩气氛下将三苯基膦(1.1g,0.0042mol)在无水四氢呋喃(50ml)中的溶液用冰冷却,并用偶氮二甲酸二异丙酯(0.85g,0.0042mol)处理。30分钟后,滴加硫羟乙酸(0.315ml,0.0042mol)和奎宁环-4-基甲醇(0.565g,0.0042mol)在无水四氢呋喃中的溶液。将该混合物在5℃放置72小时。真空浓缩后,把残余物在乙醚和1M盐酸之间分配。将水相用乙醚洗涤,然后真空浓缩,获得了固体(0.65g)。将该固体溶于乙醇,并用叔丁醇钾(0.785g,0.007mol)处理。搅拌30分钟后,加入Mutilin 14-甲磺酰氧基乙酸酯(1.38g,0.003mol)。将该混合物在氩气氛下搅拌18小时,然后真空浓缩。将残余物在氯仿和水之间分配。将有机相用盐水洗涤,用硫酸镁干燥,并真空浓缩。通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液(10/1/0.1)洗脱,获得了本标题化合物,0.478g(31%);
1H NMR(CDCl3)尤其0.74(3H,d,J 6.5Hz),0.88(3H,d,J 6.7Hz),1.17(3H,s),1.40(6H,t,J 8Hz),1.49(3H,s),2.47(2H,s),2.87(6H,t,J 8Hz),3.0(2H,s),3.36(1H,m),5.1 to 5.4(2H,m),5.75(1H,d,J 8.3Hz),6.48(1H,m);MS(+ve离子电喷雾)m/z518(MH+,100%)。
实施例49 Mutilin 14-(8-甲基-8-氮杂二环[3.2.1]辛-3-基甲基硫烷基)乙酸酯
步骤1.(8-甲基-8-氮杂二环[3.2.1]辛-3-基)甲醇
采用实施例24步骤1的方法,由8-甲基-8-氮杂二环[3.2.1]辛烷-3-甲酸盐酸盐(WO 98/05659实施例25步骤3)制得了0.78g(100%)本标题化合物;
1H NMR(CDCl3)尤其1.3-2.0(9H,m),2.25(3H,s),3.16(2H,m),3.44(2H,d,J 6.3Hz);MS(+ve离子电喷雾)m/z 156(MH+,100%)。
步骤2.Mutilin 14-(8-甲基-8-氮杂二环[3.2.1]辛-3-基甲基硫烷基)乙酸酯
采用实施例15的方法,由(8-甲基-8-氮杂二环[3.2.1]辛-3-基)甲醇和mutilin 14-甲磺酰氧基乙酸酯制得了0.101g(19%)本标题化合物;
1H NMR(CDCl3)尤其0.74(3H,d,J 6.5Hz),0.88(3H,d,J 7.0Hz),1.25(3H,s),1.49(3H,s),2.34(3H,s),2.48(2H,d,),3.1(2H,s),3.15(2H,m),3.36(1H,m),5.1-5.4(2H, m),5.74(1H,d,J 8.5Hz),6.48(1H,m);MS(+ve离子电喷雾)m/z533(MH+,85%)。
实施例50 Mutilin 14-(外-8-甲基-8-氮杂二环[3.2.1]辛-3-基硫烷基)乙酸酯
采用实施例15的方法,由内-8-甲基-8-氮杂二环[3.2.1]辛-3-醇和mutilin 14-甲磺酰氧基乙酸酯制得了0.09g(17%)本标题化合物;
1H NMR(CDCl3)尤其0.74(3H,d,J 6.7Hz),0.99(3H,d,J 7.5Hz),1.18(3H,s),1.63(3H,s),2.28(3H,s), 3.0(1H,m),3.13(2H,s),3.16(2H,m),3.36(1H,m),5.15 to 5.37(2H,m),5.77(1H,d,J 8.3Hz),6.49(1H,m);MS(+ve离子电喷雾)m/z518(MH+,100%)。
实施例51 Mutilin 14-[3-(奎宁环-4-基硫烷基)]丙酸酯
步骤1.Mutilin 14-丙烯酸酯-11-三氟乙酸酯
在室温和氩气氛下,将Mutilin 14-三氟乙酸酯(WO 97/25309实施例85步骤2)(3.0g,0.0072mol)、三乙胺(3.74g,0.037mol)和催化量的4-二甲基氨基吡啶在二氯甲烷(100ml)中用丙烯酰氯(3.33g,0.037mol)处理过夜。把该反应混合物在水和二氯甲烷之间分配。将有机层用硫酸镁干燥,把溶剂真空除去。将残余物通过硅胶色谱法纯化,用乙酸乙酯/石油醚40-60°(1∶10)洗脱,获得了1.25g(37%)本标题化合物;
1HNMR(CDCl3)尤其0.69(3H,d,J 6.6Hz),0.84(3H,d,J 7Hz),1.06(3H,s),1.52(3H,s),2.1 to 2.4(4H,m),2.65(1H,m),5.0(1H,d,6.9Hz),5.20-5.37(2H,m),5.72-5.86(2H,m),6.0-6.1(1H,m),6.3-6.5(2H,m)。
步骤2.Mutilin 14-[3-(奎宁环-4-基硫烷基)]丙酸酯
在室温和氩气氛下,用由奎宁环-4-硫醇盐酸盐(0.145g,0.0008mol)和叔丁醇钾(0.094g,0.000838mol)制得的奎宁环-4-硫醇钾在乙醇(15ml)中将Mutilin 14-丙烯酸酯-11-三氟乙酸酯(0.376g,0.008mol)处理过夜。将溶剂真空除去,把残余物通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液(10∶1∶0.1)洗脱,将色谱分离的这一产物(0.262g)溶于四氢呋喃/水(5∶1)(6ml)中,用1ml 0.5M氢氧化钠溶液在室温下处理3小时。将反应混合物真空浓缩,残余物在硅胶上色谱纯化用氯仿/甲醇/35%氨水(9∶1∶0.1)溶液洗脱,获得了本标题化合物,0.152g(总产率为36%)。
1H NMR(CDCl3)尤其0.72(3H,d,J 6.5Hz),0.87(3H,d,J 7.0Hz),1.08(3H,s),1.63(3H,s),1.69(6H,t,J 8Hz),2.00-2.47(7H,m),2.74(2H,t,J 7.8Hz),3.36(1H,m),5.17-5.38(2H,m),5.74(1H,d,J 8.5Hz),6.52(1H,m);MS(+ve离子电喷雾)m/z 518(MH+,100%)。
