DK144524B - Analogifremgangsmaade til fremstilling af 1-methyl-2-(alkylsulfonylphenoxymethyl)-5-nitro-imidazoler - Google Patents
Analogifremgangsmaade til fremstilling af 1-methyl-2-(alkylsulfonylphenoxymethyl)-5-nitro-imidazoler Download PDFInfo
- Publication number
- DK144524B DK144524B DK84177AA DK84177A DK144524B DK 144524 B DK144524 B DK 144524B DK 84177A A DK84177A A DK 84177AA DK 84177 A DK84177 A DK 84177A DK 144524 B DK144524 B DK 144524B
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- DK
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- Prior art keywords
- methyl
- nitro
- imidazole
- imidazoles
- alkyl
- Prior art date
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- -1 SULPHONYLPHENOXYMETHYL Chemical class 0.000 title description 14
- 238000000034 method Methods 0.000 title description 6
- 238000002360 preparation method Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 description 10
- 238000007254 oxidation reaction Methods 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 239000007800 oxidant agent Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 241000224421 Heterolobosea Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 241000224526 Trichomonas Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 210000003001 amoeba Anatomy 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
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 2
- 210000003754 fetus Anatomy 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- JSAQDPJIVQMBAY-UHFFFAOYSA-N (1-methyl-5-nitroimidazol-2-yl)methanol Chemical compound CN1C(CO)=NC=C1[N+]([O-])=O JSAQDPJIVQMBAY-UHFFFAOYSA-N 0.000 description 1
- NNFBAXPDEFAJJF-UHFFFAOYSA-N 1-methyl-2-[(3-methyl-4-methylsulfinylphenoxy)methyl]-5-nitroimidazole Chemical compound C1=C(S(C)=O)C(C)=CC(OCC=2N(C(=CN=2)[N+]([O-])=O)C)=C1 NNFBAXPDEFAJJF-UHFFFAOYSA-N 0.000 description 1
- OVZMTYNMHXCVSY-UHFFFAOYSA-N 1-methyl-2-[(3-methyl-4-methylsulfonylphenoxy)methyl]-5-nitroimidazole Chemical compound C1=C(S(C)(=O)=O)C(C)=CC(OCC=2N(C(=CN=2)[N+]([O-])=O)C)=C1 OVZMTYNMHXCVSY-UHFFFAOYSA-N 0.000 description 1
- MRLSLMCEWBURMB-UHFFFAOYSA-N 1-methyl-2-[(4-methylphenyl)sulfanylmethyl]-5-nitroimidazole Chemical compound CN1C(=NC=C1[N+](=O)[O-])CSC1=CC=C(C=C1)C MRLSLMCEWBURMB-UHFFFAOYSA-N 0.000 description 1
- YMIAMMYJWRZXIX-UHFFFAOYSA-N 1-methyl-2-[(4-methylsulfonylphenoxy)methyl]-5-nitroimidazole Chemical compound C1=C([N+]([O-])=O)N(C)C(COC=2C=CC(=CC=2)S(C)(=O)=O)=N1 YMIAMMYJWRZXIX-UHFFFAOYSA-N 0.000 description 1
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 description 1
- PDISGXFXQFGQFB-UHFFFAOYSA-N 2-(chloromethyl)-1-methyl-5-nitroimidazole Chemical compound CN1C(CCl)=NC=C1[N+]([O-])=O PDISGXFXQFGQFB-UHFFFAOYSA-N 0.000 description 1
- WWNFWYSAGRJRAY-UHFFFAOYSA-N 2-[(1-methyl-5-nitroimidazol-2-yl)methylsulfonyl]pyridine Chemical compound C1=C([N+]([O-])=O)N(C)C(CS(=O)(=O)C=2N=CC=CC=2)=N1 WWNFWYSAGRJRAY-UHFFFAOYSA-N 0.000 description 1
- UCJSCNUJHUVGRG-UHFFFAOYSA-N 2-[(3,4-dimethylphenyl)sulfanylmethyl]-1-methyl-5-nitroimidazole Chemical compound CN1C(=NC=C1[N+](=O)[O-])CSC1=CC(=C(C=C1)C)C UCJSCNUJHUVGRG-UHFFFAOYSA-N 0.000 description 1
- VNIZGYMFOKGFAL-UHFFFAOYSA-N 2-[(3-chloro-4-methylsulfinylphenoxy)methyl]-1-methyl-5-nitroimidazole Chemical compound C1=C([N+]([O-])=O)N(C)C(COC=2C=C(Cl)C(=CC=2)S(C)=O)=N1 VNIZGYMFOKGFAL-UHFFFAOYSA-N 0.000 description 1
