CN1237178A - 新型β－内酰胺化合物及其制备方法 - Google Patents
新型β－内酰胺化合物及其制备方法 Download PDFInfo
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- CN1237178A CN1237178A CN97199573A CN97199573A CN1237178A CN 1237178 A CN1237178 A CN 1237178A CN 97199573 A CN97199573 A CN 97199573A CN 97199573 A CN97199573 A CN 97199573A CN 1237178 A CN1237178 A CN 1237178A
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- Prior art keywords
- low alkyl
- compound
- alkyl group
- beta
- ester
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- -1 beta-Lactam compounds Chemical class 0.000 claims abstract description 50
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 41
- 150000002148 esters Chemical class 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 14
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 125000006239 protecting group Chemical group 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 231100000252 nontoxic Toxicity 0.000 claims description 13
- 230000003000 nontoxic effect Effects 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 150000007944 thiolates Chemical class 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 150000002466 imines Chemical class 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- 230000000845 anti-microbial effect Effects 0.000 abstract description 6
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
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- 125000000623 heterocyclic group Chemical group 0.000 description 4
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000001311 chemical methods and process Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- WHNQTHDJEZTVHS-UHFFFAOYSA-N 3-(1,3-benzothiazol-2-yl)propanoic acid Chemical compound C1=CC=C2SC(CCC(=O)O)=NC2=C1 WHNQTHDJEZTVHS-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 108010059993 Vancomycin Proteins 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
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- 125000006267 biphenyl group Chemical group 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
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- 239000011777 magnesium Substances 0.000 description 2
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- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
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- 150000007530 organic bases Chemical class 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
