JPS6388187A - 3-ammoniopropenylcephem derivative - Google Patents
3-ammoniopropenylcephem derivativeInfo
- Publication number
- JPS6388187A JPS6388187A JP61233356A JP23335686A JPS6388187A JP S6388187 A JPS6388187 A JP S6388187A JP 61233356 A JP61233356 A JP 61233356A JP 23335686 A JP23335686 A JP 23335686A JP S6388187 A JPS6388187 A JP S6388187A
- Authority
- JP
- Japan
- Prior art keywords
- formulas
- tables
- group
- chemical formulas
- mathematical
- 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.)
- Pending
Links
- JWISHLAFUISNMX-NHSZFOGYSA-N (6R)-4-(3-aminoprop-1-enyl)-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical class C1[C@@H]2N(C1=O)C=CC(S2)C=CCN JWISHLAFUISNMX-NHSZFOGYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 125000006239 protecting group Chemical group 0.000 claims abstract description 14
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- -1 3-Ammoniopropenyl cephem Chemical class 0.000 claims description 24
- 231100000252 nontoxic Toxicity 0.000 claims description 10
- 230000003000 nontoxic effect Effects 0.000 claims description 10
- IKWLIQXIPRUIDU-ZCFIWIBFSA-N (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=CCS[C@@H]2CC(=O)N12 IKWLIQXIPRUIDU-ZCFIWIBFSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 4
- 125000000656 azaniumyl group Chemical group [H][N+]([H])([H])[*] 0.000 claims description 3
- 230000008030 elimination Effects 0.000 claims description 2
- 238000003379 elimination reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 241000894006 Bacteria Species 0.000 abstract description 4
- 241000589517 Pseudomonas aeruginosa Species 0.000 abstract description 3
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- 241000192125 Firmicutes Species 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000002244 precipitate Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- RXYPXQSKLGGKOL-UHFFFAOYSA-N 1,4-dimethylpiperazine Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- CDZHZLQKNAKKEC-UHFFFAOYSA-N [bis(hydroxymethylamino)methylamino]methanol Chemical class OCNC(NCO)NCO CDZHZLQKNAKKEC-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 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 2
- 238000010828 elution Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 125000003607 serino group Chemical class [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 150000003871 sulfonates Chemical class 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- XDFMWQRIDPQQSC-UHFFFAOYSA-N (4-methylpiperazin-1-yl)methanimine;hydrochloride Chemical compound Cl.CN1CCN(C=N)CC1 XDFMWQRIDPQQSC-UHFFFAOYSA-N 0.000 description 1
- XOCUEKDOGKUIHR-ZCFIWIBFSA-N (6r)-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=C(CI)CS[C@@H]2CC(=O)N12 XOCUEKDOGKUIHR-ZCFIWIBFSA-N 0.000 description 1
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 description 1
- NIXQLMVKRBUSPF-UHFFFAOYSA-N 3-(dimethylamino)propanamide Chemical compound CN(C)CCC(N)=O NIXQLMVKRBUSPF-UHFFFAOYSA-N 0.000 description 1
- ULZCOWMSBOJCLT-UHFFFAOYSA-N 4-methyl-1,4-thiazinane 1,1-dioxide Chemical compound CN1CCS(=O)(=O)CC1 ULZCOWMSBOJCLT-UHFFFAOYSA-N 0.000 description 1
- NMAOAFBQWWLHQG-UHFFFAOYSA-N 4-methylpiperazine-1-sulfonamide Chemical compound CN1CCN(S(N)(=O)=O)CC1 NMAOAFBQWWLHQG-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical class OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- MSPCIZMDDUQPGJ-UHFFFAOYSA-N N-methyl-N-(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)N(C)C(=O)C(F)(F)F MSPCIZMDDUQPGJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical class C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- SLIKWWJXVUHCPJ-UHFFFAOYSA-N n-(dimethylazaniumyl)ethanimidate Chemical compound CN(C)NC(C)=O SLIKWWJXVUHCPJ-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [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
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔発明の目的〕
本発明は抗菌剤として有用な新規なセファロスポリン誘
導体に関するものである。DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The present invention relates to novel cephalosporin derivatives useful as antibacterial agents.
従来、特開昭58−174387号公報、特開昭58−
198490号公報、特開昭59−130295号公報
、特開昭59−219292号公報、特開昭60−97
983号公報。Previously, JP-A-58-174387, JP-A-58-
198490, JP 59-130295, JP 59-219292, JP 60-97
Publication No. 983.
特開昭60−197693号公報等において9本発明化
合物と同様な4級アンモニオ基を有するセファロスポリ
ン誘導体が知られている。しかし、ダラム陽性菌および
ダラム陰性菌(特に緑膿菌)のいずれにも有効な化合物
という点においては、十分満足される化合物が得られて
いるとはいえない。Cephalosporin derivatives having a quaternary ammonio group similar to the compounds of the present invention are known in JP-A-60-197693 and the like. However, it cannot be said that a sufficiently satisfactory compound has been obtained in terms of being effective against both Durham-positive bacteria and Durham-negative bacteria (particularly Pseudomonas aeruginosa).
本発明者等は9本発明化合物が、ダラム陽性苗。The present inventors applied nine compounds of the present invention to Duram-positive seedlings.
ダラム陰性菌(緑膿菌)の両者に対し優れた抗菌活性を
有することを見い出し9本発明を完成したものである。The present invention was completed based on the discovery that it has excellent antibacterial activity against both Durham-negative bacteria (Pseudomonas aeruginosa).
したがって本発明の目的は、抗菌剤として有用な新規化
合物およびその製造方法を提供することにある。Therefore, an object of the present invention is to provide a novel compound useful as an antibacterial agent and a method for producing the same.
本発明は一般式:
〔式中、R1は低級アルキル基、Aは次の基二を示し、
&は低級アルキル基、R5は低級アルキル基、スルファ
モイル基、ホルムイミドイル基またはカルバモイル基を
示す〕で表わされる3−アンモニオプロペニルセフェム
誘導体およびその非毒性塩である。The present invention is based on the general formula: [wherein R1 is a lower alkyl group, A represents the following group 2,
& represents a lower alkyl group, R5 represents a lower alkyl group, a sulfamoyl group, a formimidoyl group, or a carbamoyl group] and a nontoxic salt thereof.
