WO1997026260A1 - Isooxacephem derivatives - Google Patents
Isooxacephem derivatives Download PDFInfo
- Publication number
- WO1997026260A1 WO1997026260A1 PCT/EP1997/000057 EP9700057W WO9726260A1 WO 1997026260 A1 WO1997026260 A1 WO 1997026260A1 EP 9700057 W EP9700057 W EP 9700057W WO 9726260 A1 WO9726260 A1 WO 9726260A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- oxo
- amino
- carboxylic acid
- ene
- aza
- Prior art date
Links
- -1 carboxy, amino Chemical group 0.000 claims abstract description 157
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 56
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 28
- 150000002148 esters Chemical class 0.000 claims abstract description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 27
- 239000001257 hydrogen Substances 0.000 claims abstract description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 20
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 15
- 150000002367 halogens Chemical class 0.000 claims abstract description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- 125000002252 acyl group Chemical group 0.000 claims abstract description 14
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 14
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 13
- 150000004677 hydrates Chemical class 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 9
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 7
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 7
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims abstract description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 claims description 73
- DSIJXEVOJMBKAM-UHFFFAOYSA-M sodium;2-methyloct-2-enoate Chemical compound [Na+].CCCCCC=C(C)C([O-])=O DSIJXEVOJMBKAM-UHFFFAOYSA-M 0.000 claims description 60
- 159000000000 sodium salts Chemical class 0.000 claims description 28
- 125000006239 protecting group Chemical group 0.000 claims description 20
- 238000004519 manufacturing process Methods 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 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 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 208000035473 Communicable disease Diseases 0.000 claims description 5
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 76
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- 239000011734 sodium Substances 0.000 description 38
- 235000002639 sodium chloride Nutrition 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- 229940093499 ethyl acetate Drugs 0.000 description 25
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000003480 eluent Substances 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 0 *N(CCC1=CC(OC[C@]2[C@@]3N)=C(C(O)=O)N2C3=O)C1=O Chemical compound *N(CCC1=CC(OC[C@]2[C@@]3N)=C(C(O)=O)N2C3=O)C1=O 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- RSQIXZLBNMAHKG-STZFKDTASA-N s-(1,3-benzothiazol-2-yl) (2z)-2-(2-amino-1,3-thiazol-4-yl)-2-cyclopentyloxyiminoethanethioate Chemical compound S1C(N)=NC(C(=N\OC2CCCC2)\C(=O)SC=2SC3=CC=CC=C3N=2)=C1 RSQIXZLBNMAHKG-STZFKDTASA-N 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- NNXHTALPYXRANA-YLHCSOALSA-N benzotriazol-1-yl (2z)-2-(2-amino-1,3-thiazol-4-yl)-2-trityloxyiminoacetate Chemical compound S1C(N)=NC(C(=N\OC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)\C(=O)ON2C3=CC=CC=C3N=N2)=C1 NNXHTALPYXRANA-YLHCSOALSA-N 0.000 description 6
- DHFUXTRUZCOOBS-ODLFYWEKSA-N s-(1,3-benzothiazol-2-yl) (2z)-2-(2-amino-2-oxoethoxy)imino-2-(2-amino-1,3-thiazol-4-yl)ethanethioate Chemical compound N=1C2=CC=CC=C2SC=1SC(=O)\C(=N/OCC(=O)N)C1=CSC(N)=N1 DHFUXTRUZCOOBS-ODLFYWEKSA-N 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000012876 carrier material Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 239000001828 Gelatine Substances 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 description 4
- 238000007239 Wittig reaction Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 239000003365 glass fiber Substances 0.000 description 4
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- RBACIKXCRWGCBB-UHFFFAOYSA-N 1,2-Epoxybutane Chemical compound CCC1CO1 RBACIKXCRWGCBB-UHFFFAOYSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 229960004132 diethyl ether Drugs 0.000 description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 150000002924 oxiranes Chemical class 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 2
- SAKPCQKTTXWGQA-UHFFFAOYSA-N 2-(1-methyltetrazol-5-yl)sulfanylacetic acid Chemical compound CN1N=NN=C1SCC(O)=O SAKPCQKTTXWGQA-UHFFFAOYSA-N 0.000 description 2
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 2
- WQXUUMUOERZZAE-UHFFFAOYSA-N 3-(2,6-dichlorophenyl)-5-methyl-1,2-oxazole-4-carboxylic acid Chemical compound OC(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl WQXUUMUOERZZAE-UHFFFAOYSA-N 0.000 description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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- 235000019759 Maize starch Nutrition 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
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- 239000002671 adjuvant Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
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- 150000001412 amines Chemical class 0.000 description 2
