NO128571B - - Google Patents
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- Publication number
- NO128571B NO128571B NO93170A NO93170A NO128571B NO 128571 B NO128571 B NO 128571B NO 93170 A NO93170 A NO 93170A NO 93170 A NO93170 A NO 93170A NO 128571 B NO128571 B NO 128571B
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- denotes
- diphenyl
- imidazolyl
- acetic acid
- Prior art date
Links
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 66
- 150000001875 compounds Chemical class 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- -1 phenyl-imidazolyl Chemical group 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 150000002460 imidazoles Chemical class 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 230000008030 elimination Effects 0.000 claims description 2
- 238000003379 elimination reaction Methods 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 72
- 238000002844 melting Methods 0.000 description 33
- 230000008018 melting Effects 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000011282 treatment Methods 0.000 description 12
- 239000013078 crystal Substances 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- OMLSYNQYPRJYAR-UHFFFAOYSA-N methyl 2-(1h-imidazol-2-yl)-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)OC)C1=NC=CN1 OMLSYNQYPRJYAR-UHFFFAOYSA-N 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 230000000843 anti-fungal effect Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- BMEHATQTULZMSC-UHFFFAOYSA-N methyl 2,2-bis(4-chlorophenyl)-2-(1h-imidazol-2-yl)acetate Chemical compound C=1C=C(Cl)C=CC=1C(C=1C=CC(Cl)=CC=1)(C(=O)OC)C1=NC=CN1 BMEHATQTULZMSC-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- IZPXHZWRFDQWLT-UHFFFAOYSA-N 2-(1h-imidazol-2-yl)-1-morpholin-4-yl-2,2-diphenylethanone Chemical compound N=1C=CNC=1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C(=O)N1CCOCC1 IZPXHZWRFDQWLT-UHFFFAOYSA-N 0.000 description 3
- 241001480043 Arthrodermataceae Species 0.000 description 3
- 241000222122 Candida albicans Species 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 125000005521 carbonamide group Chemical group 0.000 description 3
- 239000000969 carrier 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
- 230000037304 dermatophytes Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- IQDLKFJCEIJFGN-UHFFFAOYSA-N ethyl 2-(1h-imidazol-2-yl)-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)OCC)C1=NC=CN1 IQDLKFJCEIJFGN-UHFFFAOYSA-N 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- PRRHXUDAIBCCOD-UHFFFAOYSA-N propyl 2-(1h-imidazol-2-yl)-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)OCCC)C1=NC=CN1 PRRHXUDAIBCCOD-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XQYVDDAXTYTKDB-UHFFFAOYSA-N 2-chloro-2,2-diphenylacetamide Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)N)C1=CC=CC=C1 XQYVDDAXTYTKDB-UHFFFAOYSA-N 0.000 description 2
- NFHKZAUDRWRXMZ-UHFFFAOYSA-N 2-chloro-2,2-diphenylacetyl chloride Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)Cl)C1=CC=CC=C1 NFHKZAUDRWRXMZ-UHFFFAOYSA-N 0.000 description 2
- RQCVNIVJMBXZRT-UHFFFAOYSA-N 2-methylpropyl 2-(1h-imidazol-2-yl)-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)OCC(C)C)C1=NC=CN1 RQCVNIVJMBXZRT-UHFFFAOYSA-N 0.000 description 2
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 208000007163 Dermatomycoses Diseases 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- 229960003942 amphotericin b Drugs 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 201000003984 candidiasis Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 2
- 229960002327 chloral hydrate Drugs 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000010411 cooking Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- YCMAVBIZWABQFF-UHFFFAOYSA-N methyl 2,2-bis(4-bromophenyl)-2-(1h-imidazol-2-yl)acetate Chemical compound C=1C=C(Br)C=CC=1C(C=1C=CC(Br)=CC=1)(C(=O)OC)C1=NC=CN1 YCMAVBIZWABQFF-UHFFFAOYSA-N 0.000 description 2
- KQPURLPHEFAXQG-UHFFFAOYSA-N methyl 2-(1h-imidazol-2-yl)-2,2-bis(4-methoxyphenyl)acetate Chemical compound C=1C=C(OC)C=CC=1C(C=1C=CC(OC)=CC=1)(C(=O)OC)C1=NC=CN1 KQPURLPHEFAXQG-UHFFFAOYSA-N 0.000 description 2
- ILVSUJHMWHCKOI-UHFFFAOYSA-N methyl 2-chloro-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)OC)C1=CC=CC=C1 ILVSUJHMWHCKOI-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 241000894007 species Species 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 description 1
- UIMCHVXWEUZKGZ-UHFFFAOYSA-N 2-(1H-imidazol-2-yl)-2,2-diphenyl-1-piperidin-1-ylethanone Chemical compound N=1C=CNC=1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C(=O)N1CCCCC1 UIMCHVXWEUZKGZ-UHFFFAOYSA-N 0.000 description 1
- XEZZSIVYLCTXPO-UHFFFAOYSA-N 2-(1h-imidazol-2-yl)-2,2-diphenylacetamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N)C1=NC=CN1 XEZZSIVYLCTXPO-UHFFFAOYSA-N 0.000 description 1
- PTKAGHMFWYFHBU-UHFFFAOYSA-N 2-(1h-imidazol-2-yl)-2,2-diphenylacetonitrile Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C#N)C1=NC=CN1 PTKAGHMFWYFHBU-UHFFFAOYSA-N 0.000 description 1
- SEHVKRKEBXXVIB-UHFFFAOYSA-N 2-(1h-imidazol-2-yl)-n,n-dimethyl-2,2-diphenylacetamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)C1=NC=CN1 SEHVKRKEBXXVIB-UHFFFAOYSA-N 0.000 description 1
- FGOQDFWSJWDDSH-UHFFFAOYSA-N 2-chloro-1-morpholin-4-yl-2,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C(=O)N1CCOCC1 FGOQDFWSJWDDSH-UHFFFAOYSA-N 0.000 description 1
- PECMDNFVBBZHDH-UHFFFAOYSA-N 2-chloro-2,2-diphenyl-1-piperidin-1-ylethanone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C(=O)N1CCCCC1 PECMDNFVBBZHDH-UHFFFAOYSA-N 0.000 description 1
- WHWDUAPSUGLGSD-UHFFFAOYSA-N 2-chloro-n,n-dimethyl-2,2-diphenylacetamide Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)N(C)C)C1=CC=CC=C1 WHWDUAPSUGLGSD-UHFFFAOYSA-N 0.000 description 1
- OHAXWRDDNKBCCD-UHFFFAOYSA-N 2-chloro-n-methyl-2,2-diphenylacetamide Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)NC)C1=CC=CC=C1 OHAXWRDDNKBCCD-UHFFFAOYSA-N 0.000 description 1
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 1
- CGJVFUZUKVZYOB-UHFFFAOYSA-N 2-methylpropyl 2-chloro-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)OCC(C)C)C1=CC=CC=C1 CGJVFUZUKVZYOB-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
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- 241000894006 Bacteria Species 0.000 description 1
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- 241000700199 Cavia porcellus Species 0.000 description 1
- CDEMHJCJMMOFMB-UHFFFAOYSA-M ClC1=CC=C([Mg]Br)C=C1 Chemical compound ClC1=CC=C([Mg]Br)C=C1 CDEMHJCJMMOFMB-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- 241000224432 Entamoeba histolytica Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- 201000002563 Histoplasmosis Diseases 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241001502500 Trichomonadida Species 0.000 description 1
- 241001045770 Trichophyton mentagrophytes Species 0.000 description 1
- ZRJNGFJIBZKXTP-UHFFFAOYSA-M [Br-].CC1=CC=C([Mg+])C=C1 Chemical compound [Br-].CC1=CC=C([Mg+])C=C1 ZRJNGFJIBZKXTP-UHFFFAOYSA-M 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- CFGHWLWBJBVEJC-UHFFFAOYSA-N benzyl 2-chloro-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C(=O)OCC1=CC=CC=C1 CFGHWLWBJBVEJC-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940007078 entamoeba histolytica Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- SLRLUHKUYPGESO-UHFFFAOYSA-N ethyl 2-(1h-imidazol-2-yl)-2-methyl-3-phenylpentanoate Chemical compound N=1C=CNC=1C(C)(C(=O)OCC)C(CC)C1=CC=CC=C1 SLRLUHKUYPGESO-UHFFFAOYSA-N 0.000 description 1
