IE860163L - ß-LACTAM ANTIBIOTICS - Google Patents
ß-LACTAM ANTIBIOTICSInfo
- Publication number
- IE860163L IE860163L IE16386A IE16386A IE860163L IE 860163 L IE860163 L IE 860163L IE 16386 A IE16386 A IE 16386A IE 16386 A IE16386 A IE 16386A IE 860163 L IE860163 L IE 860163L
- Authority
- IE
- Ireland
- Prior art keywords
- acid
- mixture
- mmole
- broad
- added
- Prior art date
Links
- 239000003782 beta lactam antibiotic agent Substances 0.000 title description 4
- 239000002132 β-lactam antibiotic Substances 0.000 title 1
- 229940124586 β-lactam antibiotics Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 149
- -1 beta-lactam compound Chemical class 0.000 claims description 81
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 68
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 241000282414 Homo sapiens Species 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 5
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 4
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 4
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 4
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 claims description 4
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims description 4
- 208000035473 Communicable disease Diseases 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 claims description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 125000003460 beta-lactamyl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 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 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 2
- RGIIAYDCZSXHGL-UHFFFAOYSA-N 2-pyridin-4-ylethanesulfonic acid Chemical compound OS(=O)(=O)CCC1=CC=NC=C1 RGIIAYDCZSXHGL-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 claims description 2
- VJXRKZJMGVSXPX-UHFFFAOYSA-N 4-ethylpyridine Chemical compound CCC1=CC=NC=C1 VJXRKZJMGVSXPX-UHFFFAOYSA-N 0.000 claims description 2
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 229960004979 fampridine Drugs 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 125000004129 indan-1-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])([H])C2([H])* 0.000 claims description 2
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- 125000005633 phthalidyl group Chemical group 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- DVECLMOWYVDJRM-UHFFFAOYSA-N pyridine-3-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=CN=C1 DVECLMOWYVDJRM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 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 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
- 125000004849 alkoxymethyl group Chemical group 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 225
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 214
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 116
- 238000001914 filtration Methods 0.000 description 85
- 238000003756 stirring Methods 0.000 description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 65
- 230000015572 biosynthetic process Effects 0.000 description 56
- 238000003786 synthesis reaction Methods 0.000 description 56
- 239000002244 precipitate Substances 0.000 description 54
- 238000005481 NMR spectroscopy Methods 0.000 description 48
- 239000000243 solution Substances 0.000 description 47
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 46
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- 238000001816 cooling Methods 0.000 description 35
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 32
- 238000002844 melting Methods 0.000 description 30
- 230000008018 melting Effects 0.000 description 30
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000000843 powder Substances 0.000 description 19
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 238000000034 method Methods 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000013078 crystal Substances 0.000 description 15
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 13
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- IBGBGRVKPALMCQ-UHFFFAOYSA-N 3,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1O IBGBGRVKPALMCQ-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- UNCACEGCFURZQB-UHFFFAOYSA-N (2-acetyloxy-4-carbonochloridoylphenyl) acetate Chemical compound CC(=O)OC1=CC=C(C(Cl)=O)C=C1OC(C)=O UNCACEGCFURZQB-UHFFFAOYSA-N 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 6
- 101150041968 CDC13 gene Proteins 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- 150000003840 hydrochlorides Chemical class 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- MIHIJWOEDDPOLG-DUXPYHPUSA-N (2e)-2-methoxyiminoacetic acid Chemical compound CO\N=C\C(O)=O MIHIJWOEDDPOLG-DUXPYHPUSA-N 0.000 description 5
- PCYGLFXKCBFGPC-UHFFFAOYSA-N 3,4-Dihydroxy hydroxymethyl benzene Natural products OCC1=CC=C(O)C(O)=C1 PCYGLFXKCBFGPC-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 229930186147 Cephalosporin Natural products 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 229940124587 cephalosporin Drugs 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- 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 4
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 4
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
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- 235000009518 sodium iodide Nutrition 0.000 description 1
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
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- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Description
59392
Novel B-lactam antibiotics
This invention relates to a novel B-lactam antibiotics, more 20 particularly to a novel penicillin series and cephalosporin series antibiotics.
Heretofore, it has been known that a B-lactam series antibiotics has antibacterial activities to gram positive bacteria and gram negative 25 bacteria and many of these compounds have actually been applied therefor. Among them, compounds which are called to as the third aged cephalosporin series antibiotics have wide range of antibacterial spectrum and particularly are evaluated in the clinical field.
However, while the several kinds of the above compounds have been used in practical use, all of them are,inferior in their antibiotical activities to Pseudomonas aeruginosa. Further, some kinds of them are finely effective to gram negative bacteria other than Pseudomonas aeruginosa but they have a disadvantage of lower activities to gram 35 positive bacteria.
GB-A-1476312 discloses penicillin and cephalosporin derivatives in *
which the beta lactam ring has a side chain of the formula
59392
\ i j, C=N-N-C0-NH-C-C0-NH-
4/ '5 '2
IT R R
wherein R* is an alkyl, cycloalkyl, cycloalkenyl, aryl, substituted
2
aryl, aralkyl or heterocyclic group; R is hydrogen or taken together
1 3 4
with R completes a carbocyclic or heterocyclic ring; R and R
are separately hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl,
aryl, aralkyl or heterocyclic group, any of which may be substituted, 3 4
or R and R taken together complete a carbocyclic or heterocyclic ring;
R is an alkyl, cycloalkyl, aryl, aralkyl, or heterocyclic group, any of which may be substituted.
US-A-4091212 discloses alpha-hydrazino carbonylamino cephalosporin derivatives having a side chain of the formula
R3R2 R1 l l l
N-N-C0-NH-CH-C0-NH
.U
wherein R is hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, trihaloethyl, tri(lower alkyl)-silyl, tri(lower alkyl) stannyl 25 or a salt forming ion of the group consisting of aluminium, alkali metal, alkaline earth metal, cyclo-lower alkylamine, dicyclo-lower alklamine or lower alkylamine;
R* is hydrogen, lower alkyl, thienyl, furyl, pyridyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 30 phenyl, mono-substituted phenyl wherein the phenyl substituent is halo,
lower alkyl or lower alkoxy;
2 3
R and R each is hydrogen or lower alkyl; and R^ is hydrogen, lower alkyl, lower alkanoyl, halo-lower alkanoyl, cyanoacetyl or substituted cyanoacetyl wherein the cyanoacetyl 35 substituent is lower alkyl or cyclo-lower alkyl.
The present inventors have intensively studied, by referring to the above situation, concerning a compound which has potent activities in
extremely wide ranges, and as a result, have found that the compound represented by the formula (I) has potent activities against gram negative bacteria including Pseudomonas aeruginosa and Serratia marcescens and other pathogenic bacteria as well as gram positive 5 bacteria and accomplished the present invention.
That is, the present invention comprises a B-lactam compound represented by the formula:
XT
I
-C-CONH-
r ^
-N^. Y
R, N S N
(I)
/ \ /rH^Vn
R,- Z CONH-A—(' V
wherein A is a group represented by the formulae
-NHC0-, NHC0NHC0-, NHC0CH=CH- or -H=C-
*6
wherein Rg is a hydrogen atom or Cj-C^ alkyl; R1 is hydrogen or a protecting group selected from formyl, trityl, chloroacetyl, t-butoxycarbonyl, and 2,2,2-trichloroethoxycarbonyl; R2 is hydrogen, acetyl, propionyl, methoxy carbonyl or ethoxycarbonyl; R^ is hydrogen 25 or methoxy; X is hydrogen, hydroxyl, halogen, C^-Cg alkoxy, nitro or hydroxyl protected by acetyl, propionyl, methoxycarbonyl or ethoxycarbonyl; n is 1 or 2; Y is a group represented by the formulae:
• ,c3* xch7
V cr
V V
1 ^ ,
COOK COOM
provided that the carbon atom attached to the COOM group is attached to the nitrogen atom of the beta lactam ring; M is hydrogen, a protecting group selected from diphenylmethyl, t-butyl, p-nitrobenzyl and trimethylsilyl, or a group which is easily hydrolyzable in a human body
and selected from acetoxymethyl, alpha-acetoxyethyl, pivaloyloxymethyl, alpha-ethoxycarbonyloxymethyl, alpha-methoxycarbonyloxymethyl, alpha-methoxycarbonyloxyethyl, alpha-ethoxycarbonyloxyethyl, 1-indanyl, phthalidyl, and 5-methyl-2-oxo-l,3-dioxol-4-yl-methyl; Ry is 5 hydrogen, methyl, ^koxymethyl or a group represented by the formula; -CH2~T where T is C2-C3 alkanoyloxy, carbamoyloxy,
quaternary ammonium derived from pyridine, 2-methyl-pyridine, 3-methylpyridine, 4-methylpyridine, 4-ethylpyridine, 2,3-dimethylpyridine, 4-aminopyridine, 3-cyanopyridine, nicotinamide, 10 isonicotinamide, 3-pyridine sulfonic acid, 4-pyridine ethanesulfonic acid, 3-hydroxypyridine, 4-hydroxypridine, nicotinic acid, isonicotinic acid, 5,6,7,8-tetrahydroisoquinoline, 5,6,7,8-tetrahydroquino1ine, pyradazine, quiniline, isoquinoline, trimethylamine, triethylamine, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine, an 15 unsubstituted 5-to 6-membered heterocyclic ring having 1-4 hetero atoms or a 5- to 6-membered heterocyclic ring having 1 to 4 hetero atoms in a ring substituted by at least one of C^-C^ alkyl, C^-Cg alkoxy, carboxymethyl, carboxyethyl, sulfoxymethyl, sulfoxyethyl, di-^-C^ alkyl)-amino ethyl, carboxy, amino, acetyl-amino and hydroxy ethyl 20 group, or T is of the formula - are hydrogen atoms or has the formula:
0-B- wherein the oxygen atom is bonded to nitrogen atom and B is a straight or branched Cj-Cg alkylene group or B is a cyclic alkylene group containing up to 6 carbon atoms wherein R^ and Rg are combined with each other to form an additional direct bond, or a
pharmaceutically acceptable salt thereof,
Preferred compounds are those wherein said substituted or unsubstituted heterocyclic ring of T or Rg is substituted or unsubstituted tetrazolyl, triazolyl, thiazolyl, thiadiazolyl, tetrazolo[l,5-b] 30 pyridazinyl, pyridyl, N-methylpyridyl, s-triazolo[l,5-a] pyrimidyl,
1-oxidopyridyl, N-carbomoylmethylpyridyl, 2-methyl-5-oxo-6-hydroxy-2, 5-dihydro-1,2,4-triaziny1, or 4-methy1-5-oxo-6-hydroxy-4,5-di hydroxy-1,2,4-triazinyl, wherein said substituent of the heterocyclic ring of T or Rg is selected from C^-C^ alkyl, C^-Cg alkoxy,
carboxymethyl, carboxyethyl, sulfoxymethyl, sulfoxyethyl, diCj-Cg-alkylaminoethyl, carboxy, amino acetylamino and hydroxyethyl.
Preferably the said pharmaceutical acceptable of the beta-lactam
compound is an alkali metal, alkaline earth metal or ammonium salt or a salt, with an organic base, organic acid, or inorganic acid, said salt is a sodium, potassium, magnesium, calcium, diisopropylamine, benzyl-amine, triethanolamine, triethylamine, N-methylmorpholine, pyridine, 5 piperazine, acetic acid, formic acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid salt.
The following matters are also considered as a part^of the invention: 10 - the pharmaceutical preparations containing an active amount of a compound as defined above,
- the pharmaceutical preparations for the treatment and prophylaxis of infectious diseases characterized by containing a pharmaceutically active amount of a compound as defined above,
- the compounds as defined above for use as a pharmaceutically active substance
- and the compounds as defined above for use in the treatment and prophylaxis of infectious diseases.
Manufacturing methods of the novel B-lactam compounds
The novel B-lactam compounds and derivatives thereof to be intended in the present invention can be produced,
roughly be mentioned, according to the following three methods.
The first method
The title compound can be obtained by reacting the compound represented by the formula (II):
R.
NH,
-N.
(II)
wherein symbols in the formula are the same as mentioned above,
with the carboxylic acid represented by the formula (III):
I4
N n-C-COOH
> ,A^A ^voR2,n
RlJJ 5 Z CONH-A—v V (HI)
wherein symbols in the formula are the same as mentioned above,
or its reactive derivative and removing a protective group, if necessary.
In this method, the compound represented by the formula 15 (III) which is used as a starting compound is a novel compound, and one of producing method of the title compound is shown by referring reaction schemes in the following:
(a)
N —C-COOC (CH^ ) 3
R, N S H
/N\
Rc Z COOCnH_
D & b
NH2NH2
N —C-COOC(CH3 )3
J
r1n s n
H / \
R5 z CONHNH2
n rr-c-cooc (ch3 ) 3
xj,
N\ jhx*
z CONH-A-^ y
R, N S H
cf3cooh
0R?>n 2 n n n-c-cooh
AJ
R. N S 1h
N\
Z CONH-.A—(/ 'y
(0Ro) (III) 2 n wherein symbols in the formula are the same as mentioned above.
(b)
R. N S H
N rr-CH-COORg nh2
N—rr
AJ
N N-CO-N N
h2nnhcooc(ch3)3
N n-CH-COOR,
R.N' S H
NHCONHNHCOOC(CH3)3
cf3cooh
N rr-CH-COOR,
JJ
NHCONHNH,
R. N S H
R. N H
N—rr-
XI
X
CH-COORQ /
(°RJn 2 n
R.N H
x
N rr-CH-COOH J_ /
NHCONH-A-^^^
(0R2}n
(III')
wherein Rg is a lower alkyl group or an aryl group and the other symbols are the same as mentioned above.
The second method
The title compound can be obtained by reacting the compound represented by the formula (IV):
N rr
.XJ
*4 R3 -C-CONH-
n
R N- • '/ ~N—Y
Klg b N 0 (IV)
R5 Z C0NHNH2
wherein symbols in the formula are the same as mentioned above,
with any one of compounds represented by the formulae:
X
CONCO
2 n wherein m is an integer of 0 or 1, and the other 5 symbols are the same as mentioned above,
and removing a protective group, if necessary.
In this method, the starting compound represented by the formula (IV) is a novel compound, and an example of the producing method is shown by referring reaction schemes 10 in the following:
Ry.
I4
N n-C-COOH
XIX
X SR5 Z CONHNH-R10
R>!
I 3
N n-C-CONH r"S
XT i I »
1^ N 0
R.N -■-H
N rr
XJ
i4
-C-CONH N i
R.
n
/\
-N.
■CONHNH.
(IV)
wherein R^q is a protective group and the other symbols are the same as mentioned above.
The third method
The compound represented by the formula (I *):
I4
C-CONH-
R,N S ■'"H
■N
N
COOM
CH2~T1
(I' )
/\ A/<0R2'n
R5 Z CONH-A-V
wherein T^ represents a quaternary ammonium or -S-Rg and the other symbols are the same as mentioned above,
can be obtained by reacting the compound represented by the formula (V):
N rr
JJ
-C-CONH-
R. N S H
Ok
^ N'
0 | CH--J
COOM
X
(0R2 > n
(V)
wherein J represents a halogen atom or an acetoxy group and the other symbols are the same as mentioned above,
with a tertiary amine or Rg-SH and by removing the 5 protective group if necessary.
In the following, producing methods of the novel 8-lactam antibiotics according to the present invention will be explained in more detail.
The first method
The reaction between the compound (II) and the compound (III) should desirably be carried out, in general, by using reactive derivatives of the compound (III) as the compound (III). As the reactive derivatives, there may be mentioned, for example, acid halides, mixed acid 15 anhydrides, active esters and the like. Further, while free carboxylic acids can be used as such, suitable condensation reagent may desirably be used in this case. As the reagent, there may be employed, for example, N,N'-dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole, 20 cyanuric chloride, Vilsmeier reagent and the like. Such reactions have been known in the field of penicillin chemistry, cephalosporin chemistry and peptide chemistry.
These reactions are usually carried out in a suitable solvent such as dichloromethane, chloroform, tetrahydro-25 furan, dioxane, dimethylformamide, dimethylacetamide, acetonitrile, acetone, water or mixed solvents of the above. Treatments after the reaction can be carried out by the methods well known in the art such as separation, purification and the like.
The second method
The reaction of the compound (IV) and </ V CO-Rg is
(^co"
(OR,)
2 n carried out by reacting them in water, methanol or ethanol at about 10 to 50 °C and the terminal point of the reaction is confirmed by a thin layer chromatography. The reaction time is about 0.5 to 48 hours.
In case of employing </ V (CH=CH)mCOOH, it can be
(bR2>n reacted as acid halides, mixed acid anhydrides or active esters, or suitable condensation reagents such as N,N*-10 dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole, cyanuric chloride, Vilsmeier reagent and the like can be employed. These reactions can be carried out at about - 10 to 20 °C for about 0.5 to 2 hours.
In case of employing //y CONCO, the reaction can easily
V7
(0R2)n
be proceeded in an inert solvent such as dimethylform-amide, dimethylacetamide, dimethylsulfoxide, dichloro-methane, chloroform, acetonitrile or a mixed solvent of the above at about 0 to 50 °C. The terminal point of the reaction should be confirmed by a thin layer chromato-20 graphy. The reaction time is about 0.5 to 6 hours.
The thus obtained compound (I) can be easily separated and purified by the known method.
The third method
When the compound (V) and a tertiary amine are reacted, the reaction is carried out in water in case of -COOM being a free carboxylic acid or a its salt, and a 5 catalyst is used if necessary. As the catalyst, there may be employed, for example, potassium thiocyanate, sodium thiocyanate, potassium bromide, sodium bromide and the like. The reaction is carried out at a temperature of 20 to 80 °C and the terminal point of the reaction is 10 confirmed by a thin layer chromatography. The reaction time is about 1 to 24 hours.
In case of -COOM being ester and J being a halogen atom, the reaction is carried out by contacting a tertiary amine in an organic solvent. However, a part of the 15 double bonds will transfer whereby isomer will likely be generated.
The reaction of the compound (V) and Rg-SH is carried out by contacting them in water or a water-soluble organic solvent such as acetone, methanol, ethanol, isopropanol, 20 acetonitrile, etc. when -COOM is a free carboxylic acid or its salt. This reaction is desirably carried out at around neutral of pH and the reaction system can be maintained at around neutral by properly adding alkaline compounds such as an alkali hydroxide, an alkali carbo-25 nate, an alkali hydrogencarbonate, an alkali dihydrogen-phosphate, an alkali monohydrogenphosphate, etc. The reaction temperature is generally about 20 to 70 °C. The terminal point of the reaction is confirmed by a thin layer chromatography. The reaction time is about 1 to 24 30 hours. Since the thus obtained compound (I*) is being dissolved as a water-soluble alkali salt in a reaction mixture, it can be carried out an adsorption, separation and purification by using adsorptive resins such as Diaion HP-20 (trade name, produced by Mitsubishi Kasei
Co.), Amberlite XAD II (trade name, produced by Rohm & Haas, Co.), etc.
