NO166940B - Analogifremgangsmaate for fremstilling av terapeutisk aktive 4 (5)-substituerte imidazol-derivater, og mellomprodukttil bruk ved fremstillingen. - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive 4 (5)-substituerte imidazol-derivater, og mellomprodukttil bruk ved fremstillingen. Download PDFInfo
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- NO166940B NO166940B NO872004A NO872004A NO166940B NO 166940 B NO166940 B NO 166940B NO 872004 A NO872004 A NO 872004A NO 872004 A NO872004 A NO 872004A NO 166940 B NO166940 B NO 166940B
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- Prior art keywords
- lower alkyl
- preparation
- formula
- alkyl
- imidazole
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Links
- 238000000034 method Methods 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title claims description 23
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 title abstract description 4
- 239000013067 intermediate product Chemical class 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 150000002460 imidazoles Chemical class 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 230000008569 process Effects 0.000 claims abstract description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 5
- 230000003000 nontoxic effect Effects 0.000 claims description 5
- 150000004791 alkyl magnesium halides Chemical class 0.000 claims description 2
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 3
- 239000002464 receptor antagonist Substances 0.000 abstract description 2
- 229940044551 receptor antagonist Drugs 0.000 abstract description 2
- 125000003342 alkenyl group Chemical group 0.000 abstract 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 2
- 101100448208 Human herpesvirus 6B (strain Z29) U69 gene Proteins 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 239000000556 agonist Substances 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- JXMXDKHEZLKQPB-UHFFFAOYSA-N detomidine Chemical compound CC1=CC=CC(CC=2[N]C=NC=2)=C1C JXMXDKHEZLKQPB-UHFFFAOYSA-N 0.000 description 5
- 229960001894 detomidine Drugs 0.000 description 5
- 229960002748 norepinephrine Drugs 0.000 description 5
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 108060003345 Adrenergic Receptor Proteins 0.000 description 3
- 102000017910 Adrenergic receptor Human genes 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 208000006550 Mydriasis Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 230000001242 postsynaptic effect Effects 0.000 description 2
- -1 sedative effects Chemical compound 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 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 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 150000000994 L-ascorbates Chemical class 0.000 description 1
- 101100108551 Mus musculus Akr1b7 gene Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000002460 anti-migrenic effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 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 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 description 1
- 229960004943 ergotamine Drugs 0.000 description 1
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 230000002474 noradrenergic effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000010344 pupil dilation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 150000003892 tartrate salts Chemical class 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
- C07D233/56—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
- C07D233/58—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 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Dental Preparations (AREA)
- Golf Clubs (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
- Epoxy Resins (AREA)
Description
Denne oppfinnelse angår en fremgangsmåte for fremstilling av nye 4(5)-substituerte imidazol-derivater og deres ugiftige salter, og nye forbindelser for anvendelse som mellomprodukt ved f remst illingen.
Imidazol-derivatene fremstillet i henhold til oppfinnelsen er potente og selektive a2-reseptor-antagonister og har den generelle formel:
hvor
R± er lavere alkyl,
R2 er lavere alkyliden.
Fremstilling av de ugiftige farmasøytisk akseptable syreaddisjonssalter av disse forbindelsene omfattes også av
oppfinnelsen. Forbindelsene med formel I danner syreaddisjonssalter med både organiske og uorganiske syrer. De kan således danne mange farmasøytisk brukbare syreaddisjonssalter, for eksempel klorider, bromider, sulfater, nitrater, fosfater, sulfonater, formiater, tartrater, maleater, citrater, benzoater, salicylater, askorbater og lignende.
Farmasøytiske preparater kan omfatte minst én forbindelse med formel (I) eller et ugiftig, farmasøytisk akseptabelt salt derav, og et forlikelig farmasøytisk akseptabelt bæremiddel.
