DK157491B - Analogifremgangsmaade til fremstilling af 4-benzylsubstituerede imidazolderivater eller farmaceutisk acceptable syreadditionssalte deraf - Google Patents

Analogifremgangsmaade til fremstilling af 4-benzylsubstituerede imidazolderivater eller farmaceutisk acceptable syreadditionssalte deraf Download PDF

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DK157491B
DK157491B DK630586A DK630586A DK157491B DK 157491 B DK157491 B DK 157491B DK 630586 A DK630586 A DK 630586A DK 630586 A DK630586 A DK 630586A DK 157491 B DK157491 B DK 157491B
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acid addition
acceptable acid
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Arto Johannes Karjalainen
Kauko Oiva Antero Kurkela
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Farmos Oy
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Description

DK 157491 B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte 4-benzylsub-stituerede imidazolderivater med den i patentkravets indledning viste almene formel I, hvor R har den sammesteds 5 angivne betydning, eller ugiftige, farmaceutisk acceptable syreadditionssalte deraf. Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i patentkravets kendetegnende del angivne.
I litteraturen (Ger. Weinheim i Arch. Pharm. 1978, 10 31 1 (2), 98-103, er forbindelsen 4-( α-fenyl)-metoxymetyl- 5-metylimidazol beskrevet, men der er ikke tilskrevet den nogen terapeutisk virkning.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser har analgetiske og antiinflammatoriske 15 egenskaber.
Forbindelserne med formel I er baser som danner syreadditionssalte med både organiske og uorganiske syrer.
De kan således danne mange farmaceutisk nyttige syreadditionssalte såsom klorider, bromider, sulfater, nitrater, 20 fosfater, sulfonater, formiater, tartrater, maleater, citrater, benzoater, salicylater og ascorbater.
Som syre der skal være til stede ved udøvelse af fremgangsmåden ifølge opfindelsen kan bruges en organisk eller uorganisk syre, fx saltsyre. Man kan derefter om 25 ønsket omdanne forbindelsen I til et farmaceutisk acceptabelt syreadditionssalt deraf.
Indgift af en forbindelse med den almene formel I eller et ugiftigt, farmaceutisk acceptabelt syreadditionssalt deraf kan ske parenteralt, intravenøst eller oralt.
30 Typisk er en effektiv mængde af vedkommende forbindelse kombineret med en passende farmaceutisk bærer. Med udtrykket "effektiv mængde" menes her mængder som giver den ønskede virkning uden at fremkalde uønskede bivirkninger.
De farmaceutiske bærere der typisk anvendes til de 35 omhandlede forbindelser kan være faste eller flydende og udvælges i almindelighed i afhængighed af den planlagte indgiftsmåde. Således er eksempler på faste bærestoffer 2
DK 157491 B
_____ laktose, sakkarose, gelatine og agar mens eksempler på “ flydende bærere er vand, sirup, jordnøddeolie og oliven olie. Kombinationen af forbindelsen og bærestoffet kan oparbejdes til mange forskellige præparattyper såsom tab-5 letter, kapsler, suppositorier, opløsninger, emulsioner og pulvere.
Den analgetiske virkning af forbindelserne med formlen I blev prøyet på følgende måde;