实施例52 Mutilin 14-[3-(奎宁环-4-基甲基硫烷基)]丙酸酯
将偶氮二甲酸二异丙酯(0.85g,0.0042mol)滴加到三苯基膦(1.1g,0.0042mol)在无水四氢呋喃(50ml)内的冰冷溶液中。30分钟后,滴加硫羟乙酸(0.335g,0.0042mol)和奎宁环-4-基甲醇(实施例28步骤1)(0.565g,0.004mol)在无水四氢呋喃(20ml)中的溶液。将该混合物在氩气氛下搅拌72小时,真空蒸发,并置于乙醚中。用1M盐酸萃取该乙醚溶液。将水萃取液用乙醚洗涤,蒸发至干,获得了固体(0.65g)。按照实施例51步骤2的方法,用上述固体和mutilin14-丙烯酸酯-11-三氟乙酸酯(实施例51步骤1)制得了0.41g(80%)本标题化合物;
1H NMR(CDCl3)尤其0.72(3H,d,J 6 18Hz),0.87(3H,d,J 7Hz),1.09(3H,s),1.45(3H,s),1.48(6H,t,8Hz),2.46(2H,s),2.52(2H,m),2.75(2H,m),2.95(6H,t,J 7.8Hz),3.44(1H,m),5.28(2H,m),5.75(1H,d,J 8.5Hz),6.52(1H,m);MS(+ve离子电喷雾)m/z 532(MH+,100%)。
实施例53 Mutilin 14-[3-(1-甲基哌啶-4-基硫烷基)]丙酸酯
用偶氮二甲酸二异丙酯(4.25g,0.021mol)处理三苯基膦(5.51g,0.021mol)的无水四氢呋喃(100ml)溶液。30分钟后,用30分钟滴加1-甲基哌啶-4-醇(2.3g,0.02mol)和硫羟乙酸(1.54g,0.02mol)在无水四氢呋喃(50ml)中的溶液。将该混合物搅拌过夜,真空浓缩,把残余物置于乙醚中。用1M盐酸萃取该乙醚溶液。将该水萃取液用乙醚洗涤,蒸发至干,并真空干燥,获得了黄色树胶状物(2.4g)。依据实施例51步骤2的方法,将一部分该树胶状物(0.252g)在乙醇中用甲醇钠(0.120g)处理,然后用mutilin 14-丙烯酸酯-11-三氟乙酸酯(实施例51步骤1)(0.376g)处理,获得了0.3g(74%)本标题化合物;
1H NMR(CDCl3)尤其0.73(3H,d,J 6.8Hz),0.87(3H,d,J 7.0Hz),1.17(3H,s),1.46(3H,s),2.18(2H,m),2.25(3H,s),2.40(2H,m),2.51(1H,m),2.80(4H,m),3.35(1H,m),5.27(2H,m),5.74(1H,d,8.3Hz),6.52(1H,m);MS(+ve离子电喷雾)m/z506(MH+,100%)。
实施例54 19,20-Dihydromutilin 14-(1-甲基哌啶-4-硫烷基)乙酸酯
步骤1.19,20-Dihydromutilin 14-甲磺酰氧基乙酸酯
采用文献中关于截短侧耳素的方法(H Egger和H Reinshagen,《抗生素杂志》(J Antibiotics),29(9),915),由19,20-二去氢截短侧耳素(A.Birch等人,《四面体》(Tetrahedron),(1996)Suppl.8 partII,359-387)制得了本标题化合物;
1H NMR(CDCl3)尤其0.71(3H,d,J 7Hz),0.77(3H,t,7.5Hz),0.95(3H,d,J 8.5Hz),0.97(3H,s),1.42(3H,s),3.21(3H,s),3.42(1H,m),4.66(2H,m),5.72(1H,d,8.2Hz)。
步骤2.19,20-Dihydromutilin 14-(1-甲基哌啶-4-硫烷基)乙酸酯
采用实施例15中所述的方法,用4-羟基-1-甲基哌啶和19,20-Dihydromutilin 14-甲磺酰氧基乙酸酯制得了0.42g(83%)本标题化合物;
1H NMR(CDCl3)尤其0.71(3H,d,J 6.8Hz),0.78(3H,t,J 7.6Hz),0.94(3H,d,J 7.6Hz),0.97(3H,s),1.43(3H,s),2.25(3H,s),2.42(1H,m),2.81(2H,m),3.42(1H,t,J 6Hz),5.63(1H,d,J 8Hz);MS(+ve离子电喷雾)m/z 494(MH+,75%)。
实施例55 19,20-Dihydromutilin 14-(8-甲基-8-氮杂二环[3.2.1]辛-3-甲基硫烷基)乙酸酯
按照实施例15的方法,由19,20-dihydromutilin 14-甲磺酰氧基乙酸酯(实施例54步骤1)和8-甲基-8-氮杂二环[3.2.1]辛-3-基甲醇制得了本标题化合物,获得了0.335g(45%)产物;
1H NMR(CDCl3)尤其0.71(3H,d,J 6.5Hz),0.79(3H,t,J 7.3Hz),0.93(3H,d,J 7.0Hz),0.97(3H,s),1.0 to 2.2(27H,m),2.28(3H,s),2.41(1H,m),3.11(2H,s),3.17(2H,m),3.42(1H,m),5.62(1H,d,J 8.3Hz);MS(+ve离子电喷雾)m/z 520(MH+,60%)。
实施例56 Mutilin 14-[4-(奎宁环-4-基硫烷基)]丁酸酯
步骤1.Mutilin 14-(4-溴丁酸酯)-11-三氟乙酸酯
用4-溴丁酰氯(0.56g,0.003mol)在无水二氯甲烷(20ml)中将mutilin 11-三氟乙酸酯(WO 97/25309,实施例85,步骤2)(1.25g,0.003mol)和吡啶(0.273g,0.003mol)处理72小时。将该混合物真空浓缩,把所得残余物通过硅胶色谱法纯化,用二氯甲烷洗脱,获得了1.5g(93%)本标题化合物;