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- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- YNNGZCVDIREDDK-UHFFFAOYSA-N aminocarbamodithioic acid Chemical compound NNC(S)=S YNNGZCVDIREDDK-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 229940062233 di-isopropylammonium Drugs 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000004993 haloalkoxycarbonyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 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
- 229910052976 metal sulfide Inorganic materials 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 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
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- DPLVEEXVKBWGHE-UHFFFAOYSA-N potassium sulfide Chemical compound [S-2].[K+].[K+] DPLVEEXVKBWGHE-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- 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
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
下式的β－内酰胺化合物、其盐或其酯:其中R1是低级烷基或OH取代的低级烷基,R2是H或低级烷基,X是O、S或NH,n是1—3,R3是－C(Ra)=NH(Ra是H、低级烷基或取代的低级烷基)。这些化合物对革兰氏阳性菌,特别是甲氧苯青霉素抗药性的葡萄球菌和甲氧苯青霉素抗药性和凝固酶阴性的葡萄球菌具有极佳的抗菌活性。
Description
技术领域
本发明涉及下式[1]所示的新型β-内酰胺化合物。
背景技术
由于第三代头孢菌素在临床上的广泛应用，革兰氏阳性菌经常被分离出来。特别是甲氧苯青霉素抗药性的葡萄球菌(以下称为MRSA)经常被分离出来，并且成了临床领域的一个严重的问题，因为由MRSA引起的感染性疾病很难治疗。例如，目前广泛用于治疗由MRSA引起的感染性疾病的万古霉素，因其副作用而在给药中存在困难，并且据推测由于施用万古霉素将来可能会导致糖肽抗药性菌的增加。此外，最近报道了甲氧苯青霉素抗药性和凝固酶阴性的葡萄球菌(MRCNS)分离的增加。在这些情况下，非常需要开发一种具有很强的抗MRSA和抗MRCNS活性的安全的药物。
发明的公开
本发明的目的是提供一种对革兰氏阳性菌、特别是MRSA和MRCNS具有极佳抗菌活性的β-内酰胺抗生素。
本发明人进行了深入的研究，发现下式[1]的化合物对革兰氏阳性菌显示出很强的作用，特别是对MRSA和MRCNS显示出极佳的抗菌活性，从而完成了本发明。
因此，本发明涉及式[1]化合物、其可药用盐或其无毒的酯：
其中R1是低级烷基或被羟基取代的低级烷基，R2是氢原子或低级烷基，X是O、S或NH,n是1-3,R3是-C(Ra)=NH，其中Ra是氢原子、低级烷基或取代的低级烷基。
此外，本发明还涉及制备式[1]化合物或其可药用盐或其无毒的酯的方法其中R1、R2、R3、X和n如上所定义，该方法包括：将式[2]化合物：
其中R2如上所定义，R1a是低级烷基、被羟基取代的低级烷基或被用保护基保护了的羟基取代的低级烷基，R4是羧基保护基，L是羟基的活性酯，与式[3]化合物：
其中X和n如上所定义，R3a是-C(Ra)=NRb，其中Ra如上所定义，Rb是氢原子或亚胺酰基(イミドイル)保护基，或R3a是氨基保护基，在碱的存在下反应；或将式[2]化合物与式[3]化合物的硫醇盐反应，生成式[4]的化合物
其中R1a、R2、R3a、R4、X和n如上所定义，
然后适宜组合进行如下反应：脱除R1a的羟基的保护基，脱除R3a的氨基的保护基并随后将脱保护的氨基进行亚胺酰基化反应，或者脱除R3a的亚胺酰基的保护基，和脱除羧基的保护基R4。
以上式[1]、[2]、[3]和[4]中，R1、R1a、R2、R3和R3a的低级烷基包括含有1-5个碳原子的烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基或正戊基。
R1或R1a的被羟基取代的低级烷基包括含有1-5个碳原子并且被羟基取代的烷基，例如，羟甲基、1-羟基乙基、2-羟基乙基、1-羟基-1-甲基乙基、1-羟基丙基和2-羟基丙基。
本发明中，取代的低级烷基上的取代基包括，例如羟基；低级烷氧基；被羟基或氨基取代的低级烷氧基；低级烷基羰酰氧基；低级烷氧羰基；氨基；被一个或两个选自低级烷基和被羟基或氨基取代的低级烷基的基团取代的氨基；胍基；被三个选自低级烷基和被羟基或氨基取代的低级烷基的基团取代的季铵基团；羧基；氨基羰基；被一个或两个选自低级烷基和被羟基或氨基取代的低级烷基的基团取代的氨基羰基；卤原子；氰基；含有1-3个碳原子的烷基脒；以及胍基羰基。这些取代基可被适宜的保护基保护。这些取代基可以位于在化学上可能的任何位置上，并且可以在一个或多个位置如1-3个位置上取代。取代的低级烷基还包括通过取代基杂原子形成3-7元环的基团。所形成的3-7元环包括环乙亚胺、氮杂环丁烷、吡咯烷、哌啶、吗啉、高哌嗪(homoperazine)和四氢呋喃。
在上式[2]和[4]中，R4羧基的保护基可以是任何常规的保护基，但优选含有1-5个碳原子的直链或支链低级烷基(例如甲基、乙基、异丙基、叔丁基等)、含有1-5个碳原子的卤代低级烷基(例如2-碘乙基、2,2,2-三氯乙基)、含有1-5个碳原子的低级烷氧基甲基(例如甲氧甲基、乙氧基甲基、异丁氧基甲基)、含有2-5个碳原子的低级脂族酰氧甲基(例如乙酰氧甲基、丙酰氧甲基、丁酰氧甲基、戊酰氧甲基)、1-(C1-C5)-烷氧基羰酰氧基乙基(1-乙氧羰酰氧基乙基)、芳烷基(例如苄基、对甲氧基苄基、邻硝基苄基、对硝基苄基)、含有3-7个碳原子的低级烯基(例如烯丙基、3-甲基烯丙基)、二苯甲基或酞基。