In the present invention, the compound (I) obtained each methods of (1), (2) and (3) as mentioned above can be converted into, if necessary, a pharmaceutically acceptable salt or an ester which is easily hydrolized in a human body when the compound has a free carboxylic acid.
Thus, the compound of formula (I) obtained according to the present invention has high antibacterial activity as well as no toxicity at an effective dosage value is
g/kg or more when intravaneous administration to mouse is carried out) and thus it is an effective compound as a medicine. For example, it shows excellent antibacterial activity against a wide range of pathogenic bacteria such as gram negative bacteria including Fseudomonas aeruginosa and gram positive bacteria.
Accordingly, the B-lactam compound according to the present invention can be effectively utilized for the sake of prevention or remedy of diseases due to the aforesaid pathogenic bacteria in human beings or animals.
The B-lactam compound according to the present invention can be administrated orally or non-orally to human beings or animals by various administrating method.
Further, said derivatives are used singly or formulating with auxiliaries, liquid diluents, binders, lubricants, humectants, etc., for example, in the form of general medicinal compositions such as tablets, granulars, sugar coating tablets, powder, capsules, gels, dry syrup,
syrup, amples, suspension, liquid, emulsion, ointments, paste, cream, suppositorys, etc.
Moreover, as the other additives which can be formulated, there may be mentioned dissolution delaying agents, absorption accelerating agents, surface active agents, etc. Any way, any forms which are pharmaceutially acceptable one can be employed.
The 3-lactam compound according to the present invention can be used as alone or mixture of two or more different kinds of derivatives and the amount of the compounds is about 0.1 to 99.5 %, preferably 0.5 to 95 % based on the weight of the all medicinal composition.
The medicinal composition according to the present invention can be formulated an other compounds which are pharmaceutically active as effective ingredients other than said novel B-lactam compound or mixtures thereof.
A dosage per day to a patient of the novel B-lactam compound according to the present invention may be varied depending upon an individual man, kinds of animals, weights thereof and a state to be remedied, but generally is in the range of 1 to 1000 mg per 1 kg of weight, preferably about 10 to 800 mg.
In the following, the present invention is explained, in detail by referring Examples.
Reference example 1
Synthesis of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-carbozoyl-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carbo-xylic acid diphenylmethyl ester«dihydrochloride
After cooling 40 ml of methanol, 1.53 g (10 mmole) of phosphorus oxychloride was added thereto and then to the mixture was added 3.4 g (4.62 mmole) of 7-[2-(2-formyl-amino-1,3-thiazol-4-yl)-2-(3-formylcarbazoyl)methoxy-
iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester and stirred for one hour under ice-cooling. The resulting mixture was added dropwise into 400 ml of ether while vigorously stirring and resulting precipitates were collected by filtration and dried to obtain 2.91.g of the title compound. (Yield: 83.7 %)
Structural formula:
1.96 (s, 3H), 3.67 (s, 2H), 4.81 (s, 2H), 5.22 (d, 1H), 5.72 - 6.10 (m, 1H), 6.90 (s, 1H), 7.33 (s, 10H) .
Reference examples 2 to 7
In the same manner as in Reference example 1, dihidro-chlorides of the compounds shown below can be obtained. The results are shown in Table 1.
1
H NMR (dg-DMSO) 6
O-B-CONHNH
2
Table 1
Reference example
B
z
Yield (%)
Melting point (©c)
*H NMR(de-DMSO)B
' 2
~CH 2~
J-!/ -S^n
1
CH3
7 9.5
/50~/56
'decomposedi
3.78 (broad s, JH), 3.82( s, JH)x #/.2~<{£/(m, 2H), « A ir ( broad s, JH)N AJJ(d, /H)x 5.7 5-6./ 3 (m, /H)x 6.8 0 i. s, /H), 7.27 ( s, /OH)
3
-ch2-
N-N
Jl II
-S-\ /\ S Cf-
9&0
3
/V-2~/</9
(decomposed!
2.6 5 ( s, JH), 3.8 0 i broad s. JH K (m, .2 H ) x ¥,8 2 ( s. 2H )N 5.2 6 (d, / H K 5.7 6-6./ 0 ( m, / H )s 6.9 0 ( s, / H ) x 7.V-0 ( s, /OH)
*
1
0
X
to
1
N - N _c II J
63.5
/10-t/8 (decomposed
3.7 5 { broad s, JH)X HA (m, iH), #7 / ( s, .2H )x
.2 7 {6, /H), 5.8 3 — 6. / 7 (m, / H)N 6.9 V- { s, /HK
7.3 8 (s, / OH), 2ir<? ( s, /H)
-ch-1
ch3
N-N
-<J H /
S
80.8
/.V5(d, 3H)S 3. 75 C broad s. .2 H ) % (m, .2 H ) x «y7(q, / H ) x 5.23(d, / H ) x £ 7 £ ~ 7 ( m, /H)x 6.8 7 { s, / H ) x 7 ,? J ( s. / 0 H ) x 7 .2 ( s, /H)
6
?H"
-c-
1
ch3
N-N
_oJ II
76.8
/ 5 6 ( s, 4H)x J. 7* ( broad s, JH)V « £ 0 ( m, JH)X 5.2 6(4, / H ) x .fc7.2~A0.5r (m, / H)x U(?(s, / H)x 7 A ( broad s, /(?H)x 7..frA(s, /H)
7
-ch2-
H
8V>2
/26-/30
deoomposed i/J(s, x?H)x 3.5#i broad s, JH)> #££(broad s, .2 H ) x i/Md, / H ) x £ £ 0 7 ,7 ( m, / H ) x 6.8 7 { s, / H ) x 7./ 3-7.62 ( s, /0H )
Reference example 8
Synthesis of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-Carbozoyl-methoxyiminoacetamido]-3-acetoxyniethyl-3-cephem-4-carbo-xylic acid'dihydrochloride
To an ice-cooled mixture comprising 24 ml of trifluoro-acetic acid and 6 ml of anisole was added 2.4 5 g (3.25 mmole) of the compound obtained in Reference example 1 and stirredfor 30 minutes under ice-cooling. The resulting mixture was added dropwise into 500 ml of ether while vigorously stirring and resulting precipitates were collected by filtration and dried to obtain 1.81 g of the title compound. (Yield: 95 %)
Structural formula:
1H NMR (dg-DMSO) 6:
2.03 (s, 3H), 3.72 (broad s, 2H), 4.80 (s, 2H), 5.17 (d, 1H), 5.63 - 6.05 (m, 1H), 7.03 (s, 1H).
Reference examples 9 to 11
In the same manner as in Reference example 8, dihydrides of the compounds represented by the following formulae were synthesized from the compounds obtained in Reference examples 3, 4 and 5, respectively. The results are shown in Table 2.
0
•2HC1
\
CH2-CONHNH2
18 -
\-CONHNH2
Table 2
Reference example
B
z
Yield (%)
Melting point f°c)
*h nmr(d-dmso)t 6
9
-ch2-
n-n
_e_li II b \
s ch
9 6
i
I</5~/5 0 (deocmposed)
17£?(s, JH )N J. 7 # ( broad s, JH), JH )N 4 £ .2 ( s , .2 H h 5.2 0 C d, / H ) x A £ $ 9 ( m, / H ) x 7.0 8 (s. / h )
to
-ch2-
n-n S
? 3
/¥&-/5 2 (deocmposed)
J. 7£ (broad s)N « (m, .2 H ) N #7J(s, JH), AJA (d, / H ) x A * A / £ ( m, /HK & ?ir(s, / H ) x 7. A A ( s, / H )
//
—ch-1
ch3
n-n
-sA >
S
9 5
/7 2-/76
decomposed)
/V8 ( d, 3H )s 3.7 7 ( s, JH), # 4* 7 (m, JH), «ntq, /H)» iJJ(d, /H), / H h 7. / 0 is, / H )» 2 £ A ( s, /H)
Example 1
Synthesis of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-(3,4-dihydroxybenzylidene)carbazoyl]methoxyiminoacetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid*hydrochloride
In 10 ml of methanol were dissolved 0.88 g (1.5 mmole) of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-carbozoylmethoxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid* dihydrochloride obtained in Reference example 8 and 0.249 g (1.8 mmole) of 3,4-dihydroxybenzaldehyde and the mixture was stirred at room temperature for one hour. The resulting mixture was added dropwise into 200 ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.85 g of the title compound.
(Yield: 84.6 %)
Structural formula:
2.06 (s, 3H), 3.62 (broad s, 2H), 4.82 (s, 2H), 5.25 (d, 1H), 5.80 - 6.05 (m, 1H), 6.90 (d, 1H), 6.85 -7.30 (m, 3H), 8.01 (d, 1H).
Example 2
Synthesis of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-(3,4-dihydroxybenzylidene)carbazoyl]methoxyiminoacetamido}-3-[(1-methyl-l,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-
OH
• HCl
XH NMR (dg-DMSO) 6:
- 21
4-carboxylic acid-hydrochloride
(I) In 10 ml of methanol were dissolved 0.485 g (0.6 mmole) of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-carbozoyl-methoxyiminoacetamido]-3-[(1-methyl-l,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester'dihydrochloride and 0.10 g (0.72 mmole) of 3,4-di-hydroxybenzaldehyde and the mixture was stirred at room temperature for one hour.
The resulting mixture was added dropwise into 150 ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.51 g of diphenylmethyl ester of the title compound. (Yield: 95.2 %)
(II) To the ice-cooled mixture comprising 4 ml of trifluoroacetic acid and 1 ml of anisole was added 0.28 g (0.314 mmole) of the above diphenylmethyl ester and the mixture was stirred for 30 minutes. Thereafter, the resulting mixture was added dropwise into 100 ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and dried to obtain 0.22 g of the title compound. (Yield: 98 %) Melting point: 131 to 136 °C (decomposed).
Structural formula:
•HCl
^"H NMR (dg-DMSO) 6:
3.75 (broad s, 2H), 3.95 (s, 3H), 4.23 (m, 2H), 4.63 (broad s, 2H), 5.16 (d, 1H), 5.75 - 6.13 (m, 1H), 6.80 (d, 1H), 6.83 - 7.43 (m, 3H), 8.01 (d, 1H).
Examples 3 to 33
In the same manner as in Example 1, hydrochlorides of the B-lactam compounds represented by the following formula were prepared. The results are shown in Table 3.
B-CONHN=C
\
Table 3
Example
B
Z
o.
q2
Yield (%)
Siting point ^
<°C)
*H NMR(d6-DMSO)t
3
-ch2-
N-N
-s-\ j-CH, s
OH
h
7 2.7
/S7~/tO
(decomposed
2.6 8 C s, JH), 3.7 2 C s, 2H )^¥¥2 Cm, JH), ¥8 ¥ C broad s. JH), 5.22(d, /H), 57 2-6.02 Cm. / H )
V-
Ditto
Ditto
-<O>-0
H
H
8 0.3
/28-/3 5 (deoomposed.
2.6 8 is, 3 H )x 3.7 2 C s, .2H)N Cm, JH), ¥83 C broad s, .2H), 5.23 ( d, /H),
570-L03 Cm, /H), £*£Cd, JH), 7. / 8 C s. /H), 7.53 C d, JH)S 8/2 Cd, /H)
Ditto
Ditto
OH OH
H
? a?
/7 7-/8 2
(deocmposed
2.68 ( s, JH), J.70 C broad s, 2H)% «v?£Cm, .2 H K ¥7 8 i broad s, .ZH), AJ0(d, /Hh 5.68-602 Cm, /H), 2 —7.3 2 Cm, 0HK (d, /H)
6
Ditto
Ditto
~^0)-OH OH
H
8 ¥2
/25-/28
decomposed)
2.6 8 C s, JH), J. 7/ C broad s, .2H )% Cm, JH K ¥.7 9 i broad s, JH), 520 id, /Hh 566-600 Cm, / H ) N 6.60-7.V0 Cm, JH K 8.50 Cm. /H)
7
Ditto
Ditto
OH
-0
OH
H
7 8. 6
/25-/30 decomposed)
2.6 9 is, 3 H)> 3.7/ is, 2 H )% ¥¥0 Cm, JH)% tftfJCs, J H ) x 5.2/id, / H ) x 568-6.03 Cm, /H )x £7.*~7.20 Cm, CH )N £<^Cd, /H)
Table 3 (contd.)
Example
B
z
Sfield (%)
Melting point (°C)
1H NMR(d »-DMSO)'
0
I i l" j •
N-N
-S A A S CH,
OH
H
9 AS
/29-/32 (deoomposed
2.69(%, JH)% 3.7 ¥ ( s, 2H\ «^J(m, JH)X V-.SO (broad s. 2H ), 5.25 ( d, /Hh 5.6 S-60 6 (m, / H K 6.S5-7.¥6{ m, £H), S. t 3 L d, /H),
9
Ditto
Ditto
CI
-0
OH
H
73.0
/VS-/57
(deoomposed
2.7 0 ( s, JH)% 3.7 V { s, JH K «C/(m, 2H )s VtS 7 {. broad s, JH)X A.27(d( /H)> 570-605 (m. /HK 6S 0-7.7 3 (m, <*Hh £<<7(d, /H)
t0
Ditto
Ditto
N0;
-0'
OH
H
SVt3
/ 73-177
decomposed
2.6 9 ( s, JH)n 3.6 S (. broad s, JH K#<<A (m, .2H), « £7 ( broad s,JH)( A JJCd, /H\ A70~£<7A(m./Hh £?A~2A£(mf <^H)X £*7(m, /H)
ft
Ditto
Ditto
OCH,
OH
n
734
/OS-/to decomposed
26 7 ( s, JH J. 7 / ( s, AH K (m, JH)n >44*7 (broad s, JJH )x 5.2t (d, /H K 5.70-5.9 S (m, t H ) \ 6S2-7 25 Cm, &53(d, /H)
/2
Ditto
Ditto
OH
CH,
75.0
J.^7(s, JH)N 2.70(.s, 3 HK 3.72(s, 2Hh t.t-OK m. JH)X # A ( broad s, JH)* AJJ(d, / H) A.6*~A.?*(m, /Hh 67 5-7.S* (m, AH)
Table 3 (contd.)
Example
B
Z
<>2
Yield (%)
Melting point (°c;
*H NMR(d6-DMSO)'
A3
I
0
1
to
1
N-N
OH
O X
CO
9 3.8
//A~/ tz (decomposed
225 C s. v7H)% 2.68 C s, JH)X 3.7 3 ( s, .2H)X H36{m, 2 H)x U80L broad s, JH), 5.23 Cd./H)x 57 2-603 irn, /H)x 6 8 5 — 7.50 Cm, AH)
W
Ditto
Ditto
<§) l
O *
ch3
8 6.3
A A0-IA7 (decomposed
2.25C s, JH)X 2.67 ( s, JH)X 37JCbroad s,.2H\ Cm, .2H )x Cbroad s,.2H ),523(d, AH), 5.6 6 —60 6 Cm, /H)x ££<7~??6Cm, AH)
A5
Ditto
Ditto
-^>-0H OH OH
ch3
9X9
/68-172 (decomposed
237 C s, JH)X .U£Cs, JH), 3.7 3 C broad s, .2H)X «^JCrr\ 2H)n # 7 7 C broad s, 2H )x A/7 Cd, /H)x 563-603{m, /H)x £J0~7AUm, 3H)
A6
Ditto
N-N
-S-U s
-^)-0H OH
H
9 0.6
A 35-/3Z (deocmposed
J.7 6 C s, JH), 4<AJCm, JH)n 18 6 Cbroad s, JHK A-J 7 C d, / H )x A.7£~£07Cm, /H)x 677-7.V-3 Cm. VH)s 8/V- Cd, /H), 9.63k%, /H)
/7°
Ditto
Ditto
OH OH
h
9 0.7
/60-/65 deocmposed)
J.7ACs, 2H)n #A0Cm, JH), «££Cbroad s, .2H)X AJACd, /H)x A70~£0,?Cm, /H\ 6.30-7.50 Cm, JHK 832 Cd, /H)x 7.A£Cs, /H)
Table 3 (contd.)
Example
B
Z
q2
field (%)
belting Doint (°c)
1H NMR(d,-DMSO)*
/S
-ch2-
N-N
-s4J S
■9
OH
ch3
9 V-
/ 03-/09 (decomposec
3H), 3.7V ( s, .2HX M3irn, 2H )x )%S&(broad s, .ZH)X S.2S (d. /H)x S.70-600
b
(m, / H )x &7 7~2£.2(m, AH)X 9.SS /H)
/?
Ditto
Ditto
OH
ch3
9 V
(
/OS—/OS 3ecomposed
.1.26 (s, JH)X J.7J (broad s, JH)X <4J7 (m, .2H)X #£.2(broad s. .2H )x A..2»y(d, /H)x S.7 2-6.00 (m, AH)X 6S7-7.V9 (rr\, AH)x?.A^(s, /H)
Ditto
Ditto
-©"OH
ch3
9 AS
•2..2ACS, JH)X 3.72 (broad s, 1H )x «^(m, 2H)S «SS (broad s, JH)V S.2V ( d, /H)x S.7 0-60# (m, / H )x 6.60—7.9V- (m. AH), C s, /H)
2/
Ditto
Ditto
-@-0h
OH
ch3
9S.S
•2.,?0($, JH)X J7.2 ( broad s, JH), <U7 (m, .2H)S
V,S*{ broad s, .2H )x S.23(d, /H)x
(m. / H )x A7A~2^0(m, £H)X SA6 ( s, /H)
22
Ditto
Ditto
OH OH
ch3
90./
/09-//3 deoomposed
2.3 7(s, JH)X J.7J (broad s, .2H)X «^J(m, .2H)X )#?£ (broad s, JH)X S.20(d, /H)x S.70-603 (m, / H )x AJ7~7AA(m, JH )x 9.S2(.s, /H)
Table 3 (contd.)
Example
B
z
92
yield (%)
Melting point ^or>^
*H NMR(d.-DMSO)I
23
-ch-1
ch3
N-N -s-lsj
OH
H
8X2
/AACd, JH)% 3.7$ ( broad s, JH)X 450 (m, JH)% «90(q, / H )x $.26 C d, /H)x 5.7$~60$( m, /H)x L90-7.$0 Cm, <*H)X 8/8 C d, /H)x 9.68 ( s, /H)
2V-
Ditto
Ditto
"(C>>-OH OH OH
H
9K2
Z73-/79
[deccmposec
/.$V(d, JH), 3.7 0 C broad s, JH)X V.V2( m, 2H)X ) «8 6 (m, / H )% $.20 Cd, /H)x $.6 $-600 Cm, /H)x 6.30-7.S0 Cm. JH)X 8V-${%. /H h 9.$2 C s, /H)
2$^
4-'
i ch3
Ditto
-<5)-oh
OH
H
9 0.$
[decomposed
/AACs, AH), J.7.2 C broad s, JH)X <AV2 Cm, .2H), )&U(d, /HXA.7.2~£/J Cm, /H)x 673-7.$${m, £H)X 8.20 Cm, /H)x 7. AA C s, /H)
2t>l)
-ch2-
N-N
oil II
N^*
1
ch,
OH OH
CH3
8$.&
^ACs, JH)X 3.6$ C broad s. J2H )x v?.7J(s, JH), #4*0 Cm, JH)X V\8 8 i. broad s, JH), $./0 C d, /H)x AAvy~A7«-Cm, / H )x 628-7.V8 Cm, JH)
27X]
-ch2-
h •
-^)-0h OH
h
9 Lb
/92-/9$
decomposec
•2.0A C s, v?H K v?.4*7 Cbroad s, 2H )x 44£/ C broad s, .2H)X ) A/?Cd, / H )x $.60-5.9 3 Cm, /H)x
667-7.V-S Cm, 4<H)
Note 1) These examples were carried out in the same manner as in Example 2.