- JMZZTLWBBMADOK-UHFFFAOYSA-N ethyl 2-(1h-imidazol-2-yl)-3-methyl-2-phenylbutanoate Chemical compound C=1C=CC=CC=1C(C(C)C)(C(=O)OCC)C1=NC=CN1 JMZZTLWBBMADOK-UHFFFAOYSA-N 0.000 description 1
- MCGGQYKHZGQEGN-UHFFFAOYSA-N ethyl 2-(4-chlorophenyl)-2-(1h-imidazol-2-yl)-2-phenylacetate Chemical compound C=1C=CC=CC=1C(C=1C=CC(Cl)=CC=1)(C(=O)OCC)C1=NC=CN1 MCGGQYKHZGQEGN-UHFFFAOYSA-N 0.000 description 1
- DRNQRIRVMLZTTF-UHFFFAOYSA-N ethyl 2-benzyl-2-(1h-imidazol-2-yl)-3-methylbutanoate Chemical compound N=1C=CNC=1C(C(=O)OCC)(C(C)C)CC1=CC=CC=C1 DRNQRIRVMLZTTF-UHFFFAOYSA-N 0.000 description 1
- MSBGLMWCKRSNHW-UHFFFAOYSA-N ethyl 2-chloro-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)OCC)C1=CC=CC=C1 MSBGLMWCKRSNHW-UHFFFAOYSA-N 0.000 description 1
- PDWBYRLVGPMRGN-UHFFFAOYSA-N ethyl 2-chloro-2-(4-chlorophenyl)-2-phenylacetate Chemical compound C=1C=C(Cl)C=CC=1C(Cl)(C(=O)OCC)C1=CC=CC=C1 PDWBYRLVGPMRGN-UHFFFAOYSA-N 0.000 description 1
- XJCMYFYVAGRANC-UHFFFAOYSA-N ethyl 2-chloro-3-methyl-2-phenylbutanoate Chemical compound CCOC(=O)C(Cl)(C(C)C)C1=CC=CC=C1 XJCMYFYVAGRANC-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- QKLCQKPAECHXCQ-UHFFFAOYSA-N ethyl phenylglyoxylate Chemical compound CCOC(=O)C(=O)C1=CC=CC=C1 QKLCQKPAECHXCQ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 230000001408 fungistatic effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- WMHPZAWGENFCAS-UHFFFAOYSA-N methyl 2,2-bis(4-fluorophenyl)-2-(1h-imidazol-2-yl)acetate Chemical compound C=1C=C(F)C=CC=1C(C=1C=CC(F)=CC=1)(C(=O)OC)C1=NC=CN1 WMHPZAWGENFCAS-UHFFFAOYSA-N 0.000 description 1
- CLZGROCYYPFPAG-UHFFFAOYSA-N methyl 2-(1h-imidazol-2-yl)-2,2-bis(4-methylphenyl)acetate Chemical compound C=1C=C(C)C=CC=1C(C=1C=CC(C)=CC=1)(C(=O)OC)C1=NC=CN1 CLZGROCYYPFPAG-UHFFFAOYSA-N 0.000 description 1
- KXAQWOCSDWVABF-UHFFFAOYSA-N methyl 2-(1h-imidazol-2-yl)-2-(2-methylphenyl)-2-phenylacetate Chemical compound C=1C=CC=CC=1C(C=1C(=CC=CC=1)C)(C(=O)OC)C1=NC=CN1 KXAQWOCSDWVABF-UHFFFAOYSA-N 0.000 description 1
- RBIZUCWGJMRQKS-UHFFFAOYSA-N methyl 2-(1h-imidazol-2-yl)-2-(4-methylphenyl)-2-phenylacetate Chemical compound C=1C=CC=CC=1C(C=1C=CC(C)=CC=1)(C(=O)OC)C1=NC=CN1 RBIZUCWGJMRQKS-UHFFFAOYSA-N 0.000 description 1
- DKQFBMYNBRIZCA-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)-2-(1h-imidazol-2-yl)-2-phenylacetate Chemical compound C=1C=CC=CC=1C(C=1C(=CC=CC=1)Cl)(C(=O)OC)C1=NC=CN1 DKQFBMYNBRIZCA-UHFFFAOYSA-N 0.000 description 1
- HZXFRXXRYDAVID-UHFFFAOYSA-N methyl 2-(2-methyl-1h-imidazol-5-yl)-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)OC)C1=CN=C(C)N1 HZXFRXXRYDAVID-UHFFFAOYSA-N 0.000 description 1
- FPFJKVGMDIAFJI-UHFFFAOYSA-N methyl 2-(4-chlorophenyl)-2-(1h-imidazol-2-yl)-2-phenylacetate Chemical compound C=1C=CC=CC=1C(C=1C=CC(Cl)=CC=1)(C(=O)OC)C1=NC=CN1 FPFJKVGMDIAFJI-UHFFFAOYSA-N 0.000 description 1
- JTCSJNCBUJSRGQ-UHFFFAOYSA-N methyl 2-chloro-2-(2-methylphenyl)-2-phenylacetate Chemical compound C=1C=CC=C(C)C=1C(Cl)(C(=O)OC)C1=CC=CC=C1 JTCSJNCBUJSRGQ-UHFFFAOYSA-N 0.000 description 1
- ZFFYVOGDTWBQSG-UHFFFAOYSA-N methyl 2-chloro-2-(4-methylphenyl)-2-phenylacetate Chemical compound C=1C=C(C)C=CC=1C(Cl)(C(=O)OC)C1=CC=CC=C1 ZFFYVOGDTWBQSG-UHFFFAOYSA-N 0.000 description 1
- BTTBHWMYJRVGNA-UHFFFAOYSA-N methyl 2-chloro-3,3-dimethyl-2-phenylbutanoate Chemical compound COC(=O)C(Cl)(C(C)(C)C)C1=CC=CC=C1 BTTBHWMYJRVGNA-UHFFFAOYSA-N 0.000 description 1
- YLHXLHGIAMFFBU-UHFFFAOYSA-N methyl phenylglyoxalate Chemical compound COC(=O)C(=O)C1=CC=CC=C1 YLHXLHGIAMFFBU-UHFFFAOYSA-N 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- CJXUYNZKJHUHLE-UHFFFAOYSA-N octyl 2-(1h-imidazol-2-yl)-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)OCCCCCCCC)C1=NC=CN1 CJXUYNZKJHUHLE-UHFFFAOYSA-N 0.000 description 1
- RYQZDZLSAGLCHR-UHFFFAOYSA-N octyl 2-chloro-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)OCCCCCCCC)C1=CC=CC=C1 RYQZDZLSAGLCHR-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- ZKSUJTQPJAGLCM-UHFFFAOYSA-N propyl 2-chloro-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)OCCC)C1=CC=CC=C1 ZKSUJTQPJAGLCM-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Analogifremgangsmåte til fremstilling av antimykotisk Analogy method for the preparation of antifungal
virksomme fenylimidazolyl-fettsyrederivater. active phenylimidazolyl fatty acid derivatives.
Oppfinnelsen vedrører analogifremgangsmåte for frem- The invention relates to an analog method for developing
stilling av antimykotisk virksomme fenyl-imidazolyl-fettsyrederivater med den generelle formel position of antifungally active phenyl-imidazolyl fatty acid derivatives with the general formula
hvor where
12 3 12 3
R , R og R betegner hydrogen eller lavere alkylrester og R , R and R denote hydrogen or lower alkyl residues and
.X betegner en karboksylgruppe eller en funksjonell .X denotes a carboxyl group or a functional
karbonsyrederivatgruppe, og carboxylic acid derivative group, and
4 4
R betegner hydrogen, alkylgrupper, lavere O-alkyl-og S-alkylrester eller halogen, NO,,, CF^- og CN-grupper, samt S0-alkyl og S02-alkyl, hvorved alkylgruppene kan inneholde. 1 - 6 C-atomer og fortrinnsvis 1-4 C-atomer og være rettlinjede eller forgrenede, mettede eller umettede, og-- R denotes hydrogen, alkyl groups, lower O-alkyl and S-alkyl residues or halogen, NO,,, CF^ and CN groups, as well as S0-alkyl and S02-alkyl, whereby the alkyl groups may contain. 1 - 6 C atoms and preferably 1-4 C atoms and be straight or branched, saturated or unsaturated, and--
n betyr 1 eller 2, og n means 1 or 2, and
m betegner et helt tall fra 0 til 6, og m denotes an integer from 0 to 6, and
R betegner en benzenring, som eventuelt er substituert med de rester som er oppført under R eller betegner en alifatisk rest, R denotes a benzene ring, which is optionally substituted with the residues listed under R or denotes an aliphatic residue,
samt deres salter, idet fremgangsmåten er karakterisert ved at man as well as their salts, as the method is characterized by the fact that
a) omsetter halogenderivater med formel a) reacts halogen derivatives with formula
hvor where
X, R , R , n og m har ovenfor nevnte betydning og X, R , R , n and m have the above-mentioned meaning and
Hal betegner halogen, Hal denotes halogen,
med eventuelt alkylsubstituerte imidazoler i nærvær av en syretil-trekkende base eller et imidazol-overskudd, eller with optionally alkyl-substituted imidazoles in the presence of an acid-attracting base or an imidazole excess, or
b) omsetter halogenderivater med formel b) reacts halogen derivatives with formula
hvor X, R , R , n, m og Hal har ovenfor angitte betydninger med where X, R , R , n, m and Hal have the meanings given above
alkali- eller sølvsalter av eventuelt alkylsubstituerte imidazoler, i et inert oppløsningsmiddel ved temperaturer mellom ca. 20 og 200°C, eller alkali or silver salts of optionally alkyl-substituted imidazoles, in an inert solvent at temperatures between approx. 20 and 200°C, or
c) omsetter oksyforbindelser med formel c) reacts oxy compounds with formula
hvor R il , R R, X, n og m har ovenfor nevnte betydninger med eventuelt where R 1 , R R , X, n and m have the meanings mentioned above with optionally
alkylsubstituerte imidazoler under vannavspaltning og de fremstilte forbindelsers salter fremstilles eventuelt på i og for seg kjent måte. alkyl-substituted imidazoles under water elimination and the salts of the compounds produced are possibly prepared in a manner known per se.
