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

Info

Publication number
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
Authority
DK
Denmark
Prior art keywords
acid addition
acceptable acid
addition salts
preparation
compounds
Prior art date
Application number
DK630586A
Other languages
English (en)
Other versions
DK630586D0 (da
DK630586A (da
DK157491C (da
Inventor
Arto Johannes Karjalainen
Kauko Oiva Antero Kurkela
Original Assignee
Farmos Oy
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Farmos Oy filed Critical Farmos Oy
Publication of DK630586D0 publication Critical patent/DK630586D0/da
Publication of DK630586A publication Critical patent/DK630586A/da
Publication of DK157491B publication Critical patent/DK157491B/da
Application granted granted Critical
Publication of DK157491C publication Critical patent/DK157491C/da

Links

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
    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/48—Preparation of compounds having groups
    • C07C41/50—Preparation of compounds having groups by reactions producing groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/30—Compounds having groups
    • C07C43/313—Compounds having groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/30—Compounds having groups
    • C07C43/315—Compounds having groups containing oxygen atoms singly bound to carbon atoms not being acetal carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/515—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an acetalised, ketalised hemi-acetalised, or hemi-ketalised hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/24—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups
    • C07C49/245—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/258—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing —CHO groups
    • 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
    • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

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)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6457579A 1979-08-07 1979-08-07
US6457579 1979-08-07

Publications (4)

Publication Number Publication Date
DK630586D0 DK630586D0 (da) 1986-12-29
DK630586A DK630586A (da) 1986-12-29
DK157491B true DK157491B (da) 1990-01-15
DK157491C DK157491C (da) 1990-06-25

Family

ID=22056899

Family Applications (2)

Application Number Title Priority Date Filing Date
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

Family Applications Before (1)

Application Number Title Priority Date Filing Date
DK338580A DK155794C (da) 1979-08-07 1980-08-06 Analogifremgangsmaade til fremstilling af 4-benzylsubstituerede imidazolderivater eller farmaceutisk acceptable syreadditionssalte deraf

Country Status (21)

Country Link
US (1) US4443466A (da)
EP (1) EP0024829B1 (da)
JP (1) JPS5632463A (da)
AT (1) ATE7226T1 (da)
AU (1) AU518569B2 (da)
BG (1) BG60426B2 (da)
CA (1) CA1154780A (da)
DD (1) DD152548A1 (da)
DE (1) DE3067618D1 (da)
DK (2) DK155794C (da)
FI (1) FI70709C (da)
HK (1) HK68587A (da)
HU (1) HU184809B (da)
IE (1) IE50080B1 (da)
IL (1) IL60723A (da)
NO (1) NO153220C (da)
NZ (1) NZ194536A (da)
SG (1) SG34987G (da)
SU (2) SU997607A3 (da)
UA (1) UA5559A1 (da)
ZA (1) ZA804787B (da)