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- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 150000005840 aryl radicals Chemical class 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
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- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229930003836 cresol Natural products 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
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- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- MUWVIMJPXKIXJK-UHFFFAOYSA-N prop-2-enyl 2-bromoacetate Chemical compound BrCC(=O)OCC=C MUWVIMJPXKIXJK-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- IHZXPLPUVVVCRM-UHFFFAOYSA-N s-(1,3-benzothiazol-2-yl) 3-(2,6-dichlorophenyl)-5-methyl-1,2-oxazole-4-carbothioate Chemical compound N=1C2=CC=CC=C2SC=1SC(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl IHZXPLPUVVVCRM-UHFFFAOYSA-N 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 229910000083 tin tetrahydride Inorganic materials 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000010555 transalkylation reaction Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- JJPVWQWOOQYHCB-UHFFFAOYSA-N triethyl(phenyl)azanium Chemical compound CC[N+](CC)(CC)C1=CC=CC=C1 JJPVWQWOOQYHCB-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HYUFXBPAIGJHRY-UHFFFAOYSA-N triphenylphosphane;dihydrochloride Chemical compound Cl.Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 HYUFXBPAIGJHRY-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to isooxacephem derivatives of the general formula I
- Rl is hydrogen or an acyl group derived from a carboxylic acid
- R is hydrogen, hydroxy, lower alkyl, cycloaikyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl, aryloxy, aryl-lower alkoxy or a heterocyclic ring
- the lower alkyl, cycloaikyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl, aryloxy, aryl-lower alkoxy and the heterocyclic ring being unsubstituted or substituted with at least one group selected from carboxy, amino, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, -CONR21R22 ; -N(R22)COOR 23 , 22CO-, R220
- the invention also relates to pharmaceutical compositions and methods of use of the above.
- acyl group derived from a carboxylic acid refers to all organic radicals derived from an organic carboxylic acid by removal of the hydroxyl group.
- group R 1 may be any one of many acyl radicals, certain acyl groups are preferred, as described below.
- acyl groups are those groups which can be used to acylate ⁇ -lactam antibiotics, including 6-aminopenicillanic acid and derivatives and 7-aminocephalosphoranic acid and derivatives; see, for example, Cephalosporins and Penicillins, edited by Flynn, Academic
- j 0, 1, 2 or 3;
- R is hydrogen, lower alkyl, cycloaikyl, carbarn oyl-lower alkyl, aryl- lower alkyl;
- RlO is hydrogen, lower alkyl, cycloaikyl, lower alkoxy, lower alkenyl or cycloalkenyl, the lower alkyl group or the lower alkenyl group being optionally substituted with at least one group selected from halogen, cyano, nitro, amino, mercapto, alkylthio or cyano- m ethyl thio;
- RU is aryl unsubstituted or substituted with at least one group selected from halogen, hydroxy, nitro, amino, cyano, carboxy, lower alkyl, lower alkoxy, carbamoyl, trifluoromethyl or aminomethyl; a heterocyclic ring unsubstituted or substituted with at least one group selected from halogen, hydroxy, nitro, amino, cyano, carboxy
- the aliphatic acyl groups used in conjunction with Rl have the formula a, wherein R ⁇ O is as defined above.
- Preferred aliphatic acyl groups are those wherein Rl is lower alkanoyl, particularly acetyl.
- aromatic or heteroaromatic acyl groups used in conjunction with Ri have the formulae b to f, wherein j, RU and Rl are as defined above.
- the aryl group in the residue R ⁇ is preferably phenyl.
- heteroaromatic acyl groups suitable for the purposes of the present invention include those groups of the above formulae b to f wherein ⁇ is isoxazolyl, 2,6-dichlorophenyl-5-methyl-isoxazolyl, tetrazolyl, 1-methyl-tetrazolyl, 2-amino-4-thiazolyl, 2-amino-5-halo-4- thiazolyl, 4-aminopyridin-2-yl, 2-amino-l,3,4-thiadiazol-5-yl, 5-amino- l,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, 4-pyridinyl, 2,6-dichloro-4- pyridinyl or 2-amino-4-benzothiazolyl.
- Preferred heteroaromatic acyl groups are those wherein Rl is a residue of the formula b, particularly 2,6-dichlorophenyl-5-methyl- isoxazol-4-yl-carbonyl. Also preferred are heteroaromatic acyl groups wherein Rl is a residue of the formula f, particularly 1-methyl-tetrazol- 5-yl-sulfanyl-acetyl.
- the oxyimino-acyl groups used in conjunction with R ⁇ have the formula g, wherein R3 and R ⁇ are as defined above.
- oxyimino-acyl groups of the formula g wherein RU is a heterocyclic ring unsubstituted or substituted with at least one group selected from halogen, hydroxy, nitro, amino, cyano, carboxy, lower alkyl, lower alkoxy, carbamoyl, trifluoromethyl or aminomethyl or substituted with optionally substituted phenyl or fused together with a benzene ring.
- the heterocyclic ring is preferably the thiazolyl ring or the thiadiazolyl ring.
- R2 is as defined under formula I and R is as defined above.