Table 3 (contd.)
Example b
z q1
°2
Yield (%)
Melting point (°C)
1 H NMR(d6-DMSO)6
28
-CH -2
jgi ch3
HO OH
H
55.6
-
3.74(broad s, 2H), 4.02(s, 3H) ,
4.43(broad s, 2H), 4.92(broad s, 2H), 5 . 36 (d, IH) , 5.79 - 6.14(m, IH) ,
6.86 - 7.38(m, 4H)
29
Ditto
Ditto
-©■08
HO
h
59.4
-
3.74(broad s, 2H), 4.01 (s, 3H), 4.42(broad s, 2H), 4.93 (broad s, 2H), 5.31 (d, 1H) , 5.82 - 6.13(m, 1H) , 6.53 - 7.54(m, 4H)
Ditto
Ditto
-^cb
OH
ch3
61.3
-
2. 28 (s, 3H) , 3 . 66 (m, 2H) , 4.02(s, 3H) , 4.48(m, 2H), 4.99(m, 2H) , 5.28(d, 1H) , 5.72 - 6.14(m, IH), 6.98 - 7.78(m, 4H)
31
Ditto
Ditto
-(O^ OCHj iO OH
h
65.3
-
3.82(broad s, 2H) , 3.88(s, 3H), 4.04(s, 3H),
4.42 (broad s, 2H), 4.90(broad s, 2H), 5. 24 (d, IH), 5.73 - 6.14 (m, IH),
6.63 - 7.42 (m, 3H)
32
-CH-
ch3
Ditto
{OS-OH
OH
h
93.0
-
1.55 (d, 3H) , 3.81(broad s, 2H), 3.92(s, 3H) , 4 .08(s, 3H), 4.45 (broad s, 2H) , 5,01(m, IH), 5.32 (d, IH), 5.74 - 6.18(m, IH), 7.08 - 7.69(m, 3H)
33
CH3
-c-ch3
Ditto
VO/-OCH3 30 OH
h
39.0
-
1.63 (s , 6H) , 3 . 80 (broad s, 2H) , 3.91(s, 3H) , 4.05(s, 3H), 4.42(broad s, 2H), 5.33(d, IH), 5.80 - 6.22(m, IH), 6.62 - 7.33{m, 3H)
Example 34
Synthesis of sodium 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzylidene)carbazoyl]ethoxyimino]-acetamido}-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylate
In 30 ml of water was suspended 0.5 g of 7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzylidene)-carbozoyl)ethoxyimino]-acetamido >-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid*hydrochloride obtained in Reference example 23 and the suspension was dissolved at pH about 7.5 by adding an aqueous 5 % sodium hydrogencarbonate solution.
After filtration thereof, the filtrate was adsorbed by 100 ml of HP 20 column filled with water and washed with water and 20 % methanol-water solution. Then, the title compound was eluted by 50 % ethanol-water solution, and after evaporation of methanol and lyophilized to obtain 0.2 g of the title compound.
Structural formula:
^"H NMR (dg-DMSO) 6:
1.52 (d, 3H), 3.62 (broad s, 2H), 4.48 (m, 2H), 4.87 (m, IH), 5.18 (d, IH), 5.65 - 5.97 (m, IH), 6.83 -7.52 (m, 4H), 8.18 (s, IH), 9.60 (s, IH).
Example 35
Synthesis of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-(3,4-diacetoxybenzoyl)carbazoyl]methoxyiminoacetamido}-3-[(5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid*hydrochloride
In 3 ml of methylene chloride was suspended 0.35 g (0.53 mmole) of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-carbazoyl-methoxyiminoacetamido]— 3— t(5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid*dihydrochloride obtained in Reference example 9 and the suspension was dissolved by adding 1.35 g (6.66 mmole) of n,0-bis(tri-methylsilyl)acetamide. To the mixture was added 0.136 g (0.53 mmole) of 3,4-diacetoxybenzoic acid chloride and the mixture was stirred at room temperature for one hour. The mixture was poured into 200 ml of ether and added thereto a small amount of methanol while stirring. The resulting precipitates were collected by filtration, washed with water and then dried to obtain 0.42 g of the title compound. (Yield: 94.1 %)
Structural formula:
OAc
XH NMR (dg-DMSO) <5 :
2.32 (s, 6H), 2.68 (s, 3H), 3.72 (broad s, 2H), 4.42 (m, 2H), 4.73 (broad s, 2H), 5.17 (d, 1H), 5.68 -6.02 (m, 1H), 6.68 - 8.08 (m, 4H).
Example 36
Synthesis of 7-{2-[2-amino-lf3-thiazol-4-yl]-2-[3-(3,4-diacetoxybenzoyl)carbazoyl]methoxyiminoacetamido}-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-5 carboxylic acid•hydrochloride
(I) In 5 ml of methylene chloride was suspended 0.566 g (0.7 mmole) of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-carba-zoylmethoxyiminoacetamido]-3-[(1-methyl-l,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid diphenyl-
methyl ester•dihydrochloride, and 1.25 g (6.15 mmole) of N,0-bis(trimethylsilyl)acetamido was added thereto to form a solution. To the solution was added 0.2 g (0.78 mmole) of 3,4-diacetoxybenzoic acid chloride and the mixture was stirred at room temperature for one hour.
The resulting mixture was poured into 200 ml of ether and a small amount of methanol was added thereto while stirring. Resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.68 g of the diphenylmethyl ester of the title compound.
(Yield: 97.9 %)
(II) A mixture comprising 6 ml of trifluoroacetic acid and 1.5 ml of anisole was ice-cooled, 0.68 g (0.685 mmole) of the above diphenylmethyl ester was added thereto and the mixture was stirred for 30 minutes under
ice-cooling. The resulting mixture was added dropwise into 150 ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.54 g of the title compound. (Yield: 95.4 %)
Structural formula:
OAc
•HCl
XH NMR (dg-DMSO) 6:
2.32 (s, 6H), 3.70 - 4.10 (m, 5H), 4.35 (m, 2H), 4.86 (broad s, 2H), 5.52 (d, IH), 5.65 - 6.03 (m, IH), 7.05 - 8.17 (m, 4H).
Examples 37 to 46
In the same manner as in Example 36, hydrochlorides of the 6-lactam compounds represented by the following formula were synthesized. The results are shown in Table 4.
:onhnhco-q3
33 -
Table 4
Example
B
Z
Qs field (%)
'h NMRCd6-DMSO)i
37
1
0
1
t-3
1
M - N
-s4sJ)
-<Q>-oac
OAc
7 8. 3
232 Cs, 6 H ) \ 3.7 3 C broad s, .2H), Mb Cm, JH), 475 {. broad s, JH), A.20Cd, /H)N 5.70-6.05 Cm, /H)x 610-8 / 0 Cm. 4H), 9.60 C s, /H)
38
Ditto
N-N
-s-lJ
1
CHB
.OAc •#
OAc
9 4 6
228 Cs, 6H)% 3.69-403 Cm. AH )s #J.2Cm, 2H K 4f 2{ broad s, 2H), 5/8 C d, /H)% A70~A?o? Cm, / H ), 6t7-7.78im, <^H)
39
Ditto
N-N ~JI II
Ditto
9 6. 6
2.30 Cs, AH)X J.76 Cs, 2H)x.«A0Cm, JH),
Cbroad s. JH)N 5.23 C d, / H ), 5.70-602 Cm, /H)x 6S6-7.73 Cm, 4H), 9.56 (s, /H)
40
Ditto
Ditto
-CH=CH-^^-OA OAc
9 9.5
c
JUJCs, 6 H)% A7ACs, JH)> «A0Cm, JH),
485(broad s, JH), A.2Md, /H), A££~A.y7Cm, /H)x 680-7.78 Cm, <<H)
41
-CH-1
CHs
Ditto
-<^-OAc OAc
9 50
/.V-6 Cd, JH)S iJACs, 6 H)x J.£.2Cbroad s, JH )N #J*Cm, JH)X 483(q, / H), A..27Cd, /H)> A.7A~£.20Cm, / H )x &70~7«,?Cm, 4*H )> SAMs, /H)
Table 4 (contd.)
Exanple b
z q3
Yield (%)
1 H NMR(dg-DMSO)5
42
-ch2-
JD
1
ch3
-/oVc^c
AcO OAc
43.8
2.35 (s , 9H) , 3.78(broad s, 2H), 4.01(s, 3H) ,
4.36 (m, 2H), 4.84(broad s, 2H), 5.26 (d, IH), 5.74 - 6.14(m, IH), 7.28 - 8.14(m, 3H)
43
Ditto
Ditto
CH=CH/5Vc
AcO 0?
3i3
c 52.3
2.38(s, 6H), 3.81(broad s, 2H) , 4.01(broad s, 6H) 4.42(m, 2H) , 4.92 (broad s,2H), 5.31(d, IH), 5.76 - 6.14(m, IH), 7.27 - 8.23(m, 3H)
44
-ch-i ch3
Ditto
A<
-^OCH, 10 CAc
54.6
1.52(d, 3H), 2.33 (s, 6H) , 3.81(broad s, 2H) ,
3. 98 (s , 3H) , 4 . 01 (s, 3H) , 4.42(m, 2H) , 5.03 (m, IH), 5.31(d, IH), 5.83 - 6.22(m, IH),
7.22 - 8.03(m, 3H)
45
Oh
1 J -c-1
CHs
Ditto
Ditto
47.3
1.53(s, 6H), 2.32 (s, 6H), 3.82(broad s, 2H), 3.97 (s , 3H) , 4 . 03 (s, 3 H) , 4.41(m, 2H) , 5.31(d,lH), 5.81 - 6.23 (m, 1H) , 7.28 - 8.07(m, 3H)
46
Ditto
Ditto
Ac
-^q^-OAc K) OAc
61.3
1.54(s, 6H) , 2.33(s, 9H) , 3.81(broad s, 2H) ,
4.03 (s , 3H) , 4 .41 (m, 2H) , 5.33(d, IH) , 5.82 - 6.20(m, IH), 7.21 - 8.13(m, 3H)
Example 47
Synthesis of ammonium 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-(3,4-dihydroxyben zoyl)carba zoyl]methoxyiminoacet-amido}-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylate
In 10 ml of methanol was dissolved 0.4 g (0.505 mmole) of 7-{2-[2-amino-l,3-thiazol-4-yl)-2-[3-(3,4-diacetoxy-benzoyl)carbazoyl]methoxyiminoacetamido}-3-[(1,3,4-thia-diazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid• hydrochloride obtained in Example 37, and 0.15 ml of 25 % aqueous ammonia was added thereto and the mixture was stirred at room temperature for one hour.
To the resulting mixture was added 20 ml of ether and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.31 g of the title compound. (Yield: 86.7 %)
Structural formula:
1H NMR (dg-DMSO) 6:
3.82 (broad s, 2H), 4.46 (m, 2H), 4.83 (broad s, 2H), 5.30 (d, IH), 5.80 - 6.10 (m, IH), 6.80 - 8.15 (m, 4H), 9.60 (s, IH).
N TT-C-CO
XJ\
N
\ °\
c-co
Example 48
Synthesis of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-((3,4-diacetoxy benzoyl) carbamoyl) carbazoyl ] methoxyiminoacet-amido}-3-[(5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid*hydrochloride
In 2 ml of methylene chloride was suspended 0.257 g (0.39 mmole) of 7-{2-[2-amino-l,3-thiazol-4-yl)-2-carbazoyl-methoxyiminoacetamido}-3-[ (5-methyl-l, 3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylie acid*dihydrochloride obtained in Reference example 9, and 1 g of N,0-bis-(trimethylsilyl)acetamide was added thereto to form a solution. To the resulting solution was added 0.22 g (0.84 mmole) of 3,4-diacetoxybenzoylisocyanate and the mixture was stirred at room temperature for 8 hours. The resulting mixture was poured into 100 ml of ether and a small amount of methanol was added thereto while stirring. Resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.33 g of the title compound. (Yield: 84.6 %)
Melting point: 73 to 76 °c (decomposed).
Structural formula:
OAc
CH
OAc *HC1
3
^"H NMR (dg-DMSO) 6:
2.34 (s, 6H), 2.71 (s, 3H), 3.74 (broad s, 2H), 4.43 (m, 2H), 4.82 (broad s, 2H), 5.22 (d, IH), 5.68 -5.98 (m, 1H), 7.08 - 8.06 (m, 4H).
Example 49
Synthesis of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-((3,4-diacetoxy benzoyl) carbamoyl) carbazoy 1 ] methoxy iminoacetamido }-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid*hydrochloride
In the same manner as in Example 48 except for using 0.387 g (0.6 mmole) of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-carbazoylmethoxyiminoacetamido}-3-[ (1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid*dihydrochloride obtained in Reference example 10, 4 ml of methylene chloride, 1 g (4.9 mmole) of n,0-bis(trimethylsilyl )acetamide and 0.332 g (1.26 mmole) of 3,4-diacet-oxybenzoylisocyanate, 0.4 9 g of the title compound was obtained. (Yield: 93.7 %)
Structural formula:
1H NMR (dg-DMSO) 6:
2.24 (s, 6H), 3.65 (broad s, 2H), 4.40 (m, 2H), 4.70 (broad s, 2H), 5.12 (d, IH), 5.58 - 5.95 (m, IH), 7.05 - 8.13 (m, 4H), 9.53 (s, IH) .
h2n
OAc
OAc *HC1
38 -
Example 50
Synthesis of ammonium 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-((3,4-dihydroxybenzoyl)carbamoyl)carbazoylImethoxy-iminoacetamido}-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylate
In 10 ml of methanol was dissolved 0.41 g (0.47 mmole) of 7-{2-[2-amino-l,3-thiazol-4-yl)-2-[3-((3,4-diacetoxy-benzoyl)carbamoyl)carbazoyl]methoxyiminoacetamido}-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylie acid hydrochloride obtained in Example 49, and 0.3 ml of 25 % aqueous ammonia was added thereto and the mixture was stirred at room temperature for one hour. To the resulting solution was added 0.22 g (0.84 mmole) of 3,4-diacetoxybenzoylisocyanate and the mixture was stirred at room temperature for 8 hours. To the resulting mixture was added 20 ml of ether and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.26 g of the title compound. (Yield: 70.3 %)
Structural formula:
1H NMR (dg-DMSO) 6:
3.64 (broad s, 2H), 4.48 (m, 2H), 4.70 (broad s, 2H), 5.12 (d, IH), 5.60 - 5.90 (m, IH), 6.75 - 7.70 (m, 4H), 9.50 (s, IH).
OH
39 -
Example 51
Synthesis of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-( ( 3,5-diacetoxybenzoyl) carbamoyl) carba zoyl ] methoxy iminoacetamido) -3- [ (1,3,4-thiadiazol-2-yl) thiomethyl 3 -3-cephem-4-5 carboxylic acid*hydrochloride
(I) In 4 ml of methylene chloride was suspended 0.486 g (0.6 mmole) of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-carba-zoylmethoxyiminoacetamido]-3-[ (1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl
ester'dihydrochloride, and 1 g (4.9 mmole) of N,0-bis-(trimethylsilyl)acetamido was added thereto to form a solution. To the solution was added 0.33 g (1.25 mmole) of 3,5-diacetoxybenzoylisocyanate and the mixture was stirred at room temperature for two hours. The resulting 15 mixture was poured into 150 ml of ether and a small amount of methanol was added thereto while stirring. Resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.59 g of the diphenylmethyl ester of the title compound.
(Yield: 94.8 %)
(II) A mixture comprising 6 ml of trif luoroacetic acid and 1.5 ml of anisole was ice-cooled, 0.59 g of the above diphenylmethyl ester was added thereto and the mixture was stirred for 30 minutes under ice-cooling. The 25 resulting mixture was added dropwise into 150 ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.48 g of the title compound. (Yield: 96.6 %)
Structural formula:
COOH 2 S /OAc
, c *1101
OAc
NMR (dg-DMSO) 6:
2.30 (s, 6H), 3.74 (broad s, 2H) , 4.50 (m, 2H), 4.80 (broad s, 2H), 5.20 (d, 1H), 5.63 - 6.00 (m, 1H), 6.98 - 7.92 (m, 4H), 9.56 (s, IH).
Reference example 12
Synthesis of 2-(2-amino-l,3-thiazol-4-yl)-2-[3-(3,4-dihydroxybenzylidene)carbazoyl]methoxyiminoacetic acid* hydrochloride
In 50 ml of ice-cooled methanol was added 5.21 g (34
mmole) of phosphorus oxychloride, and then to the mixture was added 5.4 g (17.1 mmole) of 2-(2-formylamino-l,3-. thiadiazol-4-y1)-2-(3-formylcarbazoyl)methoxyiminoacetic acid and the mixture was stirred for one hour under ice-15 cooling. The resulting mixture was added dropwise into 400 ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 4.28 g of 2-(2-amino-l,3-thiadiazol-4-yl)-2-carbazoylmethoxyiminoacetic acid* 20 dihydrochloride. (Yield: 75.4 %)
^"H NMR (dg-DMSO + D20) 6:
4.82 (s, 2H), 7.14 (s, IH).
In 40 ml of methanol was dissolved 2.325 g (7 mmole) of the above dihydrochloride, and 0.967 g (7 mmole) of 3,4-
dihyroxybenzaldehyde was added thereto and the mixture was stirred at room temperature for one hour.
The resulting mixture was added dropwise into 400 ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 2.2 0 g of the title compound.
(Yield: 75.6 %)
Structural formula:
4.82 (s, 2H), 6.85 - 7.15 (m, 4H), 7.88 - 8.22 (d, IH) .