Hvis R derimot har betydningen en alifatisk' rest, for-stås herved rettkjedede eller eventuelt forgrenede mettede eller eventuelt umettede alkylrester med 1 - 8 og fortrinnsvis 1 - 4 C-atomer. Naturligvis omfatter de alifatiske rester også eventuelt umettede cykloalifatiske rester med 3 - 6 og fortrinnsvis 5 eller 6 C-atomer i ringsystemet. Som funksjonell karbonsyregruppe (X) nevnes f.eks. ester-, karbonamid- og nitrilgruppen. If, on the other hand, R has the meaning of an aliphatic residue, this means straight-chain or optionally branched saturated or optionally unsaturated alkyl residues with 1-8 and preferably 1-4 C atoms. Naturally, the aliphatic residues also include optionally unsaturated cycloaliphatic residues with 3 - 6 and preferably 5 or 6 C atoms in the ring system. As a functional carboxylic acid group (X), e.g. the ester, carbonamide and nitrile groups.
De alkoholbestanddeler som befinner seg i estergruppen (X) kan betegne eventuelt substituerte, forgrenede eller rettkjedede, mettede eller umettede alifatiske, cykloalifatiske eller hetero-alifatiske rester. Hvis resten av en alifatisk alkohol i en ester-gruppe utgjøres av en alkylgruppe, kan denne være rettkjedet eller forgrenet, inneholde 1 - 18 og fortrinnsvis 1-12 C-atomer og eventuelt være substituert med en aromatisk rest. Hvis X betegner en karbonamidgruppe, kan denne være en fri karbonamidgruppe, en monoalkylkarbonamidgruppe eller en dialkylkarbonamidgruppe. Alkyl-restene i monoalkyl- eller dialkylkarbonamidgruppene kan inneholde 1-3 C-atomer og fortrinnsvis 1 C-atom. Dialkylkarbonamidgruppens alkylrest kan også utgjøre felles ledd i et 5-, 6- eller 7-ring-system, og i tilfelle 6-ring, kan denne inneholde et oksygen-, svovel- eller nitrogenatom som er substituert med en lavalkylgruppe med fortrinnsvis 1-4 C-atomer, hvor heteroatomene står fortrinnsvis i parastilling. The alcohol constituents found in the ester group (X) can denote optionally substituted, branched or straight-chain, saturated or unsaturated aliphatic, cycloaliphatic or hetero-aliphatic residues. If the remainder of an aliphatic alcohol in an ester group consists of an alkyl group, this may be straight-chain or branched, contain 1-18 and preferably 1-12 C atoms and optionally be substituted with an aromatic residue. If X denotes a carbonamide group, this may be a free carbonamide group, a monoalkylcarbonamide group or a dialkylcarbonamide group. The alkyl residues in the monoalkyl or dialkylcarbonamide groups can contain 1-3 C atoms and preferably 1 C atom. The alkyl residue of the dialkylcarbonamide group can also form a common link in a 5-, 6- or 7-ring system, and in the case of a 6-ring, this can contain an oxygen, sulfur or nitrogen atom which is substituted with a lower alkyl group with preferably 1-4 C atoms, where the heteroatoms are preferably in the para position.
Som salter av imidazolyl-forbindelsen (I) fremheves særlig slike med fysiologisk brukbare syrer. Eksempler på slike syrer er hydrogenhalogenidsyrene, fosforsyrer, mono- og bifunksjo-nelle karboksylsyrer og hydroksykarboksylsyrer som f.eks. eddiksyre, maleinsyre, ravsyre, fumarsyre, vinsyre, sitronsyre, salicylsyre, sorbinsyre, melkesyre, 1,5_naftalen-disulfonsyre. As salts of the imidazolyl compound (I), those with physiologically usable acids are particularly highlighted. Examples of such acids are the hydrogen halide acids, phosphoric acids, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids such as e.g. acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid, 1,5_naphthalene-disulfonic acid.
Man foretrekker forbindelser med generell formel (I) Compounds of general formula (I) are preferred
hvor where
R1 og R^ betegner hydrogen og R 1 and R 3 denote hydrogen and
R <2>betegner hydrogen eller en metylgruppe, og R<2> denotes hydrogen or a methyl group, and
X betegner en karboksylgruppe, -COOR^-gruppen hvor R^ betegner rettkjedet eller forgrenet alkyl med 1-10 C-atomer, eller en benzylrest, eller gruppen X denotes a carboxyl group, the -COOR^ group where R^ denotes straight-chain or branched alkyl with 1-10 C atoms, or a benzyl residue, or the group
7 8 7 8
R og R er like eller forskjellige og kan bety hydrogen eller metyl, eller hvor R and R are the same or different and may represent hydrogen or methyl, or where
7 8 7 8
R og R sammen med åmidnitrogenet danner en morfolin-ring eller en piperidinring eller en cyangruppe, R and R together with the amide nitrogen form a morpholine ring or a piperidine ring or a cyano group,
4 4
R betegner hydrogen, metyl, metoksy, nitro eller fluor, klor eller brom, og R denotes hydrogen, methyl, methoxy, nitro or fluorine, chlorine or bromine, and
R 5 betegner en fenylrest, eller en fenylrest som er substituert i p-stilling med fluor, klor, brom, metyl, metoksy eller nitro, eller en rettkjedet eller forgrenet alkylrest med 1-5 C-atomer, og R 5 denotes a phenyl radical, or a phenyl radical which is substituted in the p-position by fluorine, chlorine, bromine, methyl, methoxy or nitro, or a straight-chain or branched alkyl radical with 1-5 C atoms, and
n 1 og n 1 and
m = 0 - 6. m = 0 - 6.
Som særlig foretrukne forbindelser fremheves difenyl-imidazolyl-eddiksyre-metylester og dennes hydroklorid. Particularly preferred compounds are diphenyl-imidazolyl-acetic acid methyl ester and its hydrochloride.
Utgangsforbindelsene som trengs til fremstilling av de nye forbindelser er kjent eller kan fremstilles etter kjente metoder. The starting compounds needed for the production of the new compounds are known or can be produced according to known methods.
Fremstillingen av forbindelser i henhold til foreliggende oppfinnelse beskrives nøyere i forbindelse med nedenstående eksempler. The production of compounds according to the present invention is described in more detail in connection with the following examples.
Eksempel 1. Example 1.
'13 g difenyl-kloreddiksyre-metylester (0,05 mol) (kpp ^= 140°C), (fremstilt fra difenylkloreddiksyreklorid og metanol ifølge. Ber. 2_2,~ 1537 ), oppvarmes med 10 g imidazol i 100 ml acetonitril i 18 timer til koking. 1 Etter avdestillering av oppløsningsmidlet i vakuum tilsettes 50 ml vann og man frafiltrerer med metylenklorid. Etter tørking over natriums-ulfat avdestilleres oppløsningsmidlet i vakuum og residuet omkrystalliseres fra liten mengde eddikester. Således får man difenyl-imidazolyl-eddiksyremetylester som fargeløse '13 g of diphenyl-chloroacetic acid methyl ester (0.05 mol) (bp ^= 140°C), (prepared from diphenylchloroacetic acid chloride and methanol according to. Ber. 2_2,~ 1537 ), is heated with 10 g of imidazole in 100 ml of acetonitrile for 18 hours for cooking. 1 After distilling off the solvent in vacuum, add 50 ml of water and filter off with methylene chloride. After drying over sodium sulfate, the solvent is distilled off in vacuo and the residue is recrystallized from a small amount of acetic acid. Diphenyl-imidazolyl-acetic acid methyl ester is thus obtained as colourless
krystaller med smeltepunkt 155°C (dekomponering). crystals with melting point 155°C (decomposition).
Eksempel 2. Example 2.
Ved forsåping av difenyl-imidazolyl-eddiksyre-metyl-esteren ifølge eksempel 1 med alkoholisk kalilut får man den tilsvarende karboksylsyre. By saponification of the diphenyl-imidazolyl-acetic acid methyl ester according to example 1 with alcoholic potash, the corresponding carboxylic acid is obtained.