- R3 is preferably hydrogen, carbamoyl-lower alkyl or cycloaikyl, particularly hydrogen, carbamoyl-methyl or cyclopentyl.
- Preferred compounds of formula II are such where R 2 is lower alkyl, cycloaikyl, aryl-lower alkyl, aryl or a heterocyclic ring, the lower alkyl, aryl-lower alkyl, aryl and the heterocyclic ring being unsubstituted or substituted with at least one group selected from halogen, hydroxy, amino, nitro, cyano, lower alkyl or lower alkoxy.
- R 2 is isobutyl, 2,2,2-trifluoroethyl, cyclopropyl, phenyl, 3-nitrophenyl, 4- hydr oxy phenyl, 2-fluorophenyl, 2-methoxyphenyl, 4-nitrobenzyl, pyridinyl, N-methyl-pyridinium-2yl or 5-methyl-isoxazolyl.
- lower alkyl refers to both straight and branched chain saturated hydrocarbon groups having 1 to 8, preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like.
- cycloaikyl a 3-7 membered saturated carbocyclic ring e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- lower alkoxy refers to alkoxy groups in the sense of the above description of the term lower alkyl. Examples include methoxy, ethoxy, n-propoxy and the like.
- lower alkenyl refers to an unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond, e.g. allyl, vinyl and the like.
- cycloalkenyl refers to a carbocyclic ring having at least one olefinic double bond.
- lower alkynyl refers to an unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, and having at least one olefinic triple bond.
- halogen used herein refers to all four forms, that is chlorine or chloro; bromine or bromo; iodine or iodo; and fluorine or fluoro.
- aryl is meant a radical derived from an aromatic hydrocarbon by the elimination of one atom of hydrogen and can be substituted or unsubstituted.
- the aromatic hydrocarbon can be mono- nuclear or polynuclear.
- aryl radicals of the mononuclear type include phenyl, tolyl, xylyl, mesityl, cumenyl, and the like.
- aryl radicals of the polynuclear type include naphthyl, anthryl, phenanthryl, and the like.
- the aryl group can have at least one substituent selected from, as for example, halogen, hydroxy, cyano, carboxy, carbamoyl, nitro, amino, aminomethyl, lower alkyl, lower alkoxy or trifluorm ethyl.
- substituents selected from, as for example, halogen, hydroxy, cyano, carboxy, carbamoyl, nitro, amino, aminomethyl, lower alkyl, lower alkoxy or trifluorm ethyl. Examples include 2-fluorophenyl, 3- nitrophenyl, 4-nitrophenyl, 4-methoxy phenyl, 4-hydroxyphenyl and the like.
- aryl-lower alkyl is meant a lower alkyl group containing an aryl group as for example benzyl.
- aryloxy is an oxygen radical having an aryl substituent (i.e., -O-aryl).
- aryl-lower alkoxy is an oxygen radical having an aryl-lower alkyl substituent. (i.e., -O-lower-alkyl-aryl).
- heterocyclic ring refers to an unsaturated or saturated, unsubstituted or substituted 5-, 6-, or 7-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of oxygen, nitrogen, or sulfur.
- heterocyclic rings include, but are not limited to, for example, the following groups: pyridyl, pyrazinyl, piperidyl, piperidino, N-oxido-pyridyl, pyrimidyl, piperazinyl, pyrrolidinyl, pyridazinyl, N-oxide-pyridazinyl, pyrazolyl, triazinyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
- 1,3,4-thiadiazolyl 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- tetrazolyl, 2H-tetrazolyl, thienyl, furyl, hexamethyleneiminyl, oxepanyl, lH-azepinyl, thiophenyl, tetrahydrothiophenyl, 3H-l,2,3-oxathiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadithiolyl, isoxazolyl, isothiazolyl, 4H-1,2,4- oxadiazinyl, 1,2,5-oxathiazinyl, 1,2,3,5-oxathiadiazinyl
- Substituents for the heterocyclic ring include lower- alkyl, lower- alkoxy, halogen, trifluoromethyl, trichloroethyl, amino, mercapto, hydroxy, carboxy or carbamoyl.
- Preferred examples of substituted heterocyclic rings include 5-methyl-isoxazol-3-yl, N-methyl- pyridinium-2yl, 1-methyl-tetrazolyl and the like.
- the heterocyclic ring can also be substituted by an optionally substituted phenyl ring such as 2,6-dichlorophenyl. Preferred is 2,6- dichlorophenyl-5-methyl-isoxazolyl.
- a further substituent is oxo, such as in 2-oxo-oxazolidin-3-yl, 1,1- dioxo-tetrahydrothien-3-yl.
- the heterocyclic ring can also be fused together with a benzene ring.
- substituted phenyl is meant phenyl mono or di- substituted.
- salts useful in this invention include salts derived from metals, the ammonium salt, quaternary ammonium salts derived from organic bases and amino acid salts.