抹
上器一般式fIlにおけるR、、R2およびR5の低級
アルキル基としては、メチル、エチル、n−プロピル、
i−プロピル、n−ブチル、 5ec−ブチル。The lower alkyl groups of R, R2 and R5 in the general formula fIl include methyl, ethyl, n-propyl,
i-propyl, n-butyl, 5ec-butyl.
t−ブチルなどがあげられる。Examples include t-butyl.
また一般式tI+の化合物の非毒性塩としては、医薬上
許容される塩類9例えばナトリウム塩、カリウム塩など
のアルカリ金属塩;カルシウム塩、マグネシウム塩など
のアルカリ土類金属塩;塩酸塩。Non-toxic salts of the compound of general formula tI+ include pharmaceutically acceptable salts such as alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and hydrochlorides.
臭化水素酸塩、沃化水素酸塩、硫酸塩、炭酸塩。Hydrobromide, hydroiodide, sulfate, carbonate.
重炭酸塩などの無機酸塩;酢戯塩、マレイン酸塩。Inorganic acid salts such as bicarbonate; vinegar salt, maleate salt.
乳酸塩、酒石酸塩などの有機カルボン酸塩;メタンスル
ホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸
塩などの有機スルホン酸塩;アルギニン塩、リジン塩、
セリン塩、アスパラギン酸塩。Organic carboxylates such as lactate and tartrate; organic sulfonates such as methanesulfonate, benzenesulfonate and toluenesulfonate; arginine salt, lysine salt,
Serine salts, aspartates.
グルタミン酸塩などのアミノ酸塩;トリメチルアミン塩
、トリエチルアミン塩、ピリジン塩、フロカイン塩、ピ
コリン塩、ジシクロヘキシルアミン塩、 N、 N’−
ジベンジルエチレンジアミン塩、N−メチルグルカミン
塩、ジェタノールアミン塩、トリエタノールアミン塩、
トリス(ヒドロキシメチルアミノ)メタン塩、フェネチ
ルベンジルアミン塩などのアミン塩等があげられる。Amino acid salts such as glutamate; trimethylamine salt, triethylamine salt, pyridine salt, flocaine salt, picoline salt, dicyclohexylamine salt, N, N'-
Dibenzylethylenediamine salt, N-methylglucamine salt, jetanolamine salt, triethanolamine salt,
Examples include amine salts such as tris(hydroxymethylamino)methane salt and phenethylbenzylamine salt.
一般式(Ilの本発明化合物の次の部分の立体配位に関
し。Concerning the configuration of the following moiety of the compound of the present invention of general formula (Il).
C− I \Q−R。C- I \Q-R.
シン異性体(Zlとアンチ異性体Elが存在する。本発
明には両異性体とも含まれるが、抗菌力の点からはシン
異性体が望ましい。There is a syn isomer (Zl) and an anti-isomer El. Although both isomers are included in the present invention, the syn isomer is preferred from the standpoint of antibacterial activity.
本発明化合物は次に示す方法により製造することができ
る。The compound of the present invention can be produced by the method shown below.
一般式:
〔式中、R1は低級アルキル基、Xはハロゲン原子を示
す〕で表わされる化合物、そのアミノ基およびまたはカ
ルボキシル基が保護基で保護された化合物、またはそれ
らの化合物の塩に一般式二A′ 皿)
〔A′は次の化合物:
R2馬
を示し、馬は低級アルキル基、R8は低級アルキル基、
スルファモイル基、ホルムイミドイル基またはカルバモ
イル基を示す〕で表わされる化合物またはその塩を反応
させ、必要により保護基を脱離して前記一般式(Ilの
化合物またはその非毒性塩を得ることができる。General formula: [In the formula, R1 is a lower alkyl group, 2A' plate) [A' represents the following compound: R2 horse, horse is a lower alkyl group, R8 is a lower alkyl group,
sulfamoyl group, formimidoyl group or carbamoyl group] or a salt thereof, and if necessary, the protecting group is removed to obtain a compound of the general formula (Il) or a non-toxic salt thereof.
上記一般式tmのXのハロゲン原子としては、沃素原子
、臭素原子、塩素原子があげられる。Examples of the halogen atom for X in the above general formula tm include an iodine atom, a bromine atom, and a chlorine atom.
上記反応は反応温度−10°C〜60°C9好ましくは
0°C〜40°Cで行うことができる。また9反応溶媒
としては、無水の有機溶媒が望ましい。この使用するこ
とができる有機溶媒としては、アセトニトリル、プロピ
オニトリル等の低級アルキルニトリル;クロロメタン、
ジクロロメタン、クロロホルムなどのハロゲン化低級ア
ルキル;テトラヒドロフラン、ジオキサン、エチルエー
テル等のエーテル;N、N−ジメチルホルムアミドなど
のアミド;酢酸エチル等のエステル;アセトンなどのケ
トン;ベンゼン等の炭化水素あるいはこれらの混合溶媒
!1イあげられスー
保護基の脱離は、使用した保護基の種類に応じ。The above reaction can be carried out at a reaction temperature of -10°C to 60°C, preferably 0°C to 40°C. Further, as the reaction solvent, an anhydrous organic solvent is preferable. Organic solvents that can be used include lower alkylnitrile such as acetonitrile and propionitrile; chloromethane,
Lower alkyl halides such as dichloromethane and chloroform; ethers such as tetrahydrofuran, dioxane, and ethyl ether; amides such as N,N-dimethylformamide; esters such as ethyl acetate; ketones such as acetone; hydrocarbons such as benzene, or mixtures thereof solvent! 1) Elimination of the protecting group depends on the type of protecting group used.
加水分解、還元など常法により行うことができる。This can be carried out by conventional methods such as hydrolysis and reduction.
一般式(mlおよび唾の化合物の塩、一般式(IIIの
化合物のアミノ基およびカルボキシル基における保護基
としては、上記反応を妨げないものであれば通常用いら
れているものを使用することができる。As protecting groups for the amino group and carboxyl group of the salt of the compound of the general formula (ml and saliva) and the compound of the general formula (III), commonly used groups can be used as long as they do not interfere with the above reaction. .
例えば、アミン基の保護基としてはホルミル基、′アセ
チル基、クロルアセチル基、ジクロルアセチル基、t−
ブトキシカルボニル基、ベンジルオキシカルボニル基、
トリチル基、p−メトキシベンジル基、ジフェニルメチ
ル基など;カルボキ」1の保護基としては、p−メトキ
シベンジル基、p−ニトロベンジル基、t−ブチル基、
メチル基。For example, protective groups for amine groups include formyl group, 'acetyl group, chloroacetyl group, dichloroacetyl group, t-
butoxycarbonyl group, benzyloxycarbonyl group,
Trityl group, p-methoxybenzyl group, diphenylmethyl group, etc.; protective groups for carboxy 1 include p-methoxybenzyl group, p-nitrobenzyl group, t-butyl group,
Methyl group.