- ONSXEHLVPFRVIW-UHFFFAOYSA-N 2-[(4-ethylphenyl)sulfanylmethyl]-1-methyl-5-nitroimidazole Chemical compound CN1C(=NC=C1[N+](=O)[O-])CSC1=CC=C(C=C1)CC ONSXEHLVPFRVIW-UHFFFAOYSA-N 0.000 description 1
- GXTVOQVRERBPSB-UHFFFAOYSA-N 2-[(4-ethylsulfinylphenoxy)methyl]-1-methyl-5-nitroimidazole Chemical compound C1=CC(S(=O)CC)=CC=C1OCC1=NC=C([N+]([O-])=O)N1C GXTVOQVRERBPSB-UHFFFAOYSA-N 0.000 description 1
- ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 description 1
- VMKYTRPNOVFCGZ-UHFFFAOYSA-N 2-sulfanylphenol Chemical class OC1=CC=CC=C1S VMKYTRPNOVFCGZ-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- GLGRLYGELVHLDM-UHFFFAOYSA-N 5-nitro-2-(phenoxymethyl)-1h-imidazole Chemical class N1C([N+](=O)[O-])=CN=C1COC1=CC=CC=C1 GLGRLYGELVHLDM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- AHNFPOAEXIOPDW-UHFFFAOYSA-N CCC1=CSC(=C1Cl)OCC2=NC(=CN2C)[N+](=O)[O-] Chemical compound CCC1=CSC(=C1Cl)OCC2=NC(=CN2C)[N+](=O)[O-] AHNFPOAEXIOPDW-UHFFFAOYSA-N 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical class [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 description 1
- 241000224432 Entamoeba histolytica Species 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical class [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- 241001610364 Ovula Species 0.000 description 1
- 241001502500 Trichomonadida Species 0.000 description 1
- 241000223107 Trypanosoma congolense Species 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000003194 effect on trichomonads Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical class Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical class OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 239000000003 vaginal tablet Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preventing Corrosion Or Incrustation Of Metals (AREA)
Description
i U4524 o
Fra dansk patentansøgning nr. 5692/75 kendes en analogifremgangsmåde til fremstilling af l-alkyl-2-(phenoxymethyl)--5-nitro-imidazoler af formlen R2 5 ,-L^.r3
I ^cV°-(W
'-' °2N p 1 2 hvor R er methyl eller ethyl, R er trifluormethyl, tri- 10 chlormethyl, nitro, cyan, methylsulfonyl eller ethylsulfonyl, 3 og R er hydrogen, fluor, chlor, brom, iod, trifluormethyl, trichlormethyl, nitro eller cyan, hvilke forbindelser er virksomme mod forskellige protozoer, især trichomonader, amøber og trypanosomer. Ved denne analogifremgangsmåde fremstilles de 15 ønskede forbindelser ved omsætning af l-alkyl-2-methyl-5-ni-troimidazoler, der i 2-methylgruppen er substitueret med halogen, acyloxy eller arylsulfonyloxy eller med hydroxy, med 2 3 2 3 henholdsvis R - og R -substitueret phenol eller R - og R - -substitueret 1-halogen-, 1-acyloxy- eller 1-arylsulfonyloxy- 2 3 20 -benzen eller ved alkylering af R - og R -substituerede 2-phen-oxymethyl-5-nitroimidazoler.
Det har nu vist sig, at de hidtil ukendte l-methyl-2-- (alkyls.ulfonYlphenoxymethyll-5-nitro-^imidazoler af formlen 25 f\—cH9-0—fi ^—R2 1 °2N . CE3 2 3 hvori R er methylsulfonyl eller ethylsulfonyl, og R er hy- 30 drogen, methyl eller halogen som fluor, chlor, brom eller iod, har lignende virksomhed, og nærværende opfindelse angår derfor en analogifremgangsmåde til fremstilling af disse forbindelser, hvilken fremgangsmåde ifølge opfindelsen er kendetegnet ved, at man oxiderer en 1-methy1-2-phenoxymethyl-5-nitro-35 -imidazol af formlen 2 14452Λ
O
.^N
I - —CB2-0 /' \ A - R II
/''ΐ'' H 3
o2n ^ R
5 hvori A er et svovlatom eller en sulfoxidgruppe (-S0-), R er 3 methyl eller ethyl, og R er hydrogen, methyl eller halogen såsom fluor, chlor, brom eller iod.