- preferred metal salts are those derived from the alkali metals, for example, lithium (Li + ), sodium (Na + ) and potassium (K + ), and from the alkaline earth metals, for example, calcium (Ca ++ ) and magnesium (Mg ++ ), although cationic forms of other metals, such as iron (Fe ++ or Fe +++ ), aluminium (Al +++ ), and zinc (Zn ++ ) are within the scope of this invention.
- Examples of quaternary ammonium salts derived from organic bases include tetramethylammonium (N + (CH3)4), tetraethylammonium (N+(CH2CH3)4), benzyltrimethyl- ammonium (N + (C6H5CH2)(CH3)3), phenyltriethylammonium (N+(C6H5)(CH 2 CH3)3), and the like, etc.
- salts derived from amines include salts with N-ethylpiperidine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, alkylamines or dialkylamines as well as salts with amino acids such as, for example, salts with arginine or lysine.
- amino protecting group refers to protecting groups conventionally used to replace an acidic proton of an amino group. Examples of such groups are described in Green, T., Protective Groups in Organic Synthesis, Chapter 7, John Wiley and Sons, Inc. (1981), pp. 218-287. These examples include e.g. allyl, allyloxycarbonyl, t-butyl, t- butoxycarbonyl, benzyl, p-methoxybenzyl and p-nitro-benzyl. Preferred is allyloxycarbonyl.
- carboxylic acid protecting group refers to protecting groups conventionally used to replace the acidic proton of a carboxylic acid. Examples of such groups are described in Greene, T., Protective Groups in Organic Synthesis, Chapter 5, pp. 152-192 (John Wiley and
- allyl diphenylmethyl, p- nitrobenzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, t- butyldimethylsilyl. Preferred is allyl.
- esters of the compounds of formula I there are to be understood compounds of formula I, the carboxy group(s) of which (for example, the 2-carboxy group) is/are present in the form of readily hydrolyzable ester groups.
- esters which can be of the conventional type, are the lower alkanoyloxy-alkyl esters (e.g., the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1- pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g., the methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1- isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g., the phthalidyl and thiophthalidyl ester), the lower alkoxymethyl esters (e.g., the methoxymethyl ester) and the lower alkanoy
- esters e.g., the benzyl and cyanomethyl esters
- Other examples of such esters are the following: (2,2-dimethyl-l-oxopropoxy) methyl ester, 2-[(2- methylpropoxy)carbonyl]-2-pentenyl ester, l-[[(l-methylethoxy)- carbonyl]oxy] ethyl ester, l-(acetyloxy) ethyl ester, (5-methyl-2-oxo-l,3- dioxol-4-yl) methyl ester, l-[[(cyclohexyloxy)carbonylJoxy] ethyl ester and 3,3-dimethyl-2-oxobutyl ester.
- the readily hydrolyzable esters of the compounds of the present invention can be formed at a free carboxy group of the compound, for example, at the carboxy group in position 2 of the isooxacephem ring.
- the compounds of formula I as well as their salts and readily hydrolyzable esters can be hydrated.
- the hydra tion can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product.
- the compounds of the present invention are useful for the treatment and prophylaxis of infectious diseases. They also possess good oral absorption properties.
- the products in accordance with the invention can be used as medicaments, for example, in the form of pharmaceutical preparations for enteral (oral) administration.
- the products in accordance with the invention can be administered, for example, perorally, such as in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, or rectally, such as in the form of suppositories.
- compositions containing these compounds can be prepared using conventional procedures familiar to those skilled in the art, such as by combining the ingredients into a dosage form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, the usual pharmaceutical adjuvants.
- compositions of suitable oral or parenteral dosage forms can contain, as optional ingredients, any of the various adjuvants which are used ordinarily in the production of pharmaceutical preparations.
- fillers such as coprecipitated aluminum hydroxide-calcium carbonate, dicalcium phosphate or lactose; disintegrating agents, such as maize starch; and lubricating agents, such as talc, calcium stearate, and the like.
- Suitable as such carrier materials are not only inorganic, but also organic carrier materials.
- Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active substance; no carriers are, however, required in the case of soft gelatine capsules).
- Suitable carrier materials for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose.
- Suitable carrier materials for suppositiories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
- solubilizers As pharmaceutical adjuvants there are contemplated the usual preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents and antioxidants.
- the compounds of formula I and their salts, or hydrates can preferably be used for parenteral administration, and for this purpose are preferably made into preparations as lyophilisates or dry powders for dilution with customary agents, such as water or isotonic common salt solution.
- the pharmaceutical preparations can contain the compound for the prevention and treatment of infectious diseases in mammals, human and non-human, a daily dosage of about 10 mg to about 4000 mg, especially about 50 mg to about 3000 mg, is usual, with those of ordinary skill in the art appreciating that the dosage will depend also upon the age, conditions of the mammals, and the kind of diseases being prevented or treated.