Vridningsforsøg; Testforbindelserne eller fysiologisk salt-10 opløsning blev indgivet oralt til rotter og 45 minutter senere blev der intraperitonealt indgivet 1 ml l%s eddikesyre. Antallet af vridninger opnoteredes i den følgende 25 minutter lange periode (Koster et al. Fed. Proc. 18:412, 1959).
Varmpladeforsøg: Testforbindelsen eller fysiologisk salt-15 opløsning blev indgivet intraperitonealt til hanmus og 30 minutter senere blev tiden på en 55°C varm plade opnoteret. Resultaterne blev udtryktog sammenlignet med resultaterne med saltvandsopløsning.
Den antiinflammatoriske aktivitet bestemtes ved inhibe-2o ring af carrageenaninduceret ødem hos rotter, fremkaldt af testforbindelsen (C.A. Winter et al, Proc. Soc. Exp. Biol. Med. 111:544, 1962) .’
De farmakologiske egenskaber belyses i det følgende: 25 30 35
DK 157491 B
3
Analgetisk virkning.
Analgetisk aktivitet Metode Stigning i c dosis, mg/kg HP-tid (%) Aktivitet W-antal (%) x) 4-[a-(2',6'-dimetyl-fenyl)]-metoxymetyl- 10 imidazol W 100 13 + 4-[a-(2',6'-dimetyl-fenyl)J-ætoxymetyl- imidazol W 100 0,6 ++ x) HP = varmepladetest
Id W = vridningstest
Antiinflammatorisk virkning (dosis 100 mg/kg oralt) 20 Antiinflammatorisk aktivitet inhibering af carra- Aktivitet geenaninduceret ødem (%) 4-[ot-(2' , 6 ’-dimetylfenyl) ]- 2^ metoxymetylimidazol 40 + 4-[a-(2',6'-dimetylfenyl)]- ætoxymetylimidazol 35 + 30 35 4
DK 157491 B
Fremgangsmåden ifølge opfindelsen skal i det følgende belyses nærmere ved nogle eksempler. Når ^H-NMR-spektrum-ændringer er angivet i disse eksempler, blev "NMR-spektrene bestemt med et Perkin Elmer R 24 apparat med en extern tetrame-5 tylsilan-standard hvorfra de viste kemiske skifter (6, ppm) er anført. Bogstaverne s, d, t, q og mbetyder henholdsvis singlet, dublet, triplet, kvartet og multiplet. I samme forbindelse er antallet af hydrogenatomer også angivet. De forbindelser der er anført som baser er bestemt i deuteriummetanol, deuteriumacetone el-10 ler deutériumkloroform, mens værdierne for forbindelser der er anført som hydroklorider bestemtes i deuteriumoxyd.
Massespektrene bestemtes med et Perkin Elmer RMU-apparat med direkte indgangssystem. Den anvendte temperatur var den laveste temperatur der behøvedes til fordampning af forbindelsen 15 som base. I eksemplerne er de kraftigste og de vigtigste fragment-ioner, set fra et strukturelt synspunkt, anført som m/e-værdier. I parentes er anført intensiteten af fragment-ionen i relation til hovedtoppen.
20
Eksempel 1 4-(g-Fenyl)-ætoxymetylimidazol· 10 g 4-(α-fenyl)-hydroxymetylimidazol opløses i 60 ml absolut ætanol. Der føres hydrogenkloridgas ind i opløsnin-25 gen i 1 time og i denne periode holdes reaktionsblandingen på tilbagesvaling under omrøring. Blandingen inddampes derefter til tørhed. Der tilsættes 60 ml vand for at opløse destillationsremanensen og derpå gøres opløsningen alkalisk med natriumkarbonat og ekstraheres med 3 x 50 ml kloroform. De forenede kloro-30 formekstrakter vaskes med vand og tørres over natriumsulfat. Filtratet inddampes til tørhed til frembringelse af et råprodukt som efter omkrystallisation fra ætylacetat smelter ved 129-131°C.
35 . 5