1H NMR(CDCl3)尤其0.72(3H,d,J 6.7Hz),0.83(3H,d,J 7Hz),1.05(3H,s),1.43(3H,s),2.62(1H,t,J 7Hz),3.46(2H,t,J 6Hz),5.0(1H,d,J 6.7Hz),5.3(2H,m),5.69(1H,d,J 8Hz),6.37(1H,m);MS(+ve离子电喷雾)m/z 532(MH+,40%)。
步骤2.Mutilin 14-[4-(奎宁环-4-基硫烷基)]丁酸酯
在乙醇(10ml)中将奎宁环-4-硫醇盐酸盐(0.359g,0.002mol)用甲醇钠(0.216g,0.004mol)处理。30分钟后,加入Mutilin 14-(4-溴丁酸酯)-11-三氟乙酸酯(0.565g,0.001mol),将该混合物在氩气氛下放置过夜。将该反应混合物真空浓缩,把残余物在水和氯仿之间分配。将有机层用硫酸镁干燥,并真空浓缩。将残余物通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液(10∶1∶0.1)洗脱,获得了本标题化合物,0.190g(35%);
1H NMR(CDCl3)尤其0.71(3H,d,J 6.5Hz),0.87(3H,d,J 6.8Hz),1.16(3H,s),1.59(3H,s),1.81(14H,m)2.06(2H,t,J 8.5Hz),2.49(2H,t,J 7.3Hz),2.94(6H,t,J 7.3Hz),3.35(1H,m),5.29(2H,m),5.75(1H,d,J 8.5Hz),6.52(1H,m);MS(+ve离子电喷雾)m/z 532(MH+,100%)。
实施例57 1,2-Didehydromutilin 14-(1-甲基哌啶-4-基甲基硫烷基)乙酸酯
步骤1.1,2-Didehydromutilin 11-二氯乙酸酯
将1,2-didehydromutilin(1.41g,0.0044mol)(按照类似于制备1,2-二去氢截短侧耳素的方法制得,G Schulz和H Berner,《四面体》(Tetrahedron),1984,40,905-17)、吡啶(0.56ml,0.0066mol)和N,N-二甲基氨基吡啶(0.02g)在四氢呋喃(30ml)中的溶液用二氯乙酸酐(1.16g,0.0048mol)的四氢呋喃(5ml)溶液处理。18小时后,将该混合物真空浓缩,把残余物在乙酸乙酯和稀盐酸之间分配。分离出有机相,用水和盐水洗涤,用硫酸镁干燥,把溶剂真空除去。将残余物通过硅胶色谱法纯化,用其中乙酸乙酯含量是20%的己烷洗脱,获得了本标题化合物(1.3g,69%),为无色固体;
1HNMR(CDCl3)尤其4.33(1H,d,J 7.7Hz),4.57(1H,d,J 7.0Hz),5.34(1H,d,J11.2Hz),5.48(1H,d,J 17.8Hz),5.99(1H,s),6.10(1H,d,6.1Hz),6.11(1H,dd,J 17.8和11.2Hz),7.67(1H,d,J 6.1Hz)。
步骤2.1,2-Didehydromutilin 11-二氯乙酸酯-14-氯乙酸酯
在0℃,将1,2-didehydromutilin 11-二氯乙酸酯(1.2g,0.0028mol)、吡啶(0.7ml)和N,N-二甲基氨基吡啶(0.01g)在二氯甲烷(10ml)中的溶液用氯乙酰氯(0.33ml,0.0042mol)处理。在室温搅拌18小时后,将该混合物真空浓缩,把残余物在乙酸乙酯和稀盐酸之间分配。分离出有机相,用水和盐水洗涤,用硫酸镁干燥,把溶剂真空除去。将残余物通过硅胶色谱法纯化,用其中乙酸乙酯含量是20%的己烷洗脱,获得了本标题化合物(0.7g,50%),为无色固体;
1H NMR(CDCl3)尤其0.79(3H,d,J 6.8Hz),1.04(3H,d,J 7.1Hz),1.10(3H,s),1.58(3H,s),4.00(2H,s),4.60(1H,d,J 7.0Hz),5.30(1H,d,J 17.7Hz)5.36(1H,d,J 11.7Hz),5.70(1H,d,J8.6Hz),5.97(1H,s),6.10(1H,d,J 6.2Hz),6.34(1H,dd,J 17.7和11.7Hz),7.66(1H,d,J6.2Hz)。
步骤3.1,2-Didehydromutilin 11-二氯乙酸酯-14-(1-甲基哌啶-4-基甲基硫烷基)乙酸酯
采用实施例39步骤3的方法,用1,2-Didehydromutilin 11-二氯乙酸酯-14-氯乙酸酯(0.7g,0.0012mol)和(1-甲基哌啶-4-基甲基硫烷基)乙酸酯(0.224g,0.0012mol)制得了本标题化合物(0.36g,49%);
1H NMR(CDCl3)尤其0.80(3H,d,J 6.3Hz),1.03(3H,d,J 7.0Hz),1.09(3H,s),1.56(3H,s),2.26(3H,s),3.13(2H,s),4.60(1H,d,J 6.8Hz),5.30(1H,d,J17.5Hz),5.34(1H,d,J 10.7Hz),5.66(1H,d,J 8.4Hz),5.97(1H,s),6.09(1H,d,J 6.1Hz),6.34(1H,dd,J 17.5和10.7Hz),7.65(1H,d,J 6.1Hz);MS(+ve离子电喷雾)616和614(MH+)。
步骤4.1,2-Didehydromutilin 14-(1-甲基哌啶-4-基甲基硫烷基)乙酸酯
将1,2-Didehydromutilin 11-二氯乙酸酯-14-(1-甲基哌啶-4-基甲基硫烷基)乙酸酯(0.18g,0.0003mol)的二氧杂环己烷(3ml)溶液用氢氧化钾水溶液(1M,0.36ml)处理。在室温搅拌1小时后,用稀盐酸将该混合物中和,把溶剂真空蒸发。将残余物在乙酸乙酯和碳酸氢钠水溶液之间分配。分离出有机相,用水和盐水洗涤,用硫酸镁干燥,把溶剂真空除去。通过硅胶色谱法纯化,用二氯甲烷/甲醇/35%氨水溶液(20∶1∶0.1)洗脱,获得了本标题化合物(0.12g,80%),为无色固体;