- the daily dosage can be administered in a single dose or can be divided over several doses. An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, and 2000 mg can be contemplated.
- In vitro activity was determined by minimum inhibitory concentration in a microorganism spectum by the agar dilution method in Mueller Hinton agar.
- R 2 is as defined above under formula I or an ester or salt thereof, with acylating agents, or
- R 1 and/or R 2 may contain free amino, hydroxy or carboxylic group(s) cleaving off the amino, hydroxy and/or carboxy protecting group(s) or reducing a nitro group to amino in a compound having the formula IV in which R h is hydrogen or a carboxy protecting group, R f is as Rl and R ⁇ is as R 2 with the proviso that at least one of the following provisions is fulfilled: (i) R n is a carboxylic acid protecting group,
- R f is a residue defined under R 1 having nitro, protected amino, protected hydroxy and/or protected carboxylic group(s),
- R£ is a residue defined under R 2 having nitro, protected amino, protected hydroxy and/or protected carboxylic group(s), or a salt thereof, or
- reaction of compounds III with acylating agents according to embodiment (a) can be carried out in a manner known per se.
- acylating agents used in embodiment (a) are activated carboxylic acids such as acid chlorides, anhydrides, reactive esters such as N-hydroxysuccinimide esters, 2-benzothiazolyl thioesters, or 1- hydroxy-benzotriazole esters of the carboxylic acids.
- carboxylic acids such as acid chlorides, anhydrides, reactive esters such as N-hydroxysuccinimide esters, 2-benzothiazolyl thioesters, or 1- hydroxy-benzotriazole esters of the carboxylic acids.
- the 2- benzothiazolyl thioester may be reacted with the compound of the formula III in an inert organic solvent such as in dimethylformamide, methylene chloride, ethyl acetate and the like.
- the 1-hydroxybenzo- triazole ester can be employed by reacting the carboxylic acid with 1- hydroxybenzotriazole and a carbodiimide, especially N,N'- dicyclohexylcarbodiimide or N,N'-diisopropylcarbodiimide in an inert organic solvent, preferably methylene chloride, dimethylformamide, tetrahydrofuran, acetonitrile or ethyl acetate.
- an inert organic solvent preferably methylene chloride, dimethylformamide, tetrahydrofuran, acetonitrile or ethyl acetate.
- the carboxy group in compounds of the formula III can be protected; for example, by esterification to form a readily cleavable ester such as allyl-, t-butyl-, benzhydryl-, p-nitrobenzyl, p-methoxybenzyl- ester.
- a readily cleavable ester such as allyl-, t-butyl-, benzhydryl-, p-nitrobenzyl, p-methoxybenzyl- ester.
- the 7-amino group in compounds of the formula III can be protected, for example, by those groups employed in peptide chemistry, such as allyloxycarbonyl, t-butoxycarbonyl, p-nitrobenzyloxycarbonyl or benzyloxycarbonyl, trityl or benzhydryl. Preferred is allyloxycarbonyl.
- reaction of a 7-amino compond of formula III with a carboxylic acid or a reactive derivative thereof can conveniently be carried out at a temperature between about -40°C and +60°C, e.g. at room temperature.
- R2 is as defined above.
- esters other than allylesters being used by cleaving off the allyloxycarbonyl-amino-protecting group, adding the acylating agent and cleaving off the ester-goup.
- Embodiment (b) of the process of the present invention involves deprotection (removal) of protected amino, hydroxy or carboxylic groups present in a compound of formula IV and can be carried and as follows:
- the amino protecting groups may be cleaved off by acid hydrolysis (e.g. the t-butoxycarbonyl group or trityl group), using e.g. aqueous formic acid.
- acid hydrolysis e.g. the t-butoxycarbonyl group or trityl group
- Pd(0) - produced in situ by reduction of Pd-bis triphenylphosphin-dichloride with a trialkyl-tinhydride -
- Pd- ⁇ -complex scavenger like dimedon, pyrrolidin, dialkylmalonat, trialkyltinhydride, in an aprotic solvent such as dichlor-methane, hexane, diethylether, toluol or tetrahy drofuran .
- Possible hydroxy protecting groups are such as are commonly known in the art, e.g. benzyl or p-nitrobenzyl.
- trityl or acetyl For protection of hydroxyimino groups trityl or acetyl can be employed.
- ester protecting groups one may utilize an ester form which can be easily converted into a free carboxyl group under mild conditions, the ester protecting group being exemplified by, for example, t-butyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, allyl, etc.
