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 PDFInfo
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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)
- 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
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US6457579A | 1979-08-07 | 1979-08-07 | |
US6457579 | 1979-08-07 |
Publications (4)
Publication Number | Publication Date |
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DK630586A DK630586A (da) | 1986-12-29 |
DK630586D0 DK630586D0 (da) | 1986-12-29 |
DK157491B true DK157491B (da) | 1990-01-15 |
DK157491C DK157491C (da) | 1990-06-25 |
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DK338580A DK155794C (da) | 1979-08-07 | 1980-08-06 | Analogifremgangsmaade til fremstilling af 4-benzylsubstituerede imidazolderivater eller farmaceutisk acceptable syreadditionssalte deraf |
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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DK338580A DK155794C (da) | 1979-08-07 | 1980-08-06 | Analogifremgangsmaade til fremstilling af 4-benzylsubstituerede imidazolderivater eller farmaceutisk acceptable syreadditionssalte deraf |
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EP (1) | EP0024829B1 (da) |
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CA (1) | CA1154780A (da) |
DD (1) | DD152548A1 (da) |
DE (1) | DE3067618D1 (da) |
DK (2) | DK155794C (da) |
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Publication number | Priority date | Publication date | Assignee | Title |
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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 |
JPS63150266A (ja) * | 1986-12-12 | 1988-06-22 | Mitsui Petrochem Ind Ltd | ベンジルイミダゾ−ル誘導体 |
GB2206880B (en) * | 1987-07-16 | 1991-04-24 | Farmos Oy | Optical isomers of an imidazole derivative |
GB8810067D0 (en) * | 1988-04-28 | 1988-06-02 | Ucb Sa | Substituted 1-(1h-imidazol-4-yl)alkyl-benzamides |
US5255225A (en) * | 1989-04-05 | 1993-10-19 | Hitachi, Ltd. | Semiconductor integrated circuit device and memory consisting of semiconductor integrated circuit |
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Publication number | Priority date | Publication date | Assignee | Title |
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BE553516A (da) * | 1955-12-19 | |||
US2946804A (en) * | 1958-12-29 | 1960-07-26 | Abbott Lab | (5-methyl-4-imidazolyl)-diphenyl carbinol salts and lower alkyl quaternaries |
US3177223A (en) * | 1961-12-22 | 1965-04-06 | Air Prod & Chem | Preparation of substituted imidazoles |
DE2634409A1 (de) * | 1975-07-31 | 1977-02-17 | Wellcome Found | Heterocyclische entzuendungshemmende zubereitungen |
-
1980
- 1980-03-05 AU AU61071/80A patent/AU518569B2/en not_active Expired
- 1980-08-01 NZ NZ194536A patent/NZ194536A/xx unknown
- 1980-08-01 FI FI802404A patent/FI70709C/fi not_active IP Right Cessation
- 1980-08-01 AT AT80302637T patent/ATE7226T1/de not_active IP Right Cessation
- 1980-08-01 IL IL60723A patent/IL60723A/xx unknown
- 1980-08-01 DE DE8080302637T patent/DE3067618D1/de not_active Expired
- 1980-08-01 EP EP80302637A patent/EP0024829B1/en not_active Expired
- 1980-08-05 IE IE1626/80A patent/IE50080B1/en not_active IP Right Cessation
- 1980-08-06 CA CA000357663A patent/CA1154780A/en not_active Expired
- 1980-08-06 NO NO802352A patent/NO153220C/no unknown
- 1980-08-06 SU SU802959548A patent/SU997607A3/ru active
- 1980-08-06 HU HU801955A patent/HU184809B/hu unknown
- 1980-08-06 JP JP10878680A patent/JPS5632463A/ja active Granted
- 1980-08-06 UA UA2959548A patent/UA5559A1/uk unknown
- 1980-08-06 DK DK338580A patent/DK155794C/da not_active IP Right Cessation
- 1980-08-06 ZA ZA00804787A patent/ZA804787B/xx unknown
- 1980-08-07 DD DD80223182A patent/DD152548A1/de not_active IP Right Cessation
-
1981
- 1981-03-10 US US06/242,234 patent/US4443466A/en not_active Expired - Lifetime
- 1981-05-28 SU SU813289249A patent/SU1014472A3/ru active
-
1986
- 1986-12-29 DK DK630586A patent/DK157491C/da active
-
1987
- 1987-04-14 SG SG34987A patent/SG34987G/en unknown
- 1987-09-24 HK HK685/87A patent/HK68587A/xx not_active IP Right Cessation
-
1994
- 1994-01-18 BG BG98381A patent/BG60426B2/bg unknown
Also Published As
Publication number | Publication date |
---|---|
SU1014472A3 (ru) | 1983-04-23 |
UA5559A1 (uk) | 1994-12-28 |
DK630586A (da) | 1986-12-29 |
DD152548A1 (de) | 1981-12-02 |
DK630586D0 (da) | 1986-12-29 |
FI802404A (fi) | 1981-02-08 |
IE50080B1 (en) | 1986-02-05 |
SU997607A3 (ru) | 1983-02-15 |
FI70709B (fi) | 1986-06-26 |
IE801626L (en) | 1981-02-07 |
US4443466A (en) | 1984-04-17 |
DE3067618D1 (en) | 1984-05-30 |
AU6107180A (en) | 1981-02-12 |
CA1154780A (en) | 1983-10-04 |
SG34987G (en) | 1988-03-04 |
DK155794B (da) | 1989-05-16 |
NZ194536A (en) | 1983-06-17 |
HK68587A (en) | 1987-10-02 |
DK155794C (da) | 1989-11-06 |
NO153220C (no) | 1986-02-05 |
DK338580A (da) | 1981-02-08 |
EP0024829B1 (en) | 1984-04-25 |
NO802352L (no) | 1981-02-09 |
JPS5632463A (en) | 1981-04-01 |
FI70709C (fi) | 1986-10-06 |
NO153220B (no) | 1985-10-28 |
HU184809B (en) | 1984-10-29 |
BG60426B2 (bg) | 1995-03-31 |
AU518569B2 (en) | 1981-10-08 |
ZA804787B (en) | 1981-07-29 |
JPS624387B2 (da) | 1987-01-30 |
DK157491C (da) | 1990-06-25 |
IL60723A (en) | 1985-02-28 |
EP0024829A1 (en) | 1981-03-11 |
ATE7226T1 (de) | 1984-05-15 |
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