1H NMR(CDCl3)尤其0.81(3H,d,J6.5Hz),1.08(3H,d,J 7.1Hz),1.15(3H,s),1.55(3H,s),2.26(3H,s),3.12(2H,s),5.20(1H,dd,J 17.5和1.4Hz),5.36(1H,dd,J 10.9和1.4Hz),5.72(8.6Hz),6.04(1H,d,J6.1Hz),6.47(1H,dd,J 17.5和10.9Hz),7.73(1H,d,J 6.1Hz);MS(+ve离子电喷雾)504(MH+)。
实施例58 Mutilin 14-(外-8-甲基-8-氮杂二环[3.2.1]辛-3-基硫烷基)乙酸酯
将22-去氧-22-硫烷基截短侧耳素(US 4130709,1978)(0.1g,0.00025mol)在乙醇(4ml)中用甲醇钠(0.014g,0.0026mol)处理,把所得混合物搅拌30分钟。然后加入内-3-甲磺酰氧基-8-甲基-8-氮杂二环[3.2.1]辛烷(用内-8-甲基-8-氮杂二环[3.2.1]辛-3-醇和甲磺酰氯制得)(0.061g,0.00028mol)的乙醇(1ml)溶液。继续搅拌68小时,然后再加入一部分内-3-甲磺酰氧基-8-甲基-8-氮杂二环[3.2.1]辛烷(0.061g,0.00028mol),再继续搅拌18小时。将该混合物用二氯甲烷稀释,用碳酸钾水溶液洗涤2次,用盐水洗涤1次,用硫酸镁干燥,并真空浓缩。通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液(9∶1∶0.1)洗脱,获得了0.035g(27%)本标题化合物,与实施例50所述化合物相同。
实施例59 Mutilin 14-(1-甲酰氨基甲基哌啶-4-基硫烷基)乙酸酯
将Mutilin 14-(1-羧甲基哌啶-4-基硫烷基)乙酸酯(实施例37)(0.08g,0.00015mol)在二氯甲烷(3ml)中用草酰氯(0.032ml,0.00036mol)和二甲基甲酰胺(1滴)处理,并在室温搅拌2小时。然后将该混合物蒸发至干,把残余物悬浮在四氢呋喃(3ml)中,并用35%氨水溶液(25ml)处理,搅拌2小时。将该混合物蒸发至干,把残余物在饱和碳酸氢钠水溶液和氯仿之间分配。分离出有机相,干燥(硫酸钠),过滤,并蒸发至干。通过硅胶色谱法纯化,用氯仿/甲醇/35%氨水溶液(90∶9∶1)洗脱。将残余物用甲醇/乙醚研制,获得了0.035g本标题化合物;MS(+ve离子电喷雾)m/z 535(MH+,88%)。
抗菌活性
下表举例说明了代表性mutilin 14-酯的抗菌活性。活性以最小抑制浓度表示,单位是微克/毫升(10-6g/ml),是通过微量滴定用标准肉汤稀释法测定的。
生物体 | 截短侧耳素 | 硫粘菌素 | 实施例1化合物 | 实施例15化合物 | 实施例50化合物 |
S.a. | 2 | 0.25 | ≤0.06 | ≤0.06 | ≤0.06 |
S.p. | 8 | 0.25 | ≤0.06 | ≤0.06 | ≤0.06 |
E.c. | >64 | >64 | 16 | 64 | 32 |
H.i. | 2 | 2 | 0.25 | 0.5 | 0.5 |
M.c. | 0.5 | 0.125 | ≤0.06 | ≤0.06 | ≤0.06 |
S.a.=金黄色葡萄球菌Oxford;
S.p.=肺炎链球菌1629;
E.c.=大肠杆菌DCO;
H.i.=流感嗜血菌Q1;
M.c.=粘膜炎莫拉氏菌Ravasio
药物组合物
实施例1-油性喷雾制剂
鼻用喷雾制剂的载体是通过形成67%w/w分馏椰子油(中等链长度)*和33%w/w甘油单油酸酯**的混合物制得的。将0.2%w/w粉末柠檬汁调味剂加到该混合物中,然后加入0.5或1.0%药物(以溶液形式,如果不溶的话,以微粉化形式)***。
所得制剂在20℃或更高温度下的粘性可以喷雾。当喷到患者鼻子中时,该液体覆盖鼻腔并与鼻子内的水分接触(粘膜以及通常是湿润环境中的水分),使载体变稠。这延长了该喷雾制剂在鼻表面的停留时间。约100μl喷雾体积含有约0.5或1mg药物。
*市售产品Miglyol,购自Condea。
**市售产品Myverol 18-99,购自Eastman。
***例如实施例1或实施例8的化合物。
实施例2-水性喷雾制剂
组分 % 用途
药物 0.001-1.00 活性成分
氯化钠 0.5-0.9 渗透压调节剂
苯扎氯铵 0.02 防腐剂
乙二胺四乙酸二钠 0.1 部分防腐剂
吐温80 0.2 表面活性剂/增溶剂
正磷酸二氢钠 0.2 缓冲剂
水 适量 载体
使用盐酸和氢氧化钠把组合物的pH调节至约5.5。该药物分子在该pH表现出最佳稳定性。
Claims (19)
1.通式(IA)或(IB)化合物或它们的可药用盐:
其中:
R1是乙烯基或乙基;
R2是可选择性地被取代的、包含1个或2个碱性氮原子并通过环碳原子挂接的非芳香单环基团;
n和m分别独立地为0、1或2;和
X选自-O-、-S(O)-、-SO2-、-COO-、-NH-、-CONH-、-NHCONH-和一个键;或者
n是1或2、m是2且X是-S-;
或者
R2是可选择性地被取代的、包含1个或2个碱性氮原子并通过环碳原子挂接的非芳香双环基团;
n和m分别独立地为0、1或2;和
X选自-O-、-S-、-S(O)-、-SO2-、-COO-、-NH-、-CONH-、-NHCONH-和一个键;
R3是H或OH;或
或者在(IA)或(IB)的14位上的部分R2(CH2)mX(CH2)nCH2COO被RaRbC=CHCOO替代,其中Ra和Rb有一个是氢原子,另一个是R2,或者Ra和Rb一起形成R2。
2.权利要求1的化合物,其中R2选自可选择性地被取代的哌啶基、吡咯烷基、奎宁环基、氮杂二环[2.2.1]庚基、氮杂二环[4.3.0]壬基、氮杂二环[3.2.1]辛基、氮杂二环[3.3.0]辛基、氮杂二环[2.2.2]辛基、氮杂二环[3.2.1]辛烯基、氮杂二环[3.3.1]壬基和氮杂二环[4.4.0]癸基。
3.权利要求1或2的化合物,其中R2被烷基、烷氧基、链烯基或链烯氧基取代,所述烷基、烷氧基、链烯基或链烯氧基又可选择性地被一个或多个选自下述基团的取代基取代:芳基、杂环基、(C1-6)烷氧基、(C1-6)烷硫基、芳基(C1-6)烷氧基、芳基(C1-6)烷硫基、氨基、一(C1-6)烷基氨基、二(C1-6)烷基氨基、环烷基、环烯基、羧基及其酯、酰氨基、脲基、脒基、胍基、烷基磺酰基、氨基磺酰基(C1-6)酰氧基、(C1-6)酰氨基、叠氮基、羟基、和卤素。
