CN1163615A - 二环噁嗪及噻嗪噁唑烷酮抗菌剂 - Google Patents
二环噁嗪及噻嗪噁唑烷酮抗菌剂 Download PDFInfo
- Publication number
- CN1163615A CN1163615A CN95196252A CN95196252A CN1163615A CN 1163615 A CN1163615 A CN 1163615A CN 95196252 A CN95196252 A CN 95196252A CN 95196252 A CN95196252 A CN 95196252A CN 1163615 A CN1163615 A CN 1163615A
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- CN
- China
- Prior art keywords
- compound
- methyl
- phenyl
- azabicyclic
- oxazolidinyl
- Prior art date
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- Granted
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- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 title abstract description 8
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 title abstract description 8
- 125000002619 bicyclic group Chemical group 0.000 title abstract description 3
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title description 18
- 230000000844 anti-bacterial effect Effects 0.000 title description 3
- 229940088710 antibiotic agent Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 101
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 59
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 52
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 48
- -1 methoxyl group Chemical group 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 241000894006 Bacteria Species 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 claims description 2
- NCTCGHLIHJJIBK-UHFFFAOYSA-N 3-phenyl-1,3-oxazolidin-2-one Chemical class O=C1OCCN1C1=CC=CC=C1 NCTCGHLIHJJIBK-UHFFFAOYSA-N 0.000 abstract description 4
- 241000186359 Mycobacterium Species 0.000 abstract description 3
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- 239000011734 sodium Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
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- 239000011737 fluorine Substances 0.000 description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
- 150000003233 pyrroles Chemical class 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 241000191940 Staphylococcus Species 0.000 description 5
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- WMASLRCNNKMRFP-UHFFFAOYSA-N 1-fluoro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(F)=C1 WMASLRCNNKMRFP-UHFFFAOYSA-N 0.000 description 4
- QZVQQUVWFIZUBQ-UHFFFAOYSA-N 3-fluoroaniline Chemical compound NC1=CC=CC(F)=C1 QZVQQUVWFIZUBQ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 230000000845 anti-microbial effect Effects 0.000 description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
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- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
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- 239000007868 Raney catalyst Substances 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- YLNSNVGRSIOCEU-ZCFIWIBFSA-N [(2r)-oxiran-2-yl]methyl butanoate Chemical compound CCCC(=O)OC[C@H]1CO1 YLNSNVGRSIOCEU-ZCFIWIBFSA-N 0.000 description 3
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- BJQHLKABXJIVAM-UHFFFAOYSA-N bis(2-ethylhexyl) phthalate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1C(=O)OCC(CC)CCCC BJQHLKABXJIVAM-UHFFFAOYSA-N 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- BOCUKUHCLICSIY-QJWLJZLASA-N cyclothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2C1[C@H](C=C2)C[C@H]2C1 BOCUKUHCLICSIY-QJWLJZLASA-N 0.000 description 1
- 229960003176 cyclothiazide Drugs 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000005331 diazinyl group Chemical group N1=NC(=CC=C1)* 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