Example 52
Synthesis of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-(3,4-dihydroxybenzylidene)carbazoyl]methoxyiminoacetamido}-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carbo-xylic acid hydrochloride
In 10 ml of DMF were dissolved 0.93 g (2.24 mmole) of 2-(2-amino-l,3-thiazol-4-yl)-2-[3-(3,4-dihydroxybenzylidene )carbazoylJmethoxyiminoacetic acid•hydrochloride obtained in Reference example 12 and 1.11 g (2.24 mmole) of 7-amino-3-[(l,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester and the mixture was ice-cooled, and 0.598 g (2.9 mmole) of DCC was added thereto and stirred at room temperature for one
•HCl
XH NMR (dg-DMSO + DjO) 6:
hour. After filtration of the resulting mixture, to the filtrate was added the same amount of chloroform and the mixture was added dropwise into 400 ml of ether while vigorously stirring. Resulting precipitates were 5 collected by filtration, washed with ether and then dried to obtain 2.36 g of the crude product. This product was purified through column chromatography [30 g of silica gel, eluent: chloroform-methanol-formic acid (3 : 1 : 1)] to obtain 1.13 g (Yield: 56.4 %) of aimed diphenylmethyl 10 ester compound. A mixture comprising 8 ml of trifluoroacetic acid and 2 ml of anisole was ice-cooled, and to the mixture was added 1.13 g (1.26 mmole) of the diphenylmethyl ester obtained above and the mixture was stirred for 30 minutes. The resulting mixture was added 15 dropwise into 150 ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.8 9 g of the title compound as pale yellow powder. (Yield: 97.0 %) Physical properties thereof are accorded with those of 2o the compound of Example 16.
Reference example 13
Synthesis of 2-(2-amino-l,3-thiazol-4-yl)-2-t3-(3,4-dihydroxybenzoyl)carbazoyl]methoxyiminoacetic acid* hydrochloride
In 50 ml of methylene chloride was suspended 6.12 g (19.4 mmole) of 2-(2-amino-l,3-thiazol-4-yl)-2-carbazoyl-methoxyiminoacetic acid tert-butyl ester, and to the suspension was added 20.8 g (102.3 mmole) of N,0-bis-(trimethylsilyl)acetamide to form a solution. To the 30 ice-cooled solution was added 5.467 g (21.3 mmole) of 3,4-diacetoxybenzoic acid chloride and the mixture was stirred for 2 hours under ice-cooling. The resulting mixture was poured into 800 ml of ether and to the mixture was added a small amount of methanol while
stirring. Resulting precipitates were collected by filtration, washed with ether and then dried to obtain 10.2 g of 2-(2-amino-l,3-thiazol-4-yl)-2-[3-(3,4-diacet-oxybenzoyl)carbazoyl]methoxyiminoacetic acid tert-butyl 5 ester hydrochloride. (Yield: 98.2 %)
1H NMR (dg-DMSO + D20) 6:
1.54 (s, 9H), 2.28 (s, 6H), 4.82 (s, 2H), 7.10 - 8.00 (m, 4H).
In 100 ml of methanol was dissolved 5.69 g (10.6 mmole) 10 of the above hydrochloride, then 4.2 ml of 25 % aqueous ammonia was added thereto and the mixture was stirred at room temperature for one hour. The resulting mixture was concentrated, and the residue was dissolved in 200 ml of 30 % THF - ethyl acetate, dried over anhydrous magnesium 15 sulfate and then the solvent was distilled out after filtration. The resulting oily product was dissolved in 20 ml of trifluoroacetic acid and the solution was stirred at room temperature for 5 hours. Then, the resulting mixture was added dropwise into 400 ml of ether 20 while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 3.9 g of trifluoroacetic acid salt of the title compound. To 20 ml of ice-cooled methanol was added 3.1 g (20 mmole) of phosphorus oxychloride, and 3.9 g of the 25 previously obtained trifluoroacetic acid salt was added thereto and the mixture was stirred for 10 minutes. The resulting mixture was added dropwise into 400 ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and then dried 30 to obtain 3.4 g of the title compound. (Yield: 74.3 %) Melting point: 157 to 159 °C (decomposed).
Structural formula:
c-cooh II
n-o-ch -conhnhco oh oh »hc1
^h nmr (dg-dmso + djo) 6:
4.82 (s, 2H), 7.12 - 7.98 (m, 4H) .
Reference examples 14 to 22
In the same manner as in Reference example 13/ hydrochlorides of the compounds represented by the following formula were prepared. The results are shown in Table 5.
h2N
c-cooh II
n-o-b-conhnhco-q3
Table 5
Reference example
B
Yield (%>
>H NMRCd6-DMSO)
/4
-CH2-
~©-°"
747
UMs, JH)x L9 0 ( d, JH)x 7/8 C s, /H)x 7 7 9 id. 2H )
/$
Ditto
/OH
-<0^-°H OH
9 2.3
482 C s. JH)X JH)X /H)
/6
-CH-1
ch3
-(Q)-OH
8 2.3
1
/. A^Cd, /H)s i?A(d, iH), 7. 25 ( s, / H ) % 2* 7 ( d, 2H)
17
-ch2-
-/ovoh cch3
87.5
3.91 (s, 3H)/ 4.88{s, 2H) , 6.97 - 7.83(m, 4H)
18
Ditto
,°H
-\ovoh
CCHs
79.0
3.88 (s, 3H), 4.90(s, 2H) , 7.23 - 7.42 (m, 3H)
19
Ditto
HO OH
68.5
4.91 (s, 2H), 6 .83 - 7.62 (m, 3H), 7.21(s, IH)
Table 5 (contd.)
Beference example b
03
Yield (%)
1H NMR(dg-DMSO)
-ch-
ch3
"(OVOH W0H
84.5
1.54(d, 3H), 4.92(q, IH), 6.78 - 7.63(m, 4H)
21
73
-c-
1
ch3
Ditto
87.8
l;63(sr 6H) , 6.87 - 7.65(m, 4H)
22
Ditto
73.5
1.64(s, 6H), 7.12(s, 2H), 7.41(s, IH)
Example 5 3
Synthesis of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-(3,4-dihydroxybenzoyl)carbazoyl]methoxyiminoacetamido}-3-[ (1, 3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic 5 acid*hydrochloride
(I) In 10 ml of DMF were dissolved 1.295 g (3 mmole) of 2-(2-amino-l,3-thiazol-4-yl)-2-[3-(3,4-dihydroxybenzoyl)-carbazoyl]methoxyiminoacetic acid'hydrochloride obtained in Reference example 13 and 1.4 9 g (3 mmole) of 7-amino-
3-[(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carbo-xylic acid diphenylmethyl ester and the mixture was ice-cooled, and 0.825 g (4 mmole) of DCC was added thereto and stirred at room temperature for one hour. After filtration of the resulting mixture, to the 15 filtrate was added the same amount of chloroform and the mixture was added dropwise into 400 ml of ether while vigorously stirring. Resulting precipitates were collected by filtration, washed with ether and then dried to obtain 2.68 g of the diphenylmethyl ester of the title 20 compound. (Yield: 98.1 %)
(II) A mixture comprising 4 ml of trifluoroacetic acid and 1 ml of anisole was ice-cooled, and to the mixture was added 0.3 g (0.33 mmole) of the diphenylmethyl ester obtained above and the mixture was stirred for 30
minutes. The resulting mixture was added dropwise into 80 ml of ether while vigorously stirring and resulting precipitates were collected by filtration*, washed with ether and then dried to obtain 0.24 g of the title compound. (Yield: 97.7 %) Physical properties thereof 30 are accorded with those of the compound obtained in Example 47.
Examples 54 to 84
In the same manner as in Example 53, hydrochlorides of the B-lactam compounds represented by the formula shown below were prepared. The results are shown in Table 6.
XJ
C-CONH-
N
H.N ^ -5f \ N' .
2 0 O | CEj-Z
XB COOH
\
CONHNHCO-Q-,
Table 6
Example
B
Z
<?3
5field (%)
*H NMR(d6-DMSO)
54
-ch2-
N— N
sJ.sJLchs
X
0
1
8 0.6
•2.6J C s, JH)n 3.62 Cm, 2H K #A0Cm, 3H), #7/Cm, «2H)V $.08 Cd, /HX / H )x 693 Cd, oZH ), 7.87 C d, 2H )
55
Ditto
N-N
il 11
S \ p N 1
ch,
HO
7 /. $
3.63 Cbroad s, .2H), 3.9 0 C s, 3H)440(m, JH)X «£0Cbroad s, .2H)vA./.2Cd, / H ), AA*~A? 9 Cm, / H ), 67$~8/$ Cm, AH )
56
Ditto
-OOCCHg
I
"©"OH
OH
9 0.0
.2.00 Cs, ^H), 3.$ 2 Cbroad s, JH)V 4. 73 Cbroad s, .2H )x A./0 Cd, / H ), AA«2~A£ / Cm, / H ), 679~7.$3irn, 4H)
57
Ditto
-OOCNHj
Ditto
A9.9
J.70fCbrpad s, J2H)% 470 Cbroad s, «2H)N $.08 C d, /H)x $.$0~$83 Cm, /H)n £Atf~7^6Cm, VH)
58
-ch2-
Il ^
1 11
S N^ h
"©"OH
OH
6 /. 2
J.*0 Cbroad % 2H \ 44V Cm, JH), «£0C broad s, .2H )x A..20Cd, /H)x AA.2~A.9* Cm, / H), 67$~8/2(m, AH)
Table 6 (contd.)
Example b
Z
Qs
Yield (%)
*H NMR(d 6-DMSO)
59
-ch2-
N-N
OH
7 9.9
2.6$ Cs, JH)% 3.63 Cbroad s, .2H), 448 Cm, JH)
<47 J C broad s. JH), $.08 C d, /H)> $62-$88 Cm, /H)N
6.72-7.43 Cm, 4H)
60
Ditto
(/>
o —
"s6
o x
Ditt6
7 7.6
«?..2$Cs, *?H)X 3.58 Cbroad s, JH)N 426 Cm, 2H), «7£ C broad s, 2H)^ $04 C d, / H ), $.$3-$.84 Cm, /H)s L68-7.$4 Cm, 4H)
61
Ditto
N
-s-^> sX, N O
-<^-OH OH
3 6.$
3.$8-3.78 Cm, AH), «J/Cm, JH), 46 6 Cbroad s, .2H)N $.0 7Cd, / H )x $.$/-$.9 f Cm, / H ) x 671-760 (rr\, £H)
62
Ditto
M — N o II II S \ N N 1
CH3
Dittd)
7 0.6
3.7 2 C broad s, JH K 3.92(s, JH)X 433 Cm, .2H), 468 (broad s, 2H)% $.06 (d, / H ), $.$3-$.88 (m, /H)% 67$-7.$8(m, 4H)
63
Ditto
N— N
sJ! "
N f ch -c00h
Ditto
8 4 2
3.70 Cs, 2H)y 4/7~448 (rn, JH), 470(%, 2H), $.//(d, /H), $.28 Cs, 2H)n $.$2-$.9 6 Cm, /H)x 698-7.$$(m, 4H)
Table 6 (contd.)
Example
B
Z
Yield (%)
*H NMRCd 0-DMS0)
64
-ch2-
N-N
S 11 J S-s /
N
ch2-so3h
6 3.0
J.££Cbroad s, 2H), 430 Cm, ,2H)X 462 Cbroad s, .2H)S £0J(d, / H )% 5.26 C broad s, 2h )s 54s-5.9 0 Cm. /Hh 670-7.44 (n\4h)
65
Ditto
N-N
S< *
N
ch 2-ch2-oh
Ditto s 3.3
3.50-402 Cm, JH), J Cm, 4H)N A./ffCd, /H)% 5.63-5.9 8 Cm, /H)x 68 3—7.63 Cm, JH)
66
Ditto
N-N s 11 N N 1
ch2-ch-ch2
Ditto
6 97
3.70 ( broad s. 2h )n 4 20-48 7 Cm, *H)X S./S-622(cn, AH)X 6.68-743 Cm, <<H)
67
Ditto
N-N
sj n S-\.y
N
I yCh ch2-ch2-n | nch 1
Ditto
'a
3
22.5
2.24 C s, 6H)n J.6«"Cm, .2H), 3.70 (. broad s, JH), tf/fMWJCm. ^H), 464 Cbroad s, JH)% S0£Cd, /H)x 5.60—5.9 2 Cm, /H)x 6.78-7.62 Cm, 4h)
Table 6 (contd.)
Example b
7.
Q3
Yield (%)
1 H NMR(d -DMSO)
68
-CH2-
n-n II II S-s /~CH
s 3
,°H
OH
V 5 0
2.68 Cs, JH)X 3.72 { broad s, JH)N 44 4Q C m, JH), 44 7 5" C broad s,..2H)x A./?Cd, / H), 5L8-L03 Cm, /H), 6.9 / —7.28 (m, JH)
69
-ch-1
ch3
Ditto
&
1
O X
7 7.3
/.$2 Cd, 3H)S 3.60 Lm, 2H)^«V7 Cm, 2H X 447£ Cm, /H)xA0ACd, / H ) N 553-588 Cm, / H )x £?.2Cd. JH), &7 7 C s, / H X 7.8Vid, IH)
70
Ditto
-OOCCHj
OH
7 3.3
/V3 Cd, JH)n 2.0/Cs, 7H), J.AJ Cbroad s, .2H X 44 76 C broad s, .2HX 4470Cq, /H)x C d, / H X AAA~A.££ Cm, /HX £7J~7££Cm, *H)
Table 6 (contd.)
Example
B
Z
03
Yield (%)
1 H NMR(d6-DMS0)
71
-ch2-
N—• N
-s-Ci i
ch3
OH
och3
59.1
3. 69 (broad s, 2h) , 3.87(s,3h), 3.96(s, 3h) , 4.38(m, 2h), 4.81(broad s, 2h) , 5.08(d, ih), 5.54 - 5.92(m, ih), 6.84 - 7.62(m, 4h)
72
Ditto
Ditto
. OH
"<ov0h och3
55.9
3.72(broad s, 2H), 3.88(s, 3H), 3.99(s, 3H), 4 .41 (m, 2H) , 4.87 (broad s, 2H) , 5.28(d, IH) , 5.82 - 6.13(m, IH), 7.17 - 7.33(m, 3H)
73
Ditto
Ditto
HO OH
54.1
3.78(broad s, 2H), 3.98(s, 3H), 4.47(m, 2H), 4.88 (broad s, 2H) , 5.29(d, IH) , 5.80 - 6.17(m,lH), 6.92 - 7.71(m, 4H)
74
Ditto
Ditto
>-0H
-/OV OH OH
34.7
3.76(broad s, 2H), 3.99(s, 3H), 4.45(m, 2H),
4.89(broad s, 2H), 5.23(d, IH),
.72 - 6.12 (m, IH), 6.89 - 7.32 (m, 3H)
75
CH3 ch3
Ditto
Ditto
53.7
1.53 (s , 6H), 3.78(broad s, 2H), 4.01(s, 3H), 4.48(m, 2H), 5.24(d, IH), 5.74 - 6.18(m, IH) , 7. 28 (s, 311)
76
Ditto
Ditto
OH
59.4
1. 52 (s f 6H) , 3.76 (m, 2H) , 4.02(s, 3H) , 4.62(m,2H), 5.22(d, IH), 5.72 - 6.09(m, IH),
6.89 - 7.72(m/ 4H)
Table 6 (contd.)
Example
B
Z
Yield (%)
1 H NMR(dg-DMSO)
77
vh3
~S3
-JTS
-/ov oh oh
57.3
1.52 (s, 6H) , 3.77 (m, 2H) , 4.58(m, 2H) , 5.23(d,lH), 5.70 - 6.12(m, 1H) , 6.88 - 7.69(m, 4H),
8 .97 (s , IH)
78
Ditto
Ditto
.OH
-<OVOH
OH
52.8
1.52 (s , 6H) , 3.76(m, 2H), 4.59(m, 2H) , 5.22(d, 1H) , 5.78 - 6.14(m, IH), 6.93 - 7.30 (m, 3H) , 8.99(s, IH)
79
-ch2-
Ditto
^5VOH
59.6
3.70 (broad s, 2H) , 4.41(m, 2H) , 4.67 (broad s, 2h),
.16(d, IH)/ 5.80 - 6.18 (m, IH),
6.97 - 7.76(m, 4H), 8.97(s, IH)
80
(fh3
-c-1
CH3
ch3
Ditto
51.3
1.61 (s , 6H) , 2.52 (s , 3H) , 3.70(m, 2H) , 5.34(d,lH), 5.75(m, 2H)
81
Ditto
Ditto
63.4
1.58 (s, 6H) , 2.71(s, 3H) , 3.73(mf 2H) ,
4.51(ABq, 2H), 5.28(d, 1H) , 5.78 - 6.17(m, IH),
6.81 - 7.63 (m, 4H)
82
Ditto
-.u
(*nr^TJ=sC I
Ditto
58.7
1.57 (s, 6H), 3.73(broad s, 2H), 4.48(m, 2H), 4.98 - 5.57(m, 6H), 5.77 - 6.18(m, IH), 6.79 - 7.61(m. 4H)
83
Ditto chochooh l2
Ditto
57.3
1. 58 (s, 6H) , 3. 71 (broad s, 2H) , 4.24 - 4.84 (m,6H),
.27(d, IH), 5.76 - 6.20(m, 1H) ,
6.81 - 7.64(m. 4H)
84
Ditto
-s4>.A
Ditto
54.3
1.5 8 (s, 6H), 3.55 - 3.80(m, 5H) , 4.55{m, 2H) , 5. 26 (d, IH) , 5.77 - 6.14(m, 1H) , 6.79 - 7.66(m, 4H)
Reference example 2 3
Synthesis of 2-(2-amino-l,3-thiazol-4-yl)-2-{l-[3-(3,4-dihydroxybenzoyl)carbazoyl]ethoxyimino}acetic acid• hydrochloride
In 10 ml of methylene chloride was suspended 0.659 g (2 mmole) of 2-(2-amino-l,3-thiazol-4-yl)-2-(l-carbazoyl-ethoxyimino)acetic acid tert-butyl ester, and to the suspension was added 2.5 g (12.3 mmole) of N,0-bis-(trimethylsilyl)acetamide to form a solution. To the 10 ice-cooled solution was added 0.565 g (2.2 mmole) of
3,4-diacetoxybenzoic acid chloride and the mixture was stirred for 1.5 hours under ice-cooling. The resulting mixture was poured into 150 ml of ether and to the mixture was added a small amount of methanol while 15 stirring. Resulting precipitates were collected by filtration, washed with ether and then dried to obtain 1.05 g of 2-(2-amino-l,3-thiazol-4-yl)-2-{l-[3-(3,4-di-acetoxybenzoyl)carbazoyl]ethoxyimino)acetic acid tert-butyl ester'hydrochloride. (Yield: 98.0 %)
1H NMR (dg-DMSO) 6:
1.53 (broad s, 12H), 2.28 (s, 6H), 4.82 (q, IH), 7.02 - 7.88 (m, 4H).
In 25 ml of methanol was dissolved 1.05 g (1.96 mmole) of the above hydrochloride, then 0.96 ml of 25 % aqueous 25 ammonia was added thereto and the mixture was stirred at room temperature for 40 minutes. The resulting mixture was concentrated, and the residue was dissolved in 100 ml of 30 % THF - ethyl acetate, dried over anhydrous magnesium sulfate and then the solvent was distilled out 30 after filtration. The resulting oily product was dissolved in 5 ml of trifluoroacetic acid and the solution was stirred at room temperature for 2 hours. Then, the resulting mixture was added dropwise into 100
#
ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.8 g of trifluoroacetic acid salt of the title compound. To 5 ml of ice-cooled 5 methanol was added 0.77 g (5 mmole) of phosphorus oxy-
chloride, and 0.8 g of the previously obtained trifluoroacetic acid salt was added thereto and the mixture was stirred for 10 minutes. The resulting mixture was added dropwise into 100 ml of ether while vigorously stirring 10 and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.55 g of the title compound. (Yield: 62.9 %) Melting point: 157 to 159 °C (decomposed).