Ved en fremgangsmåte som er helt analog med eksempel 1 får man som eksempler 3 - 8, ut fra 13,7 g difenyl-kloreddiksyre-etylester (0,05 mol) (Ber. 22, 1537) difenyl-imidazolyl-eddiksyre-etylester, smeltepunkt 104°C, ut fra 14,4 g difeny1-kloreddiksyre-propylester (kpn 5 , o = 155°C) difenyl-imidazolyl-eddiksyre-propylester med smeltepunkt 71 C, ut fra 15,1 g difenyl-kloreddiksyre-isobutylester (kpQ2 = 150°C) difenyl-imidazolyl-eddiksyre-siobutylester som olje, ut fra 16,0 g difenyl-kloreddiksyre-oktylester (kpn 5-, = 195 C) difenyl-imidazolyl-eddiksyre-n-oktylester som en olje, ut fra 19,3 g difenyl-kloreddiksyre-decylester difenylimidazolyl-eddiksyre-decylester med smeltepunkt 48°C, og ut fra 16,8 g difenyl-kloreddiksyrebenzylester difenyl-imidazoly 1-eddiksyre-ben'zylester som en olje. Som den andre reaksjonskomponent tjente i disse eksempler imidazol. By a method which is completely analogous to example 1, examples 3 - 8 are obtained, starting from 13.7 g diphenyl-chloroacetic acid ethyl ester (0.05 mol) (Ber. 22, 1537) diphenyl-imidazolyl-acetic acid ethyl ester, melting point 104°C, from 14.4 g diphenyl-chloroacetic acid propyl ester (bpn 5 , o = 155°C) diphenyl-imidazolyl-acetic acid propyl ester with melting point 71 C, from 15.1 g diphenyl-chloroacetic acid isobutyl ester ( kpQ2 = 150°C) diphenyl-imidazolyl-acetic acid-siobutyl ester as an oil, from 16.0 g diphenyl-chloroacetic acid-octyl ester (bpn 5-, = 195 C) diphenyl-imidazolyl-acetic acid-n-octyl ester as an oil, from from 19.3 g of diphenyl-chloroacetic acid decyl ester diphenylimidazolyl acetic acid decyl ester with melting point 48°C, and from 16.8 g of diphenyl-chloroacetic acid benzyl ester diphenyl-imidazoly 1-acetic acid benzyl ester as an oil. As the second reaction component served in these examples imidazole.
Eksempel 9• Example 9•
5,9 g difenyl-klor-acetbnitril (fremstilt ut fra difeny1-kloracetamid (Ber. 41, 3539) ved oppvarming i f osf oroksyklorid, (kpQZj = 130°C), oppvarmes med 5 g imidazol i 50 ml acetonitril i 18 timer til koking. Acetonitrilet avdestilleres i vakuum. Etter behandling med 20 ml vann frafiltreres med metylenklorid. Oppløsningsmidlet avdestilleres etter tørking i vakuum. Det faste residuum omfelles fra eddikester-petroleter. Således fåes difenyl-imidazolyl-acetonitril med smeltepunkt 98°C. 5.9 g of diphenyl-chloroacetbnitrile (prepared from diphenyl-chloroacetamide (Ber. 41, 3539) by heating in phosphorus oxychloride, (kpQZj = 130°C), is heated with 5 g of imidazole in 50 ml of acetonitrile for 18 hours to boiling. The acetonitrile is distilled off in a vacuum. After treatment with 20 ml of water, filtered off with methylene chloride. The solvent is distilled off after drying in a vacuum. The solid residue is reprecipitated from ethyl acetate-petroleum ether. This gives diphenyl-imidazolyl-acetonitrile with a melting point of 98°C.
Eksempel 1Q._ Example 1Q._
13,7 g fenyl-p-tolyl-kloreddiksyre-metylester (fremstilt ut fra p-toluyl-magnesiumbromid og benzoylmaursyre-metylester og behandling med PCl^, kpQ ^ = 150°C), oppvarmes med 10 g imidazol i 100 ml acetonitril i 16 timer til koking. Acetonitrilet avdestilleres' i vakuum. Residuet- opptas etter behandling med 50 ml vann i 13.7 g of phenyl-p-tolyl-chloroacetic acid methyl ester (prepared from p-toluyl-magnesium bromide and benzoylformic acid methyl ester and treatment with PCl^, kpQ ^ = 150°C), is heated with 10 g of imidazole in 100 ml of acetonitrile in 16 hours for cooking. The acetonitrile is distilled off in vacuum. The residue is taken up after treatment with 50 ml of water in it
metylenklorid. Metylenkloridoppløsningen avdestilleres i vakuum og residuet omkrystalliseres fra en liten mengde eddikester. Således fåes fenyl-p-tolyl-imidazolyl-eddiksyre-metylester, smeltepunkt 146°C. methylene chloride. The methylene chloride solution is distilled off in a vacuum and the residue is recrystallized from a small amount of acetic acid. Thus phenyl-p-tolyl-imidazolyl-acetic acid methyl ester is obtained, melting point 146°C.
Eksempel 11- Example 11-
På analog måte får man frå fenyl-o-toluyl-kloreddiksyre-metylester (kp^^ = l60°C) fenyl-o-toluyl-imidazolyl-eddiksyre-metylester (smeltepunkt 148°C). In an analogous way, phenyl-o-toluyl-chloroacetic acid methyl ester (bp^^ = 160°C) is obtained from phenyl-o-toluyl-imidazolyl-acetic acid methyl ester (melting point 148°C).
Eksempel 12. Example 12.
14,4 g (0,05 mol) B-klbr-B-6-difenyl-propionsyreetyl-ester (fremstilt fra 8-oksy-3,6-difenyl-propionsyre-etylester) 14.4 g (0.05 mol) B-klbr-B-6-diphenyl-propionic acid ethyl ester (prepared from 8-oxy-3,6-diphenyl-propionic acid ethyl ester)
(Ber. 40, 4538), ved behandling med fosforpentaklorid, oppvarmes til kokepunktet i 100 ml acetonitril med 10 g imidazol i 16 timer. Oppløsningsmidlet avdestilleres i vakuum, residuet tilsettes 50 ml vann og opptas i metylenklorid. Etter tørking avdestilleres i vakuum. Man får B-imidazolyl-B,3-difenyl-propionsyreetylester som et krystallinsk stoff med smeltepunkt 75°C. (Ber. 40, 4538), by treatment with phosphorus pentachloride, is heated to the boiling point in 100 ml of acetonitrile with 10 g of imidazole for 16 hours. The solvent is distilled off in a vacuum, the residue is added to 50 ml of water and taken up in methylene chloride. After drying, distill off in a vacuum. B-imidazolyl-B,3-diphenyl-propionic acid ethyl ester is obtained as a crystalline substance with a melting point of 75°C.
Eksempel i3. Example i3.
5 g difenyl-imidazolyl-eddiksyre-metylester ifølge eksempel 1 oppløses i tetraklorkarbon og man innleder saltsyregass under avkjøling. Man avdekanterer tetraklorkarbonet fra det utfelte seige salt, og saltet omfelles fra aceton-eter. Man får på denne måten klorhydratet av ovenstående base med smeltepunkt 131°C (dekomp.). 5 g of diphenyl-imidazolyl-acetic acid methyl ester according to example 1 are dissolved in carbon tetrachloride and hydrochloric acid gas is introduced while cooling. The carbon tetrachloride is decanted from the precipitated tough salt, and the salt is reprecipitated from acetone-ether. In this way, the chloral hydrate of the above base with a melting point of 131°C (decomp.) is obtained.
Eksempel 14. Example 14.
15j45 g fenyl-p-klorfenyl-kloreddiksyre-etylester (0,05 mol) (fremstilt av p-klorfenyl-magnesiumbromid og benzoylmaursyre-etylester, påfølgende behandling med tionylklorid, kpg ^ 160°C), kokes med 10 g imidazol i 100 ml acetonitril i 16-timer. Etter avdestillering av oppløsningsmidlet tilsettes 50 ml vann og man ryster ut med metylenklorid. Etter tørking avdestilleres opp-løsningsmidlet i vakuum, og fenyl-p-klorfenyl-imidazolyl-eddiksyre-etylesteren fåes som en olje, som stivner etter lengre tid. 15j45 g of phenyl-p-chlorophenyl-chloroacetic acid ethyl ester (0.05 mol) (prepared from p-chlorophenyl-magnesium bromide and benzoylformic acid ethyl ester, subsequent treatment with thionyl chloride, bp ^ 160°C), is boiled with 10 g of imidazole in 100 ml acetonitrile for 16 hours. After distilling off the solvent, add 50 ml of water and shake out with methylene chloride. After drying, the solvent is distilled off in vacuum, and the phenyl-p-chlorophenyl-imidazolyl-acetic acid ethyl ester is obtained as an oil, which solidifies after a long time.
Eksempel 15- Example 15-
På analog måte får man fenyl-p-klorfeny1-imidazolyl-eddiksyre-metylester med smeltepunkt 135°C (eddikester). Eksempel 16. In an analogous manner, phenyl-p-chlorophenyl-imidazolyl-acetic acid methyl ester with melting point 135°C (acetic ester) is obtained. Example 16.
Som beskrevet i eksempel 14 fremstilte man fenyl-o-klorfenyl-imidazolyl-eddiksyre-metylester med smeltepunkt 138°C As described in example 14, phenyl-o-chlorophenyl-imidazolyl-acetic acid methyl ester with a melting point of 138°C was prepared
(eddikester). (vinegar).
Eksempel 17• 12 g fenyl-isopropyl-kloreddiksyre-etylester (kpn ., 95 o C) (0,05 mol) oppvarmes med 10 g imidazol og 100 ml acetonit'ril i 18 timer til koking. Etter avdestillering av oppløsningsmidlet i vakuum behandles med 50 ml vann og man ryster ut med metylenklorid. Metylenkloridet tørkes og avdestilleres i vakuum. Man får fenyl-isopropyl-imidazolyl-eddiksyre-etylester som en olje. Example 17• 12 g of phenyl-isopropyl-chloroacetic acid ethyl ester (b.p., 95 o C) (0.05 mol) is heated with 10 g of imidazole and 100 ml of acetonitrile for 18 hours until boiling. After distilling off the solvent in a vacuum, treat with 50 ml of water and shake out with methylene chloride. The methylene chloride is dried and distilled off in a vacuum. Phenyl-isopropyl-imidazolyl-acetic acid ethyl ester is obtained as an oil.