2、 2. 2−トIJクロロエチル基、ジフェニルメ
チル基、ピバロイルオキシメチル基などがあげられる。2, 2. Examples include 2-toIJ chloroethyl group, diphenylmethyl group, and pivaloyloxymethyl group.
また、ビス(トリメチルシリル)アセトアミド、N−メ
チル−N−(1−リメチルシリル)アセトアミド、N−
メチル−N−トリメチルシリル−トリフルオロアセトア
ミドなどのシリル化剤を使用すれば、アミノ基およびカ
ルボキーAを同時に保役できるので便利である。Also, bis(trimethylsilyl)acetamide, N-methyl-N-(1-limethylsilyl)acetamide, N-
It is convenient to use a silylating agent such as methyl-N-trimethylsilyl-trifluoroacetamide because it can hold the amino group and carboxy A at the same time.
一般式(mlおよび唾の化合物の塩としては9例えばナ
トリウム塩、カリウム塩等のアルカリ金属塩、カルシウ
ム塩、マグネシウム塩等のアルカリ土類金属塩;アンモ
ニウム塩;塩酸塩、臭化水素酸塩、硫酸塩、炭酸塩、沃
化水素酸塩9重炭酸塩等の無機酸塩;酢酸塩、トリフル
オロ酢酸塩、マレイン酸塩、乳酸塩、酒石酸塩等の有機
カルボン酸塩;メタンスルホン酸塩、ベンゼンスルホン
酸塩、トルエンスルホン酸塩等の有機スルホン酸塩;ト
リメチルアミン塩、トリエチルアミン塩、ピリジン塩、
プロ力イン塩、ピコリン塩、ジシクロヘキシルアミン塩
、N、N’−ジベンジルエチレンジアミン塩、N−メチ
ルグルカミン塩、ジェタノールアミン塩、トリエタノー
ルアミン塩、トリス(ヒドロキシメチルアミノ)メタン
塩、フェネチルベンジルアミン塩等のアミン塩;アルギ
ニン塩、アスパラギン酸塩、リジン塩、グルタミン酸塩
、セリン塩等のアミノ酸塩などの塩の中より適宜選択す
ることができる。Salts of compounds of the general formula (ml and saliva) include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; hydrochlorides, hydrobromides, Inorganic acid salts such as sulfates, carbonates, hydroiodides and 9 bicarbonates; organic carboxylates such as acetates, trifluoroacetates, maleates, lactates, tartrates; methanesulfonates, Organic sulfonates such as benzenesulfonate and toluenesulfonate; trimethylamine salt, triethylamine salt, pyridine salt,
Propylene salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, jetanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt, phenethylbenzyl Amine salts such as amine salts; salts such as amino acid salts such as arginine salts, aspartate salts, lysine salts, glutamate salts, and serine salts can be selected as appropriate.
次に実験例および実施例を示し2本発明をさらに詳しく
説明する。Next, the present invention will be explained in more detail by showing experimental examples and examples.
実験例1(原料化合物の合成)
p−メトキシベンジル 7β−C2−(5−)クチルア
ミノ−1,2,4−チアジアゾール−3−イル)−17
1−2−メトキシイミノアセトアミド〕−3−クロロメ
チル−3−セフェム−4−カルボキシレート
2−(5−トリチルアミノ−1,2,4−チアジアゾー
ル−3−イル)−iZl−2−メトキシイミノ酢酸10
0gをジメチルホルムアミドILに溶解し。Experimental Example 1 (Synthesis of raw material compound) p-methoxybenzyl 7β-C2-(5-)cutylamino-1,2,4-thiadiazol-3-yl)-17
1-2-methoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylate 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-iZl-2-methoxyiminoacetic acid 10
0g was dissolved in dimethylformamide IL.
水冷下、p−メトキシベンジル 7β−アミノ−3−4
0ロメチル−3−セフェム−4−カルボキシレート 〇
−トルエンスルホン的市’L’l−70−トリエチルア
ミン22.77 yおよびN−エチル−N’ −3−ジ
メチルアミノプロピルカルポジイミド塩酸塩139.6
yを加え、同温度で8時間撹拌した。反応液に酢酸エ
チル4Lを加えた後、水、飽和食塩水、飽和炭酸水素ナ
トリウム水溶液、飽和食塩水。Under water cooling, p-methoxybenzyl 7β-amino-3-4
0-Lomethyl-3-cephem-4-carboxylate 〇-Toluenesulfonic acid 'L'l-70-triethylamine 22.77y and N-ethyl-N'-3-dimethylaminopropylcarpodiimide hydrochloride 139.6
y was added and stirred at the same temperature for 8 hours. After adding 4 L of ethyl acetate to the reaction solution, water, saturated brine, saturated aqueous sodium bicarbonate solution, and saturated brine.
IN塩酸、飽和食塩水で順次洗浄した。これに無水硫酸
マグネシウムを加えて乾燥後、溶媒を減圧留去した。残
渣をシリカゲルカラムクロマトグラフィー(溶出;クロ
ロホルム)で精製し、目的物115gを得た。It was washed successively with IN hydrochloric acid and saturated saline. After drying by adding anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution: chloroform) to obtain 115 g of the desired product.
実験例2(原料化合物の合成)
p−メトキシベンジル 7β−(2−(5−)クチルア
ミノ−1,2,4−チアジアゾール−3−イル”)−1
ZI−2−メトキシイミノアセトアミド〕=3−ヨード
メチル−3−セフェム−4−カルボキシレート
実験例1の化合物60gをメチルエチルケトン1.21
に溶解し、これにヨウ化ナトリウム56.5 。Experimental Example 2 (Synthesis of raw material compound) p-methoxybenzyl 7β-(2-(5-)cutylamino-1,2,4-thiadiazol-3-yl")-1
ZI-2-methoxyiminoacetamide] = 3-iodomethyl-3-cephem-4-carboxylate 60 g of the compound of Experimental Example 1 was added to 1.21 g of methyl ethyl ketone.
Dissolve 56.5% of sodium iodide in this.