Structural formula:
C-COOH
N-O-CH-CONHNHCO OH
-HCl
CH-
\r>
OH
NMR (dg-DMSO + DjO) 6:
1.46 (d, 3H), 4.85 (q, IH), 6.70 - 7.43 (m, 4H).
Example 85
Synthesis of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[l-(3-(3,4-dihydroxybenzoyl)carbazoyl)ethoxyimino]acetamido}-3-20 [(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid'hydrochloride
(I) In 5 ml of DMF were dissolved 0.5 g (1.12 mmole) of 2-(2-amino-l,3-thiazol-4-yl)-2-{1-[3-(3,4-dihydroxy-benzoyl)carbazoyl]ethoxyimino>acetic acid•hydrochloride 25 obtained in Reference example 23 and 0.55 6 g (1.12 mmole) of 7-amino-3-[(l,3,4-thiadiazol-2-yl)-thiomethyl]-3-
cephem-4-carboxylic acid diphenylmethyl ester and the mixture was ice-cooled, and 0.276 g (1.34 mmole) of DCC was added thereto and stirred at room temperature for one hour. After filtration of the resulting mixture, to the 5 filtrate was added the same amount of chloroform and the mixture was added dropwise into 200 ml of ether while vigorously stirring. Resulting precipitates were collected by filtration, washed with ether and then dried to obtain 1.01 g of the diphenylmethyl ester of the title 10 compound. (Yield: 97.5 %)
(II) A mixture comprising 4 ml of trifluoroacetic acid and 1 ml of anisole was ice-cooled, and to the mixture was added 0.3 g (0.32 mmole) of the diphenylmethyl ester obtained above and the mixture was stirred for 30 15 minutes. The resulting mixture was added dropwise into 80 ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.2 g of the title compound. (Yield: 82.4 %) Melting point: 191 to 197 °C 20 (decomposed).
Structural formula:
NMR (dg-DMSO) 6:
1.50 (d, 3H), 3.81 (broad s, 2H), 4.30 (m, 2H), 4.80
(q, IH), 5.26 (q, IH), 5.76 - 6.21 (m, IH), 6.75 -7.49 (m, 4H), 9.60 (s, IH).
Reference example 24
Synthesis of 2-(2-amino-l,3-thiazol-4-yl)-2-{l-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxyimino}acetic acid-hydrochloride
In 10 ml of methylene chloride was suspended 0.7 g (1.74 mmole) of 2-(2-amino-l,3-thiazol-4-yl)-2-(1-carbazoyl-l-methylethoxyimino)acetic acid tert-butyl ester, and to the suspension was added 2.16 g (10.6 mmole) of N,0-bis-(trimethylsilyl)acetamide to form a solution. To the 10 ice-cooled solution was added 0.48 8 g (1.9 mmole) of
3,4-diacetoxybenzoic acid chloride and the mixture was stirred for one hour under ice-cooling. The resulting mixture was poured into 150 ml of ether and to the mixture was added a small amount of methanol while 15 stirring. Resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.96 g of 2-(2-amino-l/3-thiazol-4-yl)-2-{l-[3-(3,4-di-acetoxybenzoyl)carbazoyl]-1-methylethoxyimino>acetic acid tert-butyl ester•hydrochloride. (Yield: 97.9 %)
^"H NMR (dg-DMSO) 6:
1.54 (s, 15H), 2.26 (s, 6H), 6.90 - 7.78 (m, 4H).
In 25 ml of methanol was dissolved 0.9 6 g (1.7 mmole) of the above hydrochloride, then 1 ml of 25 % aqueous ammonia was added thereto and the mixture was stirred at 25 room temperature for 30 minutes. The resulting mixture was concentrated, and the residue was dissolved in 100 ml of 30 % THF - ethyl acetate, dried over anhydrous magnesium sulfate and then the solvent was distilled out after filtration. The resulting oily product was dissolved in 30 10 ml of trifluoroacetic acid and the solution was stirred at room temperature for one hour. Then, the resulting mixture was added dropwise into 200 ml of ether while vigorously stirring and resulting precipitates were
collected by filtration, washed with ether and then dried to obtain 0.88 g of trifluoroacetic acid salt of the title compound. To 10 ml of ice-cooled methanol was added 0.77 g (5 mmole) of phosphorus oxychloride, and 5 0.88 g of the previously obtained trifluoroacetic acid salt was added thereto and the mixture was stirred for 10 minutes. The resulting mixture was added dropwise into 150 ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with 10 ether and then dried to obtain 0.63 g of the title compound. (Yield: 80.6 %)
Structural formula:
H2N
N jr
JJ
c-cooh ch3 .
n-o-c-conhnhco 4 V i \=/
•HCl ch.
\n
OH
XH NMR (dg-DMSO) 6:
1.54 (s, 6H), 7.00 - 7.90 (m, 4H).
Reference example 25
Synthesis of 2-(2-amino-l,3-thiazol-4-yl)-2-[3-(2-hydroxybenzoyl)carbazoyl]methoxyimino}acetic acid* hydrochloride
In 20 ml of DMF were dissolved 3.15 g (10 mmole) of 20 2-(2-amino-l,3-thiazol-4-yl)-2-carbazoylmethoxyimino-
acetic acid, 1.66 g (12 mmole) of salicylic acid and 1.62 g (12 mmole) of 1-hydroxybenzotriazole. To the ice-cooled solution was added 2.48 g (12 mmole) of DCC, and the mixture was stirred for one hour after removal of a 25 cooling bath. After filtration of the resulting
mixture, the filtrate was dissolved in 200 ml of ethyl acetate and then washed with water followed by washing with a saturated saline solution. Then, filtration and evaporation of the solvent were carried out. After the residue was dissolved in 15 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 3 hours, the resulting mixture was added dropwise into 5 00 ml of ether while vigorously stirring. Resulting precipitates were collected by filtration, washed with ether and dried to obtain the trifluoroacetic acid salt of the title compound. To 30 ml of ice-cooled methanol were added 2.25 g (14.7 mmole) of phosphorus oxychloride and then the trifluoroacetic acid salt obtained above, and the mixture was stirred for 10 minutes. The resulting mixture was added dropwise into 1.4 liters of ether while vigorously stirring, and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 4.02 g of the title compound. (Yield: 96.7 %)
Structural formula:
h2n
1H NMR (dg-DMSO) 6:
4.78 (s, 2H), 6.95 - 8.02 (m, 5H).
Example 86
Synthesis of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[l-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]-acetamido}-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid*hydrochloride
HCl
- 61
(I) In 7 ml of DMF were dissolved 0.6 3 g (1.37 mmole) of 2-(2-amino-l,3-thiazol-4-yl)—2 — {l-[3-(3,4-dihydroxy-benzoyl)carbazoyl]-l-methylethoxyimino}acetic acid hydrochloride obtained in Reference example 24 and 0.68 g (1.37 mmole) of 7-amino-3-[(1,3,4-thiadiazol-2-yl)thiomethyl ]-3-cephem-4-carboxylic acid diphenylmethyl ester and the mixture was ice-cooled, and 0.351 g (1.7 mmole) of DCC was added thereto and stirred at room temperature for 1.5 hours. After filtration of the resulting mixture, to the filtrate was added the same amount of chloroform and the mixture was added dropwise into 200 ml of ether while vigorously stirring. Resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.94 g of the diphenylmethyl ester of the title compound. (Yield: 73.1 %)
(II) A mixture comprising 6 ml of trifluoroacetic acid and 1.5 ml of anisole was ice-cooled, and to the mixture was added 0.94 g (1 mmole) of the diphenylmethyl ester obtained above and the mixture was stirred for 30
minutes. The resulting mixture was added dropwise into 150 ml of ether while vigorously stirring and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.7 g of the title compound. (Yield: 90.6 %)
structural formula:
H2N
|rC-CONH-1—T'SN N N
-V 1 A Ji
S N O J CH-S _
\> CH, C°0H
C00H_: -Hci
CH3 COOH
\j:-CONHNHCO y/y OH CH3 X5H
1H NMR (dg-DMSO) 6:
1.58 (s, 6H), 3.80 (broad s, 2H), 4.40 (m, 2H), 5.23 (d, IH), 5.74 - 6.15 (m, 1H), 6.80 - 7.82 (m, 4H), 9.58 (s, IH).
Example 87
Synthesis Of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-(3,4-diacetoxy benzoyl) carbazoyl) methoxy iminoacetamido} -3-[(5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester
In 4 0 ml of DMF was dissolved 6.309 g (9.5 mmole) of 7-
[ 2- (2-f ormylamino-1,3-thiazol-4-yl) -2- (3-f ormylcarbazoyl) -methoxyiminoacetoamido]-3-[(5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid sodium salt and the mixture was ice-cooled, and 4.88 g (20 mmole) of 15 1-iododiethylcarbonate was added thereto and stirred at room temperature for 3 hours. To the resulting mixture was added 700 ml of ethyl acetate and the mixture was washed with water and then washed with a saturated saline solution, dried over anhydrous magnesium sulfate and the 20 solvent was distilled out. The residue was purified through silica gel column chromatography (eluent: 5 % to 10 % methanol - chloroform). To 30 ml of ice-cooled methanol was added 0.92 g (6 mmole) of phosphorus oxy-chloride and then pruified product through column, and 25 the mixture was stirred for 1.5 hours under ice-cooling. The resulting mixture was added dropwise into 800 ml of ether while vigorously stirring and resulting precipitates were collected by filtration and dried. After the resulting product was dissolved in 30 ml of methylene 30 chloride and ice-cooled, 25 ml (10 mmole) of N,0-bis-(trimethylsilyl)acetamide was added thereto and the mixture was stirred for 10 minutes. Then, 0.9 g (3.5 mmole) of 3,4-diacetoxybenzoic acid chloride was added thereto and the mixture was stirred for one hour under
ice-cooling. The resulting mixture was added dropwise into 800 ml of ether and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 3.07 g of the title compound. (Yield: 35.5 %)
Structural formula:
XH NMR (dg-DMSO) 6:
1.24 (t, 3H), 1.53 (d, 3H), 2.28 (s, 6H), 3.72 (broad s, 2H), 4.24 (m, 2H), 4.72 (m, IH), 5.14 (d, IH), 5.75 - 6.14 (m, IH), 6.78 - 8.18 (m, 4H).
Example 88
Synthesis of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-(3,4-dihydroxyben zoy1)carba zoy1)me thoxyimi noacetamido} - 3 -pyridiniummethyl-3-cephem-4-carboxylic acid betaine
In 70 ml of methylene chloride was suspended 2.159 g (5 mmole) of 2-(2-famino-l,3-thiazol-4-yl)-2-[3-(3,4-di-hydroxybenzoyl)carbazoyl]methoxyiminoacetic acid hydrochloride and the mixture was ice-cooled, and then 3.49 g (25 mmole) of triethylamine and 2.54 ml (20 mmole) of trimethylchlorosilane (TMCS) were added thereto and stirred at room temperature for one hour to form a solution. The mixture was cooled to - 40 °C and 0.38 ml of DMF and 0.55 g (2.8 mmole) of trichloromethylchloro-formate (TCF) were successively added thereto. Then, the
S
OAc
mixture was stirred at - 30 °c for 0.5 hour and at - 15 °C for 3 hours and thereafter cooled again to - 35 °C.
To the resulting mixture was added a solution obtained by mixing 1.826 g (5 mmole) of 7-amino-3-pyridiniummethyl-5 3-cephem-4-carboxylic acid betaine hydrochloride, 2.55 ml (10.4 mmole) of N,0-bis(trimethylsilyl)acetamide and 20 ml of methylene chloride and stirring them at room temperature for one hour, and the mixture was stirred for 1.5 hours while cooling with ice-salt bath. The 10 resulting mixture was poured into 200 ml of ice-cooled water and stirred well. After distilled out the solvent, precipitates were removed by filtration. The filtrate was poured and adhered to a 5 00 ml of HP-20 column filled with water, washed with water and eluted by 50 % methanol 15 - water. After condensation of fractions containing the title compound, condensate was lyophilized to obtain 0.3 g of the title compound. (Yield: 8.9 %)
Structural formula:
3.72 (broad s, 2H), 4.43 (m, 2H), 4.74 (broad s, 2H),
.20 (d, IH), 5.68 - 6.04 (m, IH), 6.78 - 7.42 (m, 4H), 7.90 - 9.42 (m, 5H).
Example 89
In the same manner as in Example 88, the compound shown 25 below was obtained.
7—{2—[2-amino-l/3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxy-benzoyl)carbazoyl)ethoxyimino]acetamido}-3-pyridinium-methyl-3-cephem-4-carboxylic acid betaine Yield: 24.6 %
Structural formula:
1.44 (d, 3H), 3.81 (broad s, 2H), 4.40 (m, 2H), 4.81 (g, IH), 5.22 (d, IH), 5.72 - 6.13 (m, IH)/ 6.70 -7.44 (m, 4H), 7.92 - 9.53 (m, 5H).
Example 90
Synthesis of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-(3,4-dihydroxy benzoyl) carbazoyl )methoxyiminoacetamido}-3- (3-carboxypyridiniummethyl)-3-cephem-4-carboxylic acid betaine
After a mixture comprising 1.679 g (2.5 mmole) of 7-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-(3,4-dihydroxybenzoyl)-carbazoyl ]methoxy iminoacetamido }-3-ace toxymethyl-3-cephem-4-carboxylic acid, 1.616 g (13 mmole) of nicotinic acid, 4.5 g (30 mmole) of sodium iodide, 0.086 ml of phosphoric acid, 1.5 ml of water and 5 ml of acetonitrile was stirred for 9 hours in a bath of 65 to 75 °C, insolubles were removed by filtration. The filtrate was added dropwise into 450 ml of acetone and resulting precipitates were collected by filtration, washed with acetone
XH NMR (dg-DMSO) 6:
and then dried to obtain 0.79 g of the title compound. (Yield: 44.3 %)
Structural formula:
3.74 (broad s, 2H), 4.45 (m, 2H), 4.76 (broad s, 2H), 5.21 (d, 1H), 5.66 - 6.06 (m, 1H), 6.76 - 7.44 (mf 4H), 7.96 - 9.06 (mf 4H).
Examples 91 and 92
In the same manner as in Example 90, the compound shown by the following formula was prepared. The results are shown in Table 7.
OH
COOH
1H NMR (dg-DMSO) 6
OH
Table 7
Example z
Yield
(4)
1 H NMR C d g-DMSO)^
91
~Nv=y C00H
4 /. /
oL7^(broad s, JH)X 444<4< Cm. .2H), 44 77 C broad s, 3H ), £.24<Cd, /H)% £A,fr~£0£Cm, /H)x L7V-~7$0 Cm, 4<HX 77Z~&71> Cm, 4*H)
92
-N£)--CONH2
/£.2
J. 7(> C broad sf .2HK 444*4 Cm, ,2Hh 44 7£ Cbroad s, .2H ) x ir. J 6 C d, / H ) % i:£4^0.2Cm, /H )x L72-7S3 Cm, 4^H)v 7£J~204<Cm, #H)
Reference example 26
Synthesis of 6-[2-(2-amino-l,3-thiazol-4-yl)-2-carbazoyl-methoxyiminoacetamido]-penicillanic acid*dihydrochloride
To 10 ml of ice-cooled DMF was added 1.23 g (8 mmole) of 5 phosphorus oxychloride under stirring and stirring was continued at 40 °C for 30 minutes. After cooling the mixture to - 30 °C, 1.262 g (4 mmole) of 2-(2-formyl-amino-1,3-thiazol-4-yl)-2-(3-formylcarbazoyl)methoxyiminoacetic acid was added thereto and the mixture was stirred 10 at - 20 to - 30 °C for one hour. A mixture comprising
0.952 g (4.4 mmole) of 6-aminopenicillanic acid (6-APA), 20 ml of methylene chloride and 1.79 g (8.8 mmole) of N,0-bis(trimethylsilyl)acetamide was stirred at room temperature for 30 minutes and cooled to - 40 °C. To the 3_5 thus obtained mixture was added the previously obtained mixture for 5 minutes under cooling, and the mixture was stirred at - 40 °C for 3 hours. The reuslting mixture was added dropwise into 100 ml of ice-cooled water and simultaneously a 5 % aqueous sodium hydrogencarbonate 20 solution was added thereto to adjust to pH 7. After separation of a methylene chloride layer, an aqueous layer washed with methylene chloride was adjusted to pH 5 with a 2N-hydrochloric acid and distilled out methylene chloride dissolved in the aqueous layer. The remaining 25 aqueous layer was adjusted to pH 2 with a 2N-hydrochloric acid and saturated with salt. Then, the aqueous layer was extracted with 100 ml of THF, the extract was dried over anhydrous magnesium sulfate and distilled out the solvent. To the oily residue were added 50 ml of water 30 and a 5 % aqueous sodium hydrogencarbonate solution to dissolve it at pH 7, and the solution was adhered to a column filled with 100 ml of HP-20, washed with water and eluted with 50 % methanol - water. Distillation of methanol from the eluant, followed by lyophilization of 35 the resulting aqueous solution yielded powder. To 5 ml
of ice-cooled methanol was added 0.28 g (183 mmole) of phosphorus oxychloride, and then the previously obtained powder was added thereto and the mixture was stirred for one hour under ice-cooling. The resulting mixture was 5 added dropwise into 150 ml of ether while vigorously stirring, and resulting precipitates were collected by filtration, washed with ether and dried to obtain 0.57 g of the title compound as a white powder. (Yield: 26.9 %) Melting point: 178 to 185 °C (decomposed).
Structural formula:
1H NMR (dg-DMSO) <5:
1.38 (s, 3H), 1.58 (s, 3H), 4.12 (s, IH), 4.72 (broad s, 2H), 5.30 - 5.72 (m, 2H), 7.28 (s, IH).
Example 93
Synthesis of 6-{2-(2-amino-l,3-thiazol-4-yl)-2-[3-(3,4-dihydroxybenzylidene)carbazoyl]methoxyiminoacetamido}-penicillanic acid*hydrochloride
To 5 ml of methanol were dissolved 0.4 g (0.754 mmole) of 6-[2-(2-amino-l,3-thiazol-4-yl)-2-carbazoylmethoxyimino-20 acetamido]penicillanic acid*dihydrochloride obtained in Reference example 26 and 0.11 g (0.8 mmole) of 3,4-dihydroxy ben zaldehyde and the mixture was stirred at room temperature for one hour. The resulting mixture was added dropwise into 150 ml of ether while vigorously 25 stirring, resulting precipitates were collected by
\
• 2HC1
0.
\
CH2-CONHNH2
filtration, washed with ether and then dried to obtain 0.4 g of the title compound as a pale yellow powder. (Yield: 86.4 %) Melting point: 177 to 183 °C (decomposed).