上式[2]和[4]中R1a的羟基的保护基，以及上式[3]和[4]中R3a的氨基的保护基可以是任何常规的保护基，但优选含有1-5个碳原子的烷氧羰基(例如叔丁氧羰基)、含有1-5个碳原子的卤代烷氧羰基(2-碘代-乙氧羰基、2,2,2-三氯乙氧羰基)、含有3-7个碳原子的取代或未取代的烯氧羰基(例如烯丙基氧羰基)、芳烷氧羰基(例如苄氧羰基、对甲氧基苄氧羰基、邻硝基苄氧羰基、对硝基苄氧羰基)或三烷基硅烷基(例如三甲基硅烷基、三乙基硅烷基、叔丁基二甲基硅烷基)。
以上式[1]化合物的可药用盐是其常规的无毒盐。所述盐包括，分子内的羧酸形成的盐，包括与无机碱如钠、钾、钙、镁、铵形成的盐，与有机碱如三乙铵、吡啶鎓、二异丙基铵形成的盐，或与3-侧链上的阳离子如季铵离子形成的分子内的盐。作为与分子内的碱形成的盐的例子，包括与无机酸如盐酸、硫酸、磷酸形成的盐，或与有机酸如甲酸、乙酸、草酸、甲磺酸、苯磺酸形成的盐。
式[1]化合物的无毒酯包括碳青霉烯抗菌剂2-羧基上的常规可药用酯，该酯在体内易于水解，例如，乙酰氧基甲基酯、新戊酰氧基甲基酯、1-(乙氧羰酰氧基)乙基酯和2-苯并[c]呋喃酮基酯。
式[1]的β-内酰胺化合物、其可药用盐或无毒的酯可以是其酸酐、水合物或溶剂化物的形式。
以下将详细描述本发明化合物的制备方法。
式[4]化合物：
其中R1a、R2、R3a、R4、X和n如上所定义，可以通过将式[2]化合物的活性酯：
其中R1a、R2、R4和L如上所定义，与式[3]的巯基化合物：
其中R3a、X和n如上所定义，在碱的存在下在惰性溶剂中反应制得；或者通过将式[2]化合物与式[3]化合物的硫醇盐在惰性溶剂中反应制得。
羟基的活性酯包括，例如取代或未取代的芳基磺酸酯(例如苯磺酸酯、对甲苯磺酸酯、对硝基苯磺酸酯、对溴苯磺酸酯等)、含有1-5个碳原子的烷基磺酸酯(例如甲磺酸酯、乙磺酸酯等)、含有1-5个碳原子的卤代烷基磺酸酯(例如三氟甲磺酸酯等)、芳基磷酸酯(例如二苯基磷酸酯等)、或卤化物如氯化物、溴化物、碘化物，所述卤化物是与卤化氢形成的酯。优选的羟基活性酯是对甲苯磺酸酯、甲磺酸酯、三氟甲磺酸酯和二苯基磷酸酯。
化合物[2]和化合物[3]在碱的存在下生成化合物[4]的反应中所用的惰性溶剂包括，例如二氧六环、四氢呋喃、二甲亚砜、二甲基甲酰胺、乙腈、苯、甲苯、六甲基磷酰胺或这些溶剂的混合物。
所述碱包括，例如无机碱如碳酸钠、碳酸钾、氢化钠、氢化钾，或有机碱如吡啶、二甲氨基吡啶、三乙胺、二异丙基乙基胺、1,8-二氮杂双环[5.4.0.]十一碳-7-烯(DBU)。特别优选的碱是DBU。碱的用量应足以进行反应，其通常的用量为巯基化合物[3]量的1-3当量。
巯基化合物[3]的用量应足以进行反应，并且可以使用大大过量的量，但其通常的用量为化合物[2]量的1-2当量。
反应在-78℃至+60℃的温度下进行，优选-40℃至+40℃。此外，在反应结束后，生成的产物可以通过常规的有机化学方法进行分离。
化合物[2]和化合物[3]的硫醇盐生成化合物[4]的反应中所用的惰性溶剂包括，例如二氧六环、四氢呋喃、二甲亚砜、二甲基甲酰胺、乙腈、苯、甲苯、六甲基磷酰胺或这些溶剂的混合物。
硫醇盐的用量应足以进行反应，并且可以使用大大过量的量，但其通常的用量为化合物[2]量的1-2当量。
反应在-78℃至+60℃的温度下进行，优选-40℃至+40℃。此外，在反应结束后，生成的产物可以通过常规的有机化学方法进行分离。
硫醇盐从巯基化合物[3]和碱制备。所述的碱包括，例如无机碱(例如氢化钠、氢化钾)、金属醇盐(例如叔丁醇钾、甲醇钠)或金属氨基化物(例如氨基钠、二异丙基氨基锂、disirazide锂)。
式[1]的β-内酰胺化合物以常规的方式从化合物[4]制得，如需要，可进行如下反应：脱除R1a的羟基的保护基，脱除R3a的氨基的保护基并随后将脱保护的氨基进行亚胺酰基化反应，或者脱除R3a的亚胺酰基的保护基，和脱除羧基的保护基R4。
脱除R1a的羟基的保护基、脱除R3a的亚胺酰基的保护基、脱除R3a的氨基的保护基以及脱除羧基的保护基R4可以通过用酸、碱或还原剂处理来完成，这些方法本身均是已知的方法，参见，例如T.W.Greene：有机合成中的保护基，J.Wiley & Sons Inc.,1981。所述的酸优选为三氟乙酸、甲酸、三氟化硼、氯化铝等，或这些酸的混合物。所述的碱优选为碱金属碳酸盐(例如碳酸钠、碳酸钾等)、碱金属硫化物(例如硫化钠、硫化钾等)。所述的还原方法包括，例如用锌和乙酸氢化、用氢气和钯炭或铂氢化等。还原反应还可以用还原剂如钯(O)或钯(Ⅱ)和三正丁基氢化锡的混合物来完成。
所用溶剂可以是不会对反应产生不利影响的任何溶剂，包括，例如水、醇(例如甲醇、乙醇)、醚(例如四氢呋喃、二氧六环)、脂肪酸(例如乙酸)或这些溶剂的混合物。可通过适当的降低或升高反应温度来抑制或促进反应。优选的反应温度为-30℃至+40℃。反应结束后，所生成的产物可以通过常规的有机化学方法进行分离，例如，将反应混合物中和，将其在吸附树脂上进行柱色谱等，收集含有所需化合物的馏份，然后将得到的物质进行冷冻干燥。
式[2]化合物是已知的化合物，公开于例如JP-B-63-55514。
巯基化合物[3]可以通过各种常规方法制备，例如，通过文献如K.Hofmann，杂环化学，第6卷(1953)；J.V.Metzger，杂环化学，34卷(1979)；I.J.Turchi，杂环化学，45卷(1986)；IntersciencePublishers,Inc.,或A.R.Katrizky，杂环化学的进展，32卷(1982),Academic Press中公开的方法制备，或通过这些方法的组合进行制备。巯基化合物[3]通过，例如如下反应路线制备。
其中R5是被保护基保护的亚胺酰基，或是氨基保护基，tBu指1,1-二甲基乙基(叔丁基)。当然，巯基化合物[3]的制备方法不应理解为仅限于上述反应路线。
上述式[1]化合物可以有基于碳青霉烯核4-、5-和6-位的不对称碳原子的光学异构体，如下式所示：