を加えて室温にて1時間撹拌した。溶媒を留去し。was added and stirred at room temperature for 1 hour. Distill the solvent.
残渣を酢酸エチルに溶解後、水、飽和チオ硫酸ナトリウ
ム水溶液、飽和食塩水で順次洗浄した後。After dissolving the residue in ethyl acetate, the solution was washed successively with water, saturated aqueous sodium thiosulfate solution, and saturated brine.
無水硫酸マグネシウムを加えて乾燥した。これを減圧濃
縮し、n−ヘキサンを加えて、生じた沈殿を炉底し、目
的物61.0gを得た。It was dried by adding anhydrous magnesium sulfate. This was concentrated under reduced pressure, n-hexane was added, and the resulting precipitate was drained to the bottom of the furnace to obtain 61.0 g of the target product.
実験例3(原料化合物の合成)
p−メトキシベンジル 7β−[2−(5−トリチルア
ミノ−1,2,4−チアジアゾール−3−イル)−1Z
)−2−メトキシイミノアセトアミド〕−3−IJフェ
ニルホスホニオメチル−3J、7エムー4−カルボキシ
レート ヨウ化物
実験例2の化合物9.54 、をベンゼン190 ml
に溶解し、トリフェニルホスフィン5.64.を加えテ
室温で1時間撹拌した。この反応液にn−ヘキサン10
0 mLを滴下し、生じた沈殿を炉底した。これをベン
ゼン−n−ヘキサン(1:1)混液およびn−ヘキサン
で洗浄して目的物11.30gを得た。Experimental Example 3 (Synthesis of raw material compound) p-methoxybenzyl 7β-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-1Z
)-2-Methoxyiminoacetamide]-3-IJ phenylphosphoniomethyl-3J,7emu 4-carboxylate Compound 9.54 of Iodide Experimental Example 2, in 190 ml of benzene
Dissolved in triphenylphosphine 5.64. was added and stirred at room temperature for 1 hour. Add 10% n-hexane to this reaction solution.
0 mL was added dropwise, and the resulting precipitate was poured into the bottom of the furnace. This was washed with a benzene-n-hexane (1:1) mixture and n-hexane to obtain 11.30 g of the desired product.
実験例4(原料化合物の合成)
p−メトキシベンジル 7β−(2−(5−トリチルア
ミノ−1,2,4−チアジアゾール−3−イル’)−f
Zl−2−メトキシイミノアセトアミド〕−3−(fZ
l−3−クロロ−1−プロペン−1−イルツー3−セフ
ェム−4−カルボキシレート実験例3の化合物30.O
yをクロロホルム250 rrtLと酢酸エチル300
mLの混液に溶解し、水冷下、IN水酸化す) IJ
ウム水溶液78.3 mlを加えて撹拌した。有機層を
分取し、これを飽和食塩水で洗浄後。Experimental Example 4 (Synthesis of raw material compound) p-methoxybenzyl 7β-(2-(5-tritylamino-1,2,4-thiadiazol-3-yl')-f
Zl-2-methoxyiminoacetamide]-3-(fZ
l-3-Chloro-1-propen-1-yl2-3-cephem-4-carboxylate Compound 30 of Experimental Example 3. O
y to chloroform 250 rrtL and ethyl acetate 300
Dissolve in mL of mixed solution and hydrate in water under water cooling) IJ
78.3 ml of an aqueous solution of umum was added and stirred. Separate the organic layer and wash it with saturated saline.
無水硫酸マグネシウムを加えて乾燥した。この有機層に
、水冷下、クロロアセトアルデヒド6.15 gのクロ
ロホルム10rnL溶液を加え、室温下で1時間撹拌し
た。反応液を濃縮し、酢酸エチル300 mlを加えて
生ずる沈殿を炉去した。p液を濃縮して粗生成物29.
3gを得た。これをシリカゲルカラムクロマトグラフィ
ー(溶出;クロロホルム)にて精製して目的物7.73
yを得た。It was dried by adding anhydrous magnesium sulfate. To this organic layer was added a solution of 6.15 g of chloroacetaldehyde in 10 rnL of chloroform under water cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, 300 ml of ethyl acetate was added, and the resulting precipitate was evaporated. Concentrate the p solution to obtain crude product 29.
3g was obtained. This was purified by silica gel column chromatography (elution: chloroform) to obtain the target product 7.73.
I got y.
実験例5(原料化合物の合成)
p−メトキシベンジル 7β−(2−(5−トリチルア
ミノ−1,2,4−チアジアゾール−3−イル)−(Z
l−2−メトキシイミノアセトアミド〕−3−((El
−3−ヨード−1−プロペン−1−イル)−3−セフェ
ム−4−カルボキシレート実験例4の化合物7.97
、をアセトン167 mlに溶解し、これにヨウ化ナト
リウム4.37 gを加えて室温で1時間撹拌した。溶
媒を留去し、残渣を酢酸エチル150mAに溶解し、飽
和チオ硫酸ナトリウム水溶液および飽和食塩水で洗浄し
、無水硫酸マグネシウムを加えて乾燥した。これを減圧
濃縮し。Experimental Example 5 (Synthesis of raw material compound) p-methoxybenzyl 7β-(2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z
l-2-Methoxyiminoacetamide]-3-((El
-3-Iodo-1-propen-1-yl)-3-cephem-4-carboxylate Compound 7.97 of Experimental Example 4
was dissolved in 167 ml of acetone, 4.37 g of sodium iodide was added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was dissolved in 150 mA of ethyl acetate, washed with a saturated aqueous sodium thiosulfate solution and saturated brine, and dried by adding anhydrous magnesium sulfate. Concentrate this under reduced pressure.
残渣にn−へキサン、石油エーテルを加えて固化し、P
取して目的物8.42 gを得た。Add n-hexane and petroleum ether to the residue to solidify it, and P
8.42 g of the target product was obtained.