Structural formula:
^■H NMR (dg-DMSO) 6:
1.37 (s, 3H), 1.59 (s, 3H), 4.13 (s, IH), 4.73 (broad s, 2H), 5.22 - 5.52 (m, 2H), 6.82 - 7.34 (m, 4H), 8.07 (d, IH).
Example 94
Synthesis of sodium 6-{2-[2-amino-l,3-thiazol-4-yl]-2-[3-(3,4-dihydroxybenzoyl)carbazoyl]methoxyiminoacetamido}-penicillanate
In 200 ml of methylene chloride was suspended 5.8 g 15 (13.43 mmole) of 2-(2-amino-l,3-thiazol-4-yl)-2-[3-(3,4-di hydroxyben zoyl)carba zoy1 ] methoxyiminoacet i c acid* hydrochloride and the suspension was ice-cooled, 9.4 ml (67.15 mmole) of triethylamine and 6.82 ml of TMCS were added thereto and the mixture was stirred for one hour. 20 After the resulting mixture was cooled to - 40 °C, 1 ml of DMF and 0.97 ml (8.06 mmole) of trichlormethylchloroformate were successively added thereto and the mixture was stirred at — 15 to — 20 °C for 2 hours and then cooled again to - 40 °c.
\
•HCl
To the thus obtained mixture was added a solution obtained by stirring a mixture comprising 3.244 g (15 mmole) of 6-APA, 100 ml of methylene chloride and 6.1 g (30 mmole) of N,0-bis-(trimethylsilyl)acetamide at room temperature for one hour, and the mixture was stirred at - 20 °c for 1.5 hours, and then for 0.5 hour while cooling with an ice-salt bath. The resulting mixture was adjusted to pH about 2 with a 5 % aqueous sodium hydrogencarbonate solution while pouring it into 200 ml of ice-cooled water. Precipitates were collected by filtration, washed with water and then with ether, and dried. After the obtained crude product was dissolved in 30 ml of DMF, 2.5 g of sodium 2-ethylhexanoate was added thereto and the mixture was stirred. After filtration, the filtrate was added dropwise into 800 ml of a 10 % methanol - ether mixture. Resulting precipitates were collected by filtration, washed with a 10 % methanol - ether and then with ether, and dried. This product was dissolved in 100 ml of water. After filtration of the solution, the filtrate was adhered to a column filled with 4 00 ml of HP-20, washed with water and eluted with 20 % methanol -water. Fractions containing the title compound were condensed and lyophilized to obtain 2.12 g of the title compound. (Yield: 25.68 %)
Structural formula:
1.52 (s, 3H), 1.54 (s, 3H), 4.08 (s, IH), 4.71 (broad s, 2H), 5.48 - 5.72 (m, 2H), 6.81 - 7.58 (m, 4H).
OH
1H NMR (dg-DMSO) 5:
Reference example 27
Synthesis of 2-(2-formylamino-1,3-thiazol-4-yl)-2-(3-t-butoxycarbonylcarbazoylamino)acetic acid ethyl ester
A suspension comprising 6.44 g (0.1014 mole) of N,N'-5 carbonyldiimidazole suspended in 70 ml of N,N-dimethyl-formamide was stirred under ice-cooling to set at 0 °C, and to the mixture was added 13.4 0 g (0.1014 mole) of t-butylcarbazate by dividing it into a small amount while maintaining the temperature of the mixture to 20 °C. 10 After completion of the addition, the mixture was further stirred for 2 hours under ice-cooling and a solution of 15.5 g (67.6 mmole) of 2-amino-2-(2-formylamino-1,3-thia-zol-4-yl)acetic acid ethyl ester dissolved in 25 ml of DMF was added thereto for 5 minutes, and stirring was 15 continued under ice-cooling for 30 minutes and at room temperature for 15 hours.
The resulting mixture was poured into 800 ml of water, neutralized with 2N hydrochloric acid to pH 4 and extracted five times with 200 ml of chloroform. The 20 obtained extracts was washed three times with 300 ml of water, dried over anhydrous magnesium sulfate and distilled the solvent under reduced pressure. The resulting amorphous residue was ground with diisopropyl ether and filtrated to obtain 19.4 g (Yield: 74 %) of 25 2-(2-formylamino-1,3-thiazol-4-yl)-2-(3-t-butoxycarbonyl-carbazoylamino)acetic acid ethyl ester as a pale yellow crystal. Melting point: 85 °C (decomposed).
Structural formula:
OHCHN &
NHCONHNHCOOC(CH3)3
1
H NMR (CDC13) 6:
1.20 (3H, t, J=8Hz), 1.40 (9H, s), 4.19 (2H, q, J=8) , 5.60 (1H, d, J=8) (which becomes singlet with D20) , 6.95 (1H, broad s, J=8) (which is disappeared with D20), 6.99 (IH, s), 7.56 (1H, broad s) (which is disappeared with D20), 7.88 (IH, broad s) (which is disappeared with D20), 8.58 (1H, s).
Reference example 28
Synthesis of 2-(2-formylamino-l,3-thiazol-4-yl)-2-(3-t-butoxycarbonylcarbazoylamino)acetic acid
In 85.6 ml of 0.5 M aqueous sodium hydroxide solution was suspended 8.3 g (21.42 mmole) of the compound obtained in Reference example 27, and the mixture was stirred at room temperature for 45 minutes. To the obtained mixture was added'150 ml of ethyl acetate, and the mixture was adjusted to pH 3 with the addition of 2N hydrochloric acid and an aqueous layer was extracted twice with 100 ml of ethyl acetate. The obtained organic layers were dried over anhydrous magnesium sulfate, the solvent was distilled under reduced pressure, and the residue was ground with ether, filtered and dried to obtain 6.99 g (Yield: 91 %) of 2-(2-formylamino-1,3-thiazol-4-yl)-2-(3-t-butoxycarbonylcarbazoylamino)acetic acid as a white crystal. Melting point: 121 °C (decomposed)
Structural formula:
OHCHN o
NHCONHNHCOOC(CH3)3
74
1H NMR (CDC13 + dg-DMSO) 6:
1.22 (3H, t, J=7Hz), 1.42 (9H, s), 4.07 (2H, q, J=7),
.4 8 (IH, d, J=8) (which becomes s with D20)r 6.72
(IH, d, J=8) (which is disappeared with D2o), 7.01
(1H, s), 7.82 (IH, s) (which is disappeared with
D20), 8.02 (IH, s) (which is disappeared with D20), 8.45 (IH, s).
Reference example 29
Synthesis of 2-(2-formylamino-l,3-thiazol-4-yl)-2-(3-t-butoxycarbonylcarbazoylamino)acetic acid ethyl ester* hydrochloride
To 20 ml of methanol was added 0.96 g (10.3 mmole) of phosphorus oxychloride under ice-cooling, and the mixture was stirred and set to 0 °C. To the mixture was added little by little dividing 2.00 g (5.16 mmole) of the product obtained in Reference example 27. The mixture was stirred at the same temperature for 1.5 hours, poured into 200 ml of ether while stirring and precipitates were collected by filtration to obtain a white crystal of the title compound 1.80 g (Yield: 88 %) as a hydrochloride.
Structural formula:
1.30 (3H, t, J=8Hz), 1.40 (9H, s), 4.11 (2H, q, J=8), 5.34 (IH, d, J=6) (which becomes singlet with substitution of D2o), 6.33 (IH, s).
h2n
S
NHCONHNHCOOC(CH3) * HCl
XH NMR (CDC13 + dg-DMSO) 6:
Reference example 30
Synthesis of 2-(l-amino-l,3-thiazol-4-yl)-2-(3-t-butoxy-carbonylcarbazoylamino)acetic acid
To 0.75 g (1.89 mmole) of the product according to 5 Reference example 29 was added 5.7 ml of a IN aqueous sodium hydroxide solution and the mixture was stirred at room temperature for one hour. After dilution of the mixture with 20 ml of water, the mixture was neutralized with 2N hydrochloric acid and adjusted to pH 3, saturated 10 by the addition of salt and extracted twice with 25 ml of tetrahydrofuran. The extracts were washed with 15 ml of a saturated saline solution, dried over anhydrous magnesium sulfate and evaporated to obtain residue.
Ether was added to the residue to be powdered to obtain 15 0.35 g of the title compound. (Yield: 56 %) Melting point: 123 °c (decomposed).
Structural formula:
N n-CH-COOH
Ji J) NHCONHNHCOOC (CH, ) _ -H2N^ S 33
1H NMR (dg-DMSO) 6:
1.40 (9H, s), 5.09 (IH, d, J=9Hz) (which becomes 20 singlet with substitution of D2°)» 6.45 (IH, s).
Reference example 31
Synthesis of 6-[2-(2-formylamino-l,3-thiazol-4-yl)-2-(3-t-butoxycarbonylcarbazoylamino)acetamido]penicillanic acid
After dissolving in 4 0 ml of THF a mixture comprising
2.00 g (5.565 mmole) of the compound obtained in Refer-
ence example 28 and 0.752 g (5.565 mmole) of 1-hydroxy-benzotriazole, the solution was ice-cooled to - 10 °C and 1.15 g (5.565 mmole) of DCC was added thereto all at once. The mixture was stirred at - 10 to 0 °C for 3 5 hours.
During this stage, to 5 0 ml of methylene chloride suspension suspended 1.20 g (5.565 mmole) of 6-APA was added 1.94 ml (13.9 mmole) of triethylamine and the mixture was stirred at room temperature to form a solution. The 10 resulting solution was added dropwise to the previously prepared mixture for 5 minutes and the mixture was stirred at 0 °C for 2 hours.
The resulting mixture was filtered, and the residue was washed with a small amount of THF. The filtrates were 15 combined and evaporated, the residue was distributed to 100 ml of 2 % aqueous sodium hydrogencarbonate solution and 70 ml of ethyl acetate, and was extracted with 30 ml of 2 % aqueous sodium hydrogencarbonate solution further from the organic layer. The aqueous layers were 20 combined, neutralized with 2N hydrochloric acid and adjusted to pH 3.5. The mixture was extracted twice with 100 ml of ethyl acetate, the extracts were dried over anhydrous magnesium sulfate and evaporated. To the residue of which a part was crystallized was added a 25 mixed solution comprising 100 ml of ether and 100 ml of isopropyl ether, and insolubles were removed by filtration yielded 1.82 g of crude crystals containing 1-hydro-xybenzotriazole. The thus obtained product was purified through silica gel column chromatography (Silicagel 60 30 Merck; 50 g) by eluting it with chloroform - methanol -formic acid (50 : 5 : 2) to obtain 0.860 g of white crystals of monoformic acid salt of the title compound. (Yield: 25.6 %)
Melting point: 194 °c (decomposed).
Structural formula:
ohchn
N jT~
JJ
CH-CONH
NHCONHNHCOOC(CH3)
XH NMR (CDC13 + dg-DMSO) 6:
1.45 (9H, s), 1.49, 1.62 (each 3H, s), 4.78 (7H, s),
.56 (3H, s) (which changes with DjO substitution),
7.04 (IH, s), 8.07 (IH, s) (HCOOH), 8.46 (IH, s).
Reference example 32
Synthesis of 6-[ 3-(2-formylamino-1,3-thiazol-4-yl)-2-carbazoylaminoacetamido]penicillanic acid*trifluoroacetic acid salt
To 0.800 g (1.44 mmole) of the product obtained in Reference example 31 were added succesively 1 ml of anisole and 5 ml of trifluoroacetic acid and the mixture was stirred for one hour under ice-cooling and further for one hour at room temperature. The resulting mixture was added dropwise into 100 ml of stirring ether, and precipitates were collected by filtration, vacuum dried to obtain 0.814 g of the title compound as its trifluoroacetic acid salt. (Yield: 99.3 %) Melting point: 119 °C (decomposed).
Structural formula:
OHCHN
N n-
JJ
CH-CONH
nhconhnh2•cf3cooh
1H NMR (dg-DMSO) 6:
1.42 (3H, s), 1.49 (3H, s), 3.14 (IH, S), 5.00 - 5.80 (3H, m), 7.10 (1H, s), 8.42 (1H, s).
Example 95
Synthesis of 6-[2-(2-formylamino-l,3-thiazol-4-yl)-2-{3-(3,4-dihydroxybenzylidene)carbazoylamino}acetamido]-penicillanic acid
In 3 ml of methanol was dissolved 300 ml of the compound according to Reference example 32, and 109 mg (0.787 mmole) of 3,4-dihydroxybenzaldehyde was added thereto at room temperature and the mixture was stirred for one hour at the same temperature. The resulting solution was added to 60 ml of ether while stirring, and precipitates were collected by filtration and vacuum dried to obtain 174 mg (Yield: 57.4 %) of the aimed white powder.
Melting point: 158 °c (decomposed).
Structural formula:
OHCHN
N—
A.
-CH-CONH-
/S\^CH
-N-
X 3
H3
COOH
,OH
NHCONHN=CH OH
LH NMR (dg-DMSO) 6:
1.39 (3H, s), 1.53 (3H, s), 3.54 (IH, s), 4.8 - 5.9
(3H, m), 6.78 (IH, s), 7.11 (2H, m), 7.41 (IH, m),
7.72 (IH, s), 8.43 (IH, s).
Example 96
Synthesis of 6-[2-(2-amino-l,3-thiazol-4-yl)-2-{3-(3,4-dihydroxybenzylidene)carbazoylamino}acetamido]penicillanic acid*hydrochloride
In 3 ml of methanol was added under ice-cooling 0.20 ml (2.15 mmole) of phosphorus oxychloride and the mixture was stirred for 5 minutes. Then, 130 mg (0.225 mmole) of the compound according to Example 92 was added thereto and the mixture was stirred at the same temperature for one hour. The resulting mixture was added dropwise to 50 ml of ether while stirring, and precipitates were collected by filtration and vacuum dried to obtain 95 mg (Yield: 72.0 %) of the title compound as a white powder. Melting point: 163 °C (decomposed).
Structural formula:
1H NMR (dg-DMSO) 6:
1.55 (6H, s), 3.72 (IH, s), 5.0 - 5.9 (3H, m), 6.87 (3H, m), 7.16 (IH, m), 7.95 (IH, s).
Reference example 33
Synthesis of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-(3-t-butoxycarbonylcarbazoylamino)acetamido]cephalosporanic acid diphenylmethyl ester
•HCl
~ 80 t.
300 mg (0.905 mmole) of the compound according to Reference example 30 and 397 mg (0.905 mmole) of 7-ACA diphenylmethyl ester in 3 ml of DMF was stirred under ice-cooling, and to the mixture was added 2 05 mg (0.996 5 mmole) of DCC and stirred for one hour at the same temperature and further for one hour at room temperature. After a small amount of ethyl acetate was added thereto, the mixture was filtered to remove insolubles and washed with ethyl acetate. The filtrate and washing solution 10 were combined and added dropwise into 150 ml of ether while stirring. Resulting precipitates were collected by filtration and vacuum dried to obtain 342 mg of the title compound as a pale orange powder. (Yield: 50.3 %)
Structural formula:
XH NMR (CDCI3) 5:
1.41 (9H, s), 1.96 (3H, s), 3.35 (2H, m), 4.83 (2H, m), 5.65 (2H, m), 6.83 (IH, m), 6.91 (2H, s), 7.38 (10H, s).
Reference example 34
Synthesis of 7-[2-(2-formylamino-l,3-thiazol-4-yl)-2-(3-t-butoxycarbonylcarbazoylamino)acetamido]-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl3-3-cephem-4-carboxylic acid diphenylmethyl ester
In 4 ml of DMF solution containing a mixture comprising 25 670 mg (1.86 mmole) of the compound according to Reference example 28 and 952 mg (1.86 mmole) of 7-amino-3-(2-methyl-1,3,4-thiazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid diphenylmethyl ester was added under ice-cooling 390 mg (1.89 mmole) of N,N'-dicyclohexylcarbodiimide (DCC) and the mixture was stirred at the same temperature for 30 minutes and at room temperature for one hour. To the 5 mixture was added 5 ml of ethyl acetate, the mixture was stirred for 5 minutes and then filtered to remove insolubles, and the residue was washed with a small amount of the same solvent. The filtrate and washing solution were combined and added dropwise into 170 ml of 10 ether while stirring, and precipitated solids were collected by filtration and vacuum dried to obtain 1.39 g (Yield: 88 %) of a white powder of the title compound. Melting point: 150 °C (decomposed).
Structural formula:
OHCHN
N rr-
AT
CH-CONH-
//
-N
N N
ch2S^\s-J^CH3
COOCHPh.
NHCONHNHCOOC(CH3)
XH NMR (CDC13)
1.39 (9H, s), 2.62 (3H, s), 3.58 (2H, m), 4.25 (2H, m), 4.87 (IH, m), 5.71 (2H, m), 6.91 (2H, s), 7.30 (10H, s), 8.47 (IH, s).
Reference examples 35 to 39
in the same manner as compounds represented prepared. The results in Reference example 34, the by the following formula were are shown in Table 8.
ohchn
XI
■ ch-conh-
■n-
0
cooh ch2-t nhconhnhcooc(ch3)3
83 -
Table 8
inference example
T
yield (%)
NMR (CDCZi + DMSO-d J <* (ppm)
s —
i r>
U
XH
9 8 4
/.3 7 (9H , s ) s 3.52(2H ,m)s V.33 (2H , m h *"Jr (/H tm)% J-.^(JH,m)s 1,9 0 {2 H , s K 7 ,30 (/OH )x 8.50 (/ H , $ )
36
— S _
i 1 6h5
9 3*
/ . ( ?H , s )% J . AA (.2H , m) v V . 00 (3H , s )s V-'. 3 0 (2 H , m ) x £ . ff A ( / H , m h 5. 6 5 (2H ,m), 6.9/ (JH,s)N 7.30(10 H,s)n j(<fo(/H,s)
37
N N
-sXNJ<
1
ch2co2ch*2
9 9 4
¥■., 7 8 (/H ,m)v A . 0 / ( .2H . s h 7.3/ (20 H ,s)N J.JM/H.s)
38
N — N — s -/ oh
101i
/ .¥3 (9 H , s ), J. JJ (JH,»)» J. 0.3r ( 3H , mh V- .07 (2H t m) x 5 . 00 ( / H ,m) y 5 .37 ( / H , m ) N 5 . 70 I / H .m)y 6 .V-S (/ H , s )% 6 . 9 / ( / H , s h 7 , VO l/OH , *')s 8 . 5 / ( / H , s )
39
CH j \ N
— S"\ >°CH^
7 9*
/ . 3 t> (9H , s ) N J . <* / ( J H , s ) N J . A A ( JH , m ) %
. 7 7 ( / H , m ) % A . 6 A ( .2 H , m ) N £ . £ 7 { / H , s ), i .n (JH , s)v 7. , s), 8 . 3V ( /H , s)
Note: measured by using CDC&3
Reference example 40
Synthesis of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-(3-t-butoxycarbonylcarbazoylamino )acetamido]-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester•hydrochloride
After 15 ml of methanol was ice-cooled to set 5 °C, 0.73 ml (7.82 mmole) of phosphorus oxychloride was added thereto and the mixture was stirred for 5 minutes. To the resulting mixture was added 3.3 3 g (3.91 mmole) of the compound according to Reference example 34, and the mixture was further stirred for 1.5 hours under ice-cooling. The resulting mixture was added into 200 ml of ether while stirring, precipitated solids were collected by filtration and the residue was vacuum dried to obtain 3.30 g (Yield: 98 %) of a white powder of the title compound. Melting point: 119 °c (decomposed).