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- 238000005538 encapsulation Methods 0.000 description 1
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- 239000012065 filter cake Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical group 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 125000002130 sulfonic acid ester group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/08—Bridged systems
Abstract
结构式I的苯基噁唑烷酮化合物或其可药用的盐,其特征在于二环噻嗪或噁嗪取代基。该化合物是有用的抗菌剂,可有效地抵抗多种人类及动物的病原体,包括革兰氏阳性的需氧细菌(例如多重耐药的葡萄球菌、链球菌和肠球菌)以及厌氧生物(例如拟杆菌属和梭状芽胞杆菌属数种)和耐酸生物(例如结核分枝杆菌、鸟结核分支杆菌和分支杆菌属数种)。
Description
发明背景
本发明公开了新的并且有用的苯基噁唑烷酮化合物,其特征在于含有二环的噻嗪或噁嗪取代基。该化合物是有用的抗菌剂,可有效地抵抗多种人类及动物的病原体,包括革兰氏阳性的需氧细菌例如多重耐药的葡萄球菌、链球菌和肠球菌以及厌氧生物例如拟杆菌属和梭状芽胞杆菌属数种和耐酸生物例如结核分枝杆菌、鸟结核分支杆菌和分支杆菌属数种。公开信息
本发明的化合物与以下出版物中公开的化合物的相关之处在于它们的苯基噁唑烷酮环结构,但不同的是本发明的化合物具有二环噻嗪或噁嗪苯基取代基。本发明的化合物具有有效的抗菌活性。
PCT/US94/08904申请公开了具有吗啉或硫代吗啉取代基的噁唑烷酮抗菌化合物。
PCT/US93/03570申请公开了含有取代的二嗪基团的噁唑烷酮及其作为抗菌剂的用途。
PCT/US92/08267申请公开了用作抗菌剂的取代的芳基和杂芳基-苯基-噁唑烷酮。
PCT/US89/03548申请公开了用作抗菌剂的5′-二氢吲哚基-5β-酰氨基甲基噁唑烷酮、3-(稠环取代的)苯基-5β-酰氨基甲基噁唑烷酮、和3-(氮取代的)苯基-5β-酰氨基甲基噁唑烷酮。
公开了各种噁唑烷酮的其它文献包括:美国专利4801600、4921869;Gregory W.A.等,药物化学杂志(J.Med.Chem.),32,1673-81(1989);Gregory W.A.等,药物化学杂志,33,2569-78(1990);Wang C.等,四面体(Tetrahedron),45,1323-26(1989);和Britteli等,药物化学杂志,35,1156(1992)。
欧洲专利申请352781公开了苯基和吡啶基取代的苯基噁唑烷酮。欧洲专利申请316594公开了3-取代的苯乙烯基噁唑烷酮。欧洲专利申请312000公开了苯甲基和吡啶甲基取代的苯基噁唑烷酮。发明概述
更优选的化合物(结构式I所描述的化合物的一个亚组)是结构式II所代表的化合物:结构式II或其可药用的盐,其中X是 (a) O,
(b) S,
(c) SO,
(d) SO2;R1彼此独立地是H、F、Cl或OMe;R2是 (a) 氢,
(b) 任意性可有可无地被一个或多个F、Cl、羟基、C1-C8烷氧
基、C1-C8酰氧基取代的C1-C8烷基,
(c) C3-C6环烷基,
(d) 氨基,
(e) C1-C8烷氨基,
(f) C1-C8二烷氨基,
(g) C1-C8烷氧基;a是0至3;b是0至2;c是0至2(条件是b和c不能同时为0);d是0至2;并且e是0至2(条件是d和e不能同时为0)。
另一方面,本发明涉及通过向需治疗的患者给予有效量的上述结构式I或II的化合物来治疗人或其它温血动物的微生物感染的方法。该化合物可以以药物组合物的形式进行口服、胃肠外或局部给药。化合物的给药量优选从大约0.1至大约100mg/kg体重/天,更优选从大约3.0至大约50mg/kg体重/天。本发明详述
本发明公开了上述结构式I和II的新的取代二环噁嗪基或噻嗪基苯基噁唑烷酮。该化合物是有用的抗菌剂,可有效地抵抗多种人类及动物的病原体,尤其是需氧的革兰氏阳性细菌(包括多重耐药的葡萄球菌和链球菌),以及厌氧生物(例如拟杆菌属和梭状芽胞杆菌属)和耐酸细菌(例如结核分枝杆菌和其它的分支杆菌属)。
“烷基”指具有指定碳原子数的直链或支链的碳链。
“烷氧基”指指定数目的碳原子与氧连接所形成的基团,如甲氧基(-OCH3)、乙氧基、丁氧基等,以及它们的异构体形式。
“酰氧基”指指定数目的碳原子形成的删除了OH基团的有机酸,例如乙酰基,CH3CO-;苯甲酰基,C6H5CO-。
“环烷基”指指定数目的碳原子形成的基团如环丙基、环丁基、环戊基、环己基等,以及它们的异构体形式。
“氨基”指NH2,“烷氨基”是指其中一个氢的位置被烷基取代,“二烷氨基”是指其中两个氢的位置均被烷基取代。
“可药用的盐”是指酸加成盐,它可以通过本领域公知的任何方法制备。酸加成盐一般包括盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、乙酸盐、丙酸盐、乳酸盐、苹果酸盐、琥珀酸盐、酒石酸盐、环己烷氨基磺酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、甲苯磺酸盐、富马酸盐和胺的其它可药用的抗衡离子。
优选X是S。
优选R1取代基均是氟,并更优选氟和氢。
R2取代基优选是氢、甲基、二氯甲基、羟甲基或甲氧基。更优选R2是氢、甲氧基或甲基。最优选R2是甲基。
本发明所要求的化合物的噁唑烷酮环中C-5位的绝对构型优选为结构式I和II所代表的构型。该绝对构型在Cahn-Ingold-Prelog命名系统下称为(S)。该(S)对映体为药理学活性的。外消旋混合物与纯的(S)对映体以同样的方式适用于同样的目的;不同之处在于必须使用两倍量的外消旋体以产生同样的抗菌效果。当结构式I和II的化合物的二环噁嗪或噻嗪片段中另外含有一个或多个手性中心时则有可能存在非对映体,这对本领域熟练技术人员是显然的。这些非对映体(外消旋形式和富含对映体的形式)也在本发明的结构式I和II的化合物的范围之内。
优选的结构式I的化合物是(S)-N-[[3-[3-氟-4-[(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺(实施例1);(S)-N-[[3-[3-氟-4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺(实施例2);(S)-N-[[3-[3-氟-4-[(1S,4S)-2-硫杂-2,2-二氧代-5-氮杂二环[2.2.1]庚-5-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺(实施例3);(S)-N-[[3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺(实施例4);(S)-N-[[3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,S-氧化物(实施例5);(S)-N-[[3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,S,S-二氧化物(实施例6);顺-(S)-N-[[3-[3-氟-4-[3-氧杂-7-氮杂二环[3.3.0]辛-7-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺(实施例7);(S)-N-[[3-[3-氟-4-[(1R,4R)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(2-硫杂-6-氮杂二环[3.2.0]庚-6-