NO143459B - Analogifremgangsmaate for fremstilling av fysiologisk aktive 2-fenylimino-imidazolidin-derivater - Google Patents
Analogifremgangsmaate for fremstilling av fysiologisk aktive 2-fenylimino-imidazolidin-derivater Download PDFInfo
- Publication number
- NO143459B NO143459B NO753314A NO753314A NO143459B NO 143459 B NO143459 B NO 143459B NO 753314 A NO753314 A NO 753314A NO 753314 A NO753314 A NO 753314A NO 143459 B NO143459 B NO 143459B
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- Norway
- Prior art keywords
- acid
- phenylimino
- preparation
- fluoro
- physiologically active
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title claims description 3
- JCOPITWIWLFFPC-UHFFFAOYSA-N n-phenyl-4,5-dihydro-1h-imidazol-2-amine Chemical class N1CCN=C1NC1=CC=CC=C1 JCOPITWIWLFFPC-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 8
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- MRJPUXFURCZQLC-UHFFFAOYSA-N 1-fluoro-2-isocyano-3-(trifluoromethyl)benzene Chemical compound FC1=CC=CC(C(F)(F)F)=C1[N+]#[C-] MRJPUXFURCZQLC-UHFFFAOYSA-N 0.000 claims description 2
- VJLADBUFZUFOCT-UHFFFAOYSA-N n-[2-fluoro-6-(trifluoromethyl)phenyl]-4,5-dihydro-1h-imidazol-2-amine Chemical compound FC1=CC=CC(C(F)(F)F)=C1NC1=NCCN1 VJLADBUFZUFOCT-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- CQSFHEFEKDRLKE-UHFFFAOYSA-N 2-fluoro-6-(trifluoromethyl)aniline Chemical compound NC1=C(F)C=CC=C1C(F)(F)F CQSFHEFEKDRLKE-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000004622 sleep time Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000007306 turnover Effects 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- GBOWGKOVMBDPJF-UHFFFAOYSA-N 1-fluoro-3-(trifluoromethyl)benzene Chemical compound FC1=CC=CC(C(F)(F)F)=C1 GBOWGKOVMBDPJF-UHFFFAOYSA-N 0.000 description 1
- LNARMXLVVGHCRP-UHFFFAOYSA-N 2-fluoro-6-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=C(F)C=CC=C1C(F)(F)F LNARMXLVVGHCRP-UHFFFAOYSA-N 0.000 description 1
- -1 2-fluoro-6-trifluoromethylphenylimino Chemical group 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- YIUIVFFUEVPRIU-UHFFFAOYSA-N 8-chlorotheophylline Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21 YIUIVFFUEVPRIU-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- RLAROPIDCNCRNR-UHFFFAOYSA-N Cl.Cl.[C-]#N Chemical compound Cl.Cl.[C-]#N RLAROPIDCNCRNR-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 150000001559 benzoic acids Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- GNYKPRZVSYJFIV-UHFFFAOYSA-N imidazolidin-1-ium;chloride Chemical compound Cl.C1CNCN1 GNYKPRZVSYJFIV-UHFFFAOYSA-N 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- YDQRFRMNKABNTE-UHFFFAOYSA-N n-[2-fluoro-6-(trifluoromethyl)phenyl]-4,5-dihydro-1h-imidazol-2-amine;hydrochloride Chemical compound Cl.FC1=CC=CC(C(F)(F)F)=C1N=C1NCCN1 YDQRFRMNKABNTE-UHFFFAOYSA-N 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- SQMCFUSVGSBKFK-UHFFFAOYSA-M sodium;5-(cyclohexen-1-yl)-1,5-dimethylpyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].O=C1N(C)C(=O)[N-]C(=O)C1(C)C1=CCCCC1 SQMCFUSVGSBKFK-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
- C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
2-fenylimino-imidazolidiner har på grunn av sine meget gode farmakologiske og terapeutiske egenskaper i lang tid vært gjenstand for sterk interesse. Forbindelser av denne type er derfor beskrevet mange steder i litteraturen og er f.eks. gjenstand for de belgiske patenter nr. 623.3o5, 653.933, 687.656, 687.657 og 7o5.944. I disse litteratursteder er også de vesentlige fremgangsmåter for fremstilling av 2-fenylimino-imidazolidiner beskrevet.