De som udgangsforbindelser anvendte l-methyl-2-phen-0xymethyl-5-nitro-imidazoler af formlen II findes beskrevet 10 i dansk patentansøgning nr. 3135/76, og de kan fås ud fra l-methyl-2-chlormethyl-5-nitro-imidazol (der kan fås som beskrevet i de tyske offentliggørelsesskrifter nr. 1.595.929 og 1.470.102) og eventuelt substituerede alkylmercaptopheno-ler eller alkylsulfinylphenoler (der kan fås ud fra de til-15 svarende mercaptophenoler og dialkylsulfat og en eventuelt derpå følgende oxidation med perbenzoesyre) i dimethylform-amid og i nærværelse af kaliumcarbonat.
Til oxidationen anvendes hensigtsmæssigt lige så store eller dobbelt så store molære mængder af et oxidations-20 middel, men ofte kan der med fordel anvendes et overskud af oxidationsmiddel. Anvendes der som udgangsforbindelse de tilsvarende sulfider (A = -S- i formel II), kræves der mindst to molækvivalenter oxidationsmiddel, men anvendes der som udgangsforbindelse de tilsvarende sulfoxider (A = -SO- i formel II), 25 kræves der kun ét molækvivalent oxidationsmiddel. Som oxidationsmiddel kan f.eks. anvendes hydrogenperoxid og persyrer som pereddikesyre, pertrifluoreddikesyre og chlorperbenzoesy-re, især 3-chlorperbenzoesyre, samt salpetersyre, chromsyre og deres salte, og endvidere chromsyreanhydrid, permanganater, 30 hypochloriter, chlorater, perchlorater, periodater og nitrogenoxider, især dinitrogentetroxid.
Oxidationsreaktionerne udføres fordelagtigt i et opløsnings- eller fordelingsmiddel, og hertil egner sig især sådanne opløsningsmidler, som ikke angribes af oxidationsmidlet, 35 f.eks. eddikesyre eller trifluoreddikesyre. Ved anvendelse af perbenzoesyre er også methylenchlorid og chloroform egnede som opløsningsmidler.
144524
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3
Oxidationsreaktionerne udføres almindeligvis ved temperaturer mellem 0 og 100°C, især ved 40-60°C, og reaktionstiderne er alt efter reaktionsbetingelserne fra nogle minutter til nogle timer.
5 Isoleringen af reaktionsprodukterne sker ved fortyn ding af reaktionsopløsningen med vand under samtidig udfældning eller ved afdampning af det organiske opløsningsmiddel i vakuum. Eventuelt kan der derefter ske en rensning ved omkrystallisation fra egnede opløsningsmidler eller opløsnings-10 middelblandinger.
l-Methyl-2-(alkylsulfonylphenoxymethyl)-5-nitro-imid-azolerne af formlen I egner sig til bekæmpelse af protozosygdomme hos mennesker og dyr som dem, der f.eks. frembrin-15 ges ved infektion med T. vag&ialis, E. histolytica og I. cruci, T. brucci og T. congolense, og de kan anvendes oralt eller lokalt. Til oral indgivning anvendes farmaceutiske præparater som tabletter eller kapsler, som til den daglige dosis indeholder mellem ca. 10 og ca. 750 mg af det virksomme stof, 20 fortrinsvis 30-300 mg, sammen med de sædvanlige tilsætninger af bærere, fortyndingsmidler og/eller strækkemidler. Til lokal anvendelse kan der bruges geleer, cremer, salver eller suppositorier.
Forbindelserne af formlen I udmærker sig ved, at de tå-25 les godt, samtidig med, at de mod trichomonader og amøber in vivo har en tydelig bedre virkning end det kendte sammenligningspræparat Metronidazol.
Forbindelserne af formlen I egner sig især til behandling af fluor-genitalis, hvortil de til lokalbehandling for-30 trinsvis opberedes til vaginal-suppositorier (ovula) eller vaginal-tabletter, som indeholder det virksomme stof i en mængde på 150-500 mg pr. dosisenhed.
I en række sammenligningsforsøg er virkningen af to forbindelser af formlen I mod Trichomonas foetus hos mus sam-35 menlignet med virkningen af fire tidligere kendte, nært beslægtede forbindelser, hvilket gav de i nedenstående tabel anførte resultater.