Adrenerge reseptorer betegner fysiologisk aktive bindings-seter som er spesifikke for noradrenalin og adrenalin og lokalisert på overflaten av cellemembranen. Adrenoseptorer av
det sympatiske nervesystem er blitt klassifisert i to ulike typer, alfa- (a) og beta- (P) reseptorer som begge ytterligere kan deles i to undergrupper, dvs. oc^ og a2 samt og P2. Av disse reseptortyper er Plt e2°9 Ql hovedsakelig lokalisert postsynaptisk på overflaten av f.eks. glatt muskulatur og
styrer således f.eks. kontraksjon eller relaksasjon av glatt muskulatur, mens a2-reseptorer hovedsakelig er lokalisert pre-synaptisk på noradrenerge nerve-ender. Dersom a2-reseptorer stimuleres av noradrenalin under fysiologiske betingelser, blokkeres noradrenalin-frigjøringen, dvs. dette er et negativt tilbakekoblings (["feedback") fenomen.
Bortsett fra. ved noradrenalin, kan dette negative tilbake-koblingsfenomen induseres av visse syntetiske a2-agonister som detomidin (forbindelse A) og noen av dens nær beslektede derivater. De primære farmakodynamiske effekter av detomidin, f.eks. sedative virkninger, er også fastslått å skyldes dets evne til å stimulere a2-reseptorer (Virtanen et al., Progress" in Neuro-Psychopharmacology and Biological Psychiatri, suppl. 1983 , s. 308) .
Behov for en selektiv a2-antagonist kan forventes, f.eks. ved enkelte sykdommer som antas å ha forbindelse med nedsatt noradrenalin-tilgjengelighet i de postsynaptiske adrenoseptorer i det sentrale og/eller perifere nervesystem. Disse sykdommer innbefatter f.eks. endogene depresjoner og astma.
Glukose- og lipid-metabolismen reguleres av en inhiberings-mekanisme hvor a2-reseptorer er involvert. cx2-antagonister kan derfor være viktige ved behandling av metabolske lidelser som diabetes og fedme.
Presynaptiske oc_reseptorer deltar også i blodplate-aggregasjonen. Det har vist seg at a2-agonister aktiverer og at antagonister inhiberer human blodplateaggregasjon (Grant & Schutter, Nature 1979, 277, 659). a2-antagonister kan derfor være klinisk anvendelige ved patogene tilstander som innebærer økt aggregasjon, f.eks. migrene. De akutte virkninger av ergotamin, en klassisk forbindelse mot migrene, ansees å skyldes dens cx-^-agonistvirkning. Forbindelser med både anta-gonistiske virkninger på a2-reseptorer og agonistvirkninger på postsynaptiske a^-reseptorer kan således ha store fordeler ved akutt og preventiv behandling av migrene.
I henhold til oppfinnelsen fremstilles forbindelser med den generelle formel (I) etter den følgende generelle fremgangsmåte. Med generell fremgangsmåte skal det her forstås en metode som ved bruk av passende utgangsmateriale, kan anvendes for fremstilling av alle forbindelser med den generelle formel (I).
Et karakteristisk trekk ved metoden er at 2-(imidazol-4(5)-yl)-2-alkyl-l-indanon, som er beskrevet i Europeisk patentpublikasjon 183492 og har formelen: hvor Ri er lavere alkyl omsettes med et alkylmagnesiumhalogenid for å gi 4(5)-(1,2-dialkyl-2,3-dihydro-l-hydroksy-lH-inden-2-yl)imidazol som har formelen
hvor R'2 er en lavere alkylgruppe.
Mellomproduktene med formel III er nye og representerer et trekk ved foreliggende oppfinnelse.
Egnede oppløsningsmidler er forskjellige etere som dietyleter, dibutyleter eller tetrahydrofuran. Omsetningen kan lett utføres ved romtemperatur.
Dehydratisering av forbindelse (III) , f.eks. ved oppvarming med kaliumhydrogensulfat eller i surt vann gir 4(5)-(2-alkyl-l-alkyliden-2,3-dihydro-lH-inden-2-yl)imidazol som har formelen hvor R er hydrogen eller en lavere alkylgruppe.