其中R1、R2、R3、X和n如上所定义，★指不对称碳原子，为了简便，这些异构体仅用一个结构式表示。但是，应当理解，本发明并不仅限于此，而是包括了基于各个不对称碳原子的所有异构体以及异构体的混合物。但是，优选的异构体是其中的R2是氢、5-碳具有R构型的化合物如(5R,6R)-化合物或(5R,6S)-化合物，以及当R2是低级烷基时，4-碳原子具有R构型并且5-碳原子具有S构型的化合物，例如(4R,5S,6S)-化合物或(4R,5S,6R)-化合物。此外，当R1是1-羟基乙基时，化合物[1]可以存在在8-位具有R-构型或S-构型的异构体，如下式所示：
其中R2、R3、X和n如上所定义，优选在8-位具有R-构型的化合物。
具有各种构型的异构体可以通过使用原料化合物[2]的各相应异构体进行制备。
此外，化合物[1]还可以具有下式所示互变异构体：
其中R1、R2、Ra、X和n如上所定义，但为了简便，式[1]用来表示所有这些互变异构体。
本发明的式[1]化合物是新的β-内酰胺化合物群，该化合物群在碳青霉烯核的3-位带有氮杂环戊二烯硫代基团，在所述氮杂环戊二烯基团的4-位带有环烯基，并且在所述环烯基环内还具有被各种亚胺酰基取代的氨基。这些化合物显示出极佳的抗菌活性，可用作药物。
下表1例举了本发明制得的代表性的式[1]化合物。
表1
化合物号 R1 R2 X n R31 CH3CH(OH)- Me S 2 -C(CH2CH3)=NH2 CH3CH(OH)- Me S 2 -C(CH2CH2CH3)=NH3 CH3CH(OH)- Me S 2 -C(CH2(CH3)2)=NH4 CH3CH(OH)- Me S 2 -C(CH2OH)=NH5 CH3CH(OH)- Me S 2 -C(CH2CH2OH)=NH6 CH3CH(OH)- Me S 2 -C(CH2NH2)=NH7 CH3CH(OH)- Me S 2 -C(CH2CONH2)=NH8 CH3CH(OH)- Me S 2 -C(CH2COOCH3)=NH9 CH3CH(OH)- Me S 2 -C(CH2CH2Cl)=NH10 HOCH2- Me S 2 -CH=NH11 HOCH2- Me S 2 -C(CH3)=NH12 CH3CH(OH)- H S 2 -CH=NH13 CH3CH(OH)- H S 2 -C(CH3)=NH14 CH3CH(OH)- Me O 2 -CH=NH15 CH3CH(OH)- Me O 2 -C(CH3)=NH16 CH3CH(OH)- Me NH 2 -CH=NH17 CH3CH(OH)- Me NH 2 -C(CH3)=NH18 CH3CH(OH)- Me S 1 -CH=NH19 CH3CH(OH)- Me S 1 -C(CH3)=NH20 CH3CH(OH)- Me S 3 -CH=NH21 CH3CH(OH) Me S 3 -C(CH3)=NH
表1所列化合物具有以上所述的立体异构体，这些例举的化合物包括它们的所有异构体。
上式[1]所示的新型β-内酰胺可用作药物。也就是说，式[1]化合物对多种致病菌具有抗菌活性，所述致病菌包括革兰氏阳性菌如金黄色葡萄球菌、表皮葡萄球菌、酿脓链球菌、肺炎链球菌、粪肠球菌；革兰氏阴性菌如大肠杆菌、变形杆菌属、肺炎杆菌、流感嗜血杆菌、淋球菌、布兰汉氏球菌属，特别是对革兰氏阳性菌以及MRSA和MRCNS显示出极佳的抗菌活性。
已知脱氢肽酶-I(DHP-I)，一种肾脏的酶，可以很容易地水解天然来源的碳青霉烯化合物，而某些本发明的化合物[1]虽然也是碳青霉烯化合物，但对DHP-I却是稳定的，可以单独使用，但在需要时也可将DHP-I抑制剂与本发明的化合物一起使用。
本发明的化合物具有极佳的物理化学性质，例如在水或含水溶液如缓冲液中具有极佳的溶解度和稳定性。
当将本发明的化合物用作抗菌剂来治疗由细菌引起的感染性疾病时，可将本发明的化合物以例如片剂、胶囊、散剂、糖浆等的形式口服给药，或通过例如静脉内注射、肌肉内注射或直肠内给药等形式非经口给药。
上述的适宜给药形式可以通过将活性成分与常规的可药用载体、赋形剂、粘合剂、稳定剂等混合进行制备。当以注射液的形式给药时，可向其中加入可药用缓冲剂、增溶剂、等渗剂等。
化合物[1]的剂量根据患者的病情、年龄、体重、给药形式、给药频率等而改变，但对于成人通常在100-3000mg/天的范围内，可将所述剂量一次给药或分成数个剂量单位进行给药。此外，化合物[1]的剂量可根据需要增加或减少。
实施例
以下通过实施例对本发明进行更详细的说明，但本发明的范围并不仅限于此。
在实施例中使用了如下缩写。
Ph：苯基
TMS：三甲基硅烷基
Me：甲基
ALOC:2-丙烯基氧羰基(烯丙基氧羰基)
实施例1
a)将(4R,5R,6S,8R)-(2-丙烯基)-3-(二苯基磷酰氧基)-4-甲基-6-(1-(三甲基硅烷氧基)乙基)-1-氮杂双环[3.2.0]庚-2-烯-7-酮-2-甲酸酯(2.02g,3.53mmol)的乙腈(5毫升)溶液于0℃下搅拌，向其中逐渐加入硫醇盐的悬浮液并将该混合物于5℃下放置72小时，其中所述硫醇盐的悬浮液通过将2-巯基-4-(4-(1-(2-丙烯基)氧羰基-1,2,5,6-四氢吡啶基))-噻唑(997mg,3.53mmol)加入氢化钠(101mg,4.23mmol)的THF(30毫升)悬浮液中制得。将该混合物于0℃下搅拌，用1N盐酸将混合物的pH值调至pH3，然后将反应混合物搅拌30分钟。
用饱和碳酸氢钠水溶液将反应混合物的pH值调至pH8.5，然后将混合物用乙酸乙酯稀释。将有机层用硫酸镁干燥，减压浓缩，将得到的残余物通过硅胶柱色谱纯化(溶剂∶己烷∶乙酸乙酯=10∶2)得到淡黄色无定形的(4R,5S,6S,8R)-(2-丙烯基)-3-(4-(4-(1-(2-丙烯基)氧羰基-1,2,5,6-四氢吡啶基))-噻唑-2-基硫)-4-甲基-6-(1-羟乙基)-1-氮杂双环[3.2.0]庚-2-烯-7-酮-2-甲酸酯(810mg，收率；41％)。1H-NMRδ(CDCl3):1.09(3H,d,J=6.6Hz),1.23(3H,d,J=7.3Hz),2.51(2H,brs),3.26(1H,m),3.50(1H,m),3.69(2H,m),4.10(2H,m),4.20(2H,m),4.6～4.8(4H,m),5.0～5.5(4H,m),5.8～6.0(2H,m),6.66(1H,s),7.36(1H,s).