På grunnlag av nyere undersøkelser er det nu fastslått at blant de strukturtrekk for 2-fenylimino-imidazolidiner som er nød-vendige for en sentral a-adrenerg stimulering, har konformasjonen en avgjørende betydning. På grunnlag av struktur-virknings-betrakt-ninger er det funnet at bare slike derivater hvis fenyl- og imidazol-idinring har en aplanar konformasjon til hverandre, viser en god blodtrykksenkende virkning.
I dette tilfelle er den frie dreibarhet av fenylringen om C-N-enkeltbindingen hindret, og de to ringer står loddrett eller tilnærmet loddrett på hverandre.
Aplanaritet hos 2-fenyliminoimidazolidiner oppnås ved at
man substituerer orto-stillingene i den aromatiske molekyldel:
Sperrende atomer eller atomgrupper i disse stillinger hindrer den frie dreibarhet av fenylringen om C-N-enkeltbindingen og dermed muligheten for en koplahar innstilling av de to ringer til hverandre.
Klonidin [2-(2,6-diklorfenylimino)-imidazolidin] er en representant for denne klasse forbindelser og er i besittelse av en meget sterk blodtrykksenkende virkning. Den er imidlertid beheftet med en rekke uønskede bivirkninger. Formålet med fore-liggende oppfinnelse er å fremstille nye forbindelser av denne type, som ved siden av en sterk hypotensiv virkning også har en forbedret virkningsprofil.
Ifølge oppfinnelsen fremstilles den terapeutisk aktive forbindelse 2-(2-fluor-6-trifluormetylfenylimino)-imidazolidin og fysiologisk forlikelige syreadddisjo.nssalter derav. Fremgangs-måten karakteriseres ved at 2-fluor-6-trifluormetyl-fenylisocyanid-diklorid omsettes med etylendiamiii, og eventuelt overføres den erholdte forbindelse til et syreaddisjonssalt.
Omsetningen foretas ved temperaturer mellom 0 og 200°C.
Som oppløsningsmidler kan anvendes polare protiske, polare aprotiske eller upolare. Omsetningen kan imidlertid også foretas uten anvendelse av oppløsningsmidler ved høyere temperatur. Det anbefales å anvende et syrebindende middel ved omsetningen. Reaksjonstiden er avhengig av reaktiviteten av de anvendte reaksjonsbestanddeler og svinger mellom noen minutter og flere timer.
Fremstillingen av det som utgangsmateriale anvendte nye 2-fluor-6-trifluormetylanilin skjer vanligvis ved den nedenfor-skjematisk beskrevne reaksjonsvei:'
Ved denne syntesevei dannes foruten benzoesyrene vanligvis også deres isomerer, som best kan separeres kolonnekromatografisk (silikagel).
Isocyaniddikloridet kan fremstilles fra anilinet som følger:
Den nye forbindelse I kan på vanlig måte overføres til sine fysiologisk forlikelige syreaddisjonssalter. Syrer som er egnet til saltdannelse, er f .eks. saltsyre, bromhydrogensyre, jodhydrogensyre, fluorhydrogensyre, svovelsyre, fosforsyre, salpetersyre, eddiksyre, propionsyre, smørsyre, kapronsyre, valeriansyre, oksalsyre, malonsyre, ravsyre, maleinsyre, fumarsyre, melkesyre, vinsyre, sitronsyre, eplesyre, benzoesyre, p-hydroksy-benzoesyre, p-aminobenzoesyre, ftalsyre, kanelsyre, salicylsyre, askorbinsyre, metansulfonsyre, etanfosforsyre og 8-klorteofyllin.