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(3-硫杂-6-氮杂二环[3.2.0]庚-6-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(3-硫杂-7-氮杂二环[3.3.1]壬-7-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(3-硫杂-9-氮杂二环[3.3.1]壬-9-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(2-硫杂-6-氮杂二环[3.2.1]辛-6-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(2-硫杂-6-氮杂二环[3.3.1]壬-6-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(7-硫杂-3-氮杂二环[4.2.1]壬-3-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(9-硫杂-3-氮杂二环[3.3.1]壬-3-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(3-氧杂-6-氮杂二环[3.2.0]庚-6-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(6-氧杂-3-氮杂二环[3.1.1]庚-3-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(3-氧杂-7-氮杂二环[3.3.1]壬-7-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(3-氧杂-9-氮杂二环[3.3.1]壬-9-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(9-氧杂-3-氮杂二环[3.3.1]壬-3-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(2-氧杂-5-氮杂二环[2.2.2]辛-5-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(2-氧杂-6-氮杂二环[3.2.1]辛-6-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(3-氧杂-7-氮杂二环[4.2.0]辛-7-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(3-氧杂-8-氮杂二环[3.2.1]辛-8-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(6-氧杂-2-氮杂二环[3.2.1]辛-2-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;(S)-N-[[3-[3-氟-4-(8-氧杂-3-氮杂二环[3.2.1]辛-3-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;和(S)-N-[[3-[3-氟-4-[(1R,4R)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺。
最优选的化合物是(S)-N-[[3-[3-氟-4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺(实施例2)。(S)-N-[[3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺(实施例4);(S)-N-[[3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,S,S-二氧化物(实施例6);
本发明的药物组合物可通过用标准常规技术将本发明的结构式I或II的化合物与可药用的固体或液体载体以及任意性可有可无的可药用辅助剂和赋形剂混合进行制备。固体形式的组合物包括粉末、片剂、可分散性颗粒、胶囊、扁囊和栓剂。固体载体可以是至少-种可以起到稀释剂、调味剂、加溶剂、润滑剂、悬浮剂、粘合剂、片剂崩解剂以及包封剂的功能的物质。惰性固体载体包括碳酸镁、硬脂酸镁、滑石、蔗糖、乳糖、果胶、糊精、淀粉、明胶、纤维素类物质、低熔点的蜡、可可脂等。液体形式的组合物包括溶液剂、悬浮剂和乳剂。例如,可提供本发明的化合物溶于水、水-丙二醇和水-聚乙二醇系统的溶液,溶液中任意性可有可无地含有适当的常规的色剂、调味剂、稳定剂以及增稠剂。
优选用常规技术以含有有效量或适当量活性成分(即本发明的结构式I的化合物)的单位剂量形式提供药物组合物。
药物组合物及其单位剂量形式中的活性成分(即本发明的结构式I或II的化合物)的量可依据具体应用、具体化合物的效力、所需浓度在宽的范围内进行变动或调节。通常,活性成分的量在组合物重量的0.5wt%至90wt%的范围内。
在治疗温血动物细菌感染的治疗应用中,可以将化合物或其药物组合物以一定的剂量进行口服和/或胃肠外给药,以使活性成分在接受治疗的动物体内达到并维持一定的浓度,即有效抗菌的量或血液浓度。通常,活性成分的抗菌有效剂量在大约0.1至大约100、更优选大约3.0至大约50mg/kg体重/天的范围内。应当理解,该剂量可以依据患者的需要、所治疗的细菌感染的严重程度以及所用的具体化合物进行变动。还应当理解,依据具体情况,给药的起始剂量可以超出上述的浓度上限以迅速达到所需的血液浓度;或可以使起始剂量低于最佳剂量并在治疗过程中逐渐增加每日剂量。如需要,还可将每日剂量分成多剂量进行给药,例如每天两至四次。
本发明的结构式I或II的化合物进行胃肠外给药,即通过注射(例如静脉内注射)或其它的胃肠外给药途径。用于胃肠外给药的药物组合物通常含有以可溶解性盐(酸加成盐或碱盐)溶于可药用液体载体(例如注射用水)的可药用量的结构式I或II的化合物和缓冲剂,以提供适当的缓冲等渗溶液,例如其pH值为大约3-7。适当的缓冲剂包括,例如正磷酸三钠、碳酸氢钠、柠檬酸钠、N-甲基葡糖胺、L(+)-赖氨酸和L(+)-精氨酸,这里只列举几个代表性的缓冲剂。通常将结构式I的化合物以一定的量溶于载体,所述量足够提供大约1mg/ml溶液至大约400mg/ml溶液范围内的可药用可注射浓度。将得到的液体药物组合物进行给药以达到上述的抗菌有效剂量。
表I-IV说明了制备对映体纯形式的结构式I和II的噁唑烷酮的优选方法。
如表I所示,将二环噁嗪和噻嗪(可购买到或是文献中已知的),例如结构式1的(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚烷(X=O)和(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚烷(X=S),与官能化的硝基苯2(Y=卤素或三氟甲磺酸酯)在适当碱(例如N,N-二异丙基乙胺)的存在下、在适当的溶剂(例如乙腈、四氢呋喃(THF)或乙酸乙酯)中于室温至回流温度下反应生成加合物3。当X=O时,将3的硝基在适当催化剂(例如10%碳载钯或W-2阮内镍)的存在下、在适当的溶剂(例如乙酸乙酯、四氢呋喃、四氢呋喃水溶液、甲醇及其混合物)中通过催化氢化还原,生成苯胺4。当X=S时,可以在室温至55℃下、用亚硫酸氢钠在四氢呋喃水溶液中将3的硝基还原生成苯胺4。或者,3(X=S)的硝基的还原反应可以在适当催化剂(例如硫化碳载铂或W-2阮内镍)的存在下、在适当的溶剂系统(例如四氢呋喃水溶液)中通过催化氢化来完成。后一种反应条件特别有用,因为可以将反应液混合物简单地用Celite等过滤以除去催化剂,然后将含有苯胺4的滤液直接用于下一步反应。为此,用常规的Schotten-Baumann条件或本领域技术人员公知的其它改变形式将苯胺4转变成它们的氨基甲酸苄酯(R3=CH2Ph)或甲酯(R3=CH3)衍生物5。然后将氨基甲酸酯5用适当的碱(例如正丁基锂、二异丙基氨基锂或二(三甲基甲硅烷基)氨基锂)在适当的溶剂(例如四氢呋喃或N,N-二甲基甲酰胺)中、在适当的温度(例如-78至-60℃)下脱质子生成锂化(lithiated)中间体,然后将其用可购买到的(-)-(R)-丁酸缩水甘油酯处理。然后升至室温直接生成富含对映体的5-(羟甲基)噁唑烷酮6。然后用例如甲磺酰氯/吡啶或甲磺酰氯/三乙胺/二氯甲烷或对甲苯磺酰氯/吡啶将化合物6转变成相应的甲磺酸酯7(R4=甲磺酰基)或芳基磺酸酯7(R4=ArSO2,例如对甲苯磺酰基)。