4.权利要求1-3任一项的化合物,其中n是0。
5.权利要求1-4任一项的化合物,其中m是0或1。
6.权利要求1-5任一项的化合物,其中R2是奎宁环基。
7.权利要求1-6任一项的化合物,其中所述化合物具有式(IA)结构式。
8.权利要求1的化合物,其中所述化合物选自:
mutilin 14-(奎宁环-4-基硫烷基)乙酸酯;
19,20-dihydromutilin 14-(奎宁环-4-基硫烷基)乙酸酯;
mutilin 14-(奎宁环-3-基氧基)乙酸酯;
mutilin 14-(奎宁环-3-基硫烷基)乙酸酯;
Mutilin 14-[N-(2,2-二甲基氮杂二环[4.3.0]壬-4-甲基)]-氨基乙酸酯;
mutilin 14-(奎宁环-4-基羰基氨基)乙酸酯;
Mutilin 14-[(3R,4R)-氮杂二环[2.2.1]庚-3-基羰基氨基]乙酸酯;
Mutilin 14-(1-甲基哌啶-4-基羰基氨基)乙酸酯;
Mutilin 14-[3-(1-甲基哌啶-4-基)]丙酸酯;
Mutilin 14-(奎宁环-4-基甲基硫烷基)乙酸酯;
19,20-Dihydromutilin 14-(奎宁环-4-基磺酰基)乙酸酯;
19,20-Dihydromutilin 14-(奎宁环-4-基硫氧基)乙酸酯;
Mutilin 14-{(3RS,4SR)-1-氮杂二环[2.2.1]庚-3-基硫烷基}乙酸酯;
Mutilin 14-(亚奎宁环-3-基)乙酸酯;
Mutilin 14-[奎宁环-3-基]乙酸酯;
Mutilin 14-[奎宁环-3-基乙酰氧基]乙酸酯;
Mutilin 14-(奎宁环-3-基甲基硫烷基)乙酸酯;
1,2-Didehydromutliin 14-(奎宁环-4-基硫烷基)乙酸酯;
2α-Hydroxymutilin 14-(奎宁环-4-基硫烷基)乙酸酯;
Mutilin 14-(奎宁环-4-基)乙酸酯;
Mutilin 14-(奎宁环-4-基甲基)氨基乙酸酯;
Mutilin 14-[3-(奎宁环-4-基)丙烯酸酯];
Mutilin 14-[3-(奎宁环-4-基)]丙酸酯;
Mutilin 14-(奎宁环-4-基甲氧基)乙酸酯;
Mutilin 14-[(3R)-奎宁环-3-基氨基]乙酸酯;
Mutilin 14-(奎宁环-4-基氨基)乙酸酯;
Mutilin 14-[4-(奎宁环-4-基)]丁酸酯;
Mutilin 14-(1-氮杂二环[3.3.0]辛-4-基甲基硫烷基)乙酸酯;
Mutilin 14-(1-氮杂二环[3.3.0]辛-3-基硫烷基)乙酸酯;
Mutilin 14-(内8-甲基-8-氮杂二环[3.2.1]辛-3-基硫烷基)乙酸酯;
Mutilin 14-(1-氮杂二环[4.3.0]壬-4-基硫烷基)乙酸酯;
19,20-Dihydromutilin 14-(1-氮杂二环[4.3.0]壬-4-基硫烷基)乙酸酯;
Mutilin 14-{(3S,4R)-1-氮杂二环[2.2.1]庚-3-基甲基硫烷基}乙酸酯;
Mutilin 14-(奎宁环-2-基甲基硫烷基)乙酸酯;
Mutilin 14-(1-氮杂二环[2.2.1]庚-4-基甲基硫烷基)乙酸酯;
Mutilin 14-{(3R,4S)-1-氮杂二环[2.2.1]庚-3-基甲基硫烷基}乙酸酯;
Mutilin 14-(1-氮杂二环[3.2.1]辛-5-基甲基硫烷基)乙酸酯;
Mutilin 14-(奎宁环-4-基甲基硫烷基)乙酸酯;
Mutilin 14-(8-甲基-8-氮杂二环[3.2.1]辛-3-基甲基硫烷基)乙酸酯;
Mutilin 14-[3-(奎宁环-4-基硫烷基)]丙酸酯;
Mutilin 14-[3-(奎宁环-4-基甲基硫烷基)]丙酸酯;
19,20-Dihydromutilin 14-(8-甲基-8-氮杂二环[3.2.1]辛-3-基甲基硫烷基)乙酸酯;
Mutilin 14-[4-(奎宁环-4-基硫烷基)]丁酸酯;和
Mutilin 14-(外-8-甲基-8-氮杂二环[3.2.1]辛-3-基硫烷基)乙酸酯,
或其可药用盐。
9.权利要求1的化合物,其是Mutilin 14-(外-8-甲基-8-氮杂二环[3.2.1]辛-3-基硫烷基)乙酸酯或其可药用盐。
10.制备如权利要求1-9任一项所述的化合物的方法,包括:
(a)将在11位有被保护羟基的mutilin或表-mutilin与羧酸R2A-(CH2)m-X-(CH2)n-CH2CO2H的活化衍生物例如酰氯偶合,其中R2A是如权利要求1中所定义的R2、或者是可转化成R2的基团,n、m和X的定义同权利要求1,需要的话,将表-mutilin转化成mutilin,并且当需要或要求时,在偶合之前或之后将mutilin核修饰以引入2-OH;19,20-二氢;或1,2-二去氢取代基;或
(b)提供在14位具有(CH2)nCH2CO作为O-酰基的mutilin或表-mutilin衍生物,其中酰基被RL取代,RL是离去基团、OH或NH,将14-O-酰基-(表)mutilin衍生物与化合物R2A(CH2)mXH或其活化衍生物偶合,如果需要的话,将表-mutilin构型转化成mutilin,并且当需要或要求时,在偶合之前或之后将mutilin核修饰以引入2-OH;19,20-二氢;或1,2-二去氢取代基。
11.制备依据权利要求10(b)的化合物的方法,其中
(a)当X是O、S或NH时,则RL是离去基团,并且与
(i)醇R2-(CH2)m-OH;
(ii)硫醇R2-(CH2)m-SH
(iii)胺R2-(CH2)m-NH2-;反应
(b)当X是CONH时,则RL是氨基,并且与酸R2A-(CH2)m-CO2H、或由其衍生的酰化剂反应;
(c)当X是COO时,则RL是羟基,并且与衍生自酸R2A-(CH2)m-CO2H的酰化剂反应。
12.一种药物组合物,其含有如权利要求1所述的化合物和可药用载体。