b)将(4R,5S,6S,8R)-(2-丙烯基)-3-(4-(4-(1-(2-丙烯基)氧羰基-1,2,5,6-四氢吡啶基))噻唑-2-基硫)-4-甲基-6-(1-羟乙基)-1-氮杂双环[3.2.0]庚-2-烯-7-酮-2-甲酸酯(610mg,1.09mmol)溶于间氯苯(15g)，向其中加入苯胺(2.03g,2.2mmol)。将该混合物在氮气氛下室温搅拌30分钟。将反应混合物冷却至0℃，向其中加入四三苯基膦钯(62.9mg,0.054mmol)，然后将该混合物继续搅拌1小时。
向反应混合物中加入饱和氯化钠水溶液(10毫升)和碳酸氢钠水溶液(pH8.0-8.5,10ml)，将该混合物用二氯甲烷洗涤两次。将水层减压浓缩除去溶剂，将得到的物质通过高分子色谱(CHP-20P)进行纯化。合并用4-8％THF水溶液洗脱的馏份并冷冻干燥得到白色无定形的(4R,5S,6S,8R)-3-(4-(4-(1,2,5,6-四氢吡啶鎓阳离子基))-噻唑-2-基硫)-4-甲基-6-(1-羟乙基)-1-氮杂双环[3.2.0]庚-2-烯-7-酮-2-甲酸盐(80mg,收率18％)。UVmaxnm(H2O):313,247(sh)；IRmaxcm-1(KBr):3388,1762,1599,13881H-NMRδ(D2O):1.10(3H,d,J=7.3Hz),1.27(3H,d,J=6.6Hz),2.83(2H,m),3.32(1H,m),3.51(3H,m),3.93(2H,m),4.26(2H,m),6.53(1H,brs),7.61(1H,s).
c)将(4R,5R,6S,8R)-3-(4-(4-(1,2,5,6-四氢吡啶鎓阳离子基))噻唑-2-基硫)-4-甲基-6-(1-羟乙基)-1-氮杂双环[3.2.0]庚-2-烯-7-酮-2-甲酸盐(145mg,0.36mmol)溶于0.1M磷酸钠缓冲液(pH7.0,4ml)，于0℃下向其中加入1N氢氧化钠水溶液将其pH值调至pH8.5。向该混合物中加入亚氨代甲酸苄酯盐酸盐(389mg,2.88mmol)，用1N氢氧化钠水溶液将其pH值调至pH8.5，然后搅拌2小时。用1N盐酸将反应液的pH值调至pH7.0，将混合物用二氯甲烷洗涤两次。将水层减压浓缩除去溶剂，将得到的物质通过高分子色谱(CHP-20P)进行纯化。合并用4％THF水溶液洗脱的馏份，冷冻干燥得到白色无定形的(4R,5S,6S,8R)-3-(4-(4-(1-亚胺代甲酰基-1,2,5,6-四氢吡啶鎓阳离子基))噻唑-2-基硫代)-4-甲基-6-(1-羟乙基)-1-氮杂双环[3.2.0]庚-2-烯-7-酮-2-甲酸盐(40mg，收率25％)。UVmaxnm(H2O):314,227IRmaxcm-1(KBr):3401,1764,1710,1596,13841H-NMRδ(D2O):0.98(3H,d,J=7.3Hz),1.19(3H,d,J=6.3Hz),2.64(2H,brs),3.18～3.24(1H,m),3.38～3.41(1H,m),3.73～3.83(2H,m),4.13～4.19(4H,m),6.40和6.45(计1H,各s),7.45和7.46(计1H,各s),7.90和7.91(计1 H,各s).