Den nye forbindelse og dens syreaddisjonssalter har verdi-fulle terapeutiske og særlig blodtrykksenkende egenskaper og kan derfor anvendes ved behandling av forskjellige former for hyper-toni. Forbindelsen kan anvendes enteralt eller også parenteralt. Doseringen ligger ved 0,1 til 80 mg, fortrinnsvis 0,5 til 30 mg.
Den nye forbindelse resp. dens syreaddisjonssalter kan også anvendes sammen med aktive stoffer av andre typer. Egnede galeniske tilberedelsesformer er f.eks. tabletter, kapsler, stikk-piller, oppløsninger eller pulvere, og for fremstilling av disse kan de vanlig anvendte hjelpemidler, bæremidler, sprengmidler eller smøremidler eller stoffer som medfører en depotvirkning, anvendes.
Den nye forbindelse og klonidin ble undersøkt med hensyn til sine blodtrykksenkende egenskaper på kaniner under uretan-nembutal-narkose. Blodtrykket ble målt direkte på arteria carotis. ED^q er den dose som medfører en vedvarende senkning av blodtrykket på 20 mm Hg.
Begge forbindelser ble undersøkt med hensyn til sin innvirkning på mavesekresjonen hos rotter ved anordningen ifølge Shay. ED5Q an9ir <3en dose som bevirker eh reduksjon av mavesaft-volumet og surhet i mavesaften på 50%.
Begge forbindelser viser en narkoseforsterkende virkning på mus. Den sovetid som fremkalles ved hjelp av heksobarbital-natrium, forlenges i forhold til en kontrollgruppe. d^q0 er ^en dose som bevirker en fordobling av sovetiden.
De følgende verdier angir bevegelses- og utforsknings-hemning hos mus ved hullbrettforsøk.
Det følgende eksempel skal tjene til å illustrere oppfinnelsen ytterligere.
Eksempel
2~( 2- fluor- 6- trifluormetylfenylimino)- imidazolidin- hydroklorid
9 g N-(2-fluor-6-trifluormetylfenyl)-isocyaniddiklorid [fremstilt fra 3-fluor-benzotrifluorid over trinnene: 2-fluor-6-trifluormetyl-benzoesyre (sm.p. 81-84°C), 2-fluor-6-trifluormetyl-anilin (oljeaktig) og 2-fluor-6-trifluormety1-formanilid (sm.p. 116-118°C)] omsettes med 21,6 ml etylendiamin (10-dobbelt overskudd) ved 10°C under omrøring i 100 ml absolutt eter. Efter 30 minutters reaksjonstid inndampes reaksjons-blandingen til tørrhet i vakuum, og den gjenværende olje oppløses i fortynnet saltsyre. Efter 2 gangers eterekstråksjon fraskilles den vandige fase og behandles med aktivt kull. Derefter ekstra-heres fraksjonert med eter ved stigende pH-verdier (alkalisering med natronlut). De tynnskiktkromatografisk rene eterfraksjoner samles, tørres og tilsettes eterisk saltsyre til kongosur reaksjon for felling av imidazolidin-hydrokloridet. Utbyttet av rent
2-(2-fluor-6-trifluormetylfenylimino)-imidazolidin-hydroklorid = 4,35 g svarende til 44,9% av det teoretiske.
Smeltepunkt: 262-264°C. Den hvite, krystallinske forbindelse løses i vann og lavere alkoholer.