13.权利要求12的药物组合物,其中所述组合物呈适于对鼻腔给药的喷雾剂剂型。
14.权利要求13的药物组合物,其中所述喷雾剂是水性喷雾剂。
15.权利要求12的药物组合物,其中所述组合物配制成局部给药。
16.权利要求12的药物组合物,其中所述组合物用于治疗皮肤和软组织感染以及痤疮。
17.如权利要求1所述的式(IA)或(IB)化合物在制备适于对鼻腔给药以减轻或消除致病生物体的经鼻感染的药物中的应用。
18.如权利要求1所述的式(IA)或(IB)化合物在制备适于对鼻腔给药以预防复发性中耳炎或复发性急性细菌窦炎的药物中的应用。
19.如权利要求1所述的式(IA)或(IB)化合物在制备用于治疗皮肤和软组织感染以及痤疮的药物中的应用。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9722817.5A GB9722817D0 (en) | 1997-10-29 | 1997-10-29 | Novel compounds |
GB9722817.5 | 1997-10-29 | ||
GB9813689.8 | 1998-06-25 | ||
GBGB9813689.8A GB9813689D0 (en) | 1998-06-25 | 1998-06-25 | Novel compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1283197A CN1283197A (zh) | 2001-02-07 |
CN1205211C true CN1205211C (zh) | 2005-06-08 |
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CNB988127318A Expired - Lifetime CN1205211C (zh) | 1997-10-29 | 1998-10-27 | 用作抗微生物剂的截短侧耳素衍生物 |
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US (3) | US6281226B1 (zh) |
EP (3) | EP1930330B1 (zh) |
JP (2) | JP4227729B2 (zh) |
KR (1) | KR100538721B1 (zh) |
CN (1) | CN1205211C (zh) |
AR (1) | AR015987A1 (zh) |
AT (2) | ATE525373T1 (zh) |
AU (1) | AU742167C (zh) |
BR (1) | BR9814747B1 (zh) |
CA (1) | CA2307551C (zh) |
CO (1) | CO5021129A1 (zh) |
CY (2) | CY2007028I2 (zh) |
CZ (1) | CZ298543B6 (zh) |
DE (2) | DE122007000076I2 (zh) |
DK (2) | DK1930330T3 (zh) |
DZ (1) | DZ2634A1 (zh) |
EG (1) | EG24177A (zh) |
ES (2) | ES2371205T3 (zh) |
FR (1) | FR07C0057I2 (zh) |
HK (1) | HK1031376A1 (zh) |
HU (2) | HU229792B1 (zh) |
IL (2) | IL135811A0 (zh) |
LU (1) | LU91372I2 (zh) |
MY (1) | MY130665A (zh) |
NL (1) | NL300304I2 (zh) |
NO (3) | NO327392B1 (zh) |
NZ (1) | NZ504203A (zh) |
PE (1) | PE123299A1 (zh) |
PL (2) | PL191927B1 (zh) |
PT (2) | PT1028961E (zh) |
SI (2) | SI1930330T1 (zh) |
TR (1) | TR200001203T2 (zh) |
TW (1) | TWI232861B (zh) |
UY (1) | UY25225A1 (zh) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN106496085A (zh) * | 2016-09-21 | 2017-03-15 | 盐城市舜宝化工有限公司 | 合成盐酸沃尼妙林的中间体化合物以及盐酸沃尼妙林的制备方法 |
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UY25225A1 (es) * | 1997-10-29 | 2000-12-29 | Smithkline Beecham Plc | Derivados de pleuromutilina utiles como agentes antimicrobianos |
WO2000027790A1 (en) * | 1998-11-11 | 2000-05-18 | Smithkline Beecham P.L.C. | Mutilin compounds |
GB9912657D0 (en) * | 1999-06-01 | 1999-07-28 | Smithkline Beecham Plc | Novel compounds |
GB9918037D0 (en) * | 1999-07-30 | 1999-09-29 | Biochemie Gmbh | Organic compounds |
GB9919839D0 (en) * | 1999-08-20 | 1999-10-27 | Smithkline Beecham Plc | Novel compounds |
ES2328109T3 (es) * | 2000-04-04 | 2009-11-10 | Smithkline Beecham Plc | Derivados de carbamato de 2-hihrosimutilina para uso antibacteriano. |