Katalytisk hydrogenering av dobbeltbindingen i formel (IV) gir forbindelser med formel (I).
Følgende forbindelser er for eksempel spesielt viktige som oc2-antagonister: 4(5)-(2,3-dihydro-2-metyl-l-metylen-lH-inden-2-yl)imidazol
4(5)-(2,3-dihydro-l-etyliden-2-metyl-lH-inden-2-yl)imidazol
a2-antagonisme ble bestemt in vitro ved hjelp av isolerte, elektrisk stimulerte mus vas deferens preparater (Marshall et al., Br. J. Pharmac. 62, 147, 151, 1978). I denne modell blokkerer oc2-agonist (Detomidine) elektrisk stimulerte muskel-kontraksjoner, og virkningen av a2-antagonisten ses ved at den administreres før agonisten og ved å bestemme dens pA2-verdi.
Den sentrale a2-blokkerende effekt av de undersøkte substanser under in vivo betingelser, ble undersøkt etter to metoder. Den første er basert på at a2-agonister hos rotte induserer pupilleutvidelse (mydriasis) og denne effekt over-føres via o<2-reseptorer i sentralnervesystemet. Til anestetiserte rotter ble en standard-dose av Detomidine gitt intravenøst. Deretter ble økende doser av den undersøkte antagonist injisert intravenøst og reverseringen av Detomidine-indusert mydriasis fulgt. ED50-verdien av antagonisten, dvs. den dose som gir 50% reversering, ble bestemt. Resultatene av denne test angis på følgende måte:
De kliniske doseringsområdene for de nye forbindelsene er blitt fastslått til 0,1-10 mg/kg pr. dag både ved oral og i.v.-administrasj on.
Eksempel 1
a) 4(5)-(2,3-dihydro-2-metyl-l-metylen-lH-inden-2-yl)imidazol 45 mmol metylmagnesiumbromid ble fremstillet i tetrahydrofuran og dette ble ved 30-40°C dråpevis tilsatt til en tetra-hydrofuranoppløsning inneholdende 3,0 g 2-(imidazol-4(5)-yl)-2-metyl-l-indanon. Etter tilsetningen ble reaksjonsblandingen omrørt ved 40°C i ytterligere 2 timer og så helt over i surt vann. Deretter ble blandingen omrørt ved 70°C i 1 time for å oppnå dehydrering. Den ble deretter avkjølt, gjort alkalisk med natriumhydroksyd og produktet, 4(5)-(2,3-dihydro-2-metyl-l-metylen-lH-inden-2-yl)imidazol, ble ekstrahert under forsiktig oppvarming i metylenklorid, hvorfra det krystalliserte ved henstand. Utbytte 2,4 g (82%), smp. 157-164°C.
b) 4(5)-(2,3-dihydro-l,2-dimetyl-lH-inden-2-yl)imidazol
Produktet fra foregående trinn (2,0 g) ble løst opp i
10 ml etanol inneholdende 2 ml 2N saltsyre. Oppløsningen ble tilsatt 10% Pd/C som katalysator, og oppløsningen ble omrørt under hydrogenatmosfære ved romtemperatur inntil hydrogenopp-
i taket opphørte. Reaksjonsblandingen ble filtrert, gjort alkalisk med natriumhydroksyd, og produktet ekstrahert over i etylacetat. Produktet kan videre omdannes til hydrokloridet i en blanding av isopropanol og etylacetat. Det således oppnådde produkt er en blanding av cis- og trans-isomerene og smelter i området 175-196°C.
