NO151239B - Analogifremgangsmaate for fremstilling av terapeutisk aktive 2-fenyliminoimidazolidiner - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive 2-fenyliminoimidazolidiner Download PDFInfo
- Publication number
- NO151239B NO151239B NO790523A NO790523A NO151239B NO 151239 B NO151239 B NO 151239B NO 790523 A NO790523 A NO 790523A NO 790523 A NO790523 A NO 790523A NO 151239 B NO151239 B NO 151239B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- acid addition
- preparation
- addition salts
- phenyliminoimidazolidines
- 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
- 230000001225 therapeutic effect Effects 0.000 title description 4
- 239000002253 acid Substances 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- JCOPITWIWLFFPC-UHFFFAOYSA-N n-phenyl-4,5-dihydro-1h-imidazol-2-amine Chemical class N1CCN=C1NC1=CC=CC=C1 JCOPITWIWLFFPC-UHFFFAOYSA-N 0.000 claims description 6
- -1 3,5-dibromo-4-aminophenyl Chemical group 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000004519 manufacturing process Methods 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
- 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
- 230000036772 blood pressure Effects 0.000 description 3
- 238000006243 chemical reaction Methods 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
- 238000003756 stirring Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 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
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000003585 thioureas Chemical class 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
- 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
- OCBDFIRXBPZHLL-UHFFFAOYSA-N 2,6-dibromo-4-n-(4,5-dihydro-1h-imidazol-2-yl)benzene-1,4-diamine;hydrochloride Chemical compound Cl.C1=C(Br)C(N)=C(Br)C=C1N=C1NCCN1 OCBDFIRXBPZHLL-UHFFFAOYSA-N 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
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VSZCDHNTTVRKGR-UHFFFAOYSA-N C[S+](C(N)=N)C(C=C1Br)=CC(Br)=C1N.I Chemical compound C[S+](C(N)=N)C(C=C1Br)=CC(Br)=C1N.I VSZCDHNTTVRKGR-UHFFFAOYSA-N 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
- 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
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-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
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 235000013832 Valeriana officinalis Nutrition 0.000 description 1
- 244000126014 Valeriana officinalis Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 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
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000001448 anilines Chemical class 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
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000059 bradycardiac effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 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
- BNJBUDJCJPWKRQ-UHFFFAOYSA-H dipotassium;hexaiodoplatinum(2-) Chemical compound [K+].[K+].[I-].[I-].[I-].[I-].[I-].[I-].[Pt+4] BNJBUDJCJPWKRQ-UHFFFAOYSA-H 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- IQXFQTQAXAPESE-UHFFFAOYSA-N imidazolidine;hydrobromide Chemical compound Br.C1CNCN1 IQXFQTQAXAPESE-UHFFFAOYSA-N 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002541 isothioureas Chemical class 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
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 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
- KFGKFKZXRFMBCP-UHFFFAOYSA-N n-(3-bromo-4-fluorophenyl)-4,5-dihydro-1h-imidazol-2-amine;hydrochloride Chemical compound Cl.C1=C(Br)C(F)=CC=C1N=C1NCCN1 KFGKFKZXRFMBCP-UHFFFAOYSA-N 0.000 description 1
- IOUVWAKVDFTALH-UHFFFAOYSA-N n-(4-fluorophenyl)-4,5-dihydro-1h-imidazol-2-amine Chemical compound C1=CC(F)=CC=C1NC1=NCCN1 IOUVWAKVDFTALH-UHFFFAOYSA-N 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
- 239000000049 pigment Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 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
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 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
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000829 suppository Substances 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
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 238000005406 washing Methods 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
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
2-fenylimino-imidazolidiner har på grunn av sine frem-ragende farmakologiske og terapeutiske egenskaper lenge vært gjenstand for stor interesse. Forbindelser av denne type er således beskrevet mange steder i litteraturen, f.eks. i de belgiske patentskrifter 623.305, 653.933, 687.656, 687.657
og 705.944. I disse litteratursteder er også angitt de vesentlige fremgangsmåter for fremstilling av 2-fenylimino-imidazolidiner.
Foreliggende oppfinnelse angår fremstilling av nye substituerte 2-fenylimino-imidazolidiner med den generelle formel
hvor R betyr en 3,5-dibrom-4-aminofenyl- eller 3-brom-4-fluorfenylrest, og syreaddisjonssalter derav, med verdifulle terapeutiske egenskaper.