実施例1
7β−(2−(5−アミノ−1,2,4−チアジアゾー
ル−3−イル’)−(Zl−2−メトキシイミノアセト
アミド) −3−((E) −3−(1−メチル−4−
スルファモイル−1−ピペラジニオ)−1−プロペン−
1−イルシー3−セフェム−4−カルボキシレート
実験例5の化合物1.0gをジクロロメタン5mlに溶
解し、水冷下、N−スルファモイル−N’ −メチルピ
ペラジン255 mgを加え、室温で一夜撹拌した。反
応液に酢酸エチル10mL+ エチルエーテル10Tn
Lを加え、生じた沈殿を戸数した。これを少量のメタノ
ール−テトラヒドロフラン混液に溶解し2酢酸エチル4
0 aLを加えた。生じた沈殿を炉取し黄色粉末731
扉gを得た。Example 1 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl')-(Zl-2-methoxyiminoacetamide) -3-((E) -3-(1-methyl -4-
Sulfamoyl-1-piperazinio)-1-propene-
1.0 g of the compound of 1-ilcy 3-cephem-4-carboxylate Experimental Example 5 was dissolved in 5 ml of dichloromethane, 255 mg of N-sulfamoyl-N'-methylpiperazine was added under water cooling, and the mixture was stirred at room temperature overnight. Add 10 mL of ethyl acetate + 10 Tn of ethyl ether to the reaction solution.
L was added, and the resulting precipitate was counted. Dissolve this in a small amount of methanol-tetrahydrofuran mixture and
Added 0 aL. The resulting precipitate was collected in a furnace to obtain yellow powder 731.
I got door g.
この化合物を、トリフルオロ酢酸5.2 mlとアニソ
ール4.4 mlの混液中に加え、水冷下で2時間撹拌
した。反応液を、エチルエーテル50 :nLとイソプ
ロピルエーテル50 rrtLの混液中に投入し、生じ
た沈殿を戸数してエチルエーテルで洗浄した。得られた
沈殿に水1mlを加え、酢酸す) IJウムでpH5,
5に調整した。不溶物を枦去した。炉液を逆相シリカゲ
ルカラムクロマトグラフィーにて精製し、目的物30m
gを得た。This compound was added to a mixed solution of 5.2 ml of trifluoroacetic acid and 4.4 ml of anisole, and stirred for 2 hours under water cooling. The reaction solution was poured into a mixture of 50 nL of ethyl ether and 50 rrtL of isopropyl ether, and the resulting precipitate was washed in portions with ethyl ether. Add 1 ml of water to the obtained precipitate, add acetic acid to pH 5,
Adjusted to 5. Insoluble matter was removed. The reactor liquid was purified by reverse-phase silica gel column chromatography, and 30 m
I got g.
実施例2
7β−(2−(5−アミノ−1,2,4−チアジアゾー
ル−3−イル)−(Z)−2−メトキシイミノアセトア
ミド:]−3−[(E)−3−(1−メチル−4−ホル
ムイミドイル−1−ピペラジニオ)−1−プロペン−1
−イルシー3−セフェム−4−カルボキシレート
実験例5の化合物1.5gをメタノール10tnLとジ
メチルホルムアミド4mLの混液に溶ML、N−メチル
ーN′−ホルムイミドイルピペラジン塩酸塩323mg
を加えて一夜撹拌した。反応液を酢酸エチル20Orr
tL中に加え、生じた沈殿を戸数した(594mg)
。Example 2 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide:]-3-[(E)-3-(1- Methyl-4-formimidoyl-1-piperazinio)-1-propene-1
-ilcy 3-cephem-4-carboxylate 1.5 g of the compound of Experimental Example 5 was dissolved in a mixture of 10 tnL of methanol and 4 mL of dimethylformamide ML, 323 mg of N-methyl-N'-formimidoylpiperazine hydrochloride
was added and stirred overnight. The reaction solution was diluted with ethyl acetate at 20Orr.
tL, and the resulting precipitate was collected (594 mg).
.
この沈殿を、トリフルオロ酢酸4.2mlとアニソール
3.6 mLの混液中に加え、水冷下、2時間撹拌した
。反応液を、エチルエーテル50 mlとイソプロピル
エーテル50 mLの混液中に加え、生じた沈殿を炉取
した。この沈殿に水1r!LLを加え、不溶物を炉去し
た。r液を逆相シリカゲルカラムクロマトグラフ、イー
にて精製して目的物20Mgを得た。This precipitate was added to a mixed solution of 4.2 ml of trifluoroacetic acid and 3.6 ml of anisole, and stirred for 2 hours under water cooling. The reaction solution was added to a mixed solution of 50 ml of ethyl ether and 50 ml of isopropyl ether, and the resulting precipitate was filtered out. Add 1 liter of water to this precipitate! LL was added and the insoluble matter was removed in the oven. The r liquid was purified using reverse phase silica gel column chromatography and E to obtain 20 Mg of the target product.
実施例3
7β−C2−(5−アミノ−1,2,4−チアジアゾー
ル−3−イル)−(Zl−2−メトキンイミノアセトア
ミド]−3−((El−3−(1−メチル−4−力ルバ
モイル−1−ピペラジニオ)−1−7’口ペン−1−1
ル)−3−セフェム−4−カルボキシレート
実験例5の化合物1.0gを酢酸エチル50 rrLl
に溶解し、N−メチル−N′−力ルバモイルピペラジン
204 mgを加えて、室温1こて一夜撹拌した。生じ
た沈殿を炉取して黄色粉末867 mgを得た。Example 3 7β-C2-(5-amino-1,2,4-thiadiazol-3-yl)-(Zl-2-methquiniminoacetamide]-3-((El-3-(1-methyl-4 -Rubamoyl-1-piperazinio)-1-7'mouth pen-1-1
)-3-cephem-4-carboxylate 1.0 g of the compound of Experimental Example 5 was added to 50 rrLl of ethyl acetate.
204 mg of N-methyl-N'-rubamoylpiperazine was added thereto, and the mixture was stirred overnight at room temperature with a trowel. The resulting precipitate was filtered to obtain 867 mg of yellow powder.
この化合物を、トリフルオロ酢酸6.2 TLLとアニ
ソール5.3rnLの混液中に加え、水冷下、2時間撹
拌した。沈殿を戸数し、これに水LmLを加え、酢酸す
) IJウムにてpH5に調整した。不溶物を炉去し、
P液を逆相シリカゲルカラムクロマトグラフィーにて精
製して目的物40 Hを得た。This compound was added to a mixed solution of 6.2 TLL of trifluoroacetic acid and 5.3 rnL of anisole, and stirred for 2 hours under water cooling. The precipitate was collected, 1 mL of water was added thereto, and the pH was adjusted to 5 with acetic acid. Insoluble matter is removed by furnace,
The P solution was purified by reverse phase silica gel column chromatography to obtain the target product 40H.