Eksempel 18. Example 18.
12,27 g difenyl-kloreddiksyreamid (0,05 mol) (Ber. Hl_, 3593) oppvarmes sammen med 11,8 g imidazol i 100 ml acetonitril i 18 timer ved kokepunktet. Etter avkjøling oppslemmes krystallene i vann og vaskes. Etter omkrystallisering fra metanol får man difenyl-imidazolyl-eddiksyre-amidet med smeltepunkt 2l8°C. 12.27 g of diphenyl-chloroacetic acid amide (0.05 mol) (Ber. Hl_, 3593) is heated together with 11.8 g of imidazole in 100 ml of acetonitrile for 18 hours at the boiling point. After cooling, the crystals are suspended in water and washed. After recrystallization from methanol, the diphenyl-imidazolyl-acetic acid amide with a melting point of 218°C is obtained.
Eksempel 19 Example 19
13 g difenyl-kloreddiksyre-metylamid (0,05 mol) (fremstilt ut fra difenyl-kloreddiksyreklorid og metylamin i henhold til Ber. Hl, 3539, smeltepunkt 108°C), kokes med 11,5 g imidazol og 13 g of diphenyl-chloroacetic acid-methylamide (0.05 mol) (prepared from diphenyl-chloroacetic acid chloride and methylamine according to Ber. Hl, 3539, melting point 108°C), is boiled with 11.5 g of imidazole and
100 ml acetonitril i 18 timer. Etter,avkjøling frafiltreres krystallene, gnis ut med vann og vaskes. Omkrystallisert fra metanol får man difenyl-imidazoly1-eddiksyre-metylamidet med smeltepunkt 237°C. 100 ml of acetonitrile for 18 hours. After cooling, the crystals are filtered off, rubbed out with water and washed. Recrystallized from methanol gives the diphenyl-imidazoly-1-acetic acid methylamide with a melting point of 237°C.
Eksempel 20, Example 20,
18,1 g difenyl-kloreddiksyre-dimetylamid (smeltepunkt 128°C, fremsi-lt analogt eksempel 19), .oppvarmes med 15,6 g imidazol i 120 ml acetonitril i 18 timer til koking. Oppløsningsmidlet avdestilleres i vakuum. Etter tilsetning av 70 ml vann ryster man ut med metylenklorid. Etter tørking avdestilleres oppløsningsmidlet i vakuum og den faste rest omkrystalliseres fra metanol. Man får difenyl-imidazolyl-eddiksyre-dimetylamid med smeltepunkt 202°C som fargeløse krystaller. 18.1 g of diphenyl-chloroacetic acid-dimethylamide (melting point 128°C, prepared analogously to Example 19) are heated with 15.6 g of imidazole in 120 ml of acetonitrile for 18 hours until boiling. The solvent is distilled off in a vacuum. After adding 70 ml of water, shake out with methylene chloride. After drying, the solvent is distilled off in vacuum and the solid residue is recrystallized from methanol. Diphenyl-imidazolyl-acetic acid-dimethylamide with a melting point of 202°C is obtained as colorless crystals.
Eksempel 21. Example 21.
Analogt eksempel 20 får man ut fra 15,5 g difenyl-kloreddiksyre-morfolid (smeltepunkt 113°C) og 11 g imidazol i 100 ml acetonitril, difenyl-imidazolyleddiksyre-morfolid som en olje. Analogously to Example 20, diphenyl-imidazolylacetic acid morpholide is obtained as an oil from 15.5 g of diphenyl-chloroacetic acid morpholide (melting point 113°C) and 11 g of imidazole in 100 ml of acetonitrile.
Ved tilsetning av eterisk saltsyre til en oppløsning By adding ethereal hydrochloric acid to a solution
av difenyl-imidazolyl-eddiksyre-morfolid i eddikester fremstilles klorhydratet av difenyl-imidazolyl-eddiksyre-morfolid med smeltepunkt 118°C. of diphenyl-imidazolyl-acetic acid morpholide in acetic ester produces the hydrochloride of diphenyl-imidazolyl-acetic acid morpholide with a melting point of 118°C.
Eksempel . 22 . Example . 22 .
På analog måte som i eksempel 20 får man fra 15,4 g difenyl-kloreddiksyre-piperidid (smeltepunkt 82°C) og 10 g imidazol i 100 ml acetonitril, difenyl-imidazolyl-eddiksyre-piperidid med smeltepunkt l60°C. In an analogous manner to example 20, diphenyl-imidazolyl-acetic acid piperidide with a melting point of 160°C is obtained from 15.4 g of diphenyl-chloroacetic acid piperidide (melting point 82°C) and 10 g of imidazole in 100 ml of acetonitrile.
Eksempel 23..., Example 23...,
162,6 g (0,434 mol) 4,4'-diklor-difenyl-brom-eddiksyre-metylester (fremstilt av 4,4'-diklor-benzilsyre-metylester) og fosforpentabromid (kpQ = 190°C), kokes sammen med 90 g (1,32 mol) imidazol i 1 liter acetonitril i 14 .timer under omrøring. Acetonitrilet avdestilleres i vakuum. Residuet utrystes med to ganger 1,3 liter vann for å fjerne imidazolen, opptas deretter i 950 ml metylenklorid og rystes på nytt med 1,8 liter vann. Etter tørking med natriumsulfat avdestilleres metylenklorid i vakuum. Residuet utkokes med 4 ganger 250 ml eter, den eteriske oppløsning utfelles etter klaring med aktivkull, med eterisk saltsyre. Peilingen vaskes i absolutt eter, opptas i metylenklorid og tilsettes eddikester etter filtrering. Ved inndampning av metylenkloridet på vannbad krystalliserer klorhydratet av bis-(4-klorfeny1)-imidazoly1-eddiksyre-metylestere med smeltepunkt 150°C (under dekomponering) som fargeløse krystaller. 162.6 g (0.434 mol) of 4,4'-dichloro-diphenyl-bromo-acetic acid methyl ester (prepared from 4,4'-dichloro-benzyl acid methyl ester) and phosphorus pentabromide (kpQ = 190°C), are boiled together with 90 g (1.32 mol) of imidazole in 1 liter of acetonitrile for 14 hours with stirring. The acetonitrile is distilled off in a vacuum. The residue is shaken twice with 1.3 liters of water to remove the imidazole, then taken up in 950 ml of methylene chloride and shaken again with 1.8 liters of water. After drying with sodium sulphate, methylene chloride is distilled off in a vacuum. The residue is boiled off with 4 times 250 ml of ether, the ethereal solution is precipitated after clarification with activated carbon, with ethereal hydrochloric acid. The bearing is washed in absolute ether, taken up in methylene chloride and added to ethyl acetate after filtration. By evaporating the methylene chloride on a water bath, the hydrochloride of bis-(4-chlorophenyl)-imidazoly-1-acetic acid methyl esters with a melting point of 150°C (during decomposition) crystallizes as colorless crystals.
Hvis man ryster klorhydratet med metylenklorid i soda-oppløsning, får man en oppløsning av basen. 'Etter tørking avdestilleres i vakuum og residuet'omkrystalliseres fra tørr eter. Man får fargeløse krystaller av bis-(4-klorfenyl)-imidazolyl-eddiksyre-metylester med smeltepunkt 132°C. If you shake the chloral hydrate with methylene chloride in soda solution, you get a solution of the base. After drying, it is distilled off in a vacuum and the residue is recrystallized from dry ether. Colorless crystals of bis-(4-chlorophenyl)-imidazolyl-acetic acid methyl ester with a melting point of 132°C are obtained.
Eksempel 24, Example 24,
Analogt eksempel 23 får man ut fra 13,3 g 4,4'-ditolyl-a-bromeddiksyre-metylester og 10 g imidazol i 100 ml acetonitril, klorhydratet av bis-(4-tolyl)-imidazolyl-eddiksyre-metylester med smeltepunkt 140°{dekomp.) som fargeløse krystaller. Analogously to example 23, one obtains from 13.3 g of 4,4'-ditolyl-a-bromoacetic acid methyl ester and 10 g of imidazole in 100 ml of acetonitrile, the hydrochloride of bis-(4-tolyl)-imidazolyl-acetic acid methyl ester with a melting point of 140 °{decomp.) as colorless crystals.