- protecting groups may be removed as follows: benzhydryl trifluoroacetic acid with anisol, phenol, cresol or triethylsilane at about -40°C to room temperature; hydrogen with Pd C in an alcohol such as ethanol or in tetrahydrofuran; BF3-etherate in acetic acid at about 0 °C to 50°C;
- t-butyl formic acid or trifluoroacetic acid with or without anisol, phenol, cresol or triethylsilane and a solvent such as dichloromethane at about -10°C to room temperature;
- p-methoxybenzyl formic acid at about 0 °C to 50°C; or trifluoroacetic acid and anisol, phenol or triethylsilane at about -40°C to room temperature;
- a carboxylic acid of formula I is preferably reacted with a corresponding halide, preferably an iodide, containing the desired ester group.
- the reaction can be accelerated with the aid of a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine such as triethylamine.
- the esterification is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylphosphoric acid triamide, dimethyl sulfoxide or, especially, dimethylform amide.
- the reaction is preferably carried out at a temperature in the range of about 0 °C to 40°C.
- the manufacture of the salts and hydrates of the compounds of formula I or the hydrates of said salts in accordance with embodiment (d) of the process provided by the present invention can be carried out in a manner known per se; for example, by reacting a carboxylic acid of formula I or a salt thereof with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone and the like).
- a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone and the like).
- salt formation is brought about by the addition of an organic or inorganic salt.
- the temperature at which the salt formation is carried out is not critical.
- the salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, for example in the range of 0°C to +50°C.
- a completely or partially anhydrous carboxylic acid of formula I or salt thereof can be exposed to a moist atmosphere (e.g. at about +10°C to +40°C).
- reaction scheme 1 shows the process for obtaining compounds in accordance with the invention, e.g. a compound of formula II.
- a base which is either an inorganic base (sodium or potassium hydroxide, sodium or potassium carbonate etc.), an organic base (tertiary amines), an organolithium compound such as butyl lithium or phenyl lithium or an epoxide such as 1,2-butyleneoxide.
- a base which is either an inorganic base (sodium or potassium hydroxide, sodium or potassium carbonate etc.), an organic base (tertiary amines), an organolithium compound such as butyl lithium or phenyl lithium or an epoxide such as 1,2-butyleneoxide.
- the preferred solvents are in the case of inorganic base being used, water and water-miscible solvents (acetone, tetrahydrofuran, or alcohols etc.); in the case of organic base being used, an inert solvent such as methylene chloride, chloroform, benzene, tetrahydrofuran; in the case of organolithium being used, benzene or tetrahydrofuran; and in the case an epoxide being used, the epoxide itself (e.g. 1,2-butyleneoxide).
- the temperature for the reaction ranges from -20 °C to 80 °C.
- the preferred conditions are exemplified in the examples.
- the E isomer is the predominant product. Invariably, less than 10% Z-isomer is formed, the amount depending on the reagents and conditions.
- the manufacture of the Wittig reagent (2) can be carried out in a manner known per se; for example, by cyclization of a N-substituted dibromide using a catalyst like Dowex as discribed in the European Patent Application EPA 0 620 255.
- the carboxylic acid protecting group R n and the amino protecting group Rf are removed and the reaction conditions used are depending on the nature of the protecting groups.
- amino protecting group being allyloxycarbonyl and the carboxy protecting group being the allyl ester
- Pd(0) generated in situ is employed.
- amino protecting group being t- butoxycarbonyl and the carboxy protecting group being benzhydryl
- trifluoroacetic acid is employed, at temperature of about -20 °C to about room temperature.
- the acylation of compound (4) can be carried out with an organic acid which is activated with known reagents, preferably anhydride, thionyl chloride, oxalyl chloride, dicyclohexylcarbodiimide, bis-[benz- thiazolyl-(2)]disulfide, N-hydroxy benzotriazole or a 2-halo N-methyl- pyridinium salt.
- the reaction is carried out with or without the base (inorganic or organic bases) depending on the method of activation and a wide range of solvents, from water and water-miscible solvent to inert solvents such as chloroform, dimethylformamide (DMF) or dimethyl- sulfoxide (DMSO) can be used.
- the R3 group if necessary, can be further deprotected with a reaction condition suitable for the removal of the protecting group.
- Scheme 2 shows the manufacture of the isooxacephemaldehydes (1) of Scheme 1.
- Examples 1-23 show the preparation of diallyl vinyl isooxacephems according to the Wittig reaction Scheme 1, 1 to 3. Subsequent thereto follow “Examples 24-51" which illustrate the manufacture of the end products of the present invention.
- reaction mixture After 3 hours the reaction mixture is cooled to room temperature, diluted with 1.5 1 ethyl acetate and saturated with sodium chloride. The reaction mixture is adjusted to pH 7 by adding 2N sodium carbonate solution. The organic phase is separated, dried over magnesium sulfate, filtered off and concentrated on a rotary evaporator. The residue is purified by chromatography over silica gel using ethyl acetate/n-hexane 7:3 as eluent.
- reaction mixture is stirred vigorously and 15.9 ml (15.6 g, 0.197 mol) pyridine are added.