実施例4
7β−(2−(5−アミノ−1,2,4−チアジアゾー
ル−3−イル’)−(Zl−2−メトキシイミノアセト
アミド) −3−(fE]−3−(1,2−ジメチル−
1−ビラゾリジニオ)−1−プロペン−1−イルクー3
−セフェム−4−カルボキシレート実験例5の化合物1
.0gをエチルエーテル150rnLに懸濁しt N、
N’−ジメチルピペラジリジン143+ngを加え、室
温で一夜撹拌した。生じた沈殿を炉底し、これをテトラ
ヒドロフラン1.5mLに溶解した。溶液に酢酸エチル
20 mLを加えて、生じた沈殿を炉底し、黄色粉末4
91 mgを得た。Example 4 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl')-(Zl-2-methoxyiminoacetamide) -3-(fE]-3-(1,2- dimethyl-
1-Vyrazolidinio)-1-propene-1-ylcu 3
-Cephem-4-carboxylate Compound 1 of Experimental Example 5
.. 0g was suspended in 150rnL of ethyl ether, tN,
143+ng of N'-dimethylpiperaziridine was added, and the mixture was stirred at room temperature overnight. The resulting precipitate was poured into the bottom of the furnace and dissolved in 1.5 mL of tetrahydrofuran. Add 20 mL of ethyl acetate to the solution, drain the resulting precipitate to the bottom of the oven, and make a yellow powder.
91 mg was obtained.
この化合物を、トリフルオロ酢酸3.5mlとアニソー
ル3.0 mlの混液中に加え、水冷下、2時間撹拌し
た。反応液を、エチルエーテル50 mlとイソプロピ
ルエーテル50 mlの混液中に加え、生じた沈殿を炉
底した。この沈殿に水1mLを加え、酢酸ナトリウムで
pH6,0に調整した。不溶物を枦去し、P液を逆相シ
リカゲルカラムクロマトグラフィーで精製して目的物1
9mg(2種の立体異性体A、 Bの合計、 A :
8 my、 B : l1mg)を得た。This compound was added to a mixed solution of 3.5 ml of trifluoroacetic acid and 3.0 ml of anisole, and the mixture was stirred for 2 hours under water cooling. The reaction solution was added to a mixed solution of 50 ml of ethyl ether and 50 ml of isopropyl ether, and the resulting precipitate was poured into the bottom of the furnace. 1 mL of water was added to this precipitate, and the pH was adjusted to 6.0 with sodium acetate. Insoluble materials were removed, and the P solution was purified by reverse phase silica gel column chromatography to obtain the desired product 1.
9 mg (total of two stereoisomers A and B, A:
8 my, B: 11 mg) was obtained.
実施例5
7β−(2−(5−アミノ−1,2,4−チアジアゾー
ル−3−イル) −fZ) −2−メトキシイミノアセ
トアミド)−3−(に1−3−(1,1−ジオキソ−4
−メチル−4−チオモルホリニオ’)−1−プロペン−
1−イル)−3−セフェム−4−カルボキシレート
実験例5の化合物i、ogをジクロロメタン3 mlに
溶解し、4−メチルチオモルホリン 1,1−ジオキサ
イド327 mgを加え、室温で一夜撹拌した。Example 5 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl)-fZ)-2-methoxyiminoacetamide)-3-(to 1-3-(1,1-dioxo -4
-Methyl-4-thiomorpholinio')-1-propene-
1-yl)-3-cephem-4-carboxylate Compound i, og of Experimental Example 5 was dissolved in 3 ml of dichloromethane, 327 mg of 4-methylthiomorpholine 1,1-dioxide was added, and the mixture was stirred at room temperature overnight.
反応液に酢酸エチル10rILLを加え、生じた沈殿を
炉底した( 783 mg)。10 rILL of ethyl acetate was added to the reaction solution, and the resulting precipitate was poured into the bottom of the furnace (783 mg).
この化合物を、トリフルオロ酢酸5.6 rnlとアニ
ソール4.8mLの混液中に加え、水冷下、2時間撹拌
した。反応液をエチルエーテル100 mL中に加え。This compound was added to a mixed solution of 5.6 rnl of trifluoroacetic acid and 4.8 mL of anisole, and stirred for 2 hours under water cooling. Add the reaction solution to 100 mL of ethyl ether.
生じた沈殿を炉底した。これに水1rnLを加え、酢酸
す) IJウムでpH7,0に調整した。不溶物を炉去
し、P液を逆相シリカゲルカラムクロマトグラフィーに
て精製して目的物29 mgを得た。The resulting precipitate was drained to the bottom of the furnace. 1 rnL of water was added to this, and the pH was adjusted to 7.0 with IJ acetate. Insoluble matter was removed in the oven, and the P solution was purified by reverse phase silica gel column chromatography to obtain 29 mg of the target product.
実施例6
7β−C2−(5−アミノ−1,2,4−チアジアゾー
ル−3−イル)−(Z) −2−メトキシイミノアセト
アミド)−3−((E)−3−(1,4−ジアザビシク
ロC2,2〕オクタン−1−イオ)−1−プロペン−1
−イル〕−3−セフェムー4−カルボキシレート
実験例5の化合物1.0gをエチルエーテル150rr
tLに溶解し、1,4−ジアザビシクロ〔2.2゜2〕
オクタン148mgを加え、室温にて一夜撹拌した。生
じた沈殿を炉底し、テトラヒドロフラン2mlに溶解し
た。この溶液を酢酸エチル2OmL中に加え、生じた沈
殿を戸数して黄色粉末746111gを得た。Example 6 7β-C2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide)-3-((E)-3-(1,4- DiazabicycloC2,2]octane-1-io)-1-propene-1
-yl]-3-cephemu-4-carboxylate 1.0 g of the compound of Experimental Example 5 was added to 150 rr of ethyl ether.
Dissolve in tL, 1,4-diazabicyclo[2.2゜2]
148 mg of octane was added, and the mixture was stirred at room temperature overnight. The resulting precipitate was taken to the bottom of the furnace and dissolved in 2 ml of tetrahydrofuran. This solution was added to 20 mL of ethyl acetate, and the resulting precipitate was separated to obtain 746,111 g of yellow powder.
この化合物を、トリフルオロ酢酸5.3mLと7ニソー
ル3.4rlLLの混液中に加え、水冷下、2時間撹拌
した。反応液をエチルエーテル100 mL中に加え。This compound was added to a mixture of 5.3 mL of trifluoroacetic acid and 3.4 mL of 7-nisole, and stirred for 2 hours under water cooling. Add the reaction solution to 100 mL of ethyl ether.