GB0017073D0 (en) * | 2000-07-11 | 2000-08-30 | Univ London | Microorganism |
GB0017031D0 (en) | 2000-07-11 | 2000-08-30 | Biochemie Gmbh | Antimicrobials |
PE20020676A1 (es) * | 2000-09-13 | 2002-08-27 | Biochemie Gmbh | Compuestos de mutilina como antibacterianos |
GB0024811D0 (en) | 2000-10-10 | 2000-11-22 | Smithkline Beecham Plc | Novel compounds |
GB0027705D0 (en) * | 2000-11-11 | 2000-12-27 | S P A | Novel compounds |
FR2835186B1 (fr) * | 2002-01-28 | 2006-10-20 | Aventis Pharma Sa | Nouveaux composes heterocycliques, actifs comme inhibiteurs de beta-lactamases |
GB0207495D0 (en) * | 2002-03-28 | 2002-05-08 | Biochemie Gmbh | Organic compounds |
AU2003257493A1 (en) * | 2002-07-24 | 2004-02-16 | Sandoz Ag | Pleuromutilin derivatives as antimicrobbials |
GB0218578D0 (en) * | 2002-08-09 | 2002-09-18 | Glaxo Group Ltd | Novel method |
GB0308114D0 (en) * | 2003-04-08 | 2003-05-14 | Glaxo Group Ltd | Novel compounds |
EP1663220B1 (en) * | 2003-09-03 | 2009-12-02 | Glaxo Group Limited | Novel process for the preparation of pleuromutilin derivatives |
EP1747219A4 (en) * | 2004-05-13 | 2010-05-26 | Glaxo Group Ltd | Antagonists of muscarinic acetylcholine receptor |
GB0504314D0 (en) * | 2005-03-02 | 2005-04-06 | Glaxo Group Ltd | Novel polymorph |
JP2008534444A (ja) * | 2005-03-10 | 2008-08-28 | スミスクライン・ビーチャム・コーポレイション | 新規な方法 |
EP2298733B1 (en) * | 2005-06-27 | 2016-05-25 | Nabriva Therapeutics AG | Pleuromutilin derivatives containing a hydroxyamino- or acyloxyaminocycloalkyl group |
GB0513058D0 (en) * | 2005-06-27 | 2005-08-03 | Sandoz Ag | Organic compounds |
WO2007037518A1 (ja) * | 2005-09-29 | 2007-04-05 | Dainippon Sumitomo Pharma Co., Ltd. | ムチリン誘導体及びそれを含有する医薬組成物 |
WO2007079173A2 (en) * | 2005-12-30 | 2007-07-12 | Emergent Biosolutions Inc. | Novel 2-heteroaryloxy-phenol derivatives as antibacterial agents |
RU2441868C2 (ru) | 2007-02-09 | 2012-02-10 | Астеллас Фарма Инк. | Аза-кольцевое соединение с внутренним мостиком |
WO2008117796A1 (ja) * | 2007-03-28 | 2008-10-02 | Dainippon Sumitomo Pharma Co., Ltd. | 新規ムチリン誘導体 |
US8222407B2 (en) | 2007-05-24 | 2012-07-17 | Kyorin Pharmaceutical Co., Ltd. | Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position |
US20090076071A1 (en) * | 2007-09-13 | 2009-03-19 | Protia, Llc | Deuterium-enriched retapamulin |
WO2009070307A1 (en) * | 2007-11-26 | 2009-06-04 | Teva Pharmaceutical Industries Ltd. | Amorphous retapamulin and processes for preparation thereof |
US20090149655A1 (en) * | 2007-12-05 | 2009-06-11 | Lilach Hedvati | Process for the preparation of Retapamulin and its intermediates |