DK 15749 1 B
NMR: 0,85 (t, 3H), 3,15 (q, 2H), 4,9 (s, IH), 5,1 (s, IH), 6,45 (s, IH), 7,0 (s, 5H), 7,25 (s, IH).
Eksempel 2 4" [g-(2'-Metylfeny1)1-ætoxymetylimidazol 5 Fremgangsmåden i eksempel 1 gentages med den forskel at der bruges 4-(g-(2’-metylfenyl)]-hydroxymetylimidazol i stedet for 4-(a-fenyl)-hydroxymetylimidazol.
NMR: 1,0 (t, 3H), 2,1 (s, 2H), 3,45 (q, 2H), 4,4 (s, 2H), 5,65 (s, IH), 7,1 (m, 5H), 9,15 (s, IH).
10 Eksempel 3 4-[g-(21,61“Dimetylfenyl)]-ætoxymetyl-5-metylimidazol
Fremgangsmåden ifølge eksempel 1 gentages med den forskel at der bruges 4-[a-(2*,6'-dimetylfenyl)]-hydroxymetyl-5-metylimidazol.
15 NMR (HCl-salt): 1,05 (1, 3H), 1,65 (s, 3H), 2,1 (s, 6H), 3,4 (q, 2H) , 4,65 (s, 2H) , 5,95 (s, IH), 6,95 (s,· 3H) , 8,5 (s, IH). MS: 244 (38%), 229 (9%), 215 (15%), 199 (39%), 183 (100%), 162 (39%), 139 (29%), 133 (35%), 111 (25%), 109 (17%), 105 - (13%).
20 Eksempel 4 4- [g-(2*,6’-Dimetylfenyl)]-Ætoxymetylimidazol
Fremgangsmåden i eksempel 1 gentages med den forskel at der bruges 4-[g-(2’,6'-dimetylfenyl)]-hydroxymetylimidazol. Produktet smelter ved 142-147°C. Det tilsvarende hydroklorid, frem-25 stillet i en blanding af ætylacetat og isopropanol, smelter ved 136-139°C.
NMR (HCl-salt): 1,1 (t, 3H), 2,15 (s, 6H), 3,4 (q, 2H), 4,6 (s, 2H), 6,0 (s, IH), 6,85 (s, IH), 7,05 (m, 3H), 8,65 (s, IH).
Eksempel 5 30 4-[g-(3 *-Metylfenyl)]-Ætoxymetylimidazol
Fremgangsmåden i eksempel | gentages med den forskel at -V ί DK 157491 Β 6 der bruges 4-[g-(3'-metyIfenyl)]-hydroxymetylimidazol. Hydro-kloridet, fremstillet i isopropanol/ætylacetat, smelter ved 135-140°C.
NMR (HCl-salt): 1,2 (t, 3H) , 2,25 (s, 3H), 3,55 (q, 2H), 4,75 5 (s, 2H), 5/55 (s, IH), 7,1 (s, IH), 8,7 (s, IH).
MS: 216 (23%), 187 (6%), 172 (53%), 171 (100%), 170 (20%), 155 (7%), 144 (15%), 143 (27%), 97 (20%), 95 (23%), 91 (15%).
Eksempel 6 4-[a-(31-Metoxyfenyl)3-ætoxymetylimidazol 10 Fremgangsmåden i eksempel 1 gentages med den forskel at der bruges 4-[a-(3'-metoxyfenyl)]-hydroxymetylimidazol.
NMR (HCl-salt): 1,05 (t, 3H), 3,4 (q, 2H), 3,6 (s, 3H), 4,75 (s, 2H), 5,45 (s, IH), 6,9 (m, 5H), 8,65 (s, IH).
Eksempel 7 15 4-[g-(4'-Metoxyfenyl)]-ætoxymetylimidazol
Fremgangsmåden i eksempel 1 gentages med den forskel at der bruges 4-[g-(4'-metoxyfenyl)]-hydroxymetylimidazol.
NMR (HCl-salt):. 1,0 (t, 3H), 3,3 (q, 2H) , 3,55 (s, 3H) , 4,7 '(s, 2H), 5,4 (s, IH), 6,95 (m, 5H), 8,6 (s, IH).
20 Eksempel 8 4-[g-(2 *,6'-Dimetylfenyl)3-metoxymetylimidazol 10 g 4-[g-(21,6'-dimetylfenyl)]-hydroxymetylimidazol opløses i 60 ml metanol. Der føres hydrogenkloridgas ind i opløsningen i 1 time og i denne periode holdes blandingen på 25 tilbagesvaling. Derefter inddampes blandingen til tørhed. Der tilsættes 100 ml vand og opløsningen gøres alkalisk med natriumkarbonat. Derefter ekstraheres opløsningen med 3 x 50 ml kloroform. De forenede kloroformekstrakter vaskes med vand, tørres over natriumsulfat og filtreres hvorpå filtratet ind-30 dampes til tørhed. Det tilsvarende hydroklorid, fremstillet i ætylacetat/isopropanol, har smp. 176-179 C.
NMR (HCl-salt): 2,2 (s, 6H), 3,3 (s, 3H), 4,7 (s, 2H), 6,0 (s, IH), 6,9 (s, IH), 7,15 (s, 3H), 8,7 (s, IH).