Eksempel 2
4(5)-(2,3-dihydro-l-etyliden-2-metyl-lH-inden-2-yl)imidazol
Etyl-magnesiumbromid (0,07 mol) i 15 ml tørr tetrahydro-
furan ble tilsatt til tetrahydrofuranoppløsningen (20 ml) av 3,0 g 2-(lH-imidazol-4(5)-yl)-2-metyl-l-indanon ved 40°C. Etter tilsetningen ble reaksjonsblandingen omrørt ved 40°C i 2 timer, avkjølt og helt over i surt vann. Tetrahydrofuran ble inn-
dampet, saltsyre tilsatt, og blandingen ble omrørt ved 70°C
for å oppnå vannavspaltning, hvorpå den ble avkjølt og gjort alkalisk. Produktet, 4(5)-(2,3-dihydro-l-etyliden-2-metyl-lH-inden-2-yl)imidazol ble ekstrahert med metylenklorid. Det uløselig bunnfall (del av produktet) ble frafiltrert. Metylen-
klorid ble fordampet. Råproduktet ble løst opp i metylenklorid hvorfra produktet utfeltes. Utbytte 2,1 g, smp. 194-202°C.
^•H NMR (80MHz, CDC13 og noe MeOH-d4) : S 1,54 (3H, s, CH3) ; 2,01
(3H, d, J 7,4HZ, =CHCH3); 3,00 og 3,37 (4H, AB q, J 16,2Hz,
CH2)J 5,46 (1H, q, J 7,4Hz, =CHCH3); 6,81 (1H, d, <4>J 1,0Hz, im-
5(4)); 7,15-7,70 (4H, m, aromatisk); 7,46 (1H, d, <4>J 1,0Hz, im-
2).
Claims (2)
1. Analogifremgangsmåte for fremstilling av terapeutisk aktive 4(5)-substituerte imidazoler med formel (I):
hvor
Ri er lavere alkyl,
R2 er lavere alkyliden,
og deres ugiftige syreaddisjonssalter, karakterisert ved at
en forbindelse med formel
hvor R^ er lavere alkyl, omsettes med et alkylmagnesiumhalogenid for å gi 4(5)-(1,2-dialkyl-2,3-dihydro-l-hydroksy-lH-inden-2-yl)imidazol som har formelen:
hvor R2 er en lavere alkylgruppe, denne forbindelse dehydrati-seres for å gi 4(5)-(2-alkyliden-l-alkenyl-lH-inden-2-yl)imidazol som har formelen:
hvor R er hydrogen eller en lavere alkylgruppe, og eventuelt omdannes den fremstilte forbindelse til et ugiftig syreaddisjons-salt.
2. Ny forbindelse,
karakterisert ved formelen:
hvor
Ri er som angitt i krav 1 og R2 er lavere alkyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO882728A NO167735C (no) | 1986-05-15 | 1988-06-21 | Analogifremgangsmaate for fremstilling av terapeutisk aktive 4(5)-substituerte imidazol-derivater. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI862039A FI862039A0 (fi) | 1986-05-15 | 1986-05-15 | Nytt foerfarande foer framstaellning av 4(5)-substituerade imidazolderivat. |
| FI870462A FI870462A0 (fi) | 1987-02-04 | 1987-02-04 | Foerfarande foer framstaellning av 4(5)-substituerade imidazolderivat. |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO872004D0 NO872004D0 (no) | 1987-05-14 |
| NO872004L NO872004L (no) | 1987-11-16 |
| NO166940B true NO166940B (no) | 1991-06-10 |
| NO166940C NO166940C (no) | 1991-09-25 |
Family
ID=26157963
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO872004A NO166940C (no) | 1986-05-15 | 1987-05-14 | Analogifremgangsmaate for fremstilling av terapeutisk aktive 4 (5)-substituerte imidazol-derivater, og mellomprodukttil bruk ved fremstillingen. |
Country Status (18)
| Country | Link |
|---|---|
| US (2) | US4933359A (no) |
| EP (1) | EP0247764B1 (no) |
| JP (1) | JP2561272B2 (no) |