Eksempel 25- Example 25-
19,4 g 4,4'-dibrom-difenyl-bromeddiksyre-metylester (fremstilt fra 4,4<1->dibrom-difenyl-eddiksyre-metylester og bromsuccinimid) kokes med 8,4-g imidazol i 8,5 ml acetonitril i 15 timer. Acetonitrilet avdestilleres i vakuum. Residuet rystes to ganger ut med hver gang 110 ml vann og dekanteres. Resten opptas i 100 ml metylenklorid og rystes igjen ut med 80 ml vann. Etter tørking av metylenkloridet avdestilleres dette i vakuum. Residuet utkokes med 4 ganger 100 ml absolutt eter. Eterblandingen klares med aktivkull og utfelles med eterisk saltsyre. Det utfelles et klumpaktig klorhydrat som gnis ut to ganger med absolutt eter, og opptas i metylenklorid. Etter filtrering tilsettes eddikester og metylenkloridet inndampes på vannbad. Etter avkjøling krystalliserer klorhydratet av bis-(4-bromfenyl)-imidazolyl-eddiksyre-metylesteren ut med smeltepunkt 140°C som fargeløse krystaller. 19.4 g of 4,4'-dibromo-diphenyl-bromoacetic acid methyl ester (prepared from 4,4<1->dibromo-diphenyl-bromoacetic acid methyl ester and bromosuccinimide) is boiled with 8.4 g of imidazole in 8.5 ml of acetonitrile for 15 hours. The acetonitrile is distilled off in a vacuum. The residue is shaken out twice with 110 ml of water each time and decanted. The residue is taken up in 100 ml of methylene chloride and shaken out again with 80 ml of water. After drying the methylene chloride, this is distilled off in a vacuum. The residue is boiled off with 4 times 100 ml of absolute ether. The ether mixture is clarified with activated charcoal and precipitated with ethereal hydrochloric acid. A lumpy chlorohydrate is precipitated, which is triturated twice with absolute ether and taken up in methylene chloride. After filtration, acetic acid is added and the methylene chloride is evaporated on a water bath. After cooling, the hydrochloride of the bis-(4-bromophenyl)-imidazolyl-acetic acid methyl ester crystallizes out with a melting point of 140°C as colorless crystals.
Klorhydratet rystes ut med metylenklorid og sodaopp-løsning. Baseoppløsningen i metylenklorid tørkes og destilleres i vakuum. Residuet omkry stalliseres- fra en liten mengde absolutt eter. Man får på denne måten fargeløse krystaller av bis-(4-brom-fenyl)-imidazolyl-eddiksyre-metylester med smeltepunkt 135°C. Eksempel 26, The hydrochloride is shaken out with methylene chloride and soda solution. The base solution in methylene chloride is dried and distilled in vacuum. The residue is crystallized from a small amount of absolute ether. Colorless crystals of bis-(4-bromo-phenyl)-imidazolyl-acetic acid methyl ester with a melting point of 135°C are obtained in this way. Example 26,
På samme måte som i eksempel 23 får man av 40,1 g 4,4'-difluor-difenyl-bromeddiksyre-metylester (kpQ ^ = l43°C, fremstilt av 4,4'-difluor-difenyl-eddiksyre-metylester og N-bromravsyre-imid) og 23,6 g imidazol i 236 ml acetonitril, klorhydratet av bis-(4-fluor-fenyl)-imidazolyl-eddiksyre-metylester med smeltepunkt l47°C. Av dette får man med sodaoppløsning i- metylenklorid den frie base In the same way as in example 23, 40.1 g of 4,4'-difluoro-diphenyl-bromoacetic acid methyl ester is obtained (kpQ ^ = 143°C, prepared from 4,4'-difluoro-diphenyl-bromoacetic acid methyl ester and N -bromosuccinic acid imide) and 23.6 g of imidazole in 236 ml of acetonitrile, the hydrochloride of bis-(4-fluoro-phenyl)-imidazolyl-acetic acid methyl ester with a melting point of 147°C. From this, the free base is obtained with a soda solution in methylene chloride
med smeltepunkt 128°C. with melting point 128°C.
Eksempel 27- Example 27-
På samme måte som i eksempel 23 får man fra 4,4'-dimetoksy-benzilsyre-metylester (smeltepunkt 110°C) med fosforpentaklorid over 4,4'-dimetoksy-fenyl-a-kloreddiksyre-metylester med imidazol i acetonitril, forbindelsen bis-(4-metoksy-fenyl)-imidazolyl-eddiksyre-metylester med smeltepunkt 131°C. In the same way as in example 23, from 4,4'-dimethoxy-benzyl acid methyl ester (melting point 110°C) with phosphorus pentachloride over 4,4'-dimethoxy-phenyl-a-chloroacetic acid methyl ester with imidazole in acetonitrile, the compound bis -(4-methoxy-phenyl)-imidazolyl-acetic acid methyl ester with melting point 131°C.
Eksempel 28, Example 28,
På samme måte som i eksempel 23 med analog opparbeid-else får man fra 10,25 g 4,4'-dinitro-difeny1-bromeddiksyreetylester (smeltepunkt 130°C, fremstilt fra 4,4'-dinitro-difeny1-eddiksyre-etylester og N-bromsuccinimid) og 5 g imidazol i 70 ml acetonitril, klorhydratet av bis-(4-nitro-fenyl)-imidazoly1-eddiksyre-etylester med smeltepunkt 130°C (dekomp.) i form av fargeløse krystaller. Eksempel 29. In the same way as in example 23 with analogous work-up, 10.25 g of 4,4'-dinitro-diphenyl-1-bromoacetic acid ethyl ester is obtained (melting point 130°C, prepared from 4,4'-dinitro-diphenyl-1-bromoacetic acid ethyl ester and N-bromosuccinimide) and 5 g of imidazole in 70 ml of acetonitrile, the hydrochloride of bis-(4-nitro-phenyl)-imidazoly-1-acetic acid ethyl ester with melting point 130°C (decomp.) in the form of colorless crystals. Example 29.
Analogt eksempel 12 får man fenyl-isopropyl-imidazolyl-propionsyre-etylester som en olje og av denne med eterisk saltsyre klorhydratet med smeltepunkt 194°C. Analogous to example 12, phenyl-isopropyl-imidazolyl-propionic acid ethyl ester is obtained as an oil and from this with ethereal hydrochloric acid the hydrochloride with a melting point of 194°C.
Eksempel 30, Example 30,
Analogt eksempel 12 får man fenyl-isopenty1-imidazolyl-propionsyre-etylester som en olje. Analogous to example 12, phenyl-isopenty-1-imidazolyl-propionic acid ethyl ester is obtained as an oil.
. Eksempel 31. . Example 31.
Analogt eksempel 32 får man fenyl-etyl-imidazolyl-isosmørsyre-etylester som en olje. Analogously to example 32, phenyl-ethyl-imidazolyl-isobutyric acid ethyl ester is obtained as an oil.
Eksempel 32. Example 32.
13 g difenyl-a-klor-eddiksyre-metylester (0,05 mol) kokes med 12,1 g 2-metyl-imidazol i 100 ml acetonitril i 20 timer. Acetonitrilet avdestilleres i vakuum. Residuet tilsettes 200 ml vann og opptas i 200 ml metylenklorid. Metylenkloridet rystes ut med to ganger 150 ml vann, tørkes og avdestilleres i vakuum. Residuet omkrystalliseres fra en liten mengde eddikester. Man får på denne måte difenyl-2-metyl-imidazolyl-eddiksyre-metylester med smeltepunkt 136°C. 13 g of diphenyl-α-chloro-acetic acid methyl ester (0.05 mol) is boiled with 12.1 g of 2-methyl-imidazole in 100 ml of acetonitrile for 20 hours. The acetonitrile is distilled off in a vacuum. The residue is added to 200 ml of water and taken up in 200 ml of methylene chloride. The methylene chloride is shaken out with twice 150 ml of water, dried and distilled off in a vacuum. The residue is recrystallized from a small amount of acetic acid. Diphenyl-2-methyl-imidazolyl-acetic acid methyl ester with a melting point of 136°C is obtained in this way.
Eksempel Example
12,7 g (0,05 mol) fenyl-tert.-butyl-kloreddiksyre-metylester (kpQ ^ = 96°C), oppvarmes med 10 g imidazol og 100 ml acetonitril i 17 timer til koking. Etter avdestillering av oppløs-ningsmidlet i vakuum behandles med 70 ml vann og man ryster ut med metylenklorid. Metylenkloridet rystes i vakuum ut med 30 ml vann, .tørkes og inndampes i vakuum. Man får fenyl-tert.-butyl-imidazolyl-eddiksyre-metylester som en olje, som stivner etter lengre tids henstand. 12.7 g (0.05 mol) of phenyl tert-butyl chloroacetic acid methyl ester (kpQ ^ = 96°C), is heated with 10 g of imidazole and 100 ml of acetonitrile for 17 hours to boiling. After distilling off the solvent in a vacuum, treat with 70 ml of water and shake out with methylene chloride. The methylene chloride is shaken out in a vacuum with 30 ml of water, dried and evaporated in a vacuum. Phenyl-tert-butyl-imidazolyl-acetic acid methyl ester is obtained as an oil, which solidifies after a longer period of standing.
Eksempel gf<y.>Example gf<y.>
Ut fra difenyl-imidazolyl-eddiksyre-metylester ifølge eksempel 1 og de tilsvarende syrer får man følgende salter av di-feny1-imidazoly1-eddiksyre-metylester: • From diphenyl-imidazolyl-acetic acid methyl ester according to example 1 and the corresponding acids, the following salts of diphenyl-imidazolyl-1-acetic acid methyl ester are obtained: •
Som allerede nevnt har forbindelser i henhold til oppfinnelsen og deres slater en utpreget antimykotisk virkning hvilket fremgår av de følgende forsøk in vivo og in vitro. As already mentioned, compounds according to the invention and their slates have a pronounced antifungal effect, which is evident from the following experiments in vivo and in vitro.
Den fremragende antimykotiske virkning in vitro for de nye forbindelser fremgår av tabellene 1 og 2. The outstanding antifungal activity in vitro for the new compounds can be seen in Tables 1 and 2.