Families Citing this family (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US5073566A (en) * 1989-11-30 1991-12-17 Eli Lilly And Company Angiotensin ii antagonist 1,3-imidazoles and use thereas
US5086064A (en) * 1990-03-27 1992-02-04 Warner-Lambert Company 3,5-di-tertiary-butyl-4-hydroxyphenyl thiazolyl, oxazolyl, and imidazolyl methanones and related compounds as antiinflammatory agents
GB2256135B (en) 1991-05-31 1995-01-18 Orion Yhtymae Oy Transdermal administration of 4-substituted imidazoles
US5401851A (en) * 1992-06-03 1995-03-28 Eli Lilly And Company Angiotensin II antagonists
ES2076085B1 (es) * 1993-06-15 1997-03-01 Lilly Co Eli Antagonistas de angiotensina ii.
DE69432263T2 (de) * 1993-11-15 2003-12-04 Schering Corp., Kenilworth Phenylalkyl-imidazole als h3-rezeptor-antagonisten
US5922751A (en) * 1994-06-24 1999-07-13 Euro-Celtique, S.A. Aryl pyrazole compound for inhibiting phosphodiesterase IV and methods of using same
KR100385095B1 (ko) * 1997-07-15 2003-08-19 주식회사 엘지생명과학 파네실전이효소저해효능을갖는2환또는3환방향족화합물
US6329369B1 (en) 1997-12-04 2001-12-11 Allergan Sales, Inc. Methods of treating pain and other conditions
US6841684B2 (en) 1997-12-04 2005-01-11 Allergan, Inc. Imidiazoles having reduced side effects
US6503935B1 (en) 1998-08-07 2003-01-07 Abbott Laboratories Imidazoles and related compounds as α1A agonists
WO2000069823A1 (en) * 1999-05-12 2000-11-23 Neurosearch A/S Ion channel modulating agents
TWI283669B (en) * 1999-06-10 2007-07-11 Allergan Inc Compounds and method of treatment having agonist-like activity selective at alpha 2B or 2B/2C adrenergic receptors
JP2002262119A (ja) * 2001-02-28 2002-09-13 Sharp Corp 画像処理装置、画像処理方法、画像処理プログラムを記録した機械読取可能な記録媒体および画像処理プログラム
FR2825926A1 (fr) * 2001-06-14 2002-12-20 Sod Conseils Rech Applic Derives d'imidazoles modulant les canaux sodiques
MX2007015917A (es) * 2005-06-22 2008-03-10 Chemocentryx Inc Compuestos de azaindazol y metodos de uso.
US7777035B2 (en) * 2005-06-22 2010-08-17 Chemocentryx, Inc. Azaindazole compounds and methods of use
CN101374832B (zh) 2006-01-27 2013-03-06 弗·哈夫曼-拉罗切有限公司 4-咪唑衍生物用于cns病症的用途
US20090252779A1 (en) * 2006-06-22 2009-10-08 Chemocentryx, Inc. Azaindazole compounds and methods of use
CA2666762C (en) 2006-10-19 2014-12-30 F. Hoffmann-La Roche Ag Aminomethyl-4-imidazoles
EP2086959B1 (en) 2006-11-02 2011-11-16 F. Hoffmann-La Roche AG Substituted 2-imidazoles as modulators of the trace amine associated receptors
MX2009005047A (es) 2006-11-16 2009-05-25 Hoffmann La Roche 4-imidazoles sustituidos.
MX2009005920A (es) 2006-12-13 2009-06-16 Hoffmann La Roche Nuevos 2-imidazoles como ligandos para receptores asociados con trazas de amina.
US20080146523A1 (en) 2006-12-18 2008-06-19 Guido Galley Imidazole derivatives
US8013169B2 (en) 2007-01-12 2011-09-06 Allergan, Inc Naphthylmethylimidizoles as therapeutic agents
WO2008088937A1 (en) * 2007-01-12 2008-07-24 Allergan, Inc. Quinolynylmethylimidizoles as therapeutic agents