| KR (1) | KR950002158B1 (no) |
| AT (1) | ATE66211T1 (no) |
| AU (1) | AU600725B2 (no) |
| CA (1) | CA1299186C (no) |
| DE (1) | DE3772104D1 (no) |
| DK (1) | DK172422B1 (no) |
| ES (1) | ES2037712T3 (no) |
| FI (1) | FI81092C (no) |
| GR (1) | GR3002928T3 (no) |
| HU (1) | HU197314B (no) |
| IE (1) | IE59609B1 (no) |
| IL (1) | IL82541A (no) |
| NO (1) | NO166940C (no) |
| NZ (1) | NZ220306A (no) |
| PT (1) | PT84881B (no) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2225782A (en) * | 1988-12-09 | 1990-06-13 | Farmos Group Limited | Imidazole derivatives useful for treatment of diabetes |
| CA1321751C (en) * | 1989-02-21 | 1993-08-31 | Eugene C. Crichlow | Mechanism mediating ruminal stasis in ruminal lactic acidosis |
| GB2244431A (en) * | 1990-05-31 | 1991-12-04 | Farmos Oy | Treatment of age related memory impairment and other cognitive disorders |
| FR2669030B1 (fr) * | 1990-11-14 | 1992-12-31 | Adir | Nouveaux derives d'imidazole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
| GB9127050D0 (en) * | 1991-12-20 | 1992-02-19 | Orion Yhtymae Oy | Substituted imidazole derivatives and their preparation and use |
| GB9312669D0 (en) | 1993-06-18 | 1993-08-04 | Orion Yhtymae Oy | New opticla isomers |
| FR2735776B1 (fr) * | 1995-06-22 | 1997-07-18 | Synthelabo | Derives de 2,3-dihydro-1h-indole, leur preparation et leur application en therapeutique |
| GB9520150D0 (en) | 1995-10-03 | 1995-12-06 | Orion Yhtymae Oy | New imidazole derivatives |
| JP2002534511A (ja) * | 1999-01-18 | 2002-10-15 | ノボ ノルディスク アクティーゼルスカブ | 置換型イミダゾール、それらの調製及び使用 |
| US6388090B2 (en) * | 2000-01-14 | 2002-05-14 | Orion Corporation | Imidazole derivatives |
| PE20011321A1 (es) | 2000-05-08 | 2002-01-03 | Orion Corp | Indanilimizadoles policiclicos nuevos con actividad adrenergica alfa 2 |
| US8188126B2 (en) | 2002-05-16 | 2012-05-29 | Pierre Fabre Medicament | Imidazolic compounds and use thereof as alpha-2 adrenergic receptors |
| FR2839719B1 (fr) * | 2002-05-16 | 2004-08-06 | Pf Medicament | Nouveaux composes imidazoliques, leur procede de preparation et leur utilisation a titre de medicaments |
| AU2006287070A1 (en) * | 2005-08-30 | 2007-03-08 | Queen's University At Kingston | Potentiation of the therapeutic action of an opioid receptor agonist and/or inhibition or reversal of tolerance to an opioid receptoi agonists using an ultralow dose of an alpha-2 receptor antagonist |
| CL2008003553A1 (es) * | 2007-12-05 | 2009-11-27 | Grindeks Jsc | Proceso para preparar atipamezol o clorhidrato de 5-(2-etil-2,3-dihidro-1h-inden-2-il)-1h-imidazol: y loa compuestos intermediarios considerados en el proceso |
| CN102548951A (zh) * | 2009-07-24 | 2012-07-04 | 帝斯曼医药化学雷根斯堡技术有限公司 | 作为中间体的二氢化茚衍生物 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7908922A (nl) * | 1979-12-12 | 1981-07-16 | Akzo Nv | Carboximidamide derivaten. |
| US4480118A (en) * | 1981-01-13 | 1984-10-30 | Sumitomo Chemical Company, Limited | Carboxylic acid ester and an insecticidal and/or acaricidal composition containing the same |