生じた沈殿を炉底した。これに水1.8mLを加え。The resulting precipitate was drained to the bottom of the furnace. Add 1.8 mL of water to this.
不溶物を枦去した。炉液を逆相シリカゲルカラムクロマ
トグラフィーにて精製し、目的物83 mgを得た。Insoluble matter was removed. The reaction solution was purified by reverse phase silica gel column chromatography to obtain 83 mg of the target product.
実施例1〜6と同様にして1次の実施例7〜12の化合
物を製造した。The primary compounds of Examples 7 to 12 were produced in the same manner as Examples 1 to 6.
実施例7
7β−(2−(5−アミノ−1,2,4−チアジアゾー
ル−3−イル)−tZl−2−メトキシイミノアセトア
ミド)−3−(CEI−3−(1,4−ジメチル−1−
ピペラジニオ)−1−プロペン−1−イル)−3−セフ
ェム−4−カルポキシレート実験例5の化合物1.0g
と1,4−ジメチルピペラジン1つ3μLを反応させ、
保護基を脱離して目的物15mgを得た。Example 7 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl)-tZl-2-methoxyiminoacetamide)-3-(CEI-3-(1,4-dimethyl-1 −
Piperazinio)-1-propen-1-yl)-3-cephem-4-carpoxylate 1.0 g of the compound of Experimental Example 5
and 3 μL of 1,4-dimethylpiperazine,
The protecting group was removed to obtain 15 mg of the target product.
実施例8
7β−[’2−(5−アミノ−1,2,4−チアジアゾ
ール−3−イル>−(z+−12−メトキシイミノアセ
トアミド)−3−1:(Ej−3−(1−メチル−4−
カルバモイル−1,2,3,6−チトラハイドロヒリジ
ニオ)−1−プロペン−1−イル)−3−セフェム−4
−カルボキシレート
実験例5の化合物600 myと1−メチル−4−カル
バモイル−1,2,3,6−チトラハイドロビリジン1
37zgを反応させ、保護基を脱離して目的物45mg
を得た。Example 8 7β-['2-(5-amino-1,2,4-thiadiazol-3-yl>-(z+-12-methoxyiminoacetamide)-3-1:(Ej-3-(1-methyl -4-
Carbamoyl-1,2,3,6-titrahydrohyridinio)-1-propen-1-yl)-3-cephem-4
-Carboxylate Compound 600 my of Experimental Example 5 and 1-methyl-4-carbamoyl-1,2,3,6-titrahydrobiridine 1
37zg was reacted and the protecting group was removed to obtain 45mg of the target product.
I got it.
実施例9
7β−C2−(5−アミノ−1,2,4−チアジアゾー
ル−3−イル)−(Zl−2−メトキシイミノアセトア
ミド:]−3−(Ej−3−[N、 N−ジメチル−N
−(2−カルバモイルエチル)アンモニオ〕=1−プロ
ペンー1−イル〕−3−セフェム−4−カルボキシレー
ト
実験例5の化合物500■と3−ジメチルアミノプロピ
オ・ンアミド127mgを反応させ、保護基を脱離して
目的物12mgを得た。Example 9 7β-C2-(5-amino-1,2,4-thiadiazol-3-yl)-(Zl-2-methoxyiminoacetamide:]-3-(Ej-3-[N, N-dimethyl- N
-(2-Carbamoylethyl)ammonio]=1-propen-1-yl]-3-cephem-4-carboxylate 500 μl of the compound of Experimental Example 5 and 127 mg of 3-dimethylaminopropioamide were reacted to remove the protective group. After desorption, 12 mg of the target product was obtained.
実施例10
7β−C2−(5−アミノ−1,2,4−チアジアゾー
ル−3−イル’)−12)−2−メトキシイミノアセト
アミド)−3−〔(El−3−(1,1−ジメチル−1
−ヒドラジニオ)−1−フロペン−1−イル〕−3−セ
フェムー4−カルボキシレート実験例5の化合物600
mgと1,1−ジメチル−1−ヒドラジン60 mg
を反応させ、保護基を脱離して目的物50 rygを得
た。Example 10 7β-C2-(5-amino-1,2,4-thiadiazol-3-yl')-12)-2-methoxyiminoacetamide)-3-[(El-3-(1,1-dimethyl -1
-Hydrazinio)-1-flopen-1-yl]-3-cephemu 4-carboxylate Compound 600 of Experimental Example 5
mg and 60 mg of 1,1-dimethyl-1-hydrazine
was reacted and the protecting group was removed to obtain the target product 50 ryg.
実施例11
7β−(2−(5−アミノ−1,2,4−チアジアゾー
ル−3−イル) −fZl−2−メトキシイミノアセト
アミド)−3−11:(E)−3−(N、 N−ジメチ
ル−N−ヒドラジノカルボニルメチルアンモニオ)−1
−プロペン−1−イル〕−3−セフェムー4実験例5の
化合物500 mgとN、N−ジメチルアセトヒドラジ
ド110mgを反応させ、保護基を脱離して目的物14
mgを得た。Example 11 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl)-fZl-2-methoxyiminoacetamide)-3-11:(E)-3-(N, N- dimethyl-N-hydrazinocarbonylmethylammonio)-1
-propen-1-yl]-3-cephemu 4 500 mg of the compound of Experimental Example 5 was reacted with 110 mg of N,N-dimethylacetohydrazide to remove the protecting group and obtain the target compound 14.
mg was obtained.
実施例12
7β−1:2−(5−アミノ−1,2,4−チアジアゾ
ール−3−イル)−(Zl−2−メトキシイミノアセト
アミド)−3−C(Ej−3−(1,5−ジアザビシク
ロ[3,3,O)オクタン−1−イオ)−1−プロペン
−1−イル〕−3−セフェムー4−カルボキシレート
実験例5の化合物750 mgと1,5−ジアザビシク
ロ[3,3,0)オクタン280 mgを反応させ、保
護基を脱離して目的物35 mgを得た。Example 12 7β-1:2-(5-amino-1,2,4-thiadiazol-3-yl)-(Zl-2-methoxyiminoacetamide)-3-C(Ej-3-(1,5- Diazabicyclo[3,3,O)octane-1-io)-1-propen-1-yl]-3-cephemu 4-carboxylate 750 mg of the compound of Experimental Example 5 and 1,5-diazabicyclo[3,3,0 ) 280 mg of octane was reacted and the protecting group was removed to obtain 35 mg of the target product.