WO2008088936A1 (en) * 2007-01-12 2008-07-24 Allergan, Inc. Quinolynylmethylimidizoles as therapeutic agents
MX2009008255A (es) 2007-02-02 2009-08-12 Hoffmann La Roche Nuevas 2-aminooxazolinas como ligandos taar1.
KR101222412B1 (ko) 2007-02-15 2013-01-15 에프. 호프만-라 로슈 아게 Ｔａａｒ1 리간드로서의 2-아미노옥사졸린
EA015529B1 (ru) 2007-05-22 2011-08-30 Кемосентрикс, Инк. 3-(имидазолил)пиразоло[3,4-b]пиридины
CN101687812A (zh) 2007-07-02 2010-03-31 弗·哈夫曼-拉罗切有限公司 对痕量胺相关受体(taar)具有良好亲和性的2-咪唑啉化合物
WO2009003867A1 (en) 2007-07-03 2009-01-08 F. Hoffmann-La Roche Ag 4-imidazolines and their use as antidepressants
WO2009016048A1 (en) 2007-07-27 2009-02-05 F. Hoffmann-La Roche Ag 2-azetidinemethaneamines and 2-pyrrolidinemethaneamines as taar-ligands
BRPI0814758A2 (pt) 2007-08-03 2015-03-03 Hoffmann La Roche Piridinacarboxamida e derivados de benzamida como ligantes taar1
CA2724293A1 (en) * 2008-05-13 2009-11-19 Allergan, Inc. Quinolynylmethylimidizoles as therapeutic agents
US8258167B2 (en) * 2008-05-13 2012-09-04 Allergan, Inc Naphthylmethylimidizoles as therapeutic agents
US8242153B2 (en) 2008-07-24 2012-08-14 Hoffmann-La Roche Inc. 4,5-dihydro-oxazol-2YL derivatives
DK2323663T3 (da) 2008-09-11 2015-06-01 Chemocentryx Inc 4-amino-3-(imidazolyl)-pyrazolo[3,4-d]pyrimidiner
CN101747280B (zh) * 2008-11-28 2011-11-09 上海迪赛诺医药发展有限公司 制备地托咪定及其中间体的方法
US8354441B2 (en) 2009-11-11 2013-01-15 Hoffmann-La Roche Inc. Oxazoline derivatives
US9452980B2 (en) 2009-12-22 2016-09-27 Hoffmann-La Roche Inc. Substituted benzamides
CN101941944A (zh) * 2010-09-07 2011-01-12 江阴希迪医药科技有限公司 兽药麻醉剂盐酸地托咪啶盐的合成方法
RU2448095C1 (ru) * 2010-12-09 2012-04-20 Олег Геннадьевич Еремин Способ получения детомидина или его нетоксичных фармацевтически приемлемых солей
RU2448094C1 (ru) * 2010-12-09 2012-04-20 Олег Геннадьевич Еремин Улучшенный способ получения медетомидина или его нетоксичных фармацевтически приемлемых солей
MX2014008856A (es) * 2012-02-13 2014-12-15 Hoffmann La Roche Derivados de imidazolilcetona como inhibidores de aldosterona sintasa.
RU2478622C1 (ru) * 2012-02-16 2013-04-10 Федеральное государственное бюджетное учреждение науки Новосибирский институт органической химии им. Н.Н. Ворожцова Сибирского отделения Российской академии наук (НИОХ СО РАН) (1-гидрокси-4,5-диметил-1н-имидазол-2-ил)(фенил)метаноноксим, проявляющий антиаритмические свойства
CN107922399A (zh) * 2015-07-16 2018-04-17 内布拉斯加大学董事委员会 吡咯霉素及其使用方法
HK1257353A1 (en) * 2015-12-25 2019-10-18 Otsuka Pharmaceutical Factory, Inc. Phenylimidazole compound
JP6814814B2 (ja) 2016-03-17 2021-01-20 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｔａａｒのアゴニストとしての活性を有する５−エチル−４−メチル−ピラゾール−３−カルボキサミド誘導体
CN107814771A (zh) * 2017-11-14 2018-03-20 安徽诺全药业有限公司 一种盐酸地托咪定的制备方法
US20210323929A1 (en) * 2018-07-18 2021-10-21 Clexio Biosciences Ltd. Purified Detomidine, Process of Preparing and Methods of Use
EP4688717A1 (en) * 2023-03-30 2026-02-11 Bayer Aktiengesellschaft Palladium-catalyzed chemoselective mono-alpha-arylation of o-protected hydroxyacetone