如表II所示,将生成的磺酸酯衍生物7与可产生叠氮化物的物质(例如叠氮化钠或叠氮化钾)在非质子溶剂(例如N,N-二甲基甲酰胺(DMF)或1-甲基-2-吡咯烷酮)中、任意性可有可无地存在催化剂(例如18-冠-6)的条件下,在50-90℃的温度下反应生成叠氮化物8。然后将该叠氮化物用碳载钯或铂催化剂在适当的溶剂(例如乙酸乙酯或甲醇)中氢化还原生成相应的胺9。或者(优选在X=S的情况下),可以通过用三价磷化合物(例如三苯膦)在适当的溶剂(例如四氢呋喃)中处理并随后加入水将叠氮化物还原。或者,可以将化合物7的甲磺酸酯或芳基磺酸酯基团用邻苯二甲酰亚胺钾盐在乙腈中于回流温度下置换,生成中间体邻苯二甲酰亚胺10。然后将邻苯二甲酰亚胺10用甲胺水溶液在回流的乙醇中脱保护生成胺9。又一种方法是,将甲磺酸酯7与氢氧化铵在热的异丙醇或异丙醇/四氢呋喃中反应,优选在密封的反应器内,直接生成胺9。然后用本领域技术人员公知的反应将胺9酰化生成结构式11的噁唑烷酮。例如,可以将胺与酰氯或酸酐在碱性溶剂(例如吡啶)中于-30至30℃的温度范围内反应生成酰化的化合物11(R2=任意性可有可无地取代的烷基)。可以用常规的酰化方法,例如在March,J.“高等有机化学”,第四版;JohnWiley&Sons:New York,1992;417-425页中讲述的方法,将本发明范围内的其它酰基连接到胺9上,生成11的其它例子,这对本领域技术人员是显然的。结构式11的化合物代表结构式11的二环噁嗪和噻嗪取代的噁唑烷酮抗菌剂(本发明的主题物)的例子。
如表III所示,可以将噁唑烷酮11(它们本身即为结构式II的抗菌剂的例子)进一步转变为其它的结构式11的化合物。具体地讲,可以将11(X=S)用偏高碘酸钠在水和甲醇的混合物中氧化成相应的亚砜12(X=SO)。本领域技术人员可以理解,内和外亚砜均可能存在,而两种异构体形式以及它们的混合物均在本发明的范围之内。另外,还可以将化合物11或化合物12用4-甲基吗啉N-氧化物和催化剂四氧化锇在丙酮水溶液中处理,将其氧化成相应的砜13(X=SO2)。本领域技术人员可以理解,将化合物11(X=S)氧化成12或13的其它条件是已知的,例如在March,J.“高等有机化学”,第四版;John Wiley&Sons:New York,1992;1201-1202页中讲述的方法。
如表IV所示,引入了噻吩并吡咯烷的化合物的合成首先是用氢化铝锂作为还原剂将二酯14还原成二醇15。然后将化合物15与甲磺酰氯和碱三烷基胺反应将其转变为二甲磺酸酯16。将16与硫化钠反应使其环化成噻吩并吡咯烷17,然后通过与氢气在适当催化剂(例如碳载钯)的存在下反应将化合物17脱苄基得噻吩并吡咯18。然后按照表I和II中所述的方法(只是用18代替1)从18制得实施例4的化合物。用表III中所示的相同方法将实施例4的化合物氧化,制得实施例5和6的化合物。
用鼠分析方法在体内测试抗菌活性。将各组的雌性小鼠经腹膜内注射细菌,所述细菌在使用前刚刚融化并且悬浮于含有4%布鲁尔氏酵母UC9213(金黄色酿脓葡萄球菌)的脑心输注液(brain hear tinfusion)或脑心输注液(葡萄球菌属数种)中。抗菌治疗时,每个药物以六个剂量水平在感染后的一小时和五小时通过口服或皮下的途径进行给药。每日观察存活率并持续六天。基于死亡率的ED50值用概率分析进行计算。本发明的化合物以公知的抗菌剂(万古霉素)作为对照进行比较。数据列于表1。
表1对金黄色酿脓葡萄球菌UC9213的体内活性
实施例号 | ED50(mg/kg) | |
实施例,PO | 万古霉素,SC | |
1 | 7.7 | 11.2 |
2 | 4.2 | 4.0 |
4 | 4.3 | - |
5 | 10.0 | - |
6 | 3.5 | - |
以下事实对本领域技术人员是显而易见的,即所述的合成方法仅仅是代表性的,使用专利及公开文献中的其它已知的二环噁嗪和噻嗪可以制备结构式I的化合物的其它例子。实施例1:(S)-N-[[3-[4-[(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺步骤1:4-[(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟硝基苯
将可购买到的(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚烷盐酸盐(0.200g,1.47mmol)、磷酸氢二钾(1.030g,5.90mmol)和3,4-二氟硝基苯(0.195mL,1.77mmol)的混合物的二甲基亚砜(6mL)溶液在室温和N2氛围下搅拌。3小时后TLC分析(5%MeOH/CHCl3)显示原料硝基苯被消耗掉。将反应混合物用H2O(60mL)稀释并用CHCl3萃取。将合并的有机萃取液用水和盐水洗涤、Na2SO4干燥、过滤并减压浓缩至黄色固体。在硅胶(60g)上进行色谱分离,用梯度为0-2%的MeOH/CHCl3洗脱,将适当的级分浓缩后得到0.314g(90%)黄色固体状的标题化合物,mp=106.5-108℃,MS(EI)=238(M+)。步骤2:N-(苄氧羰基)-4-[(1S、4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-
基]-3-氟苯胺
将4-[(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟硝基苯(0.160g,0.672mmol)在3∶1 THF/H2O(4mL)中的溶液用乙酸(0.115mL)处理,然后用10%钯/碳(0.020g)在N2气流下处理。通过反复地抽空和填充将气体氛围用H2(气囊)代替,并将混合物在室温下进行搅拌。2小时后,TLC分析(6%CH3CN/CHCl3)显示还原反应完全。将反应混合物用Celite过滤并将滤液立即置于N2氛围下并用K2CO3(0.464g,3.36mmol)处理,随后用氯甲酸苄酯(0.117mL,0.864mmol)处理。0.5小时后TLC分析(6%CH3CN/CHCl3)显示反应完全。将该反应混合物减压浓缩并在硅胶(20g)上进行色谱分离,用梯度为1-5%的CH3CN/CHCl3洗脱。将适当的级分浓缩得到0.226g(98%)白色固体状标题化合物,mp=120-121℃,MS(EI)=342(M+)。步骤3:(R)-[3-[4-[(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟
苯基]-2-氧代-5-噁唑烷基]甲醇
将N-(苄氧羰基)-4-[(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟苯胺(0.169g,0.494mmol)在干燥THF(2mL)中的溶液在N2氛围下冷却至-78℃,然后用正丁基锂(0.312mL 1.6M的己烷溶液,0.499mmol)处理。在-78℃搅拌10分钟后,将反应混合物用(R)-丁酸缩水甘油酯(0.070mL,0.499mmol)处理。加完后,移走冷却浴并让混合物在室温下搅拌过夜,在此期间内有米色沉淀出现。TLC分析(5%MeOH/CHCl3)显示反应完全。将反应混合物用约5滴饱和NH4Cl水溶液处理,使反应混合物成为均相溶液。将反应混合物减压浓缩至米色固体。在硅胶上生行色谱分离,用梯度为1-5%的MeOH/CHCl3洗脱,将适当的级分浓缩后得到0.116g(84%)白色固体状标题化合物,mp=138-140℃,MS(EI)=308(M+)。另外,还得到0.018g(10%)琥珀色油状的第二种组分,经1H NMR分析证实为标题化合物的丁酸酯。步骤4:(R)-[[3-[4-[(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟
苯基]-2-氧代-5-噁唑烷基]甲基]甲磺酸酯