- a solution of 21 ml (23.81 g, 0.197 mol ) allylchloroformiate in 100 ml methylene chloride is added dropwise within 30 minutes raising the temperature to -10 °C.
- the reaction mixture is stirred at -10 °C for a further 2 hours, diluted with 500 ml methylene chloride and extracted in succession with water (500 ml), 0.1 M HC1 (500 ml) and 20% sodium chloride solution (500 ml).
- the organic phase is dried over magnesium sulfate, filtered off and concentrated on a rotary evaporator.
- the residue is purified by chromatography over silica gel using ethyl acetate/n-hexane 1:1 as eluent.
- the temperature is raised to -20 °C, kept at -20 °C for one hour, cooled again to -78 °C and treated with a saturated solution of ammonium chloride (200 ml).
- the temperature is raised to 0 °C.
- the reaction mixture is adjusted to pH 5 by adding 2N HC1.
- 300 ml ethyl acetate are added.
- the organic phase is washed with water (300 ml ) and aqueous sodium chloride solution (300 ml).
- the organic solution is dried over magnesium sulphate and concentrated on a rotary evaporator.
- the residue is chromatographed over silica gel using ethyl acetate/n-hexane 3:7 as eluent.
- reaction is controlled via thin layer chromatography (eluent: ethyl acetate/n- hexane 1:1, Rf educt: 0.39, Rf product: 0.16). After 3 hours the reaction mixture is diluted with 100 ml methylenchloride. The organic phase is washed with 150 ml of a saturated solution of sodium chloride and dried over magnesium sulfate. The solvent is evaporated and the residue is chromatographed over silica gel using ethyl acetate/n-hexane 1:1 as eluent.
- Dimethylformamide is evaporated.
- the residue is taken up in 3 ml ethyl acetate.
- the obtained crystals are filtered off over glass fiber under suction and dissolved in 3 ml dimethylformamide.
- 0.1 ml (0.2 mmol) 2N sodium 2-ethyl-capronate solution are added.
- the solvent is evaporated, 1,5 ml water are added and the aqueous phase is chromatographed over a polymeric hydrophobic gel (eluent: water- acetonitrile). The fractions containing the product are combined and lyophilized.
- the obtained crystals are filtered off over glass fiber under suction and dissolved in 3 ml dimethylformamide. Then 0.2 ml (0.4 mmol) 2N sodium 2-ethyl- capronate solution are added. The solvent is evaporated, 3 ml water are added and the aqueous phase is chromatographed over a polymeric hydrophobic gel (eluent: water-acetonitrile). The fractions containing the product are combined and lyophilized.
- HKcm' 1 3434, 1778, 1676, 1635, 1565, 1532, 1334.
- the trityl-protecting group is cleaved off to give (E)-(6S,7S)-7-[(Z)-2-(2- amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-l-(2- fluoro-phenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt.
- the trityl-protecting group is cleaved off to give (E)-(6S,7S)-7-[(Z)-2-(2- amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-l-(4-nitro- benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl] -4-oxa- 1-aza-bicyclo [4.2.0. ] oct- 2-ene-2-carboxylic acid sodium salt.
- the trityl-protecting group is cleaved off to give (E)-(6S,7S)-7-[(Z)-2-(2- amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-l-(5- methyl-isooxazolyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt .
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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JP9525647A JP2000503654A (en) | 1996-01-16 | 1997-01-09 | Isoxacephem derivative |
EP97900972A EP0879237A1 (en) | 1996-01-16 | 1997-01-09 | Isooxacephem derivatives |
AU14399/97A AU718495B2 (en) | 1996-01-16 | 1997-01-09 | Isooxacephem-derivatives |
BR9706980A BR9706980A (en) | 1996-01-16 | 1997-01-09 | Isooxacefem derivatives |
Applications Claiming Priority (2)
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EP96100538 | 1996-01-16 | ||
EP96100538.6 | 1996-01-16 |
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WO1997026260A1 true WO1997026260A1 (en) | 1997-07-24 |
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PCT/EP1997/000057 WO1997026260A1 (en) | 1996-01-16 | 1997-01-09 | Isooxacephem derivatives |
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US (1) | US5811419A (en) |
EP (1) | EP0879237A1 (en) |
JP (1) | JP2000503654A (en) |
KR (1) | KR19990077266A (en) |
CN (1) | CN1208416A (en) |
AR (1) | AR005454A1 (en) |
AU (1) | AU718495B2 (en) |
BR (1) | BR9706980A (en) |
CA (1) | CA2242909A1 (en) |
TR (1) | TR199801366T2 (en) |