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
SE7608611L (sv) * 1975-07-31 1977-02-01 Wellcome Found Sett att framstella en oralt intagbar farmaceutisk komposition

Also Published As

Publication number Publication date
IL60723A (en) 1985-02-28
CA1154780A (en) 1983-10-04
AU518569B2 (en) 1981-10-08
US4443466A (en) 1984-04-17
IE50080B1 (en) 1986-02-05
JPS5632463A (en) 1981-04-01
SG34987G (en) 1988-03-04
AU6107180A (en) 1981-02-12
HU184809B (en) 1984-10-29
FI70709B (fi) 1986-06-26
NO153220B (no) 1985-10-28
ZA804787B (en) 1981-07-29
DD152548A1 (de) 1981-12-02
DK338580A (da) 1981-02-08
DK630586D0 (da) 1986-12-29
DK630586A (da) 1986-12-29
SU1014472A3 (ru) 1983-04-23
UA5559A1 (uk) 1994-12-28
JPS624387B2 (da) 1987-01-30
DK155794B (da) 1989-05-16
IE801626L (en) 1981-02-07
NZ194536A (en) 1983-06-17
DK157491C (da) 1990-06-25
EP0024829A1 (en) 1981-03-11
NO153220C (no) 1986-02-05
FI802404A7 (fi) 1981-02-08
EP0024829B1 (en) 1984-04-25
HK68587A (en) 1987-10-02
FI70709C (fi) 1986-10-06
DE3067618D1 (en) 1984-05-30
SU997607A3 (ru) 1983-02-15
ATE7226T1 (de) 1984-05-15
BG60426B2 (bg) 1995-03-31
DK155794C (da) 1989-11-06
NO802352L (no) 1981-02-09

Similar Documents

Publication Publication Date Title
DK157491B (da) Analogifremgangsmaade til fremstilling af 4-benzylsubstituerede imidazolderivater eller farmaceutisk acceptable syreadditionssalte deraf
US4675319A (en) Antianaphylactic and antibronchospastic piperazinyl-(N-substituted phenyl)carboxamides, compositions and use
US4013668A (en) 5-(1,1-diphenyl-3-(5- or 6-hydroxy-2-azabicyclo(2.2.2)oct-2-yl)propyl)-2-alkyl-1,3,4-oxadiazoles and related compounds
IE914339A1 (en) New 1,4-disubstituted piperazines, process for the preparation thereof, and pharmaceutical compositions containing them
US5001134A (en) Piperidines, processes of preparation and medications containing them
EP0198456A2 (en) 1,7-Naphthyridine derivatives and medicinal preparations containing same
US3532702A (en) 2-(o-aminophenoxy or phenylthio) phenyl-1-substituted (piperidyl or pyrrolidinyl) ketones
US5095022A (en) Piperidine derivatives and pharmaceutical compositions comprising the same
GB1569251A (en) Pyridobenzodiazepines
JPS60120864A (ja) 新規カルボスチリル誘導体を含有する気管支拡張剤
RUBAT et al. Synthesis and analgesic effect of N-substituted 5-arylidene-6-methyl-3-(4H)-pyridazinones
DE69011901T2 (de) 1-Arylsulfonyl-2-piperidinon-Derivate, Verfahren und Zwischenprodukte zu ihrer Herstellung, ihre Verwendung als Arzneimittel und sie enthaltende Zusammensetzungen.
HUT61297A (en) Process for producing tert butylphenyl-1-cyclic amino-4-hydroxybutane derivqtives and pharmaceutical compositions comprising such compounds
IT8247807A1 (it) 2,1,3-benzotiadiazoli e 2,1,3,-benzossadiazoli, loro preparazione e loro applicazione come medicamenti
RU2021256C1 (ru) Аралкиламиновые производные или их фармацевтически приемлемые соли
US3509141A (en) 2-amino-quinazolines
CA1132983A (fr) Procedes de preparation de nouvelles piperazines monosubstituees
US4138482A (en) 3-Cyano-N-(N,N-dimethylaminopropyl)-iminodibenzyl and salts thereof
Ellefson et al. Synthesis and biological evaluation of some 2-amino-4-aryl-3H-1, 5-benzodiazepine analogs of clozapine
IT8267060A1 (it) Nuovi derivati dall&#39;acido guandino cicloesancarbossilico e procedimento per la loro produzione
US3691176A (en) 1-(4-fluorophenoxypropyl)-4-anilino-piperidines
US5179089A (en) Isoquinoline compounds, compositions and use
Kierstead et al. 16-Aza steroids
PL72585B1 (en) 6-methyl-8-piperazinyl-methylergalene (ergoline) derivatives[us3583991a]
US3726868A (en) Phenyl and substituted phenylsulfonylallyl amines and substituted amines