将(R)-[3-[4-[(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟苯基]-2-氧代-5-噁唑烷基]甲醇(0.765g,2.48mmol)在干燥CH2Cl2(30mL)中的溶液在N2氛围下冷却至0℃,依次用Et3N(0.518mL,3.73mmol)和甲磺酰氯(0.202mL,2.61mmol)处理。0.5小时后TLC分析(5%MeOH/CHCl3)显示反应完全。将反应混合物用水和盐水洗涤、Na2SO4干燥、过滤并真空浓缩得0.992g(约100%)褐色固体状标题化合物。通过用5%CH2Cl2/i-PrOH重结晶制得分析用样品。该样品的mp=124.5-126℃,MS(EI)=386(M+)。步骤5:(R)-[[3-[4-[(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟
苯基]-2-氧代-5-噁唑烷基]甲基]叠氮化物
在室温和N2下,将(R)-[[3-[4-[(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟苯基]-2-氧代-5-噁唑烷基]甲基]甲磺酸酯(0.869g,2.25mmol)在干燥DMF(10mL)中的溶液用固体NaN3(0.732g,11.3mmol)处理。然后将该混合物加热至65℃并用TLC监测反应进程。该温度下7.5小时后,TLC分析(5%MeOH/CHCl3)显示反应完全。将反应混合物用EtOAc(100mL)稀释,用H2O(3×15mL)和盐水洗涤,Na2SO4干燥,过滤并减压浓缩得0.692g(92%)褐色固体状标题化合物。通过用1∶1 EtOAc/己烷重结晶制得米色固体状分析用样品,mp=101-102.5℃,MS(EI)=333(M+)。步骤6:(S)-N-[[3-[4-[(1S、4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]-3-
氟苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺
在N2气流下,将(R)-[[3-[4-[(1 S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟苯基]-2-氧代-5-噁唑烷基]甲基]叠氮化物(0.652g,1.96mmol)在MeOH(20mL)和CH2Cl2(10mL)中的溶液用10%钯/碳(0.095g)处理。通过反复地抽空和填充将气体氛围用H2(气囊)代替,并将混合物在室温下和H2下进行搅拌。3小时后,TLC分析(5%MeOH/CHCl3)显示还原反应完全。将反应混合物用Celite过滤并将滤液减压浓缩。将5-(氨甲基)噁唑烷酮粗品溶于CH2Cl2(20mL)并依次用吡啶(0.190mL,2.35mmol)和乙酸酐(0.222mL,2.35mmol)处理。0.5小时后TLC分析(5%MeOH/CHCl3)显示乙酰化反应完全。将该反应液混合物用H2O和盐水洗涤,Na2SO4干燥,过滤并真空浓缩得米色固体。在硅胶(70g)上进行色谱分离,用梯度为1-3%的MeOH/CHCl3洗脱,将适当的级分浓缩后得到0.517g(76%)白色固体状标题噁唑烷酮抗菌剂,mp=60-65℃,MS(EI)=349(M+)。实施例2:(S)-N-[[3-[3-氟-4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺步骤1:4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟硝基苯
将可购买到的(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚烷盐酸盐(0.500g,3.30mmol)、二异丙基乙胺(1.434mL,8.24mmol)和3,4-二氟硝基苯(0.437mL,3.96mmol)的混合物的干燥乙腈(15mL)溶液在N2氛围下加热至回流温度并保持1小时,然后冷却至室温过夜。将反应混合物减压浓缩得到黄色糖浆。在硅胶(50g)上进行色谱分离,用氯仿洗脱,将适当的级分浓缩后得到0.700g(84%)黄色固体状标题化合物,mp=97-98℃,MS(EI)=254(M+)。步骤2:N-(苄氧羰基)-4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-
基]-3-氟苯胺
在N2气流下,将4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟硝基苯(1.64g,6.46mmol)在20%H2O/THF(50mL)中的溶液用硫化碳载铂(0.200g)处理。通过反复地抽空和填充将气体氛围用H2(气囊)代替。12小时后,TLC分析显示仍有大量起始原料存在。将反应混合和物转移至Parr装置中并在45psiH2下振摇。2小时后TLC分析显示仍有部分起始原料存在。将反应混合物用Celite过滤,并将含有所需的苯胺中间体和起始的硝基苯衍生物的滤液冷却至0℃并用NaHCO3(2.170g,25.8mmol)和氯甲酸苄酯(1.02mL,7.10mmol)处理。0.5小时后,将反应混合物减压浓缩至黄/绿色糖浆。将该物质溶于CHCl3,用水和盐水洗涤、Na2SO4干燥、过滤并真空浓缩。通过一段硅胶柱过滤,用20-30%的EtOAc/己烷洗脱,将适当的级分浓缩后得到起始的硝基苯衍生物和标题化合物的混合物。将该物质溶于20%H2O/THF(50mL)并用W-2阮内镍(大约0.400g)处理。将反应混合物于Parr装置中在45psiH2下振摇。3小时后,将反应混合物用Celite过滤并将滤液冷却至0℃,依次用NaHCO3(2.00g,23.8mmol)和氯甲酸苄酯(0.600mL,4.19mmol)处理。0.5小时后,将反应混合物减压浓缩并将残余物在硅胶(125g)上色谱分离,用10-20%的EtOAc/己烷洗脱,将适当的级分浓缩后得到2.20g(95%)黄色固体状标题化合物,mp=91-93℃,MS(EI)=358(M+)。步骤3:(R)-[3-[4-[(1S.4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟
苯基]-2-氧代-5-噁唑烷基]甲醇
将N-(苄氧羰基)-4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟苯胺(0.359g,1.00mmol)在干燥THF(4mL)中的溶液在N2氛围下冷却至-78℃,然后用正丁基锂(0.633mL 1.6M的己烷溶液,1.01mmol)处理。将反应混合物在-78℃搅拌15分钟,然后用(R)-丁酸缩水甘油酯(0.151mL,1.00mmol)处理。加完后,移走冷却浴并将反应混合物升至室温过夜。TLC分析(5%MeOH/CHCl3)显示反应完全但含有少量标题化合物的丁酸酯。加入5滴25重量%的NaOMe/MeOH溶液,随后在室温下搅拌20分钟,可将该中间体有效地转变为标题化合物。将反应液混合物用饱和NH4Cl水溶液(10滴)处理,然后减压浓缩至油状物。将该物质溶于CH2Cl2,用水和盐水洗涤,Na2SO4干燥,过滤并真空浓缩得产物粗品。在硅胶(50g)上进行色谱分离,用1-3%的MeOH/CHCl3洗脱,将适当的级分浓缩后得到0.132g(41%)油状标题化合物。与EtOAc一起研制得到沉淀,将其分离并真空干燥得到米色固体,mp=156-157℃,MS(EI)=324(M+)。步骤4:(R)-[[3-[4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟
苯基]-2-氧代-5-噁唑烷基]甲基]甲磺酸酯