WO (1) | WO1997026260A1 (en) |
Cited By (1)
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---|---|---|---|---|
US6114541A (en) * | 1997-03-10 | 2000-09-05 | Hoffmann-La Roche Inc. | Method for the preparation of α-Bromo-Lactam derivatives |
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KR100380324B1 (en) * | 2000-02-24 | 2003-04-16 | 한국과학기술연구원 | Novel cephem compounds and preparation thereof |
EP1638612A4 (en) * | 2003-06-25 | 2010-09-29 | Univ Vanderbilt | Cox-2-targeted imaging agents |
CN109400630B (en) * | 2018-11-23 | 2021-07-02 | 浙江普洛得邦制药有限公司 | Synthetic method of flucloxacillin sodium |
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EP0313081A2 (en) * | 1987-10-22 | 1989-04-26 | Otsuka Pharmaceutical Co., Ltd. | 2-Oxa-isocephem compounds, compositions containing the same and processes for preparing the same |
EP0405217A1 (en) * | 1989-06-24 | 1991-01-02 | Bayer Ag | 2-Isocephems and 2-oxa-isocephems, process for their preparation and their application as and in medicines |
WO1993015085A1 (en) * | 1992-01-22 | 1993-08-05 | Smithkline Beecham Plc | 2-isocephem and oxacephem derivatives, processes for their preparation, intermediates thereof and use as antibacterial agents |
EP0620225A1 (en) * | 1993-04-16 | 1994-10-19 | F. Hoffmann-La Roche Ag | Cephalosporin derivatives |
WO1996026943A1 (en) * | 1995-02-27 | 1996-09-06 | F.Hoffmann-La Roche Ag | Derivatives of 3-pyrrolidylidene-2-one-cephalosporines |
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US3971778A (en) * | 1972-05-12 | 1976-07-27 | Glaxo Laboratories Limited | Cephalosporins having (α-etherified oximino)acylamido groups at the 7-position |
DE2716677C2 (en) * | 1977-04-15 | 1985-10-10 | Hoechst Ag, 6230 Frankfurt | Cephem derivatives and processes for their preparation |
CH648317A5 (en) * | 1977-06-10 | 1985-03-15 | Yamanouchi Pharma Co Ltd | 7ALPHA-METHOXY-7BETHA- (1,3-DITHIETAN-2-CARBOXAMIDO) CEPHALOSPORANIC ACID DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. |
JPS5854157B2 (en) * | 1977-06-10 | 1983-12-02 | 山之内製薬株式会社 | New derivatives of cephalosporin compounds and their production method |
US5523400A (en) * | 1993-04-16 | 1996-06-04 | Hoffmann-La Roche Inc. | Cephalosporin antibiotics |
-
1996
- 1996-12-17 US US08/768,369 patent/US5811419A/en not_active Expired - Fee Related
-
1997
- 1997-01-09 CN CN97191738A patent/CN1208416A/en active Pending
- 1997-01-09 JP JP9525647A patent/JP2000503654A/en active Pending
- 1997-01-09 KR KR1019980705411A patent/KR19990077266A/en not_active Application Discontinuation
- 1997-01-09 BR BR9706980A patent/BR9706980A/en not_active Application Discontinuation
- 1997-01-09 CA CA002242909A patent/CA2242909A1/en not_active Abandoned
- 1997-01-09 AU AU14399/97A patent/AU718495B2/en not_active Ceased
- 1997-01-09 EP EP97900972A patent/EP0879237A1/en not_active Withdrawn
- 1997-01-09 WO PCT/EP1997/000057 patent/WO1997026260A1/en not_active Application Discontinuation
- 1997-01-09 TR TR1998/01366T patent/TR199801366T2/en unknown
- 1997-01-14 AR ARP970100128A patent/AR005454A1/en unknown
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EP0313081A2 (en) * | 1987-10-22 | 1989-04-26 | Otsuka Pharmaceutical Co., Ltd. | 2-Oxa-isocephem compounds, compositions containing the same and processes for preparing the same |
EP0405217A1 (en) * | 1989-06-24 | 1991-01-02 | Bayer Ag | 2-Isocephems and 2-oxa-isocephems, process for their preparation and their application as and in medicines |
WO1993015085A1 (en) * | 1992-01-22 | 1993-08-05 | Smithkline Beecham Plc | 2-isocephem and oxacephem derivatives, processes for their preparation, intermediates thereof and use as antibacterial agents |
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Cited By (1)
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---|---|---|---|---|
US6114541A (en) * | 1997-03-10 | 2000-09-05 | Hoffmann-La Roche Inc. | Method for the preparation of α-Bromo-Lactam derivatives |
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AU718495B2 (en) | 2000-04-13 |
JP2000503654A (en) | 2000-03-28 |
KR19990077266A (en) | 1999-10-25 |
EP0879237A1 (en) | 1998-11-25 |
AR005454A1 (en) | 1999-06-23 |
AU1439997A (en) | 1997-08-11 |
CN1208416A (en) | 1999-02-17 |
TR199801366T2 (en) | 1998-10-21 |
US5811419A (en) | 1998-09-22 |
CA2242909A1 (en) | 1997-07-24 |
BR9706980A (en) | 1999-04-06 |
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