Claims (1)
- Analogi fremgangsmåte for fremstilling av den terapeutisk aktive forbindelse 2-(2-fluor-6-trifluormetylfenyl-imino)-imidazolidin og fysiologisk forlikelige syreaddisjonssalter derav, karakterisert ved at 2-fluor-6-trifluormetyl-fenylisocyaniddiklorid omsettes med etylendiamin, og eventuelt overføres den erholdte forbindelse til et syreaddisjonssalt.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2446758A DE2446758C3 (de) | 1974-10-01 | 1974-10-01 | 2-(2-Fluor-6-trifluormethylphenylimino)-imidazolidin, dessen Säureadditionssalze, Verfahren zur Herstellung dieser Verbindungen und deren Verwendung bei der Bekämpfung der Hypertonie |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO753314L NO753314L (no) | 1976-04-02 |
| NO143459B true NO143459B (no) | 1980-11-10 |
| NO143459C NO143459C (no) | 1981-02-18 |
Family
ID=5927202
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO753314A NO143459C (no) | 1974-10-01 | 1975-09-30 | Analogifremgangsmaate for fremstilling av fysiologisk aktive 2-fenylimino-imidazolidin-derivater |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS6018653B2 (no) |
| AT (1) | AT344159B (no) |
| BE (1) | BE834051A (no) |
| BG (2) | BG25220A3 (no) |
| CA (1) | CA1056836A (no) |
| CH (5) | CH620682A5 (no) |
| CS (1) | CS193524B2 (no) |
| DD (1) | DD123602A5 (no) |
| DE (1) | DE2446758C3 (no) |
| DK (1) | DK441875A (no) |
| ES (4) | ES441385A1 (no) |
| FI (1) | FI61883C (no) |
| FR (1) | FR2286649A1 (no) |
| GB (1) | GB1515019A (no) |
| HU (1) | HU178469B (no) |
| IE (1) | IE42130B1 (no) |
| IL (1) | IL48214A (no) |
| LU (1) | LU73472A1 (no) |
| NL (1) | NL7511490A (no) |
| NO (1) | NO143459C (no) |
| NZ (1) | NZ178810A (no) |
| PH (1) | PH13653A (no) |
| PL (2) | PL98984B1 (no) |
| SE (1) | SE418497B (no) |
| SU (1) | SU575026A3 (no) |
| YU (1) | YU230281A (no) |
| ZA (1) | ZA756185B (no) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2630060C2 (de) * | 1976-07-03 | 1984-04-19 | C.H. Boehringer Sohn, 6507 Ingelheim | 2-(2-Brom-6-fluor-phenylimino)-imidazolidin, dessen Säureadditionssalze, diese enthaltende Arzneimittel und Verfahren zu deren Herstellung |
| DE2806811A1 (de) * | 1978-02-17 | 1979-08-23 | Boehringer Sohn Ingelheim | Neue substituierte 2-phenylimino- imidazolidine, deren saeureadditionssalze, diese enthaltene arzneimittel und verfahren zur herstellung derselben |
| DE2806775A1 (de) * | 1978-02-17 | 1979-08-30 | Boehringer Sohn Ingelheim | Neue substituierte 2-phenylimino- imidazolidine deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
| ZA801680B (en) * | 1979-04-03 | 1981-03-25 | Fujisawa Pharmaceutical Co | 2-imidazoline derivatives,process for the preparation thereof and the pharmaceutical composition of the same |
| HU192986B (en) | 1984-05-23 | 1987-08-28 | Egyt Gyogyszervegyeszeti Gyar | Process for production of imidasodiline derivatives |
| JP2009524619A (ja) * | 2006-01-27 | 2009-07-02 | エフ．ホフマン−ラ ロシュ アーゲー | Ｃｎｓ障害の処置のための２−イミダゾールの使用 |
| KR101174191B1 (ko) | 2007-02-02 | 2012-08-14 | 에프. 호프만-라 로슈 아게 | 중추 신경계 장애의 치료용 ｔａａｒ1 리간드로서 2-아미노옥사졸린 |
| WO2008098857A1 (en) | 2007-02-15 | 2008-08-21 | F. Hoffmann-La Roche Ag | 2-aminooxazolines as taar1 ligands |
| US8242153B2 (en) | 2008-07-24 | 2012-08-14 | Hoffmann-La Roche Inc. | 4,5-dihydro-oxazol-2YL derivatives |