将(R)-[3-[4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟苯基]-2-氧代-5-噁唑烷基]甲醇(1.68g,5.19mmol)在干燥CH2Cl2(100mL)中的溶液在N2氛围下冷却至0℃,依次用Et3N(0.793mL,5.70mmol)和甲磺酰氯(0.442mL,5.70mmol)处理。该温度下0.5小时后,TLC分析(5%MeOH/CHCl3)显示反应近乎完全。将该混合物用H2O、饱和NaHCO3水溶液和盐水洗涤,Na2SO4干燥,过滤并真空浓缩得1.65g(79%)白色固体状标题化合物,mp-139-142℃,MS(EI)=402(M+)。步骤5:(S)-N-[[3-[3-氟-4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-
基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺
将(R)-[[3-[4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]-3-氟苯基]-2-氧代-5-噁唑烷基]甲基]甲磺酸酯(1.56g,3.88mmol)、1∶1THF/i-PrOH(4mL)和30%NH4OH(4mL)的混合物在封闭管内加热至95℃并保持14小时,然后冷却至室温。TLC分析(5%MeOH/CHCl3)显示反应完全。将反应混合物用CH2Cl2(75mL)稀释,用饱和NaHCO3水溶液(15mL)和盐水(15mL)洗涤,Na2SO4干燥,过滤并减压浓缩得糖浆。将粗品5-(氨甲基)噁唑烷酮中间体溶于CH2Cl2(75mL)并依次用吡啶(0.345mL,4.27mmol)和乙酸酐(0.430mL,4.27mmol)在室温下处理。1小时后,TLC分析(5%MeOH/CHCl3)显示酰化反应完全。将该反应混合物用H2O和盐水洗涤,Na2SO4干燥,过滤并减压浓缩得琥珀色固体。在硅胶(125g)上进行色谱分离,用1-3%的MeOH/CHCl3洗脱,将适当的级分浓缩后得到1.23g(87%)固体状标题噁唑烷酮抗菌剂,mp=90-95℃,MS(EI)=365(M+)。实施例3:(S)-N-[[3-[3-氟-4-[(1S,4S)-2-硫杂-2,2-二氧代-5-氮杂二环[2.2.1]庚-5-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺
室温下,将(S)-N-[[3-[3-氟-4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺(0.300g,0.82mmol)在25%H2O/丙酮(16mL)中的溶液依次用4-甲基吗啉-N-氧化物(0.288g,2.47mmol)和四氧化锇(0.102mL 2.5重量%的叔丁醇溶液,0.008mmol)处理。18小时后,TLC分析(10%MeOH/CHCl3)显示氧化反应完全。将反应混合物用饱和NaHSO3水溶液处理,然后用CHCl3萃取。将合并的有机萃取液用盐水洗涤,Na2SO4干燥,过滤并减压浓缩。将残余物在硅胶(10g)上进行色谱分离,用1-3%的MeOH/CHCl3洗脱,将适当的级分浓缩后得到O.321g(98%)白色固体状标题噁唑烷酮抗菌剂,mp=95-105℃。实施例4:(S)-N-[[3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺步骤1:顺-1-(苯甲基)-3,4-吡咯烷二甲醇
(顺)-1-(苯甲基)-3,4-吡咯烷二甲酸二甲酯根据Y.Terao等的方法(药物化学公报(Chem.Pharm.Bull.),1985,33,2762-66)制备。在N2下,将该二酯(12.14g,43.8mmol)在干燥THF(175mL)中的溶液冷却至0℃,搅拌下于15分钟内滴加氢化铝锂(1M的THF溶液,87mL,87mmol)溶液。将该反应混合物在0℃搅拌1小时,然后在室温下18小时。将反应混合物冷却至0℃,依次加入H2O(3.2mL)、5NNaOH(3.2mL)和H2O(11.7mL)终止反应。反应混合物变得非常粘稠并且搅拌困难。将反应混合物用乙醚(500mL)稀释并用一个小的硅藻土垫过滤。将滤饼用乙醚(250mL)洗涤。滤液用H2O(1×300mL)洗涤,将有机层干燥(MgSO4),过滤并浓缩得到9.3g(41.8mmol,96%)黄色粘稠油状的所需二醇。使用时无需进一步纯化。HRMS(FAB):C13H19NO2+H的计算值222.1494,实测值222.1490。步骤2:顺-1-(苯甲基)-3,4-二(甲磺酰氧基)甲基吡咯烷
搅拌下,向冷却至0℃的顺-1-(苯甲基)-3,4-吡咯烷二甲醇(9.2g,41.6mmol)的CH2Cl2(240mL)溶液中加入三乙胺(29mL,208.1mmol),随后加入甲磺酰氯(8.1mL,104.0mmol)。将该反应混合物在0℃搅拌15分钟,然后在室温下1.5小时。将反应混合物倒入H2O(240mL)中并将两相分离。将水相用CH2Cl2(1×100mL)萃取。将合并的有机相干燥(MgSO4),过滤并浓缩。残余物通过闪式色谱进行纯化,用乙酸乙酯作为洗脱剂,得到14.2g(37.5mmol,90%)黄色粘稠油状的所需二甲磺酸酯。HRMS(EI):C15H23NO6S2的计算值377.0967,实测值377.0958。步骤3:六氢-5-(苯甲基)-1H-噻吩并[3,4-c]吡咯
向搅拌下的顺-1-(苯甲基)-3,4-二(甲磺酰氧基)甲基吡咯烷(9.2g,mmol)的干燥DMSO(48mL)溶液中加入无水硫化钠(5.7g,73.3mmol)。将该黑色反应混合物在120℃加热18小时。将冷却的反应混合物倒入冰水中(150mL)。将得到的混合物用乙醚(3×200mL)萃取。将合并的有机层干燥(MgSO4),过滤并浓缩。得到的残余物通过闪式色谱进行纯化,用乙酸乙酯作为洗脱剂,得到4.2g(19.1mmol,78%)黄色粘稠油状的所需产物。HRMS(EI):C13H17NS的计算值219.1082,实测值219.1080。元素分析C13H17NS的计算值:C,71.19;H,7.81;N,6.39。实测值:C,70.82;H,7.83;N,6.35。步骤4:六氢-1H-噻吩并[3,4-c]吡咯,盐酸盐
搅拌下,向冷却至0℃的六氢-5-(苯甲基)-1H-噻吩并[3,4-c]吡咯(1.2g,5.3mmol)的CH2Cl2(21mL)溶液中通过注射器滴加氯甲酸1-氯乙酯(1.15mL,10.7mmol)。将该反应混合物在0℃搅拌20分钟,然后在室温下90分钟。将反应混合物浓缩。得到的残余物通过闪式色谱纯化,用25%乙酸乙酯的己烷溶液作为洗脱剂,得到611.3mg(2.6mmol,49%)氨基甲酸1-氯乙酯。将色谱柱用20%甲醇氨(methanolic ammonia)的氯仿溶液洗涤,得160.5mg(1.24mmol,23%)游离碱形式的所需胺。将氨基甲酸1-氯乙酯(611.3mg,2.6mmol)溶于甲醇(15mL)并加热回流90分钟。将冷却的反应混合物浓缩得到408.0mg(2.5mmol,47%)HCl盐形式的所需胺(基于氯代氨基甲酸酯)。mp149-151℃;HRMS(EI):C6H11NS的计算值129.0612,实测值129.0614。元素分析C6H12ClNS的计算值:C,43.50;H,7.30;N,8.45;Cl,21.39;S,19.35。实测值:C,43.39;H,7.23;N,8.24;Cl,21.08;S,19.12。步骤5:5-(2-氟-4-硝基苯基)-六氢-1H-噻吩并[3,4-c]吡咯
搅拌下,向六氢-5-1H-噻吩并[3,4-c]吡咯盐酸盐(147.3mg,0.89mmol)的乙腈(5mL)溶液中加入3,4-二氟硝基苯(0.11mL,0.98mmol),随后加入二异丙基乙胺(0.36mL,2.05mmol)。将所得均相反应混合物加热回流18小时。将冷却的反应混合物浓缩。得到的残余物用EtOAc(50mL)稀释并用饱和NH4Cl水溶液(1×25mL)洗涤。将水层用EtOAc(1×30mL)萃取。合并的有机层用饱和NaHCO3(1×40mL)、盐水(1×40mL)洗涤,干燥(MgSO4),过滤并浓缩。残余物通过闪式色谱纯化,用20%乙酸乙酯的己烷溶液作为洗脱剂,得到202.5mg(0.75mol,89%)浅黄色固体状的所需硝基化合物。mp107-109℃;元素分析C12H13FN2O25的计算值:C,53.72;H,4.88;N,10.44;S,11.95。实测值:C,53.38;H,5.03;N,10.34;S,11.89。步骤6:3-[3-氟-4-(四氢-1H-噻吩并[3,4-C]吡咯-5(3H)-基)苯基氨基甲