实施例2
按照与实施例1相同的方式，但在步骤(c)中使用亚氨代乙酸乙酯盐酸盐，制得白色无定形的(4R,5R,6S,8R)-3-(4-(4-(1-亚胺代乙酰基-1,2,5,6-四氢吡啶鎓阳离子基))-噻唑-2-基硫代)-4-甲基-6-(1-羟乙基)-1-氮杂双环[3.2.0]庚-2-烯-7-酮-2-甲酸盐。UVmaxnm(H2O):313,229；IRmaxcm-1(KBr):3354,1762,1603,1381；1H-NMRδ(D2O):1.05(3H,d,J=7.3Hz),1.25(3H,d,J=6.3Hz),2.37和2.41(计3H,各s),2.69(2H,brs),3.29(1H,m),3.47(1H,m),3.78～3.83(2H,m),4.20～4.34(4H,m),6.47(1H,s),7.53和7.54(计1H，各s).
参考实施例
以下说明式[3]巯基化合物制备方法的一个例子。在以下参考实施例中使用了如下缩写。
Bn： 苄基
Et： 乙基
ALOC:2-丙烯基氧羰基(烯丙基氧羰基)
a)将1-苄基4乙氧羰基吡啶鎓溴化物(580g,1.80mol)悬浮于乙醇(900毫升)和水(900毫升)的混合物中，向其中分批加入硼氢化钠(74.9g,1.98mol)，同时将反应混合物的温度保持在10℃以下。将反应混合物于10℃下搅拌3小时。将反应混合物减压浓缩，残余物溶于氯仿。将混合物用水洗涤，用硫酸钠干燥，然后减压浓缩除去溶剂。将残余物溶于氯仿(500毫升)，在1小时内于回流下向其中滴加氯甲酸乙酯(215g,1.98mol)。将混合物继续回流30分钟，减压浓缩。向残余物中加入浓盐酸(504g)和水(150g)，然后将混合物回流10小时。将反应混合物冷却至室温，减压浓缩。向残余物中加入异丙醇(500毫升)，搅拌混合物。抽滤收集沉淀出的结晶，用少量醚洗涤，风干得到白色结晶状1,2,5,6-四氢异烟酸盐酸盐(151.7g,52％)。1H-NMRδ(D2O):2.48(2H,m),3.29(2H,m),3.79(2H,m),6.81(1H,m).
b)将1,2,5,6-四氢异烟酸盐酸盐(150g,0.92mol)加入到碳酸钠(194g,1.83mol)的水(920毫升)溶液中，冰浴冷却下于1小时内向其中滴加氯甲酸2-丙烯基酯(116g,0.96mol)。加料后，将混合物在冰浴冷却下继续搅拌5小时。将浓盐酸(191g)和二氯甲烷(1000毫升)冷却，然后向其中分批滴加上述反应混合物。将混合物分液，用二氯甲烷萃取水层两次。合并有机层，用饱和氯化钠水溶液洗涤，用硫酸镁干燥，减压浓缩除去溶剂得到白色固体状1-(2-丙烯基氧羰基)-1,2,5,6-四氢异烟酸(198.9g,定量收率)。1H-NMRδ(CDCl3):2.42(2H,m),3.60(2H,m),4.17(2H,m),4.63(2H,m),5.19～5.34(2H,m),5.94(1H,m),7.01(1H,s),10.47(1H,brs).
c)将1(2-丙烯基氧羰基)-1,2,5,6-四氢异烟酸(114.2g,0.54mol)溶于THF(450毫升)，室温下向其中加入羰基二咪唑(105g,0.65mol)，将混合物搅拌30分钟。将该混合物于室温下滴加到二(丙二酸单叔丁酯)镁(129.6g,0.38mol)的THF(800毫升)溶液中，然后将该混合物放置过夜。将反应混合物用乙酸乙酯稀释，依次用1N盐酸、饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤，用硫酸镁干燥，浓缩除去溶剂得到淡黄色油状的4-(1-(2-丙烯基)氧羰基-1,2,5,6-四氢吡啶基)羰基乙酸叔丁酯(141.4g,86％)。1H-NMRδ(CDCl3):1.45～1.65(9H,m),2.41(2H,m),3.56～3.70(4H,m),4.21(2H,m),4.63(2H,m),5.20～5.3 5(2H,m),5.94(1H,m),6.77(1H,s).
d)将4-(1-(2-丙烯基)氧羰基-1,2,5,6-四氢吡啶基)-羰基乙酸叔丁酯(141.1g,0.46mol)溶于二氯甲烷(400毫升)并向其中加入叔丁醇(33.8g,0.46mol)。将该混合物冷却至-15至-20℃，搅拌下向其中逐渐滴加磺酰氯(38.8ml,0.48mol)。然后，将混合物搅拌1小时。将反应混合物升温至室温，向其中加入饱和碳酸氢钠水溶液。将混合物分液，有机层用硫酸镁干燥，浓缩除去溶剂。将残余物溶于二氯乙烷(350毫升)，向其中加入甲磺酸(12.4g,0.13mol)。将混合物升温至70℃，搅拌4小时。将反应混合物冷却至室温，向其中加入饱和碳酸氢钠水溶液。将混合物用乙酸乙酯萃取，有机层用硫酸镁干燥，浓缩除去溶剂。将残余物通过硅胶柱色谱纯化(己烷∶乙酸乙酯=10∶3)得到淡黄色固体状氯甲基4-(1-(2-丙烯基)氧羰基-1,2,5,6-四氢吡啶基)酮(52.9g,47％)。1H-NMRδ(CDCl3):2.44(2H,m),3.60(2H,m),4.27(2H,m),4.43(2H,s),4.63(2H,m),5.22～5.38(2H,m),5.95(1H,m),6.85(1H,s).