| DE3271003D1 (en) * | 1981-09-15 | 1986-06-12 | Ici Plc | Amino-substituted tetralins and related homocyclic compounds |
| US4661522A (en) * | 1984-05-24 | 1987-04-28 | Akzo N.V. | Cycloalkane-indene-carboximidamide derivatives |
| GB2167408B (en) * | 1984-11-23 | 1988-05-25 | Farmos Oy | Substituted imidazole derivatives and their preparation and use |
-
1987
- 1987-04-15 FI FI871655A patent/FI81092C/fi not_active IP Right Cessation
- 1987-04-24 DK DK198702082A patent/DK172422B1/da not_active IP Right Cessation
- 1987-05-14 AT AT87304304T patent/ATE66211T1/de not_active IP Right Cessation
- 1987-05-14 NO NO872004A patent/NO166940C/no unknown
- 1987-05-14 DE DE8787304304T patent/DE3772104D1/de not_active Expired - Lifetime
- 1987-05-14 HU HU872181A patent/HU197314B/hu unknown
- 1987-05-14 NZ NZ220306A patent/NZ220306A/xx unknown
- 1987-05-14 JP JP62118077A patent/JP2561272B2/ja not_active Expired - Lifetime
- 1987-05-14 ES ES198787304304T patent/ES2037712T3/es not_active Expired - Lifetime
- 1987-05-14 KR KR1019870004746A patent/KR950002158B1/ko not_active IP Right Cessation
- 1987-05-14 EP EP87304304A patent/EP0247764B1/en not_active Expired - Lifetime
- 1987-05-14 US US07/049,882 patent/US4933359A/en not_active Expired - Lifetime
- 1987-05-14 IE IE125887A patent/IE59609B1/en not_active IP Right Cessation
- 1987-05-15 IL IL82541A patent/IL82541A/xx not_active IP Right Cessation
- 1987-05-15 PT PT84881A patent/PT84881B/pt unknown
- 1987-05-15 CA CA000537323A patent/CA1299186C/en not_active Expired - Lifetime
- 1987-05-15 AU AU73102/87A patent/AU600725B2/en not_active Ceased
-
1989
- 1989-11-06 US US07/431,959 patent/US5026868A/en not_active Expired - Lifetime
-
1991
- 1991-10-17 GR GR91401554T patent/GR3002928T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0247764B1 (en) | 1991-08-14 |
| GR3002928T3 (en) | 1993-01-25 |
| DK208287D0 (da) | 1987-04-24 |
| US5026868A (en) | 1991-06-25 |
| DK208287A (da) | 1987-11-16 |
| AU7310287A (en) | 1987-11-19 |
| NO872004L (no) | 1987-11-16 |
| JP2561272B2 (ja) | 1996-12-04 |
| NZ220306A (en) | 1990-02-26 |
| CA1299186C (en) | 1992-04-21 |
| FI81092B (fi) | 1990-05-31 |
| DK172422B1 (da) | 1998-06-08 |
| PT84881B (pt) | 1990-02-08 |
| KR880009941A (ko) | 1988-10-06 |
| KR950002158B1 (ko) | 1995-03-14 |
| US4933359A (en) | 1990-06-12 |
| FI81092C (fi) | 1990-09-10 |
| FI871655A (fi) | 1987-11-16 |
| ATE66211T1 (de) | 1991-08-15 |
| FI871655A0 (fi) | 1987-04-15 |
| IL82541A0 (en) | 1987-11-30 |
| IL82541A (en) | 1992-06-21 |
| PT84881A (en) | 1987-06-01 |
| EP0247764A1 (en) | 1987-12-02 |
| HU197314B (en) | 1989-03-28 |
| JPS62289566A (ja) | 1987-12-16 |
| AU600725B2 (en) | 1990-08-23 |
| HUT45234A (en) | 1988-06-28 |
| NO166940C (no) | 1991-09-25 |
| ES2037712T3 (es) | 1993-07-01 |
| IE59609B1 (en) | 1994-03-09 |
| IE871258L (en) | 1987-11-15 |
| NO872004D0 (no) | 1987-05-14 |
| DE3772104D1 (de) | 1991-09-19 |
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