| 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 |
| WO2017157873A1 (en) | 2016-03-17 | 2017-09-21 | F. Hoffmann-La Roche Ag | 5-ethyl-4-methyl-pyrazole-3-carboxamide derivative having activity as agonist of taar |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3236857A (en) * | 1961-10-09 | 1966-02-22 | Boehringer Sohn Ingelheim | 2-(phenyl-amino)-1, 3-diazacyclopentene-(2) substitution products |
| DE1670807A1 (de) * | 1967-02-17 | 1971-03-11 | Bayer Ag | Verfahren zur Herstellung von cyclischen Guanidinen |
| DE1670918A1 (de) * | 1967-09-07 | 1971-04-08 | Bayer Ag | Verfahren zur Herstellung von 2-Aryl-amino-substituierten stickstoffhaltigen Heterocyclen |
| BE787683A (fr) * | 1971-08-20 | 1973-02-19 | Boehringer Sohn Ingelheim | 2-phenylimino-imidazolidines, leurs sels d'addition avec des acides et procedes pour les fabriquer |
-
1974
- 1974-10-01 DE DE2446758A patent/DE2446758C3/de not_active Expired
-
1975
- 1975-09-22 AT AT722875A patent/AT344159B/de not_active IP Right Cessation
- 1975-09-23 SU SU7502174605A patent/SU575026A3/ru active
- 1975-09-26 PH PH17613A patent/PH13653A/en unknown
- 1975-09-29 BG BG7500031110A patent/BG25220A3/xx unknown
- 1975-09-29 DD DD188613A patent/DD123602A5/xx unknown
- 1975-09-29 BG BG7500032014A patent/BG25221A3/xx unknown
- 1975-09-29 LU LU73472A patent/LU73472A1/xx unknown
- 1975-09-29 CS CS756573A patent/CS193524B2/cs unknown
- 1975-09-30 NZ NZ178810A patent/NZ178810A/xx unknown
- 1975-09-30 DK DK441875A patent/DK441875A/da not_active Application Discontinuation
- 1975-09-30 IL IL48214A patent/IL48214A/xx unknown
- 1975-09-30 PL PL1975197816A patent/PL98984B1/pl unknown
- 1975-09-30 CH CH1267875A patent/CH620682A5/de not_active IP Right Cessation
- 1975-09-30 BE BE160578A patent/BE834051A/xx not_active IP Right Cessation
- 1975-09-30 FI FI752728A patent/FI61883C/fi not_active IP Right Cessation
- 1975-09-30 ES ES441385A patent/ES441385A1/es not_active Expired
- 1975-09-30 CA CA236,670A patent/CA1056836A/en not_active Expired
- 1975-09-30 GB GB40012/75A patent/GB1515019A/en not_active Expired
- 1975-09-30 NL NL7511490A patent/NL7511490A/xx not_active Application Discontinuation
- 1975-09-30 ZA ZA756185A patent/ZA756185B/xx unknown
- 1975-09-30 JP JP50118196A patent/JPS6018653B2/ja not_active Expired
- 1975-09-30 NO NO753314A patent/NO143459C/no unknown
- 1975-09-30 HU HU75BO1573A patent/HU178469B/hu unknown
- 1975-09-30 PL PL1975183670A patent/PL97003B1/pl unknown
- 1975-10-01 SE SE7511028A patent/SE418497B/xx not_active IP Right Cessation
- 1975-10-01 FR FR7530117A patent/FR2286649A1/fr active Granted
- 1975-10-01 IE IE2150/75A patent/IE42130B1/en unknown
-
1976
- 1976-02-04 ES ES444900A patent/ES444900A1/es not_active Expired
- 1976-02-04 ES ES444898A patent/ES444898A1/es not_active Expired
- 1976-02-04 ES ES444901A patent/ES444901A1/es not_active Expired
-
1980
- 1980-07-01 CH CH506280A patent/CH627452A5/de not_active IP Right Cessation
- 1980-07-01 CH CH506480A patent/CH626352A5/de not_active IP Right Cessation
- 1980-07-01 CH CH506380A patent/CH627453A5/de not_active IP Right Cessation
- 1980-07-01 CH CH506580A patent/CH627454A5/de not_active IP Right Cessation
-
1981
- 1981-09-24 YU YU02302/81A patent/YU230281A/xx unknown
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