e)将氯甲基-4(1(2-丙烯基)氧羰基-1,2,5,6-四氢吡啶基)酮(29.4g,0.12mol)溶于乙醇(200毫升)和THF(200毫升)的混合物，向其中加入二硫代氨基甲酸铵(14.2g,0.14mol)。将混合物室温搅拌2小时。将反应混合物减压浓缩，向残余物中加入二氯甲烷。将混合物用水和饱和氯化钠水溶液洗涤，用硫酸镁干燥，然后浓缩除去溶剂。将残余物溶于乙醇(200毫升)和THF(200毫升)的混合物，然后将该混合物搅拌下回流2小时。将反应混合物冷却至室温并在室温下减压浓缩得到2-巯基-4-(4-(1-(2-丙烯基)氧羰基-1,2,5,6-四氢吡啶基))-噻唑(34g，定量收率)。1H-NMRδ(CDCl3):2.41(2H,m),3.68(2H,m),4.19(2H,s),4.64(2H,m),5.21～5.35(2H,m),5.95(1H,m),6.28(1H,s),6.44(1H,s),11.98(1H,brs).
Claims (8)
1．式[1]的β-内酰胺化合物、其可药用盐或其无毒的酯：
其中R1是低级烷基或被羟基取代的低级烷基，R2是氢原子或低级烷基，X是O、S或NH,n是1-3,R3是-C(Ra)=NH，其中Ra是氢原子、低级烷基或取代的低级烷基。
2．权利要求1所述的β-内酰胺化合物、其可药用盐或其无毒的酯，其中n是2。
3．权利要求2所述的β-内酰胺化合物、其可药用盐或其无毒的酯，其中X是硫原子或氧原子。
4．权利要求3所述的β-内酰胺化合物、其可药用盐或其无毒的酯，其中R1是1-(R)-羟基乙基。
5．权利要求4所述的β-内酰胺化合物、其可药用盐或其无毒的酯，其中X是硫原子。
6．制备式[1]化合物或其可药用盐或其无毒酯的方法：
其中R1是低级烷基或被羟基取代的低级烷基，R2是氢原子或低级烷基，X是O、S或NH,n是1-3,R3是-C(Ra)=NH，其中Ra是氢原子、低级烷基或取代的低级烷基，该方法包括：
将式[2]化合物：
其中R2如上所定义，R1a是低级烷基、被羟基取代的低级烷基或被用保护基保护了的羟基取代的低级烷基，R4是羧基保护基，L是羟基的活性酯，与式[3]化合物：
其中X和n如上所定义，R3a是-C(Ra)=NRb，其中Ra如上所定义，Rb是氢原子或亚胺酰基保护基，或R3a是氨基保护基，在碱的存在下反应；或将式[2]化合物与式[3]化合物的硫醇盐反应，生成式[4]的化合物：
其中R1a、R2、R3a、R4、X和n如上所定义，
然后适宜组合进行如下反应：脱除R1a的羟基的保护基，脱除R3a的氨基的保护基并随后将脱保护的氨基进行亚胺酰基化反应，或者脱除R3a的亚胺酰基的保护基，脱除R4的羧基的保护基。
7．含有权利要求1、2、3、4和5中任意一项所述的β-内酰胺化合物、其可药用盐或其无毒酯的药物。
8．含有权利要求1、2、3、4和5中任意一项所述的β-内酰胺化合物、其可药用盐或其无毒酯的抗菌剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8255450A JPH1077285A (ja) | 1996-09-04 | 1996-09-04 | 新規なβ−ラクタム化合物およびその製造法 |
| JP255450/96 | 1996-09-04 |
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| Publication Number | Publication Date |
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| CN1237178A true CN1237178A (zh) | 1999-12-01 |
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| CN97199573A Pending CN1237178A (zh) | 1996-09-04 | 1997-09-03 | 新型β－内酰胺化合物及其制备方法 |
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| Country | Link |
|---|---|
| US (1) | US6265396B1 (zh) |
| EP (1) | EP0934942A4 (zh) |
| JP (1) | JPH1077285A (zh) |
| KR (1) | KR20010029454A (zh) |
| CN (1) | CN1237178A (zh) |
| AU (1) | AU712039B2 (zh) |
| BR (1) | BR9711994A (zh) |
| CA (1) | CA2264806A1 (zh) |
| NZ (1) | NZ334317A (zh) |
| WO (1) | WO1998009965A1 (zh) |
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| WO2002038564A1 (en) * | 2000-11-08 | 2002-05-16 | Sumitomo Pharmaceuticals Company, Limited | NOVEL β-LACTAM COMPOUNDS AND PROECSS FOR PRODUCING THE SAME |
| WO2002044178A1 (en) * | 2000-11-30 | 2002-06-06 | Sumitomo Pharmaceuticals Company, Limited | NOVEL β-LACTAM COMPOUNDS AND PROCESS FOR PRODUCING THE SAME |
| US7148257B2 (en) | 2002-03-04 | 2006-12-12 | Merck Hdac Research, Llc | Methods of treating mesothelioma with suberoylanilide hydroxamic acid |
| EP1797879A4 (en) * | 2004-10-08 | 2009-05-06 | Dainippon Sumitomo Pharma Co | NEW ANTIMICROBIAL MEDICAMENT |
| TW200930722A (en) * | 2007-12-12 | 2009-07-16 | Dainippon Sumitomo Pharma Co | Stable crystal of β-lactam compound |
| KR100968278B1 (ko) * | 2008-03-28 | 2010-07-06 | 삼성전기주식회사 | 절연시트 및 그 제조방법과 이를 이용한 인쇄회로기판 및그 제조방법 |
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| IE51861B1 (en) | 1978-10-24 | 1987-04-15 | Merck & Co Inc | 6-,1-and 2-substituted-1-carbapen-2-em-3-carboxylic acids,processes for the preparation of such compounds and pharmaceutical compositions comprising such compounds |