Virkningstypen for forbindelsene in vitro er hoved-sakelig fungistatisk. Fungicide virkninger med en reduksjon av inokulatet på 95% oppnås på 24 timer med to til tre ganger minimal inhiberingskonsentrasj on. The type of action of the compounds in vitro is mainly fungistatic. Fungicidal effects with a reduction of the inoculum of 95% are achieved in 24 hours with two to three times the minimum inhibitory concentration.
' Bestemmelsen av de angitte minimale inhiberingskonsen-trasjoner i gamma pr. ml næringsoppløsning ifølge tabell 1 og 2, foretok man The determination of the specified minimum inhibition concentrations in gamma per ml nutrient solution according to tables 1 and 2, was carried out
a) for dermatophyter og sopp i Sabouraud's miljøprøve, b) for gjær i en buljong av druesukker/kjøttvann. Inkubasjonstemperaturen var 28°C og inkubasjonstiden 48 - 96 timer. a) for dermatophytes and fungi in Sabouraud's environmental test, b) for yeast in a dextrose/broth broth. The incubation temperature was 28°C and the incubation time 48 - 96 hours.
For. eksempel fant man for de nedenfor oppregnede forbindelser fremragende virkning in vivo: difenyl-imidazolyl-eddiksyre-metylester (eksempel 1) difenyl-imidazolyl-eddiksyre-etylester (eksempel 3) difenyl-imidazolyl-eddiksyre-n-propylester (eksempel 4) difenyl-imidazolyl-eddiksyre-isobutylester (eksempel 5) feny1-2-metylfenyl-imidazoly1-eddiksyre-metylester (eksempel 11) difenyl-imidazolyl-eddiksyre-metylester-klorhydrat (eksempel 13) difenyl-imidazolyl-eddiksyre-morfolid-klorhydrat (eksempel 21) bis-(4-klorfenyl)-imidazolyl-eddiksyre-metylester (eksempel 23) bis-(4-klorfenyl)-imidazoly1-eddiksyre-metylester-klorhydrat For. example, the compounds listed below were found to have excellent in vivo activity: diphenyl-imidazolyl-acetic acid methyl ester (example 1) diphenyl-imidazolyl-acetic acid ethyl ester (example 3) diphenyl-imidazolyl-acetic acid n-propyl ester (example 4) diphenyl- imidazolyl-acetic acid isobutyl ester (Example 5) phenyl-1-2-methylphenyl-imidazolyl-1-acetic acid methyl ester (Example 11) diphenyl-imidazolyl-acetic acid methyl ester chlorohydrate (Example 13) diphenyl-imidazolyl-acetic acid morpholide chlorohydrate (Example 21) bis-(4-chlorophenyl)-imidazolyl-acetic acid methyl ester (Example 23) bis-(4-chlorophenyl)-imidazolyl-1-acetic acid methyl ester chlorohydrate
(eksempel 23) (example 23)
bis - ( 4-bromfenyl)-imidazoly1-eddiksyre-metylester (base) bis-(4-bromophenyl)-imidazoly1-acetic acid methyl ester (base)
(eksempel 25) (example 25)
bis-(4-bromfenyl)-imidazoly1-eddiksyre-metylester-klorhydrat bis-(4-bromophenyl)-imidazoly-1-acetic acid methyl ester chlorohydrate
(eksempel 25) (example 25)
bis-(4-fluorfenyl)-imidazoly1-eddiksyre-metylester-klorhydrat bis-(4-fluorophenyl)-imidazoly-1-acetic acid methyl ester chlorohydrate
(eksempel 26) (example 26)
bis-(4-metoksyfenyl)-imidazolyl-eddiksyre-metylester (base) bis-(4-methoxyphenyl)-imidazolyl-acetic acid methyl ester (base)
(eksempel 27) (example 27)
bis-(4-nitrofenyl)-imidazoly1-eddiksyre-etylester-klorhydrat bis-(4-nitrophenyl)-imidazoly-1-acetic acid ethyl ester chlorohydrate
(eksempel 28) (example 28)
A. Oral behandling av eksperimentell Candidose hos hvite mus med forbindelser ifølge eksemplene 1, 3, 4, 5, 11, 13, 21, 23, 25, 26, 27 og 28. A. Oral treatment of experimental candidiasis in white mice with compounds according to examples 1, 3, 4, 5, 11, 13, 21, 23, 25, 26, 27 and 28.
Hanmus av stammen CF-, SPF med vekt 20 - 22 g, ble infisert intravenøst med 2 - 5 x 10 Candida-albicans-celler pr. mus. Ved denne forsøksanordning døde ubehandlede dyr i løpet av 6 dager av infeksjonen. Hvis man 1-2 ganger daglig ga 30 - 60 mg av de.ovenfor nevnte forbindelser pr. kg kroppsvekt til de infiserte dyr, oralt, overlevet på sjette dag etter infeksjonen gjennom-snittlig 13 - 16 av 20 dyr. Når dyrene ble behandlet med forbindelsen ifølge eksempel 13, overlevet sogar 19 - 20 dyr. Den optimale dosering for forbindelser ifølge eksemplene 1, 3, 5,- 13, 23 og 28 var 2 x 50 mg/kg kroppsvekt daglig, for forbindelsene etter eksemplene -4, 11, 21, 25 og 26 og 27 2 x 60 mg/kg daglig. Male mice of the strain CF-, SPF with a weight of 20 - 22 g were infected intravenously with 2 - 5 x 10 Candida albicans cells per mouse. In this experimental setup, untreated animals died within 6 days of the infection. If one gave 1-2 times a day 30 - 60 mg of the above-mentioned compounds per kg body weight of the infected animals, orally, survived on the sixth day after the infection on average 13 - 16 out of 20 animals. When the animals were treated with the compound according to Example 13, even 19-20 animals survived. The optimal dosage for compounds according to examples 1, 3, 5, - 13, 23 and 28 was 2 x 50 mg/kg body weight daily, for the compounds according to examples -4, 11, 21, 25 and 26 and 27 2 x 60 mg/ kg daily.
For oral anvendelse ble preparatene suspendert i 0,25%-ig glukose-agar og gitt med en svelgesonde. For oral use, the preparations were suspended in 0.25% glucose agar and given with a swallowing tube.
B. Parenteral behandling av eksperimentell Candidose og Histoplasmose hos mus med forbindelsen fra eksempel 13. B. Parenteral treatment of experimental Candidosis and Histoplasmosis in mice with the compound from Example 13.
Ved parenteral administrasjon av forbindelsen fra eksempel 13 i en dose på 2 x 25 mg/kg pr. dag, overlevet 18 av 20 dyr 6 dager etter infeksjonen. C. Lokal behandling av eksperimentell marsvin-Tricho-phytie med forbindelsen fra eksempel 13. By parenteral administration of the compound from example 13 in a dose of 2 x 25 mg/kg per day, 18 out of 20 animals survived 6 days after the infection. C. Topical Treatment of Experimental Guinea Pig Trichophytia with the Compound of Example 13.
Dyrene ble infisert med Trichophyton mentagrophytes. 3. dag etter infeksjonen ble infeksjonsstedet behandlet ved på-frøing av, 0,5 ml 1%- ig oppløsning av virksomt stoff i polyetylen-glykol 400 en gang daglig. Denne behandling ble fortsatt inntil 14 dager etter infeksjon. I løpet av behandlingstiden ble derma-tosen helbredet. Hos ubehandlede, infiserte kontrolldyr opptrådte inntil ca. 30 dager etter infeksjon blodige ulterasjoner av infeksjonsstedet og håravfall. The animals were infected with Trichophyton mentagrophytes. On the 3rd day after the infection, the site of infection was treated by seeding 0.5 ml of a 1% solution of active substance in polyethylene glycol 400 once a day. This treatment was continued until 14 days after infection. During the treatment period, the derma-toses healed. In untreated, infected control animals, up to approx. 30 days after infection bloody ulturation of the site of infection and hair loss.
Forbindelsene med formel (I), viser seg overraskende The compounds of formula (I) prove surprising
å ha en fremragende antimykotisk virkning, og øker behandlings-mulighetene innen medisinen, og kan finne anvendelse ved følgende sykdommer: to have an outstanding antifungal effect, and increases the treatment options within medicine, and can be used in the following diseases:
a) innen humanmedisin: a) in human medicine:
1. dermatomykoser som forårsakes av soppartene Tricho-phyter, Mikrosporium, Epidermophyter, Aspergillus, Candida albicans og andre gjærsopper, 2. Organmykoser som forårsakes av gjær, muggsopp og Dermatophyter, 1. dermatomycoses caused by the fungal species Trichophytes, Microsporium, Epidermophytes, Aspergillus, Candida albicans and other yeasts, 2. Organ mycoses caused by yeasts, molds and Dermatophytes,
b) innen veterinærmedisinen: b) in veterinary medicine:
Dermatomykoser og organmykoser forårsaket av gjær, Dermatomycoses and organ mycoses caused by yeast,
muggsopp og Dermatophyter. molds and dermatophytes.
De nye forbindelser med generell formel I og deres salter kan gis oralt, parenteralt eller lokalt.. The new compounds of general formula I and their salts can be administered orally, parenterally or topically.
I alminnelighet har det vist seg gunstig å benytte mengder på ca. 20 til ca. 50 mg/kg kroppsvekt pr. dag for å oppnå gode resultater. Det kan eventuelt likevel være nødvendig eller gunstig å gå utenom disse mengder, avhengig av forsøksdyrets kroppsvekt og administrasjonsmåte, men også på grunn av dyrearten og dens individuelle forhold overfor medikamentet samt preparatets art og tidspunktet samt mellomrom mellom behandlingene. I noen tilfeller kan det således være tilstrekkelig å benytte mindre enn ovenstående minimalmengde, mens man i andre tilfeller må overskride nevnte øvre grense. Hvis det skal gis større mengder, kan aet være gunstig å fordele disse i flere enkeltdoser i løpet av dagen. For anvendelse innen humanmedisinen forutsettes samme doserings-spillerom. Likeledes gjelder de anmerkninger som er anført ovenfor. In general, it has proven beneficial to use amounts of approx. 20 to approx. 50 mg/kg body weight per day to achieve good results. It may still be necessary or beneficial to go beyond these quantities, depending on the experimental animal's body weight and method of administration, but also because of the species of animal and its individual relationship to the drug as well as the nature of the preparation and the time and intervals between treatments. In some cases, it may thus be sufficient to use less than the above minimum quantity, while in other cases the mentioned upper limit must be exceeded. If larger amounts are to be given, it may be beneficial to divide these into several individual doses during the day. For use in human medicine, the same dosage leeway is required. The comments listed above also apply.
Disse kjemoterapeutika kan enten brukes som sådanne eller helst kombinert med farmasøytisk brukbare bærestoffer. Preparatene kan i kombinasjon med forskjellige inerte bæremidler ha form som tabletter, kapsler, pulvere, spray-preparater, vandige suspensjoner, injiserbare oppløsninger, eliksirer, siruper og lignende. Slike bærestoffer omfatter faste fortynningsmidler eller fyllstoffer, et sterilt vandig medium og forskjellige ugiftige organiske oppløsningsmidler og lignende. Naturligvis kan tabletter og lignende beregnet for oral bruk tilsettes søtningsstoffer og lignende. De terapeutisk virksomme forbindelser har i dette tilfelle en konsentrasjon på mellom ca. 0,5 og 90 vekt% av totalbland-ingen, og foreligger i mengder som er tilstrekkelige til å falle innenfor ovennevnte doseringsområde. These chemotherapeutics can either be used as such or preferably combined with pharmaceutically usable carriers. The preparations, in combination with various inert carriers, can take the form of tablets, capsules, powders, spray preparations, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, a sterile aqueous medium and various non-toxic organic solvents and the like. Naturally, tablets and the like intended for oral use can have sweeteners and the like added to them. The therapeutically active compounds in this case have a concentration of between approx. 0.5 and 90% by weight of the total mixture, and are present in quantities sufficient to fall within the above-mentioned dosage range.
For oral bruk kan tablettene naturligvis også tilsettes natriumcitrat, kalsiumkarbonat og. dikalsiumfosfat sammen med forskjellige tilsetningsstoffer som stivelse, fortrinnsvis potetstivelse og lignende, samt bindemidler som polyvinylpyrroli-don, gelatin og lignende. Videre kan man tilsette glidemidler som magnesiumstearat, natriumlaurylsulfat og talkum for tabletterings-formål. Når det gjelder vandige suspensjoner og/eller eliksirer tenkt for oral bruk, kan det virksomme stoffet brukes sammen med smaksforbedrere, fargestoffer, emulgerings- og/eller sammen med fortynningsmidler som vann, etanol, propylenglykol, glycerol og lignende forbindelser. For oral use, the tablets can of course also have sodium citrate, calcium carbonate and. dicalcium phosphate together with various additives such as starch, preferably potato starch and the like, as well as binders such as polyvinylpyrrolidone, gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be added for tableting purposes. In the case of aqueous suspensions and/or elixirs intended for oral use, the active substance can be used together with flavor enhancers, dyes, emulsifiers and/or together with diluents such as water, ethanol, propylene glycol, glycerol and similar compounds.
For parenteral bruk kan oppløsningene innblandes i sesamolje eller jordnøttolje eller i vandig propylenglykol eller N,N-dimetylformamid, eller som sterile, vandige preparater når det gjelder vannoppløselige forbindelser. Slike vandige oppløsninger bør være pufret på kjent måte og videre bør det flytende fortynnings-middel være innstilt isotonisk ved tilsetning av den nødvendige mengde salt eller glukose. Slike vandige oppløsninger egner seg særlig for intravenøse, intramuskulære eller intraperitoneale in-jeksjoner. For parenteral use, the solutions can be mixed in sesame oil or peanut oil or in aqueous propylene glycol or N,N-dimethylformamide, or as sterile, aqueous preparations in the case of water-soluble compounds. Such aqueous solutions should be buffered in a known manner and furthermore the liquid diluent should be set isotonic by adding the required amount of salt or glucose. Such aqueous solutions are particularly suitable for intravenous, intramuscular or intraperitoneal injections.
Fremstillingen av slike sterile, vandige media skjer The preparation of such sterile, aqueous media takes place
på kj ent måte. in a familiar way.
Den lokale anvendelse skjer i form av 0,5 - 5%-ige The local application takes place in the form of 0.5 - 5%
og fortrinnsvis 1%- ige oppløsninger (f.eks. i dimetylformamid, glycerol, vann, alkoholer som etanol og isopropanol eller puffer-oppløsninger) eller også som emulsjoner, suspensjoner, pulvere og tabletter. and preferably 1% solutions (e.g. in dimethylformamide, glycerol, water, alcohols such as ethanol and isopropanol or buffer solutions) or also as emulsions, suspensions, powders and tablets.
Forbindelsene med formel (I) kan gis form som kapsler, The compounds of formula (I) can be given in the form of capsules,
tabletter, pastiller, drasjeer, ampuller, osv., i form av doserings-enheter som er slik at hver doseringsenhet leverer en enkeltdose av det aktive stoff. tablets, lozenges, dragees, ampoules, etc., in the form of dosage units such that each dosage unit delivers a single dose of the active substance.
De hittil kjente antimykotika er som allerede nevnt bare virksomme mot gjærsopper som f.eks. Amphotericin B eller bare mot trådsopper som f.eks. Griseofulvin. As already mentioned, the antimycotics known to date are only effective against yeasts such as e.g. Amphotericin B or only against filamentous fungi such as e.g. Griseofulvin.
Derimot virker forbindelser ifølge foreliggende oppfinnelse også ved oral bruk både mot gjærsopper og trådsopper. In contrast, compounds according to the present invention also work when used orally both against yeasts and filamentous fungi.
Det skal særlig nevnes at forbindelsene i henhold til foreliggende oppfinnelse er vesentlig mindre giftige enn Amphotericin B og at virkningen er betraktelig kraftigere enn Griseo-fulvins. It should be mentioned in particular that the compounds according to the present invention are significantly less toxic than Amphotericin B and that the effect is considerably stronger than Griseo-fulvins.
Ved siden av den antimykotiske virkning har forbindelsene ifølge oppfinnelsen også virkning mot patogene protozoer som f.eks. Trypanosomer, Trichomonader, Entamoeba histolytica, Malaria-befordrende organismer og overfor grampositive Kokker, som f.eks. Staphylokokker og mot gramnegative bakterier som f.eks. E. coli. In addition to the antifungal effect, the compounds according to the invention also have an effect against pathogenic protozoa such as e.g. Trypanosomes, Trichomonads, Entamoeba histolytica, Malaria-carrying organisms and towards Gram-positive Cocci, such as e.g. Staphylococci and against gram-negative bacteria such as e.g. E.coli.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19691925994 DE1925994C3 (en) | 1969-05-21 | Phenyl imidazolyl fatty acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO128571B true NO128571B (en) | 1973-12-10 |
Family
ID=5734834
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO93170A NO128571B (en) | 1969-05-21 | 1970-05-20 |
Country Status (7)
| Country | Link |
|---|---|
| ES (1) | ES379870A1 (en) |
| IE (1) | IE34289B1 (en) |
| IL (1) | IL34516A (en) |
| NO (1) | NO128571B (en) |
| PH (1) | PH12184A (en) |
| PL (1) | PL80851B1 (en) |
| RO (1) | RO56292A (en) |
-
1970
- 1970-05-13 IE IE63070A patent/IE34289B1/en unknown
- 1970-05-13 IL IL34516A patent/IL34516A/en unknown
- 1970-05-19 PH PH11460A patent/PH12184A/en unknown
- 1970-05-20 PL PL14074470A patent/PL80851B1/pl unknown
- 1970-05-20 RO RO6340570A patent/RO56292A/ro unknown
- 1970-05-20 NO NO93170A patent/NO128571B/no unknown
- 1970-05-21 ES ES379870A patent/ES379870A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| PL80851B1 (en) | 1975-08-30 |
| IE34289B1 (en) | 1975-04-02 |
| PH12184A (en) | 1978-11-21 |
| IL34516A (en) | 1973-01-30 |
| IE34289L (en) | 1970-11-21 |
| RO56292A (en) | 1974-08-01 |
| IL34516A0 (en) | 1970-07-19 |
| ES379870A1 (en) | 1972-09-16 |
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