US8278313B2 (en) | 2008-03-11 | 2012-10-02 | Abbott Laboratories | Macrocyclic spiro pyrimidine derivatives |
US8436005B2 (en) | 2008-04-03 | 2013-05-07 | Abbott Laboratories | Macrocyclic pyrimidine derivatives |
US20100184987A1 (en) * | 2008-11-13 | 2010-07-22 | Teva Pharmaceutical Industries Ltd. | Preparation of Retapamulin via its Pleuromutilin-thiol precursor |
WO2010100720A1 (ja) * | 2009-03-03 | 2010-09-10 | 独立行政法人放射線医学総合研究所 | コリンエステラーゼ活性測定用試薬 |
CA2767233A1 (en) | 2009-07-14 | 2011-01-20 | Albany Molecular Research, Inc. | 5-ht3 receptor modulators, methods of making, and use thereof |
CN102344397B (zh) * | 2011-08-23 | 2013-09-04 | 浙江升华拜克生物股份有限公司 | 一种伐奈莫林盐酸盐的提纯方法 |
CN103626693B (zh) * | 2012-08-28 | 2016-09-14 | 中国科学院上海药物研究所 | 一类截短侧耳素衍生物、其药物组合物及其合成方法与用途 |
CN103709093B (zh) * | 2012-09-28 | 2016-06-08 | 山东亨利医药科技有限责任公司 | 含有并环的截短侧耳素类抗生素 |
CN106659368B (zh) | 2014-07-21 | 2020-04-17 | 恩多巧爱思股份有限公司 | 多焦、多相机内窥镜系统 |
WO2017151492A1 (en) | 2016-03-02 | 2017-09-08 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules |
CN113321672A (zh) * | 2016-03-02 | 2021-08-31 | 比尔及梅琳达盖茨基金会 | 含硼小分子 |
US10874679B2 (en) | 2016-03-02 | 2020-12-29 | Bill & Melinda Gates Foundation | Boron-containing small molecules |
TWI762573B (zh) | 2017-02-10 | 2022-05-01 | 奧地利商納畢瓦治療有限責任公司 | 截短側耳素之純化 |
CN111574395B (zh) * | 2020-06-18 | 2021-07-02 | 华南农业大学 | 一种具有酰胺侧链的截短侧耳素衍生物及制备与应用 |
AT523646B1 (de) | 2020-07-21 | 2021-10-15 | Gerd Dr Ascher | Pharmazeutische Verbindungen, ihre Anwendung alleine oder in Kombination, zur Prophylaxe und lokalen Initial-Therapie bei bakteriellen und viralen Infektionen, insbesondere Coronaviren |
US11155514B1 (en) * | 2020-12-19 | 2021-10-26 | Shaanxi University Of Science And Technology | Pleuromulin acitretin ester with antibacterial activity and a method of preparing the same |
US11332430B1 (en) * | 2021-01-25 | 2022-05-17 | Xi'an Taikomed Pharmaceutical Technology Co., Ltd. | Pleuromulin lauric acid ester with antibacterial activity and a method of preparing the same |
CN112919463B (zh) * | 2021-04-09 | 2021-10-26 | 南京理工大学 | 一种利用泰妙菌素废盐制备的活性炭及其制备方法 |
CN113121355B (zh) * | 2021-04-13 | 2023-05-09 | 西安康诺化工有限公司 | 一种截短侧耳素大黄酸酯及其制备方法和应用 |
CN114736194A (zh) * | 2022-03-29 | 2022-07-12 | 中牧实业股份有限公司 | 一种具有抗病原微生物活性的含吡啶季铵盐侧链的截短侧耳素衍生物及其制备方法与应用 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106496085A (zh) * | 2016-09-21 | 2017-03-15 | 盐城市舜宝化工有限公司 | 合成盐酸沃尼妙林的中间体化合物以及盐酸沃尼妙林的制备方法 |
CN106496085B (zh) * | 2016-09-21 | 2018-01-26 | 盐城市舜宝化工有限公司 | 合成盐酸沃尼妙林的中间体化合物以及盐酸沃尼妙林的制备方法 |
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