Structural formula:
*H NMR (CDC13 + dg-DMSO) 6:
1.41 (9H, s), 2.66 (3H, s), 3.77 (2H, m), 4.39 (2H, m), 5.15 (IH, m), 5.73 (2H, m), 6.96 (2H, s), 7.41 (10H, s).
COOCHPh
2
NHCONHNHCOOC(CH3)3
•HCl
Reference examples 41 to 4 5
In the same manner as in Reference example 40 by treating the compounds according to Reference examples 35 to 39, the compounds represented by the following formula were 5 prepared. The results are shown in Table 9.
•HCl
COOCHPh
2
NHCONHNHCOOC (CH-j) 3
Table 9
Reference exanrole
Starting material (Ref. ex. No.
T
yield {%
Melting point
NMR i (ppm)
41
N N
-U. JL„
s
9 1
/ 7 SX,
(decomposec
(CDC/j+DMSO-d i )
/ .VO (9 H , s X 3 . 72\ 2H ,m)N 4^ . J J (J2H , m ) N > J.W(/H,m)^ ^.^(JH,m), t> . S 9 ( 2H , s X 7 . (/0H , s X 7 . /# (/H . s )
42
36
N N
-4. J
N
1
CH j
9S
—
-
43
37
1 1
S~\
i N 1
CHjCOjCHtfj
7 3
-
(CDCij ) .
/.J?(9H , s X J . £0(.2H ,mX ^//UH.m), it.JM/H.m), i",00UH ,mX ,Jr. £0 {J2H , mX J.^(JHfm), £.J#(/H,sh 6.JJ(.2H,sh
7 . Ji" U0H , 5 )
44
38
1
in
° JL
o
X
9 0
—
(CDCZg+DMSO-d 6)
/ .V219H ,*)* 3 , 29 (3H . *)s 3 .&/ (2H , m)N I .0Jr (JH ,mX £.2 (/H ,mX .5". J 7 { / H , m X S.70 (/ H ,mX 4 . #4 (/H , s h £.7JM / H , s X 7 . J J ( /0H , s )
45
39
CH,
N
-S-/ y- OCHtf 2 *0
9 0
—
—
Reference example 4 6
Synthesis of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-carbazoyl-aminoacetamido]-3-[(2-methyl-l,3,4-thiadiazol-5-yl)thiomethyl ]-3-cephem-4-carboxylic acid*dihydrochloride
After 15 ml of trifluoroacetic acid and 3 ml of anisole were ice-cooled to 0 °c, to the mixture was added 3.00 g (3.49 mmole) of the compound according to Reference example 40 and the mixture was stirred at the same temperature for one hour. After to the resulting mixture was added 1 ml of conc. hydrochloric acid, the mixture was stirred at the same temperature for one minute and added into 250 ml of ether, and the mixture was further stirred for 10 minutes. Precipitated solids were collected by filtration and vacuum dried to obtain 2.15 g (Yield: 98 %) of a pale yellow solid of the title compound as dihydrochloride.
Structural formula:
JCJ
CH-CONH
h2n- S
NHCONHNH,
N N
A
COOH
CH2S' "S' CH3
•2HC1
XH NMR (dg-DMSO) 6:
2.67 (3H, s), 3.68 (2H, m), 4.36 (2H, m), 5.05 (IH, 20 m), 5.56 (2H, m), 6.70 (IH, s).
Reference examples 47 to 52
In the same manner as in Reference example 46 by treating the compounds according to Reference example 33 and Reference examples 41 to 45, the compounds represented by 5 the following formula were prepared. The results are shown in Table 10.
CH-CONH
S
h2n
0
CH2-T •2HCl
COOH
NHCONHNH
2
cd xi
E a a
•o
-o ■o
1
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EC
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z==f
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1.
X
h z=z 8
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1
m
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1
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1
Starting material (Fef. ex. No m m
H
CN ■*r .
CO ■*r
in •c"
8
§5
<y i1
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& 8
r-•*3*
00 ■"3"
CT\
<a>
0 in
1—i in
CN
m
Example 97
Synthesis of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-{3-(3,4-dihydroxybenzylidene)carbazoylamino)acetamido]-3-t(2-methyl-1,3, 4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid*hydrochloride
To 3 ml methanol solution containing 200 mg (0.317 mmole) of the compound obtained in Reference example 46 was added 50 mg (0.362 mmole) of 3,4-dihydroxybenzaldehyde and the mixture was stirred at room temperature for 1.5 hours. The resulting mixture was added dropwise into 70 ml of ether while stirring, precipitated solids were collected by filtration and vacuum dried to obtain 195 mg (Yield: 86 %) of a white powder of the title compound.
Structural formula:
h2n
N rr xJ
-ch-conh-
Z-1
"N
1 n n cooh
, oh nhconhn=ch 4 \ oh
-HCl
1H NMR (dg-DMSO) 6:
2.67 (3H, s), 3.65 (2H, m), 4.37 (2H, m), 5.10 (IH, m), 5.62 (2H, m)f 6.83 (3Hf broad s), 7.14 (1H, broad s), 7.75 (1H, s), 9.45 (IH, IH, d, J=9).
Examples 98 to 113
In the same manner as in Example 97, hydrochlorides of the B-lactam compounds represented by the following
~ 91 -
formula were prepared. The results are shown in Table 11.
N n-CH-CONH-
JO
H2N' S
■N
NHCONHN=C
/°2
COOH
ch2-T
V
- £6 -
101
100
vo vo
VO CO
Example l
1
CO
° 1 " z 2
i '
o-^f o
■ i
1
c/>
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M
X
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w
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1
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U
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Example 114
Synthesis of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-{3-(3,4-diacetoxybenzoyl)carbazoylamino}acetamido]-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic 5 acid'hydrochloride
In 6 ml of dried THF were dissolved 143 mg (0.60 mmole) of 3,4-diacetoxybenzoic acid and 81 mg (0.60 mmole) of 1-hydroxybenzotriazole, the mixture was ice-cooled to maintain 0 °C, and then 136 mg (0.66 mmole) of DCC was 10 added thereto and the mixture was stirred at the same temperature for 25 minutes and at room temperature for one hour. The resulting mixture was ice-cooled to 0 °C, and to the mixture was added dropwise for 5 minutes a separately prepared solution comprising 315 mg (0.500 25 mmole) of the compound obtained in Reference example 46
dissolved in 4 ml of DMF - 0.14 ml of triethylamine. The mixture was then stirred at the same temperature for 30 minutes and at room temperature for 2 hours.
To the resulting mixture was added 25 ml of THF and the 20 mixture was stirred for 5 minutes and filtered to remove insolubles. The filtrate was added into 150 ml of ether while stirring and after 10 minutes stirring, precipitated solids were collected by filtration. The obtained residue was washed twice with 25 ml of methylene chloride 25 and ether, respectively, and then vacuum dried to obtain 304 mg (Yield: 75 %) of a white powder of the title compound. Melting point: 123 °C (decomposed).
Structural formula:
N—
.A
-CH-CONH-
h2N s
^ N N
/-N\A A A
I | CEjS S
COOH
/0AC -HCl
NHCONHNHCO J x OAc
CH-
2H NMR (dg-DMSO) 6:
2.30 (6H, s), 2.67 (3H, s), 3.06 (2H, m), 4.24 (2H, m), 4.9 - 5.7 (3H, m), 6.41 (1H, s), 7.33 (1H, d), 5 7.70 (2H, m).
Example 115
Synthesis of 7-[2-(2-amino-l/3-thiazol-4-yl)-2-{3-(3/4-diacetoxy ben zoyl) carbazoylamino) acetamido ] -3- [ (2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic 10 acid*hydrochloride
In 4 ml of dried methylene chloride was suspended 400 mg (0.634 mmole) of the compound obtained in Reference example 46, and to the mixture was added 1.75 ml (7.17 mmole) of N,0-bis(trimethylsilyl)acetamide and the 15 mixture was stirred at room temper at ue for 30 minutes to obtain a transparent solution. To the solution was added 202 mg (0.789 mmole) of 3,4-diacetoxybenzoylchloride at room tepmerature while stirring and stirring was continued at the same conditions for 45 minutes.
The resulting mixture was added into 100 ml of ether and addition of 10 ml methanol thereto under stirring caused
precipitation of solids. Ten minutes later, the precipitates were collected by filtration, and the residue was washed with ether and vacuum dried to obtain 427 mg (Yield: 83 %) of the title compound. This compound was accorded with the compound obtained in Example 109 in both of TLC and NMR.
Examples 116 to 119
In the same manner as in Example 115, hydrochlorides of the B-lactam compounds represented by the following formula were prepared. The results are shown in Table 12.
ch-conh
S
0
cooh ch2-t nhconhnhcoq3
Table 12
Example
T
Qs
Yield ( % )
Melting point
( TC )
1 HNMR (d4-D M S 0 ) J
116
P
CO
1
OAc
89 .S
//7"C
lecamposec
•2.J0(6H,s), 3.70(2H,m), V.V2(2H,m). $.//(/H,m), £.7£(/H,s),
)
7.^(jH,m), 7.77(/H,m), 7.^(/H,s)
117
N- N
- S—IL S.J-CH,
OAC
OAc
9/ .0
(
/OO'C iecanposec
2.28(6H,s), 2.66(3H,s), 3.6S(2H,m), ¥.3S(2H,m), S.06(/H,m), .5" .57 (.2H ,m) , ^6.7S(/H,s), 7./8(/H,br o ad s), 7.SJ(2H, broad s)
118
N- .N
-aj
Ditto
86 . A
(
90 "C
decompose*
2.29(6 H.s), 3.72(2H,m), V .M-(2H ,m) , jj S.A.ff0(/H,s), 7..2.2(/H,m) , 7.^y(JH,m), 7.^(/H,s)
0 119
Ditto
OAc
-NHCO OAc
72.0
-
J.J7(6Hts), 3.68(2H,m), V- .V2(2H ,m) , S.//(/H.m), , 6.78(/H,s), 7.V/(/H,m), 7.88(2H,m), 9.S6(/H,«)
Note < ) 3/4-diacetoxybenzoylisocyanate was employed in place of acid chloride.
Example 120
Synthesis of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-{3-(3,4-dihydroxybenzoyl)carbazoylamino)acetamido]-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic
In 3 ml methanol solution containing 385 mg (0.474 mmole) of the compound obtained in Example 109 was added 0.38 ml of 25 % aqueous ammonia and the mixture was stirred at room temperature for 2 hours. The resulting mixture was 10 added into 100 ml of ether and the mixture was stirred for 10 minutes. Then, solids precipitated were collectedr by filtration, and the residue was vacuum dried to obtain 406 mg of crude powder. This powder was purified through silica gel column chromatography (Silica gel 20 g, 15 eluent: CHC13 - MeOH - HCOOH 50 : 20 : 6) to obtain 115 mg (Yield: 32 %) of monoformix acid salt of the title compound. Melting point: 193 °C (decomposed).
Structural formula:
acid h2N
COOH
CH
3
OH
1H NMR (dg-DMSO) 6:
2.68 (3H, s), 3.75 (2H, m), 4.41 (3H, m), 5.15 (IH m), 5.57 (IH, m), 6.88 (IH, m), 7.33 (3H, m).
- "lOfr -
Reference example 53
Synthesis of 2-(2-formylamino-l,3-thiazol-4-yl)-2-ethoxalylaminoacetic acid tert-butyl ester
In 100 ml of methylene chloride was dissolved 5.5 g (21.4 5 mmole) of 2-amino-2-(2-formylamino-l,3-thiazol-4-yl)-
acetic acid tert-butyl ester, and 2.165 g (21.4 mmole) of triethylamine was added thereto. Then, the mixture was cooled to - 45 °c and a solution of 2.92 g (21.4 mmole) of ethyl chlorooxalate dissolved in 10 ml of methylene 10 chloride was added dropwise thereto for 10 minutes.
Then, a cooling bath was removed, and the mixture was stirred for 30 minutes. After the mixture was washed with water, it was dried over anhydrous magnesium sulfate and the solvent was evaporated to obtain 7.5 g of the 15 oily title compound. (Yield: 98 %)
Structural formula:
Reference example 54
Synthesis of 2-(2-amino-l,3-thiazol-4-yl)-2-carbazoyl-carbonylaminoacetic acid tert-butyl ester
In 30 ml ethanol was dissolved 7.5 g (21.0 mmole) of 2-(2-formylamino-l,3-thiazol-4-yl)-2-ethoxalylaminoacetic 25 acid tert-butyl ester obtained in Reference example 53,
1H NMR (CDCI3) 6s
1.33 (t, 3H), 1.44 (s, 9H), 4.30 (q, 2H), 5.53 (d, IH), 7.02 (s, IH), 8.25 (d, 1H), 8.72 (s, IH).
2.53 g (50 mmole) of hydrazine hydrate was added thereto and the mixture was refluxed for one hour. After cooling, precipitates were collected by filtration, washed with ethanol and dried to obtain 5.4 2 g of the 5 title compound. (Yield: 81.8 %)
Structural formula:
1.48 (s, 9H), 5.51 (d, IH), 6.98 (s, IH).
Reference example 55
Synthesis of 2-(2-formylamino-l,3-thiazol-4-yl)-2-(3-
formylcarbazoyl)carbonylaminoacetic acid tert-butyl ester
After stirring of a mixed solution comprising 3 ml of anhydrous acetic acid and 1.3 ml of formix acid at 55 °C for one hour, cooled by standing, 2.73 g (8.66 mmole) of 15 2-(2-amino-l,3-thiazol-4-yl)-2-carbazoylcarbonylamino-acetic acid tert-butyl ester obtained in Reference example 54 was added thereto and the mixture was stirred at room temperature for 3 hours. The resulting mixture was 100 ml of diisopropyl ether to obtain powder, and the 20 powder was collected by filtration and dried to obtain 3.15 g of the title compound. (Yield: 97.9 %)
Structural formula:
h2n s
1
H NMR (dg-DMSO) 6
OHCHN s
1H NMR (dg-DMSO) 6:
1.45 (s, 9H), 5.55 (d, 1H), 7.31 (s, IH), 8.10 (s, IH), 8.55 (s, IH).
Reference example 56
Synthesis of 2-(2-formylamino-l,3-thiazol-4-yl)-2-(3-formylcarbazoyl)carbonylaminoacetic acid
In 20 ml of trifluoroacetic acid was dissolved 3.91 g (10.5 mmole) of 2-(2-formylamino-l,3-thiazol-4-yl)-2-(3-formylcarbazoyl)carbonylaminoacetic acid tert-butyl ester 10 obtained in Reference example 55 and the mixture was stirred at room temperature for 3 hours.
The resulting mixture was added dropwise into 250 ml of ether while vigorously stirring, and resulting precipitates were collected by filtration, washed with ether and 15 dried to obtain 3.21 g of the title compound. (Yield: 97.0 %)
Structural formula:
N n-CH-COOH
J) NHCOCONHNHCHO
OHCHN S
"4? NMR (dg-DMSO) 6:
.56 (d, IH), 7.34 (s, IH), 8.12 (s, lH), 8.53 (s, 20 IH).
Reference example 57
Synthesis of 7-[2-(2-formylamino-1,3-thiazol-4-yl)-2-(3-formylcarbazoyl)carbonylaminoacetamido]-3-[(1,3,4-thia-
diazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester
In 30 ml of DMF were dissolved 3.1 g (9.8 mmole) of 2-(2-f ormylamino-1,3-thiazol-4-yl )-2- ( 3-f ormylcarbazoyl )-5 carbonylaminoacetic acid obtained in Reference example 56 and 4.867 g (9.8 mmole) of 7-amino-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester, and to the mixture was added under ice-cooling and stirring 2.476 g (12 mmole) of DCC and the 10 mixture was stirred for 30 minutes under ice-cooling and further for one hour at room temperature.
After filtration of the resulting mixture, to the filtrate was added the same amount of chloroform and the mixture was added dropwise into 700 ml of ether while 15 vigorously stirring. Resulting precipitates were collected by filtration, washed with ether and dried to obtain 5.49 g of the title compound. (Yield: 70.6 %)
Structural formula:
OHCHN
CH-CONH
0
NHCOCONHNHCHO*
N
\:h2SAsJ
N N
(COOCHPh2
1H NMR (dg-DMSO) 6:
4.47 (m, 2H), 5.13 (d, IH), 5.49 - 5.86 (m, 2H), 7.38 (broad s, 11H), 8.15 (s, IH), 8.54 (s, IH), 9.61 (s, IH) .
Reference example 58
Synthesis of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-carbazoyl-carbonylaminoacetamido]-3-[ (1,3,4-thiadiazol-2-yl)thiomethyl ]-3-cephem-4-carboxylic acid diphenylmethyl ester* 5 dihydrochloride
Methanol (100 ml) was ice-cooled and 2.15 g of phosphorus oxychloride was added dropwise under stirring. To this mixture was added 5.49 g (6.91 mmole) of 7-[2-(2-formyl-amino-1,3-thiazol-4-yl)-2-(3-formylcarbazoyl)carbonyl-10 aminoacetamido]-3-[(l,3,4-thiadiazol-2-yl)thiomethyl]-
3-cephem-4-carboxylic acid diphenylmethyl ester obtained in Reference example 57, and the mixture was stirred for 3 hours under ice-cooling.
After filtration of the resulting mixture, the filtrate 15 was added dropwise into 700 ml of ether while vigorously stirring and precipitates were collected by filtration, washed with ether and dried to obtain 3.75 g of the title compound. (Yield: 66.9 %).
Structural formula:
h2N
JO
-CH-CONH
NHCOCONHNH,
COOCHPh.
•2HC1
H NMR (dg-DMSO) 6:
4.48 (m, 2H), 5.15 (d, IH), 5.50 (broad s, 11H), 9.58 (s, IH).
- 5.88 (m, 2H), 7.36
** 106 ~
Example 121
Synthesis of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-{3-(3,4-dihydroxybenzylidene)carbazoylcarbonylamino}acetamido]-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic 5 acid*hydrochloride
In 20 ml of methanol was dissolved 0.81 g (1 mmole) of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-carbazoylcarbonylamino-acetamido]-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester dihydrochloride 10 obtained in Reference example 58, and 0.138 g (1 mmole) of 3,4-dihydroxybenzaldehyde was added thereto and the mixture was stirred at room temperature for one hour.