4
O
U452A
Overlevelsesgraden
Dosis i mg/kg mus for Trichomonas foetus
Fprb._per os_ i 4 mus
Eks. (A) 2 x 25 0 0 0 0 5 2 X 12,5 0000 2 x 6,25 0 0 0 0 2 X 3,125 0111
Eks. (C) 2 X 25 0 0 0 0 10 2 x 12,5 0000 2 X 6,25 0 0 0 0 _2 X 3,125_0 12 1_ M 2x 25 0000 2 x 12,5 0000 15 2 x 6,25 1122 2 x 3,125 2333 N 2 x 100 0000 2 x 50 2 2 3 3 20 2 x 25 3 3 3 4 0 2 x 100 0 0 0 0 2 x 50 0 1 2 2 2 x 25 2 2 3 3 25 P 2x 25 0000 2 x 12,5 0000 2 x 6,25 1 2 2 1 _2 x 3,125_2 3 3 3_ 30 Infektions- kontrol_-___ 3 4 4 4 _ M l-Methyl-2-(2-pyridylsulfonylmethyl)-5-nitro-imidazol DE-Pat. 23 29 376, eksempel 1.
N 1-Methyl-2-hydroxymethyl-5-nitro-imidazol 35 Dansk patent 107.618, eksempel 1.
0 2-Methyl-5-nitro-l-[2-(3-pyridyloxy)-ethyl]-imidazol Dansk patent 135.166, eksempel 1.
P l-Methyl-2-(pyridyl-2-thiomethyl)-5-nitro-imidazol DE-pat. 23 25 159, eksempel 1.
5 14452Λ
O
Af disse resultater fremgår det klart, at de to forbindelser af formlen I er de kendte forbindelser langt overlegne, og lignende virksomhed har de øvrige af formlen I omfattede forbindelser.
5 Fremgangsmåden ifølge opfindelsen illustreres nærme re gennem følgende eksempel.
Eksempel (A) l-Methyl-2-(4-methylsulfonyl-phenoxymethyl)-5-nitro-imidazol 10 I 250 ml iseddike opløses 27,9 g (0,1 mol) l-methyl-2- -(4-methylthiophenoxymethyl)-5-nitro-imidazol (smp. 116°C), og under omrøring tildryppes ved stuetemperatur 24,3 g (0,25 mol) 35%'s hydrogenperoxid, hvorunder temperaturen ved den exoterme reaktion stiger til ca. 45°C. Derefter opvarmes der i endnu 15 1 time til 60°C under omrøring, og efter afkøling til stuetem peratur hældes reaktionsblandingen ud på 800 ml af en is/vand--blanding, hvorpå udfældningen suges fra, vaskes med vand og omkrystalliseres fra isopropanol under tilsætning af aktivkul.
Der fås herved 29 g (dvs. 93% af det teoretiske) l-methyl-2-20 -(4-methylsulfonylphenoxymethyl)-5-nitro-imidazol i form af gullige krystaller med smp. 157°C.
I stedet for udgangsforbindelsen 1-methyl-2-(4-methylthiophenoxymethyl) -5-nitro-imidazol kan der også anvendes det tilsvarende sulfoxid l-methyl-2-(4-methylsulfinylphenoxymethyl)-25 -5-nitro-imidazol (smp. 130°C), og det er da tilstrækkeligt at anvende den halve mængde hydrogenperoxid.
På samme måde kan fremstilles følgende forbindelser: (Bl 1-Methyl-2-(4-ethylsulfonylphenoxymethyl)-5-nitro-imidazol 30 med smp. 132°C ved oxidation af l-methyl-2-(4-ethylthiophenoxy-methyl)-5-nitro-imidazol (smp. 90°C) eller l-methyl-2-(4-ethyl-sulfinylphenoxymethyl)-5-nitro-imidazol (smp. 103°C).
(C) 1-Methyl-2-(3-methyl-4-methylsulfonylphenoxymethyl)-5-ni-35 tro-imidazol med smp. 141°C ved oxidation af l-methyl-2-(3-me-thyl-4-methylthiophenoxymethyl)-5-nitro-imidazol (smp. 108°C)
O
144524 6 eller l-methyl-2-(3-methyl-4-methylsulfinylphenoxymethyl)--5-nitro-imidazol (smp. 121°Cl.