| EP0082133A3 (en) | 1979-04-19 | 1983-07-20 | Merck & Co. Inc. | A process for preparing intermediates useful for preparing 2-substituted-6-substituted-1-carbadethiapen-2-em-3-carboxylic acids |
| EP0060612A1 (en) | 1981-02-04 | 1982-09-22 | Beecham Group Plc | Process for the preparation of azabicyclo(3.2.0)-hept-2-ene derivatives |
| EP0061231A1 (en) | 1981-02-04 | 1982-09-29 | Beecham Group Plc | Process for the preparation of azabicyclo(3.2.0)-hept-2-ene derivatives |
| ES8404184A1 (es) | 1981-08-03 | 1984-04-16 | Merck & Co Inc | Un procedimiento para la prepracion de nuevos derivados de acidos 2-carbamimidoil-1-,carbadestiapen-2-en-3-carboxilados. |
| EP0160876A1 (en) | 1984-04-23 | 1985-11-13 | Merck & Co. Inc. | 1-Hetero-6-/1-Hydroxyethyl/-2-SR8-1-carbadethiapen-2-EM-3-carboxylic acids |
| JPS615081A (ja) | 1984-06-18 | 1986-01-10 | Sankyo Co Ltd | １−置換カルバペネム−３−カルボン酸誘導体の製造法 |
| JPS6363680A (ja) | 1986-09-05 | 1988-03-22 | Nippon Redarii Kk | （１ｒ）−１−メチルカルバペネム−３−カルボン酸誘導体 |
| DE3640715A1 (de) | 1986-11-28 | 1988-06-09 | Bayer Ag | Benzazolylthio-carbapenem-antibiotika |
| EP0597821A1 (en) | 1988-04-01 | 1994-05-18 | Sankyo Company Limited | 2-(Heterocyclylthio)carbapenem derivatives their preparation and their use as antibiotics |
| CA2050255C (en) | 1990-09-07 | 1997-02-04 | Tameo Iwasaki | 1-methylcarbapenem derivatives and process for preparation thereof |
| GB9304156D0 (en) | 1992-03-26 | 1993-04-21 | Zeneca Ltd | Antibiotic compounds |
| EP0704446A4 (en) | 1993-06-16 | 1996-06-12 | Sumitomo Pharma | NOVEL BETA-LACTAM COMPOUND AND PROCESS FOR PRODUCING THE SAME |
| JPH072856A (ja) | 1994-04-27 | 1995-01-06 | Sankyo Co Ltd | １−メチルカルバペネム誘導体 |
| AU3215395A (en) | 1994-07-29 | 1996-03-04 | Merck & Co., Inc. | Carbapenem compounds, compositions and methods of treatment |
-
1996
- 1996-09-04 JP JP8255450A patent/JPH1077285A/ja active Pending
-
1997
- 1997-09-03 AU AU50351/98A patent/AU712039B2/en not_active Ceased
- 1997-09-03 CN CN97199573A patent/CN1237178A/zh active Pending
- 1997-09-03 KR KR1019997001726A patent/KR20010029454A/ko not_active Application Discontinuation
- 1997-09-03 CA CA002264806A patent/CA2264806A1/en not_active Abandoned
- 1997-09-03 US US09/254,175 patent/US6265396B1/en not_active Expired - Fee Related
- 1997-09-03 WO PCT/JP1997/003078 patent/WO1998009965A1/ja not_active Application Discontinuation
- 1997-09-03 EP EP97939146A patent/EP0934942A4/en not_active Withdrawn
- 1997-09-03 BR BR9711994A patent/BR9711994A/pt not_active IP Right Cessation
- 1997-09-03 NZ NZ334317A patent/NZ334317A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BR9711994A (pt) | 1999-08-24 |
| WO1998009965A1 (en) | 1998-03-12 |
| EP0934942A1 (en) | 1999-08-11 |
| AU5035198A (en) | 1998-03-26 |
| KR20010029454A (ko) | 2001-04-06 |
| US6265396B1 (en) | 2001-07-24 |
| CA2264806A1 (en) | 1998-03-12 |
| EP0934942A4 (en) | 2000-01-19 |
| NZ334317A (en) | 2000-09-29 |
| AU712039B2 (en) | 1999-10-28 |
| JPH1077285A (ja) | 1998-03-24 |
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