Claims (7)
表等があります▼、▲数式、化学式、表等があります▼
、▲数式、化学式、表等があります▼、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼、▲数式、化学式、表等があります▼
、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼、 を示し、R_2は低級アルキル基、R_3は低級アルキ
ル基、スルファモイル基、ホルムイミドイル基またはカ
ルバモイル基を示す〕で表わされる3−アンモニオプロ
ペニルセフェム誘導体およびその非毒性塩。(1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R_1 is a lower alkyl group, A is the following group: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas ,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
3-Ammoniopropenyl cephem derivatives and non-toxic salts thereof, represented by ▼, R_2 is a lower alkyl group, R_3 is a lower alkyl group, a sulfamoyl group, a formimidoyl group or a carbamoyl group.
アゾール−3−イル)−(Z)−2−メトキシイミノア
セトアミド〕−3−〔(E)−3−(1−メチル−4−
スルファモイル−1−ピペラジニオ)−1−プロペン−
1−イル〕−3−セフェム−4−カルボキシレートおよ
びその非毒性塩である特許請求の範囲第1項記載の化合
物。(2) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide]-3-[(E)-3-(1-methyl -4-
Sulfamoyl-1-piperazinio)-1-propene-
1-yl]-3-cephem-4-carboxylate and its non-toxic salts.
アゾール−3−イル)−(Z)−2−メトキシイミノア
セトアミド〕−3−〔(E)−3−(1,2−ジメチル
−1−ピラゾリジニオ)−1−プロペン−1−イル〕−
3−セフェム−4−カルボキシレートおよびその非毒性
塩である特許請求の範囲第1項記載の化合物。(3) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide]-3-[(E)-3-(1,2 -dimethyl-1-pyrazolidinio)-1-propen-1-yl]-
The compound according to claim 1, which is 3-cephem-4-carboxylate and its non-toxic salt.
アゾール−3−イル)−(Z)−2−メトキシイミノア
セトアミド〕−3−〔(E)−3−(1−メチル−4−
カルバモイル−1−ピペラジニオ)−1−プロペン−1
−イル〕−3−セフェム−4−カルボキシレートおよび
その非毒性塩である特許請求の範囲第1項記載の化合物
。(4) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide]-3-[(E)-3-(1-methyl -4-
Carbamoyl-1-piperazinio)-1-propene-1
-yl]-3-cephem-4-carboxylate and its non-toxic salts.
アゾール−3−イル)−(Z)−2−メトキシイミノア
セトアミド〕−3−〔(E)−3−(1,4−ジアザビ
シクロ〔2,2,2〕オクタン−1−イオ)−1−プロ
ペン−1−イル〕−3−セフェム−4−カルボキシレー
トおよびその非毒性塩である特許請求の範囲第1項記載
の化合物。(5) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide]-3-[(E)-3-(1,4 -The compound according to claim 1, which is diazabicyclo[2,2,2]octane-1-io)-1-propen-1-yl]-3-cephem-4-carboxylate and its nontoxic salt. .
アゾール−3−イル)−(Z)−2−メトキシイミノア
セトアミド〕−3−〔(E)−3−(1,1−ジオキソ
−4−メチル−4−チオモルホリニオ)−1−プロペン
−1−イル〕−3−セフェム−4−カルボキシレートお
よびその非毒性塩である特許請求の範囲第1項記載の化
合物。(6) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide]-3-[(E)-3-(1,1 -Dioxo-4-methyl-4-thiomorpholinio)-1-propen-1-yl]-3-cephem-4-carboxylate and its non-toxic salts.
示す〕で表わされる化合物、そのアミノ基およびまたは
カルボキシル基が保護基で保護された化合物、またはそ
れらの塩に一般式: A′(III) 〔A′は次の化合物: ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼、▲数式、化学式、表等があります▼
、▲数式、化学式、表等があります▼、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼、▲数式、化学式、表等があります▼
、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼、 を示し、R_2は低級アルキル基、R_3は低級アルキ
ル基、スルファモイル基、ホルムイミドイル基またはカ
ルバモイル基を示す〕で表わされる化合物またはその塩
を反応させ、必要により保護基を脱離することを特徴と
する一般式: ▲数式、化学式、表等があります▼( I ) 〔式中、R_1は前記の通り、AはA′に対応する4級
アンモニオ基を示す〕で表わされる化合物またはその非
毒性塩の製造方法。(7) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R_1 is a lower alkyl group and X is a halogen atom] Compounds whose amino and/or carboxyl groups are protected A compound protected by a group or a salt thereof has the general formula: A'(III) [A' is the following compound: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, where R_2 is a lower alkyl group, R_3 is a lower alkyl group, a sulfamoyl group, a formimidoyl group, or a carbamoyl group] or a salt thereof is reacted, and if necessary, a protecting group is added. General formulas characterized by elimination: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R_1 is as described above, and A represents a quaternary ammonio group corresponding to A'] A method for producing a compound or a non-toxic salt thereof.
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61233356A JPS6388187A (en) | 1986-10-02 | 1986-10-02 | 3-ammoniopropenylcephem derivative |
DE3650157T DE3650157T2 (en) | 1985-12-26 | 1986-12-26 | CEPHALOSPORINE COMPOUNDS. |
EP87900286A EP0329785B1 (en) | 1985-12-26 | 1986-12-26 | Cephalosporin derivatives |
AT87900286T ATE114657T1 (en) | 1985-12-26 | 1986-12-26 | CEPHALOSPORIN COMPOUNDS. |
PCT/JP1986/000655 WO1987003875A1 (en) | 1985-12-26 | 1986-12-26 | Cephalosporin derivatives |
US07/861,717 US5373000A (en) | 1985-12-26 | 1992-04-01 | 7Beta-(thiadiazolyl)-2-iminoacetamido-3cephem compounds |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61233356A JPS6388187A (en) | 1986-10-02 | 1986-10-02 | 3-ammoniopropenylcephem derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS6388187A true JPS6388187A (en) | 1988-04-19 |
Family
ID=16953866
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP61233356A Pending JPS6388187A (en) | 1985-12-26 | 1986-10-02 | 3-ammoniopropenylcephem derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS6388187A (en) |
-
1986
- 1986-10-02 JP JP61233356A patent/JPS6388187A/en active Pending
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