(D} l-Methyl-2-(3-methyl-4-ethylsulfonylphenoxymethyl)-5-njtro-5 -imldazol med smp. 115°C ved oxidation af l-methyl-2-(3-methyl--4-ethylthiophenoxymethyl)-5-nitro-imidazol (smp. 80°C) eller l-methyl-2-(3-methyl-4-ethylsulfinylphenoxymethyll-5-nitro-imidazol (smp. 95°C] .
10 (El 1-Methy1-2-(3-chlor-4-methyIsulfonylphenoxymethylI-5-nitro--imidazol med smp. 153°C ved oxidation af l-methyl-2-(3-chlor--4-methylthiophenoxymethyl)-5-nitro-imidazol eller l-methyl-2--(3-chlor-4-methylsulfinylphenoxymethyl)-5-nitro-imidazol.
15 (Fl l-Methyl-2-(3-chlor-4-ethylsulfonylphenoxymethyll-5-nitro--imidazol med smp. 98°C ved oxidation af l-methyl-2-(3-chlor--4-ethylthiophenoxymethyl)-nitro-imidazol eller l-methyl-2-(3--chlor-4-ethylsulfinylphenoxymethyll-5-nitro-imidazol.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762607789 DE2607789A1 (de) | 1974-12-16 | 1976-02-26 | Verfahren zur herstellung von 1-methyl-2-(alkylsulfonyl)-phenoxy-methyl)- 5-nitro-imidazolen |
| DE2607789 | 1976-02-26 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK84177A DK84177A (da) | 1977-08-27 |
| DK144524B true DK144524B (da) | 1982-03-22 |
| DK144524C DK144524C (da) | 1982-09-06 |
Family
ID=5970911
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK84177A DK144524C (da) | 1976-02-26 | 1977-02-25 | Analogifremgangsmaade til fremstilling af 1-methyl-2-(alkylsulfonyl-phenoxymethyl)-5-nitro-imidazoler |
Country Status (12)
| Country | Link |
|---|---|
| AT (1) | AT361468B (da) |
| CA (1) | CA1079738A (da) |
| CH (1) | CH624942A5 (da) |
| DK (1) | DK144524C (da) |
| EG (1) | EG13828A (da) |
| ES (1) | ES456117A2 (da) |
| FI (1) | FI770599A7 (da) |
| IT (1) | IT1115608B (da) |
| LU (1) | LU76834A1 (da) |
| NL (1) | NL7701838A (da) |
| NO (1) | NO770648L (da) |
| SE (1) | SE7702126L (da) |
-
1977
- 1977-02-21 NL NL7701838A patent/NL7701838A/xx not_active Application Discontinuation
- 1977-02-21 ES ES456117A patent/ES456117A2/es not_active Expired
- 1977-02-23 EG EG111/77A patent/EG13828A/xx active
- 1977-02-24 FI FI770599A patent/FI770599A7/fi not_active Application Discontinuation
- 1977-02-24 LU LU76834A patent/LU76834A1/xx unknown
- 1977-02-24 IT IT20658/77A patent/IT1115608B/it active
- 1977-02-24 CA CA272,551A patent/CA1079738A/en not_active Expired
- 1977-02-24 CH CH231377A patent/CH624942A5/de not_active IP Right Cessation
- 1977-02-25 NO NO770648A patent/NO770648L/no unknown
- 1977-02-25 AT AT128477A patent/AT361468B/de not_active IP Right Cessation
- 1977-02-25 SE SE7702126A patent/SE7702126L/xx unknown
- 1977-02-25 DK DK84177A patent/DK144524C/da not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ES456117A2 (es) | 1978-03-01 |
| NL7701838A (nl) | 1977-08-30 |
| IT1115608B (it) | 1986-02-03 |
| LU76834A1 (da) | 1977-09-26 |
| FI770599A7 (da) | 1977-08-27 |
| DK84177A (da) | 1977-08-27 |
| NO770648L (no) | 1977-08-29 |
| CA1079738A (en) | 1980-06-17 |
| SE7702126L (sv) | 1977-08-27 |
| DK144524C (da) | 1982-09-06 |
| EG13828A (en) | 1982-09-30 |
| ATA128477A (de) | 1980-08-15 |
| CH624942A5 (en) | 1981-08-31 |
| AT361468B (de) | 1981-03-10 |
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| Date | Code | Title | Description |
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| PBP | Patent lapsed |