Claims (1)

  1. 5 OR ,-CH3 n·—i— ch —(f Γν T C„.5 ^ ch3 H 10 hvor R er metyl eller ætyl, eller ugiftige, farmaceutisk acceptable syreadditionssalte deraf, kendetegnet ved at man omsætter en forbindelse med den almene formel ?H /-\ CH-3 ,5 N >_<^C 3 ^ CH3 H med en forbindelse med den almene formel ROH, hvor R 20 har den ovenfor angivne betydning, i nærværelse af en syre til dannelse af en forbindelse med den almene formel I, hvorefter man om ønsket omdanner den vundne forbindelse til et ugiftigt, farmaceutisk acceptabelt syreadditionssalt deraf. 25 30 35
DK630586A 1979-08-07 1986-12-29 Analogifremgangsmaade til fremstilling af 4-benzylsubstituerede imidazolderivater eller farmaceutisk acceptable syreadditionssalte deraf DK157491C (da)

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DK630586D0 DK630586D0 (da) 1986-12-29
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DK157491C DK157491C (da) 1990-06-25

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DK630586A DK157491C (da) 1979-08-07 1986-12-29 Analogifremgangsmaade til fremstilling af 4-benzylsubstituerede imidazolderivater eller farmaceutisk acceptable syreadditionssalte deraf

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GB2069481B (en) * 1980-02-13 1983-07-27 Farmos Oy Substituted imidazole derivatives
US4374843A (en) * 1980-10-14 1983-02-22 Pfizer Inc. 2-Guanidino-4-heteroarylthiazoles
GB2092569B (en) * 1981-02-05 1984-09-19 Farmos Oy Substituted imidazole derivatives and their preparation and use
GB2101114B (en) * 1981-07-10 1985-05-22 Farmos Group Ltd Substituted imidazole derivatives and their preparation and use
GB2110663B (en) * 1981-12-04 1985-08-07 Farmos Group Ltd Imidazole derivatives
FI833794A0 (fi) * 1983-10-18 1983-10-18 Farmos Oy Substituerade 2-merkapto-imidazoler
JPH0658947B2 (ja) * 1984-02-24 1994-08-03 株式会社日立製作所 半導体メモリ装置の製法
DE3539629A1 (de) * 1985-11-08 1987-05-14 Basf Ag Dialkoxyketone und ein verfahren zu ihrer herstellung
GB8626287D0 (en) * 1986-11-04 1986-12-03 Ucb Sa Substituted 1h-imidazoles
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DK155794B (da) 1989-05-16
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ZA804787B (en) 1981-07-29
US4443466A (en) 1984-04-17
NO153220B (no) 1985-10-28
SU1014472A3 (ru) 1983-04-23
UA5559A1 (uk) 1994-12-28
ATE7226T1 (de) 1984-05-15
FI802404A7 (fi) 1981-02-08
HU184809B (en) 1984-10-29
SG34987G (en) 1988-03-04
NO802352L (no) 1981-02-09
IE801626L (en) 1981-02-07
FI70709B (fi) 1986-06-26
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SU997607A3 (ru) 1983-02-15
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IL60723A (en) 1985-02-28
AU518569B2 (en) 1981-10-08
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BG60426B2 (bg) 1995-03-31
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DK157491C (da) 1990-06-25
IE50080B1 (en) 1986-02-05
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