After filtration of the resulting mixture, the filtrate was added dropwise into 250 ml of ether while vigorously 15 stirring, and precipitates were collected by filtration, washed with ether and then dried to obtain 0.78 g of diphenylmethyl ester of the title compound. (Yield: 87.2 %)
After a mixed solution comprising 4 ml of trifluoroacetic 20 acid and 1 ml of anisole was ice-cooled, 0.47 g (0.525 mmole) of the previously obtained diphenylmethyl ester was added thereto and the mixture was stirred for 30 minutes under ice-cooling. This mixture was added dropwise into 100 ml of ether while vigorously stirring 25 and precipitates were collected by filtration, washed with ether and then dried to obtain 0.375 g of the title compound. (Yield: 98.1 %)
Melting point: 240 °C (decomposed)
* 107 -
Structural formula:
S
h2n
COOH
OH
HCl
NHCOCONHN=CH
OH
1
H NMR (dg-DMSO) 6:
4.50 (m, 2H), 5.15 (df 1H) , 5.55 - 5.87 (m, 2H), 6.70 - 7.55 (m, 4H), 8.48 (m, 1H), 9.61 (s, IH).
Reference example 59
Synthesis of 2-(2-formylamino-l,3-thiazol-4-yl)-2-carba-zoylaminoacetic acid ethyl ester•trifluoroacetic acid salt
After a mixture comprising 30 ml of trifluoroacetic acid and 10 ml of anisole was ice-cooled, 3.8 7 g (10 mmole) of the compound of Reference example 27 was added thereto while stirring and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 18 hours. The resulting mixture was added dropwise into a mixed solution comprising 100 ml of ether and 150 ml of diisopropyl ether while stirring, and precipitated crystals were collected by filtration and vacuum dried to obtain 3.82 g (Yield: 95.2 %) of a white crystal of the title compound.
- 108 ~
Structural formula:
OHCHN
CH-COOEt I
NHCONHNH2 •CF3COOH
XH NMR (dg-DMSO) 6:
1.17 (3H, tf J=8), 4.12 (2H, q, J=8), 5.43 (IH, d, J=9), 7.23 (1H, s), 8.49 (1H, s).
Reference example 60
Synthesis of 2-(2-amino-l,3-thiazol-4-yl)-2-carbazoyl-aminoacetic acid ethyl ester•dihydrochloride
In 30 ml of ethanol was added under ice-cooling 1.77 ml (19.04 mmole) of phosphorus oxychloride, and after the mixture was stirred for 5 minutes, 3.82 g (9.52 mmole) of the compound according to Reference example 59 was added thereto at the same temperature and the mixture was stirred for 2 hours. The resulting mixture was added dropwise into 500 ml of ether while stirring, and precipitated crystals were collected by filtration and dried to obtain 2.45 g (Yield: 77.6 %) of the title compound as dihydrochloride.
Structural formula:
H2N
S
2
2HC1
Melting point: 155 °C (decomposed)
1H NMR (dg-DMSO) 6:
1.20 (3H, t, J=8), 4.15 (2H, q, J=8), 3.46 (IH, d J=9), 6.80 (IH, s).
Reference example 61
Synthesis of 2-(amino-l,3-thiazol-4-yl)-2-[3-(3,4-di-acetoxybenzoyl)carbazoylamino]acetic acid ethyl ester* hydrochloride
After 2.45 g (7.37 mmole) of the compound according to Reference example 60 was suspended in 40 ml of methylene chloride, 9.01 ml (36.85 mmole) of N,0-bis(trimethylsilyl )acetamide was added thereto and the mixture was stirred for 30 minutes whereby the starting materials were dissolved completely. To the mixture was added 2.10 g (8.18 mmole) of crystals of 3,4-diacetoxybenzoyl chloride and the mixture was stirred at room temperature for 50 minutes. After the mxiture was added into 400 ml of diisopropyl ether, 20 ml of methanol was added thereto while stirring so that white crystals were precipitated at once. These crystals were collected by filtration and vacuum dried to obtain 6.02 g of hydrochloride of the title compound containing acetamide. This compound was employed for the next reaction without further drying.
Structural formula:
NMR (dg-DMSO) 6:
1.20 (3H, t, J=8), 1.82 (about 10H, s; acetylmethyl protons of acetamide), 3.29 (6H, s), 4.14 (2H, q,
N
CH-COOEt
J=8) , 5.4 7 (IH, broad s, J=8), 6.80 (1H, s), 7.38 (IH, d, J=8), 7.79 (1H, s), 7.86 (IH, d, J=8).
Reference example 62
Synthesis of 2-(2-amino-l,3-thiazol-4-yl)-2-[3-(3,4-5 dihydroxybenzoyl)carbazoylamino]acetic acid
In 37 ml of IN aqueous sodium hydroxide solution was dispersed 6.02 g of crystals of 2-(2-amino-l,3-thiazol-4-yl)-2-[3-(3,4-diacetoxybenzoyl)carbazoylamino]acetic acid ethyl ester•hydrochloride containing acetamide according 10 to Reference example 61, and the mixture was stirred at room temperature for 1.5 hours. During stirring,
crystals were dissolved completely. To this mixture was added 2N hydrochloric acid while stirring, and pH of the mixture was adjusted to 3.5. After further stirring for 15 10 minutes, precipitated crystals were collected by filtration, and the residue was washed well with water and vacuum dried over phosphorus pentoxide to obtain 1.36 g (Yield: 50.2 %) of pale yellow crystals of the title compound.
Melting point: 197 °c (decomposed).
Structural formula:
N
CH-COOH
1
H NMR (dg-DMSO) 6:
4.48 (IH, s), 6.79 (2H, broad s, J=9), 7.31 (3H, m).
- Ill -
Example 122
Synthesis of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-{3-(3,4-dihydroxybenzoyl)carbazoylamino}acetamido]-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester
In 9 ml of dried dimethylformamide was dissolved a mixture comprising 1.00 g (2.72 mmole) of the compound obtained in Reference example 62 and 1.39 g (2.72 mmole) of 7-amino-3-(2-methyl-l,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester, and 0.674 g (3.27 mmole) of DCC was added thereto under ice-cooling and stirring and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 18 hours. After filtration of the mixture and the residue was washed with a small amount of dimethylformamide, the filtrate and washing were combined and added dropwise into 250 ml of ether while stirring.
After 10 minutes stirring, precipitated solid was collected by filtration, washed well with ether and vacuum dried to obtain 1.96 g (Yield: 84 %) of pale yellow powder of the title compound.
Melting point: 150 °C (decomposed).
Structural formula:
CH-CONH
0
1 N N
S^XH2 S JLCIJ3
COOCHPh2
1H NMR (dg-DMSO) 6:
2.63 (3H, s), 3.73 (2H, m), 4.35 (2H, m), 5.0 - 5.9 (3H, m), 6.92 (2H, m), 7.41 (13H, m) .
Example 123
Synthesis of 7-[2-(2-amino-l,3-thiazol-4-yl)-2-{3-(3,4-dihydroxybenzoyl)carbazoylamino)acetamido]-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid*ditrifluoroacetic acid salt
To 300 mg (0.349 mmole) of the compound according to 10 Example 117 were added successively 1 ml of anisole and 5 ml of trifluoroacetic acid and the mixture was stirred under ice-cooling for one hour. The reaction mixture was added dropwise into 100 ml ether while stirring, and precipitated solids were collected by filtration, washed 15 with ether and vacuum dried to obtain 295 mg (Yield: 91.7 %) of ditrifluoroacetic acid salt of the title compound as a pale yellow powder. This compound was confirmed that NMR data thereof were accorded with those of the compound obtained in Example 115.
Reference example 63
The minimun inhibition concentrations (MIC) of the compounds obtained by the present invention were measured according to the standard method of Japanese Chemotherapy Association. The results are shown in Tables 13 and 14.
In Table 13, As comparative compounds, cephotaxim
(abbreviated to as CTX), cephazoline (abbreviated to as CAZ), cephothiam (abbreviated to as CTM) and latamoxiceph (abbreviated to as LMOX) were used.
Table 13
M 1 C ( v9/t>il)
Strain
Example 2
Exanple 59 Example 6
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C A Z
IMOX
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s.
faecal Is 1 F03826
>/00
>/00
>/00
>/00
>/00
>/00
>/00
B.
subt11 is ATCC6633
0.39
0.39
0.39
0.39
6.2$
3./3
0.3 9
S.
anatum 677-69
00$
0.02$
0.02$
0./
* 0.78
OJ
0.2
S.
newport $63
0.0$
00$
0.0$
0./
0.78
OJ
0.39
s.
paratyphi A /¥¥■-/2-93
0.0$
0.02$
0.02$
0.2
/$6
0.2
0.39
s.
paratyphi B
0.02$
0.0/2
0.0/2
OJ
0.78
0.0$
0.2
s.
para typh1 C 33-76
0.0/2
0.0/2
0.0/2
<J0.006
0./
0.02$
0.0$
s.
typhi /099-77
&.0.006
g.0.006
<J).006
OJ
0.39
0.0$
OJ
s.
typhlmurlum ATCC/33//
0.0$
0./
0.02$
0.0$
0.39
0.0$
OJ
&
typhlmurlum IFO /2$29
039
0./
0.0$
0.2
0.78
OJ
0.2
s.
boyadii GDC+2064-59
0.78
0.39
0.39
0.3 9
6.2$
3J 3
0.39
s.
dysenterlae V-379-60
0.02$
0.0$
0.02$
0.0/2
0.2
0.0$
0.0$
s.
flexnerl 2a COC+V807-62
0/
0.2
0./
0.02$
0.2
OJ
OJ
Table 13 . (cofttd.)
Strain ■—
MIC( M9/mt )
Sxample 2
Exaitple 59 Example 6:
\ CTX
CAZ
LMOX
CTM
S.
f lexner 1 Y NCTC+9730
0.7 8
0.78
0.78
0.0 $
0.3 9
3.13
0.78
S.
sonne 1 SH72-V/$
0.0$
0.0$
0.0$
0.0$
0.3 9
OJ
0.2
E.
coll ATCC2S9Z2
0.2
OJ
0.2
OJ
0.3 9
0.1
0.2
E.
col 1 N 1 H J JC -2
0.3 9
0.3 9
0.78
OJ
0.78
0.1
0.2
C.
freundli IFO/ 268 /
0.39
0.78
0.3 9
OJ
0.3 9
o.t
3J3
S.
marcescens IFO/ 26V-8
0.39
0.3 9
0.39
0.2
0.3 9
0.1
6.2$
E.
cloacae ATCC(30V-7
3/3
/$6
3J3
3J3
3J3
0.18
$0
K.pneumoniae ATCC.277*y£
0.02$
0.0/2
0.0/2
OJ
0.78
o.o$
OJ
P.
mirabills IFO38V9
0.2
0.39
0.39
0.0$
0.2
OJ
0.7 8
P.
rettgeri A1CC/V$0$
0.39
0.78
/.$ 6
OJ
0.39
OJ
3J3
P.
vulgaris ATCC6380
0.2
0.3 9
0.39
0.0$
0.2
0.1
>/00
P.
vulgaris ATCC6398
0.0$
0.0$
0.0$
<>aoo6
OJ
0.1
>/00
P.
aeruginosa ATCC77.2/
0.2
OJ
OJ
3J3
/$6
3J3
>/00
P.
cepacia ATCC2$V/6
0.78
0.39
0.78
0.78
6.2$
6.1$
0.39
P.
ma 1tophIlia ATCC/3637
/$6
0.78
/.$ 6
$0
/ 2.$
2$
>/00
P.
putlda ATCC/2633
/.$6
078
/$ 6
$0
(2.$
2$
>/00
P.
fluorescens A'TCC/3525
/2.$
/ 2.$
/ 2.$
2$
3J3
Table 14
^^^Exaiaple No.
Strain
M 1 C
( M ? /Bli)
104
118
E.Co 1 1 GH5V82
0 .
7 Z
/
. S L
E.cloacae GH7&7/
3
/ 3
6
. 25
C. ireundl 1 GN737/
/ 00
>/ 00
S.marcescens GN/OSS/
/ 00
/ 00
P.rettger1 GNW30
0
2
0
. 3 9
P.morgani1 GNS¥07
0
3 9
0
. 7S
P.vulgaris GN79/7
SO
/ 00
P.aeruginosa GW/O
b
2 S
6
. 2S
E.coll Yl3630/Rrns2/2
0
3 9
0
. 3 9
E.coll YJ3£>30srtms2/3
0
/
0
. 2
E.coll W3&30/R te/£>
0 .
2
0
. 3 9
- m -
Claims (11)
1. A beta-lactam compound represented by the formula i4 3 N- ~ nr-ir ^ * H A ° X (I} / \ /pr* ^(CR-} 10 2 CONE->-</ 2 n wherein A is a group represented by the formulae -NHC0-, -NHC0NHC0-, NHC0CH=CH- or 15 -N=C- R6 wherein Rg is a hydrogen atom or Cj-C^ alkyl; R* is hydrogen or a protecting group selected from formyl, trityl, chloroacetyl, 20 t-butoxycarbonyl, and 2,2,2-trichloroethoxycarbonyl; R£ is hydrogen, acetyl, propionyl, methoxy carbonyl or ethoxycarbonyl; R^ is hydrogen or methoxy; X is hydrogen, hydroxyl, halogen, C^-Cg alkoxy, nitro or hydroxyl protected by acetyl, propionyl, methoxycarbonyl or ethoxycarbonyl; n is 1 or 2; Y is a group represented by the formulae: 25 x CH, CH-5 \ / 3 1 2 _ C or C-H7 \ / \ \s CH CH NC I 3 i COOK COOM 30 provided that the carbon atom attached to the COOM group is attached to the nitrogen atom of the beta lactam ring; M is hydrogen, a protecting group selected from diphenylmethyl, t-butyl, p-nitrobenzyl and trimethylsilyl, or a group which is easily hydrolyzable in a human body and selected from acetoxymethyl, alpha-acetoxyethyl, pivaloyloxymethyl, 35 alpha-ethoxycarbonyloxymethyl, alpha-methoxycarbonyloxymethyl, alpha-methoxycarbonyloxy-ethyl, alpha-ethoxycarbonyloxyethyl, 1-indanyl, phthalidyl, and 5-methyl-2-oxo-l,3-dioxol-4-yl-methyl; R^ is hydrogen, methyl, ^2~^7 alkoxymethyl or a group represented by - 117 - the formula: -Cl^-T where T is carbamoyloxy, quaternary ammonium derived from pyridine, 2-methyl-pyridine, 3-methylpyridine, 4-methylpyridine, 4-ethylpyridine, 2,3-dimethylpyridine, 4-aminopyridine, 3-cyanopyridine, nicotinamide, isonicotinamide, 5 3-pyridine sulfonic acid, 4-pyridine ethanesulfonic acid, 3-hydroxypyridine, 4-hydroxypridine, nitotinic acid, isonicotinic acid, 5,6,7,8-tetrahydroi soquno1i ne, 5,6,7,8-tetrahydroqu i noli ne, pyradaz i ne, quinoline, isoquinoline, trimethylamine, triethylamine, N-methylpiperidine, N-methylpyrrol idine and N-methylmorpholine, an 10 unsubstituted 5- to 6-membered heterocyclic ring having 1-4 hetero atoms or a 5- to 6-membered heterocyclic ring having 1 to 4 heteroatoms in a ring substituted by at least one of C^-C^ alkyl, C^-Cg alkoxy, carboxymethyl, carboxyethyl, sulfoxymethyl, sulfoxyethyl, di-(C^-C^ alkyl)-amino ethyl, carboxy, amino, acetyl-amino and 15 hydroxy ethyl group, or T is of the formula - S-Rg where Rg is acetyl, propionyl, furoyl or a substituted or unsubstituted heterocyclic ring as defined under T, R4 and Rg are each hydrogen or together form an additional direct bond; Z is a direct bond or a carbonyl group when R^ and Rg are hydrogen atoms, or has the 20 formula: 0-B- where the oxygen atom is bonded to nitrogen atom and B is a straight, or branched Cj-Cg alkylene group or B is a cyclic alkylene group containing up to 6 carbon atoms where R^ and Rg are combined with each other to form an additional direct bond, or a pharmaceutically acceptable salt thereof. 25
2. A compound according to claim 1, wherein said substituted or unsubstituted heterocyclic ring of T or Rg is substituted or unsubstituted tetrazolyl, triazolyl, thiazolyl, thiadiazolyl, tetrazolo-[l,5-b]pyridazinyl, pyridyl, N-methylpyridyl, S-triazolo[l,5-a] 30 pyrimidyl, 1-oxidopyridyl, N-carbomoylmethylpyridyl, 2-methyl-5-oxo-6-hydroxy-2,5-dihydro-l,2,4-triazinyl, or 4-methyl-5-oxo-6-hydroxy-4,5-dihydroxy-1,2,4-triazinyl, wherein said substituent of the heterocyclic ring of T or Rg is selected from C^-C^ alkyl, Cj-Cg alkoxy, carboxymethyl, carboxyethyl, sulfoxymethyl, sulfoxyethyl, 35 diCj-Cg-alkylaminoethyl, carboxy, amino acetylamino and hydroxyethyl.
3. A compound according to claim 1 or 2 characterized in that said - 118 -
I pharmaceutically acceptable salt of the beta-lactam compound is an alkali metal, alkaline earth metal or ammonium salt or a salt, with an organic base, organic acid, or inorganic acid. 5 4. A compound according to claim 3, wherein said salt is a sodium, potassium, magnesium, calcium, diisopropylamine, benzylamine, triethanolamine, triethylamine, N-methylmorpholine, pyridine, piperazine, acetic acid, formic acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, 10 hydrobromic acid, sulfuric acid or phosphoric acid salt.
5. A pharmaceutical preparation characterized by containing a pharmaceutically active amount of a compound according to any one of claims 1 to 4. 15
6. A pharmaceutical preparation for the treatment and prophylaxis of infectious diseases characterized by containing a pharmaceutically active amount of a compound according to any one of claims 1 to 4. 20
7. A compound in accordance with any one of claims 1 to 4, as a pharmaceutically active substance.
8. A compound in accordance with any one of claims 1 to 4, as a pharmaceutically active substance for the treatment and prophylaxis of 25 infectious diseases.
9. A beta-lactam compound, as claimed in claim 1, substantially as hereinbefore described with reference to the Examples. 30
10. A pharmaceutical preparation, as claimed in claim 5, substantially as hereinbefore described with reference to the Examples.
11. A pharmaceutical preparation, as claimed in claim 6, substantially as hereinbefore described with reference to the Examples. 35 TOMKINS & CO. - 119 -
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP858785 | 1985-01-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE860163L true IE860163L (en) | 1986-07-21 |
| IE59392B1 IE59392B1 (en) | 1994-02-23 |
Family
ID=11697125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE16386A IE59392B1 (en) | 1985-01-21 | 1986-01-20 | Novel beta-lactam antibiotics |
Country Status (2)
| Country | Link |
|---|---|
| IE (1) | IE59392B1 (en) |
| ZA (1) | ZA86395B (en) |
-
1986
- 1986-01-20 ZA ZA86395A patent/ZA86395B/en unknown
- 1986-01-20 IE IE16386A patent/IE59392B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IE59392B1 (en) | 1994-02-23 |
| ZA86395B (en) | 1986-09-24 |
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| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |