US3682953A - Substituted 5-nitrofuryl-pyrazoles - Google Patents
Substituted 5-nitrofuryl-pyrazoles Download PDFInfo
- Publication number
- US3682953A US3682953A US15209A US3682953DA US3682953A US 3682953 A US3682953 A US 3682953A US 15209 A US15209 A US 15209A US 3682953D A US3682953D A US 3682953DA US 3682953 A US3682953 A US 3682953A
- Authority
- US
- United States
- Prior art keywords
- nitro
- pyrazole
- furyl
- formula
- furaldehyde
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- DICJXPWWJZEDCX-UHFFFAOYSA-N 5-(5-nitrofuran-2-yl)-1h-pyrazole Chemical class O1C([N+](=O)[O-])=CC=C1C1=CC=NN1 DICJXPWWJZEDCX-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 239000002253 acid Substances 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 21
- 238000000034 method Methods 0.000 abstract description 16
- 125000000217 alkyl group Chemical group 0.000 abstract description 5
- 208000015181 infectious disease Diseases 0.000 abstract description 5
- 239000011368 organic material Substances 0.000 abstract description 5
- 230000000813 microbial effect Effects 0.000 abstract description 4
- 230000000845 anti-microbial effect Effects 0.000 abstract description 3
- CWXKGLABGMLZQJ-UHFFFAOYSA-N 5-amino-1-methyl-3-(5-nitrofuran-2-yl)pyrazole-4-carbonitrile Chemical group N#CC1=C(N)N(C)N=C1C1=CC=C([N+]([O-])=O)O1 CWXKGLABGMLZQJ-UHFFFAOYSA-N 0.000 abstract description 2
- VBBXWPCMBTVGBO-UHFFFAOYSA-N 3-amino-5-(5-nitrofuran-2-yl)-1H-pyrazole-4-carbonitrile Chemical class NC1=NNC(C=2OC(=CC=2)[N+]([O-])=O)=C1C#N VBBXWPCMBTVGBO-UHFFFAOYSA-N 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 125000003226 pyrazolyl group Chemical group 0.000 abstract 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- SXINBFXPADXIEY-UHFFFAOYSA-N 5-Nitrofurfural Chemical compound [O-][N+](=O)C1=CC=C(C=O)O1 SXINBFXPADXIEY-UHFFFAOYSA-N 0.000 description 10
- -1 -halo compound Chemical group 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000013543 active substance Substances 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 239000000969 carrier Substances 0.000 description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 5
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 4
- 235000019759 Maize starch Nutrition 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- JPIPRHICKKLMOR-UHFFFAOYSA-N 5-(furan-2-yl)-4-nitro-1h-pyrazole Chemical class [O-][N+](=O)C1=CNN=C1C1=CC=CO1 JPIPRHICKKLMOR-UHFFFAOYSA-N 0.000 description 3
- MSTIMYPUVPXGHI-UHFFFAOYSA-N 5-amino-1-(2-hydroxyethyl)-3-(5-nitrofuran-2-yl)pyrazole-4-carbonitrile Chemical compound OCCN1C(N)=C(C#N)C(C=2OC(=CC=2)[N+]([O-])=O)=N1 MSTIMYPUVPXGHI-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000249 desinfective effect Effects 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 150000007857 hydrazones Chemical class 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 235000014676 Phragmites communis Nutrition 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
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- 229920002678 cellulose Polymers 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 235000013681 dietary sucrose Nutrition 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000036074 healthy skin Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- SIQHWVZQRBMPOT-UHFFFAOYSA-N n-[(5-nitrofuran-2-yl)methylideneamino]methanamine Chemical compound CNN=CC1=CC=C([N+]([O-])=O)O1 SIQHWVZQRBMPOT-UHFFFAOYSA-N 0.000 description 2
- 239000003883 ointment base Substances 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 150000000183 1,3-benzoxazoles Chemical class 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical class C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 1
- GHNLOXXXEAREPT-UHFFFAOYSA-N 5-amino-3-(5-nitrofuran-2-yl)-1-pentylpyrazole-4-carbonitrile Chemical group NC1=C(C(=NN1CCCCC)C=1OC(=CC1)[N+](=O)[O-])C#N GHNLOXXXEAREPT-UHFFFAOYSA-N 0.000 description 1
- IRBUATMUMJELLE-UHFFFAOYSA-N 5-amino-3-(5-nitrofuran-2-yl)-1-propylpyrazole-4-carbonitrile Chemical group NC1=C(C(=NN1CCC)C=1OC(=CC1)[N+](=O)[O-])C#N IRBUATMUMJELLE-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
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- 241000607142 Salmonella Species 0.000 description 1
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- 235000021355 Stearic acid Nutrition 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
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- 206010052428 Wound Diseases 0.000 description 1
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- 239000000205 acacia gum Substances 0.000 description 1
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- 229960000583 acetic acid Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000842 anti-protozoal effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003904 antiprotozoal agent Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- DKVNPHBNOWQYFE-UHFFFAOYSA-N carbamodithioic acid Chemical class NC(S)=S DKVNPHBNOWQYFE-UHFFFAOYSA-N 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- GPTXWRGISTZRIO-UHFFFAOYSA-N chlorquinaldol Chemical compound ClC1=CC(Cl)=C(O)C2=NC(C)=CC=C21 GPTXWRGISTZRIO-UHFFFAOYSA-N 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000002192 coccidiostatic effect Effects 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical class C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
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- FGYRQJUIILOLEG-UHFFFAOYSA-N ethyl 5-amino-4-cyano-3-(5-nitrofuran-2-yl)pyrazole-1-carboxylate Chemical group NC1=C(C(=NN1C(=O)OCC)C=1OC(=CC1)[N+](=O)[O-])C#N FGYRQJUIILOLEG-UHFFFAOYSA-N 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical class C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
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- 239000007940 sugar coated tablet Substances 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- 229960002597 sulfamerazine Drugs 0.000 description 1
- QPPBRPIAZZHUNT-UHFFFAOYSA-N sulfamerazine Chemical compound CC1=CC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 QPPBRPIAZZHUNT-UHFFFAOYSA-N 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical class NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
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- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- KUAZQDVKQLNFPE-UHFFFAOYSA-N thiram Chemical compound CN(C)C(=S)SSC(=S)N(C)C KUAZQDVKQLNFPE-UHFFFAOYSA-N 0.000 description 1
- 229960002447 thiram Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- KVSKGMLNBAPGKH-UHFFFAOYSA-N tribromosalicylanilide Chemical compound OC1=C(Br)C=C(Br)C=C1C(=O)NC1=CC=C(Br)C=C1 KVSKGMLNBAPGKH-UHFFFAOYSA-N 0.000 description 1
- 230000000654 trypanocidal effect Effects 0.000 description 1
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- 230000001018 virulence Effects 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the alkyl moiety constituting or forming part of the group R contains from one to five carbon atoms, but is preferably a straightor branched-chain radical containing from one to three carbon atoms.
- alkyl moieties include the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl and n-pentyl groups. If R represents a carbalkoxy group, then it is preferred that it should be an ethoxy-carbonyl group.
- the present invention also provides salts of nitrofuryl-pyrazoles of formula I with organic and inorganic acids.
- organic and inorganic acids examples include hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, ethandisulphonic, acetic, trichloroacetic, oxalic, succinic, maleic, fumaric, malic, tartaric, citric and mandelic acids.
- the compounds of the present invention are prepared by reacting the corresponding nitrofurylnitrilimine, which in one of its canonical forms may be represented by the formula II,
- X represents a halogen atom, with a base.
- the process may, if desired, be effected in the presence of a further conventional hydrogen halide acceptor.
- the halogen present in the halohydrazone of formula III is preferably chlorine or bromine.
- the nitrofuryl-a-halo-hydrazones of formula III are new compounds. They are produced, for example, by reacting the corresponding nitrofuryl-hydrazones having the formula IV,
- the present invention also provides a modification of the process for producing a nitrofuryl-pyrazole of formula I, which comprises reacting the corresponding nitrofuryl-hydrazone of formula IV with an N-halo compound and treating the reaction mixture thus ob tained with malononitrile in the presence of a base.
- the intermediate product from the reaction of the nitrofuryl-hydrazone of formula IV with the N-halo compound is not isolated before contacting with the malononitrile.
- the alkyl-substituted hydrazones of formula IV are prepared by reacting 5-nitro-2-furylaldehyde with an alkylor carbalkoxyhydrazine in an anhydrous solvent, e.g. anhydrous ethanol, according to methods described by Howarth et al, J. Org. Chem, 28, 864(1963), Sasaki, Pharm. P. Bull. (Japan), 2, 123(1954) and British Pat. No. 905,459. Hydroxyalkylhydrazones, although new, can also be prepared in a similar manner described in the above-cited references.
- anhydrous solvent e.g. anhydrous ethanol
- N-halo compounds which may be used in both these processes are N-halo benzotriazoles and N-halo succinimides.
- N-halo succinimides the N-chloro compound may be used, but the N-bromo derivative is preferred.
- the compounds of the invention having formula I have valuable antimicrobial properties, and in particular having antibacterial, anthelminthic, antiprotozoal, coccidiostatic, trypanocidal and antimalarial activity of value in human or veterinary medicine.
- the compounds are particularly valuable in the treatment of infections of the intestinal and urinary tracts.
- the compounds may also be used to protect a high molecular weight hydrophobic or other organic material susceptible to bacterial or other microbial deterioration by contacting, impregnating or otherwise treating the organic material with the compounds in amounts up to about 5 percent by weight.
- the compounds also find application as growth-promoting additives to animal feedstuffs, to which they may be added in proportions of from 5 to 500 parts per million.
- the antimicrobial activity of the compounds of formula I can be demonstrated in a variety of in vitro and in vivo tests.
- standard in vitro tests for example 5- amino-4-cyanol -methyl-3-( 5-nitro-2-furyl )-pyrazole and 5-amino-4-cyano-l -(2-hydroxyethyl)-3-(5-nitro- 2-furyl)-pyrazole, have an excellent inhibiting activity on the growth of Staphylococcus, Escherichia coli, Klebsiella, Salmonella, Candida alb. and other bacteria.
- mice are infected by intraperitoneal injection of 0.2 ml of a suspension of pathogenic germs which causes a mortality rate of 100 percent in a group of untreated control mice.
- the test compound is ad-v ministered per os by means of a stomach tube, twice on the day of infection.
- the duration of the therapy is adapted to the virulence of the pathogenic germ.
- the mice are now observed and the surviving mice are counted on the fourth day. For each dose of the test compound, the cumulative mortality is then calculated according to the method of L]. Reed and M. Muench, Am.J.I-lyg. 27, 493 (1938).
- the curative dosage necessary for the survival of 50 percent of the test animals is calculated by the same method of Reed and Muench.
- the CD thus determined is found to be far below the toxic dose, and indicates that 5-amino-4-cyano-l-( 2-hydroxyethyl)-3-(5-nitro-2-furyl)-pyrazole has an excellent activity against Staphylococcus aureus.
- the compounds of formula I are administered orally in daily dosages of from about lto about 50 mg/kg, although the exact dosage has to be adjusted to the type of infection, the age, weight and the particular condition of the host being treated.
- the compounds of formula I are administered advantageously in form of pharmaceutical compositions comprising an antimicrobially effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.
- the type of carrier actually used depends to a great extent on the intended application; for external use, for example in disinfecting healthy skin, disinfecting wounds and in treating dermatoses and infections of the mocus membranes caused by bacteria, ointments, powders and tinctures are used in particular.
- the ointment bases may be anhydrous, for instance they can consist of mixtures of wool fat and soft parafi'm, or they can consist of aqueous emulsions in which the active substance is suspended.
- Suitable carriers for powders are, for instance, rice starch and other starches; the bulk weight of the carriers may be lighter, if desired, for example by adding highly dispersed silicic acid, or may be made heavier by adding talcum.
- the tinctures may contain at least one active ingredient of the formula I in aqueous ethanol, in particular 45 to 75 percent ethanol, to which 10 percent to 20 percent of glycerol may be added, if desired.
- Solutions prepared from polyethylene glycol and other conventional solubility promoters, and also, optionally, from emulsifying agents, may be used with particular advantage in disinfecting healthy skin.
- the content of active ingredient in pharmaceutical compositions for external application is preferable in the range of from 0.1 percent to 5 percent.
- Gargles or concentrates for their preparation, and tablets for slow dissolution in the mouth are suitable for the disinfection of the mouth and throat.
- the former are preferably prepared from alcoholic solutions containing 1 to 5 percent of active substance to which glycerol or flavorings may be added. Lozenges,
- solid dosage units preferably have a relatively high content of sugar or similar substances and a relatively low content of active substance, for instance 0.2 percent to 20 by weight, as well as the usual conventional additives such a binding agents and flavorings.
- Solid dosage units in particular tablets, drages (sugar coated tablets) and capsules, are convenient for use in intestinal disinfection and for the oral treatment of urinary tract infections. These units preferably contain from 10 to percent of the compound formula I, to enable the administration of daily doses of from 0.1 to 2.5 grams to adults, or of suitable reduced doses to children. Tablets and drage cores are produced by combining the compounds of formula I with solid, pulverulent carriers such as lactose, saccharose, sorbitol, maize starch, potato starch or amylopectin, cellulose derivatives or gelatins, preferably with the addition of lubricants such a magnesium or calcium stearate or polyethylene glycols of suitable molecular weight.
- solid, pulverulent carriers such as lactose, saccharose, sorbitol, maize starch, potato starch or amylopectin, cellulose derivatives or gelatins, preferably with the addition of lubricants such a magnesium or calcium stearate
- Drage cores may then be coated, for example with concentrated sugar solutions which can also contain gum arabic, talcum and/or titanium dioxide, or they may be coated with a lacquer dissolved in volatile organic solvents or mixture of solvents.
- Dyestuffs can be added to these coatings, for instance to diflerentiate between varying dosages.
- Soft gelatine capsules and other closed capsules consist, for example, of a mixture of gelatines and glycerol, and may contain, for example, mixtures of the compound of formula I with polyethylene glycol.
- Hard gelatine capsules contain, for example, granulates of an active substance with solid pulverulent carriers, for instance lactose, saccharose, sorbitol, mannitol, starches (such as potato starch, maize starch or amylopectin), cellulose derivatives of gelatines, and magnesium stearate or stearic acid.
- solid pulverulent carriers for instance lactose, saccharose, sorbitol, mannitol, starches (such as potato starch, maize starch or amylopectin), cellulose derivatives of gelatines, and magnesium stearate or stearic acid.
- a compound of formula I can be present as sole active ingredient, or it may also be combined with other known pharmacologically active, especially antibacterially and/or antimycotically or otherwise antimicrobially active substances, for example to broaden the range of application.
- the invention also provides a method of protecting an organic material susceptible to bacterial or other microbial attack which comprises treating the material with a nitrofuryl-pyrazole of formula I.
- the organic material may be, for instance a natural or synthetic polymeric material, a proteinaceous or carbohydrate EXAMPLE 1 a.
- the product is 5-amino4-cyano-l-ethoxycarbonyl- 3-(5-nitro-2-furyl)-pyrazole having melting point 207 C.
- the product is S-nitro-furaldehyde a-chloro-N'- ethoxycarbonylhydrazone having melting point 125 C.
- the mixture is diluted with 500 millilitres of iced water and the precipitate is collected, washed with water and dried. The dried solid is recrystallized from ethyl acetate.
- the product is 5-amino-4-cyano-l-methyl-3-(5- nitro-2-furyl)-pyrazole having melting point 250 C with decomposition.
- EXAMPLE 4 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N'-isopropylhydrazone as starting material-instead of 5-nitro-2-furaldehyde N'- methylhydrazone, the reaction conditions being the same.
- the product is 5-amino-4-cyano-1-is0propyl-3-(5- nitro-2-furyl)-pyrazole.
- EXAMPLE 5 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N'-n-pentylhydrazone as starting material instead of 5-nitro-2-furaldehyde N'- methylhydrazone, the reaction conditions being the same.
- the product is 5-amino-4-cyano-l-(n-pentyl)-3-(5- nitro-2-furyl)- pyrazole.
- Example 6 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N'-(2-hydroxyethyl)- hydrazone as starting material instead of 5-nitro-2-furaldehyde N-methylhydrazone, the reaction conditions being the same.
- the product is 5-amin0-4-cyanol -(2-hydroxyethyl 3-( 5-nitro-2-furyl)-pyrazole, having melting point 216 C.
- EXAMPLE 7 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N'-ethylhydrazone as starting material instead of S-nitro-Z-furaldehyde N'- methylhydrazone, the reaction conditions being the same.
- the product is 5-amino-4-cyanol -ethyl-3-( 5-nitro-2 -furyl)-pyrazole, having melting point 1 89 C.
- EXAMPLE 8 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N'-n-propylhydrazone as starting material instead of S-nitro-Z-furaldehyde N'- methylhydrazone, the reaction conditions being the same.
- the product is 5-amino-4-cyano-3-(5-nitro-2-furyl)- l-n-propyl-pyrazole, having melting point 1 65 C.
- the product is 5-amino-4-cyano-3-(5-nitro-2-furyl)- 1 -n-pentoxycarbonyl-pyrazole.
- EXAMPLE 10 The procedure described in Example 2 is repeated using 5-nitro-2-furaldehyde N'-(2-hydroxyethyl) hydrazone as starting material in place of 5-nitro-2-furaldehyde N'-methyl hydrazone, the reaction conditions being the same.
- EXAMPLE 1 Preparation of Tablets 100 g of amino-4-cyano-1-(2-hydroxyethyl)-3-(5- nitro-2-furyl)-pyrazole are mixed with 60.0 g of maize starch and 35.0 g of lactose, the mixture is moistened with a solution of 5.0 g of gelatin and 3.0 g of glycerol in 70.0 g of water and granulated through a sieve. The granulate is mixed with a mixture of 15.0 g of talcum, 10.0 g of maize starch and 2.0 g of magnesium stearate. The resulting mixture is pressed into 1.000 tablets, each containing 100 mg of active substance. If desired, the tablets can be grooved for better adaption of the dosage.
- Composition 1 is granulated in the heat with composition 11 through a sieve of 1.2 mm mesh diameter. The dried granulate is mixed with composition Ill and the resulting mixture is pressed into 1.000 drage cores. These are then coated with composition IV and dried. The drages obtained weigh 255.0 mg and contain 100 mg of active substance.
- Citric acid 1.0 g Sodium cyclamate 5.0 g Distilled water 610.0 g Glycerol 100.0 g Sodium carboxymethyl cellulose 4.0 g Sugar 320.0 g
- R is unsubstituted or hydroxy-substituted alkyl having from one to five carbon atoms, or carbalkoxy having from one to five carbon atoms in the alkyl moiety.
- a compound according to claim 1, wherein R is methyl. 4. A compound according to claim 1, wherein R is ethyl. 5. A compound according to claim 1, wherein R is n-propyl. 6. A compound according to claim 1, wherein R is 2-hydroxyethyl. 7. A compound according to claim 1, wherein R is ethoxycarbonyl.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Compressor (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1106469 | 1969-03-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
US3682953A true US3682953A (en) | 1972-08-08 |
Family
ID=9979338
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15209A Expired - Lifetime US3682953A (en) | 1969-03-01 | 1970-02-27 | Substituted 5-nitrofuryl-pyrazoles |
Country Status (18)
Country | Link |
---|---|
US (1) | US3682953A (es) |
AT (1) | AT290516B (es) |
BE (1) | BE746655A (es) |
BG (1) | BG17313A3 (es) |
BR (1) | BR7017106D0 (es) |
CA (1) | CA925515A (es) |
CH (1) | CH526581A (es) |
CS (2) | CS167277B2 (es) |
DE (1) | DE2009394A1 (es) |
DK (1) | DK124032B (es) |
ES (1) | ES376964A1 (es) |
FR (1) | FR2034589B1 (es) |
GB (1) | GB1290913A (es) |
IE (1) | IE34038B1 (es) |
IL (1) | IL33980A (es) |
NL (1) | NL7002459A (es) |
NO (1) | NO125819B (es) |
SE (1) | SE366317B (es) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3980794A (en) * | 1974-05-13 | 1976-09-14 | Eli Lilly And Company | Method for promoting growth of poultry with 3-(5-nitro-2-imidazolyl)pyrazoles |
US5698580A (en) * | 1994-06-21 | 1997-12-16 | Rational Drug Design Laboratories | Antiviral agent containing benzodithiin derivative as active ingredient |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB880256A (en) * | 1958-12-05 | 1961-10-18 | Ciba Ltd | New pyrazoles and a process for their manufacture |
GB905459A (en) * | 1958-06-24 | 1962-09-12 | Norwich Pharma Co | Anti-coccidial compositions comprising nitrofuran derivatives |
-
1969
- 1969-03-01 GB GB1106469A patent/GB1290913A/en not_active Expired
-
1970
- 1970-02-11 CH CH195570A patent/CH526581A/de not_active IP Right Cessation
- 1970-02-20 NO NO0615/70A patent/NO125819B/no unknown
- 1970-02-20 NL NL7002459A patent/NL7002459A/xx unknown
- 1970-02-20 DK DK83270AA patent/DK124032B/da unknown
- 1970-02-26 SE SE02505/70A patent/SE366317B/xx unknown
- 1970-02-27 FR FR707007169A patent/FR2034589B1/fr not_active Expired
- 1970-02-27 AT AT182370A patent/AT290516B/de not_active IP Right Cessation
- 1970-02-27 IL IL33980A patent/IL33980A/xx unknown
- 1970-02-27 CS CS8973*A patent/CS167277B2/cs unknown
- 1970-02-27 BR BR217106/70A patent/BR7017106D0/pt unknown
- 1970-02-27 IE IE263/70A patent/IE34038B1/xx unknown
- 1970-02-27 BG BG014069A patent/BG17313A3/xx unknown
- 1970-02-27 US US15209A patent/US3682953A/en not_active Expired - Lifetime
- 1970-02-27 DE DE19702009394 patent/DE2009394A1/de active Pending
- 1970-02-27 CA CA076047A patent/CA925515A/en not_active Expired
- 1970-02-27 CS CS1361A patent/CS167276B2/cs unknown
- 1970-02-27 ES ES376964A patent/ES376964A1/es not_active Expired
- 1970-02-27 BE BE746655D patent/BE746655A/xx unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB905459A (en) * | 1958-06-24 | 1962-09-12 | Norwich Pharma Co | Anti-coccidial compositions comprising nitrofuran derivatives |
GB880256A (en) * | 1958-12-05 | 1961-10-18 | Ciba Ltd | New pyrazoles and a process for their manufacture |
Non-Patent Citations (2)
Title |
---|
Burch J. Med. Chem. Vol. 11, pages 79 83 (1968), RS1.J5. * |
Sasaki et al. J. Heterocycl. Chem. Vol. 5, pages 243 8 (1968), QD400.J6. * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3980794A (en) * | 1974-05-13 | 1976-09-14 | Eli Lilly And Company | Method for promoting growth of poultry with 3-(5-nitro-2-imidazolyl)pyrazoles |
US5698580A (en) * | 1994-06-21 | 1997-12-16 | Rational Drug Design Laboratories | Antiviral agent containing benzodithiin derivative as active ingredient |
Also Published As
Publication number | Publication date |
---|---|
BR7017106D0 (pt) | 1973-01-04 |
DK124032B (da) | 1972-09-04 |
IE34038B1 (en) | 1975-01-08 |
BE746655A (fr) | 1970-08-27 |
NO125819B (es) | 1972-11-06 |
ES376964A1 (es) | 1972-09-16 |
NL7002459A (es) | 1970-09-03 |
IL33980A (en) | 1973-03-30 |
CS167276B2 (es) | 1976-04-29 |
IL33980A0 (en) | 1970-04-20 |
CH526581A (de) | 1972-08-15 |
IE34038L (en) | 1970-09-01 |
FR2034589B1 (es) | 1973-01-12 |
BG17313A3 (bg) | 1973-07-25 |
CS167277B2 (es) | 1976-04-29 |
FR2034589A1 (es) | 1970-12-11 |
DE2009394A1 (de) | 1971-09-16 |
GB1290913A (es) | 1972-09-27 |
CA925515A (en) | 1973-05-01 |
SE366317B (es) | 1974-04-22 |
AT290516B (de) | 1971-06-11 |
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