酸苯甲酯
搅拌下,向5-(2-氟-4-硝基苯基)-六氢-1H-噻吩并[3,4-c]吡咯(1.44g,5.4mmol)的乙醇(70mL)悬浮液中加入2MCuSO4水溶液(2.9mL)。将该混合物冷却至0℃并分批加入硼氢化钠(1.10g,26.8mmol)(注意:大量放热!)。然后将得到的黑色反应混合物加热回流2小时。将冷却的反应混合物在EtOAc和H2O之间进行分配。将两相分离。水相用EtOAc(3×100mL)萃取。将合并的有机层干燥(MgSO4),过滤并浓缩。将得到的黑色残余物溶于丙酮/H2O(2∶1,60mL)。搅拌下将该溶液冷却至0℃,依次加入固体NaHCO3(1.35g,16.1mmol)和氯甲酸苄酯(1.9mL,13.4mmol)。将该反应混合物在0℃搅拌15分钟,然后在室温搅拌2小时。小心地加入10%NaHSO4水溶液(30mL)终止反应。将反应混合物倒入EtOAc(250mL)中并将两相分离。将水层用EtOAc(1×100mL)萃取。将合并的有机层干燥(MgSO4),过滤并浓缩。残余物通过闪式色谱纯化,用20%乙酸乙酯的己烷溶液作为洗脱剂,得到1.6g(4.3mmol,81%)所需氨基甲酸酯。mp101-102℃;元素分析C20H21FN2O2S的计算值:C,64.50;H,5.68;N,7.52;S,8.61。实测值:C,64.33;H,5.56;N,7.53;S,8.61。步骤7:(5R)-3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯
基]-5-(羟甲基)-2-噁唑烷酮
在N2和搅拌的条件,向冷却至-78℃的3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯基氨基甲酸苯甲酯(1.36g,3.6mmol)的干燥THF(14mL)溶液中加入正丁基锂(1.6M的己烷溶液,2.4mL,3.8mmol)。将反应混合物在-78℃搅拌35分钟,然后加入R-(-)丁酸缩水甘油酯(0.54mL,3.8mmol)。将反应混合物在-78℃搅拌30分钟,然后在室温下过夜。有粘稠的沉淀形成。用饱和NH4Cl水溶液(14mL)终止反应并将反应混合物倒入EtOAc(50mL)中。将两相分离。有机层用饱和NaHCO3水溶液(1×30mL)、盐水(1×30mL)洗涤,干燥(MgSO4),过滤并浓缩。残余物通过闪式色谱纯化,用乙酸乙酯作为洗脱剂,得到801.6mg(2.4mmol,65%)所需产物。mp165-167℃;元素分析C16H19FN2O3S的计算值:C,56.79;H,5.66;N,8.28;S,9.48。实测值:C,56.88;H,5.74;N,8.21;S,9.33。步骤8:(5R)-3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯
基]-5-[[(甲磺酰基)氧基]甲基]-2-噁唑烷酮
搅拌下,向冷却至0℃的(5R)-3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯基]-5-(羟甲基)-2-噁唑烷酮(656.5mg,1.9mmol)的CH2Cl2(20mL)溶液中依次加入三乙胺(0.41mL,2.9mmol)和甲磺酰氯(0.18mL,2.3mmol)。将反应混合物在0℃搅拌15分钟,然后在室温下18小时。将反应混合物倒入H2O(20mL)中。将两相分离。水层用CH2Cl2(1×50mL)萃取。将合并的有机层干燥(MgSO4),过滤并浓缩。将残余物与乙醚/己烷一起研制,滤出固体并干燥,得到773.9mg(1.9mmol,96%)所需的甲磺酸酯。mp148-150℃;元素分析C17H21FN2O5S2的计算值:C,49.03;H,5.08;N,6.73;S,15.40。实测值:C,48.56;H,5.12;N,6.48;S,15.41。实测值:C,48.46;H,5.25;N,6.38。步骤9:(S)-N-[[3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯
基]-2-氧代-5-噁唑烷基]甲基]乙酰胺
搅拌下,将(5R)-3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯基]-5-[[(甲磺酰基)氧基]甲基]-2-噁唑烷酮(208.5mg,0.5mmol)在THF(3mL)和甲醇氨(3mL)中的悬浮液于100℃下在封闭管中加热48小时(反应混合物在大约80℃变为均相)。将冷却的反应混合物浓缩,得到的残余物溶于CH2Cl2(5mL)并冷却至0℃。搅拌下,向该悬浮液中依次加入吡啶(0.12mL,1.5mmol)和乙酸酐(60μL,0.6mmol)。该均相的反应混合物在0℃搅拌15分钟,然后在室温下1小时,然后浓缩。残余物通过闪式色谱纯化,用7%甲醇的EtOAc溶液作为洗脱剂,得148.2mg(0.4mmol,78%)所需乙酰胺。mp143-144℃;KF-H2O:0.52%;元素分析C18H22FN3O3S+0.52%H2O,计算值:C,56.68;H,5.87;N,11.01;S,8.40。实测值:C,56.31;H,5.90;N,10.74;S,8.30。实施例5:(S)-N-[[3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,S-氧化物
搅拌下,向冷却至0℃的(S)-N-[[3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺(216.8mg,0.57mmol)在甲醇(4mL)和H2O(4mL)的溶液中加入偏高碘酸钠(134.4mg,0.63mmol)。将反应混合物在0℃搅拌1小时,然后在室温下18小时。滤出固体沉淀。将固体用CHCl3(50mL)洗涤。滤液用H2O(1×30mL)洗涤。将水层用CHCl3(2×25mL)萃取。合并的有机层干燥(MgSO4),过滤并浓缩。残余物通过闪式色谱纯化,用7%甲醇的CH2Cl2溶液作为洗脱剂,得195.7mg(0.5mmol,87%)所需亚砜mp162-164℃;HRMS(EI):C18H22FN3O4S的计算值395.1315,实测值395.1309。KF-H2O:2.87%;元素分析C18H22FN3O4S+2.87%H2O,计算值:C,53.09;H,5.76;N,10.32;S,7.87。实测值:C,53.07;H,6.01;N,10.20;S,7.87。实施例6:(S)-N-[[3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,S,S-二氧化物
搅拌下,向(S)-N-[[3-[3-氟-4-(四氢-1H-噻吩并[3,4-c]吡咯-5(3H)-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺(213.9mg,0.56mmol)在25%丙酮/H2O(8mL)的溶液中依次加入N-甲基吗啉-N-氧化物(198.1mg,1.7mmol)和四氧化锇的叔丁醇溶液(2.5重量)(30μL,0.08mmol)。将反应混合物在室温下搅拌18小时。小心地加入饱和亚硫酸氢钠(8mL)终止反应。将混合物倒入CH2Cl2(50mL)中并将两相分离。将水相用CH2Cl2(2×25mL)萃取。合并的有机层用盐水(1×30mL)洗涤,干燥(MgSO4),过滤并浓缩。残余物通过闪式色谱纯化,用7%甲醇的CHCl3溶液作为洗脱剂,得194.3mg(0.47mmol,84%)所需砜mp135-137℃;HRMS(EI):C18H22FN3O5S的计算值411.1264,实测值411.1263。KF-H2O:1.10%;元素分析C18H22FN3O5S+1.10%H2O,计算值:C,51.96;H,5.45;N,10.10;S,7.71。实测值:C,51.73;H,5.62;N,9.96;S,7.75。实施例7:顺-(S)-N-[[3-[3-氟-4-[3-氧杂-7-氮杂二环[3.3.0]辛-7-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺
按照实施例2的通用方法,作一些非关键性的改变,只是用六氢-1H-呋喃并(3,4-c)吡咯(Miller,A.D.,美国专利3975532,1976)(23.3g,20.66mmol)代替(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚烷,制得标题化合物,mpl24-126℃。
表II
Claims (15)
2.权利要求1的化合物,其中X是S。
3.权利要求1的化合物,其中各R1彼此独立地是H或F。
4.权利要求3的化合物,其中各R1是F。
5.权利要求1的化合物,其中R2是氢、C1-C8烷氧基或被-个或多个Cl或OH任意性可有可无地取代的C1-C8烷基。
6.权利要求1的化合物,其中R2是甲基、二氯甲基、羟甲基或甲氧基。
7.权利要求1的化合物,它们是:a)(S)-N-[[3-[3-氟-4-[(1S,4S)-2-氧杂-5-氮杂二环[2.2.1]庚-5-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;b)(S)-N-[[3-[3-氟-4-[(1S,4S)-2-硫杂-5-氮杂二环[2.2.1]庚-5-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺;或c)(S)-N-[[3-[3-氟-4-[(1S,4S)-2-硫杂-2,2-二氧代-5-氮杂二环[2.2.1]庚-5-基]苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺。
8.权利要求1的化合物,为S-对映体的形式。
9.权利要求1的化合物,其中c和b均是1。
10.权利要求9的化合物,其中d和e均是1。
11.权利要求10的化合物,其中a是0。
12.结构式I的化合物在制备用于治疗细菌感染的药物中的用途,所述治疗通过向需要治疗的患者给予有效量的结构式I的化合物来完成。
13.一种结构式II的化合物:结构式II或其可药用的盐,其中:X是 (a) O,
(b) S,
(c) SO,
(d) SO2;R1彼此独立地是H、F、Cl或OMe;和R2是 (a) 氢,
(b) 任意性可有可无地被一个或多个F、Cl、羟基、C1-C8烷氧
基、C1-C8酰氧基取代的C1-C8烷基,
(c) C3-C6环烷基,
(d) 氨基,
(e) C1-C8烷氨基,
(f) C1-C8二烷氨基,
(g) C1-C8烷氧基。
14.权利要求13的化合物,为S-对映体的形式。
15.结构式II的化合物在制备用于治疗温血动物细菌感染的药物中的用途,所述治疗通过向需要治疗的患者给予有效量的结构式II的化合物来完成。
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US33997994A | 1994-11-15 | 1994-11-15 | |
US08/339,979 | 1994-11-15 |
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CN1163615A true CN1163615A (zh) | 1997-10-29 |
CN1046520C CN1046520C (zh) | 1999-11-17 |
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US (1) | US5952324A (zh) |
EP (1) | EP0792273B1 (zh) |
JP (1) | JPH10508844A (zh) |
KR (1) | KR100392216B1 (zh) |
CN (1) | CN1046520C (zh) |
AT (1) | ATE233766T1 (zh) |
AU (1) | AU702733B2 (zh) |
BR (1) | BR9509673A (zh) |
DE (1) | DE69529838T2 (zh) |
DK (1) | DK0792273T3 (zh) |
ES (1) | ES2193201T3 (zh) |
MX (1) | MX9703543A (zh) |
NO (1) | NO972222L (zh) |
NZ (1) | NZ295528A (zh) |
PT (1) | PT792273E (zh) |
RU (1) | RU2128660C1 (zh) |
WO (1) | WO1996015130A1 (zh) |
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CN108348507A (zh) * | 2015-07-17 | 2018-07-31 | 结核病药物开发全球联盟公司 | 用于抗微生物治疗的经取代苯基噁唑烷酮 |
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-
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- 1995-10-31 US US09/051,466 patent/US5952324A/en not_active Expired - Fee Related
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1330647C (zh) * | 1999-08-12 | 2007-08-08 | 奥索-麦克尼尔药品公司 | 杂双环取代的苯基唑烷酮抗菌剂 |
CN108348507A (zh) * | 2015-07-17 | 2018-07-31 | 结核病药物开发全球联盟公司 | 用于抗微生物治疗的经取代苯基噁唑烷酮 |
CN108348507B (zh) * | 2015-07-17 | 2021-10-08 | 结核病药物开发全球联盟公司 | 用于抗微生物治疗的经取代苯基噁唑烷酮 |
CN113603683A (zh) * | 2015-07-17 | 2021-11-05 | 结核病药物开发全球联盟公司 | 用于抗微生物治疗的经取代苯基噁唑烷酮 |
Also Published As
Publication number | Publication date |
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PT792273E (pt) | 2003-06-30 |
NO972222D0 (no) | 1997-05-14 |
ES2193201T3 (es) | 2003-11-01 |
AU702733B2 (en) | 1999-03-04 |
KR100392216B1 (ko) | 2003-10-17 |
DK0792273T3 (da) | 2003-06-16 |
CN1046520C (zh) | 1999-11-17 |
WO1996015130A1 (en) | 1996-05-23 |
BR9509673A (pt) | 1997-09-30 |
RU2128660C1 (ru) | 1999-04-10 |
JPH10508844A (ja) | 1998-09-02 |
US5952324A (en) | 1999-09-14 |
EP0792273B1 (en) | 2003-03-05 |
MX9703543A (es) | 1997-08-30 |
DE69529838D1 (de) | 2003-04-10 |
NZ295528A (en) | 1999-03-29 |
DE69529838T2 (de) | 2003-11-13 |
AU3889095A (en) | 1996-06-06 |
NO972222L (no) | 1997-05-14 |
EP0792273A1 (en) | 1997-09-03 |
ATE233766T1 (de) | 2003-03-15 |
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