De nye forbindelser fremstilles i henhold til oppfinnelsen ved følgende fremgangsmåte:
Omsetning av en forbindelse med den generelle formel
hvor R har den ovenfor angitte betydning, og R"*" betyr et hydrogenatom eller en alkylgruppe med opptil 4 karbonatomer,
eller syreaddisjonssalter derav, med etylendiamin eller syreaddisjonssalter derav.
Omsetningen foretas ved temperaturer mellom 0 og 200°C.
Som oppløsningsmidler kan anvendes polare protiske, polare aprotiske eller upolare. Omsetningen kan imidlertid også fore-
tas ved forhøyet temperatur uten anvendelse av oppløsnings-
midler. Reaksjonstiden er avhengig av reaktiviteten av de anvendte komponenter og varierer mellom noen minutter og flere timer.
For fremstilling av utgangsforbindelsene med formel II overføres de tilsvarende aniliner med tiocyanat til tiourinstoffene. Tiourinstoffene kan derefter ved hjelp av alkylerings-midler overføres til isotiouroniumsalter. Fra disse syreaddisjons-forbindelser kan man med baser utvinne de tilsvarende isotio-urinstoffer.
De nye 2-fenylimino-imidazolidiner med den generelle formel I kan på vanlig måte overføres til sine fysiologisk forlikelige syreaddisjonssalter. Syrer som er egnet for salt-dannelse, 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-hydroksybenzoesyre, p-aminobenzoesyre, ftalsyre, kanelsyre, salicylsyre, askorbinsyre, metansulf onsyre , 8-klorteofyHin og lignende.
De nye 2-fenylimino-imidazolidiner med den generelle formel I og deres syreaddisjonssalter har verdifulle terapeutiske egenskaper. De virker sterkt bradykard og er derfor egnet til behandling av coronarlidelser. Innvirkningen på hjertefrekvensen er undersøkt på kaniner og spinalbedøvede katter. Forbindelsene med formel I kan anvendes enteralt eller parenteralt.
Doseringen ligger ved ca. 0,1 til 80 mg, fortrinnsvis 0,5 til 30 mg.
Forbindelsene med formel I og deres syreaddisjonssalter kan anvendes sammen med andre typer aktive stoffer. Egnede galeniske tilberedelsesformer er f.eks. tabletter, kapsler, stikkpiller oppløsninger eller pulvere, og for fremstilling av disse kan man anvende de vanlig anvendte galeniske hjelpestoffer, bæremidler, sprengmidler eller smøremidler eller stoffer som medfører en depotvirkning.
De nedenstående forbindelser ble undersøkt på et statistisk signifikant antall kaniner under uretan-narkose med hensyn til sin blodtrykk- og hjertefrekvens-forandrende virkning.' Blod-trykket ble målt kontinuerlig på Arteria carotis ved hjelp av et kvikksølvmanometer før og efter intravenøs administrering av prøveforbindelsene. På samme måte ble pulsfrekvensen bestemt før og efter administrering av forbindelsene. Følgende verdier ble oppnådd: Teknikkens stand
Sammenligningsforsøkene viser at forbindelsene fremstilt ifølge oppfinnelsen delvis har like sterk hjertefrekvens-reduserende virkning som de kjente forbindelser, men har den fordel at de ikke fører til blodtrykksenkning, og har delvis betydelig sterkere hjertefrekvenssenkende virkning enn de kjente forbindelser.
E ksempel 1
2- ( 4- amino- 3, 5- dibromfenylimino)- imidazolidin- hydroklorid
30,35 g 2-(4-amino-3,5-dibromfenyl)-S-metyl-isotiouronium-hydrojodid (0,065 mol) kokes under tilbakeløpskjøling med 6,5 ml etylendiamin i 65 ml metanol i 10 timer. Derefter avdampes metanolen i vakuum, og det viskøse residuum oppløses i metanol. Oppløsningen filtreres og gjøres alkalisk med 50%ig KOH under tilsetning av is. Herunder utskilles imidazolidin-basen som krystalliserer efter utrøring med eter. Sm.p.: imidazolidin-base
203-205°C. For saltfremstilling oppløses basen i litt CH3OH
og tilsettes eterisk HC1 til kongosur reaksjon, og derefter foretas felning med eter.
Efter isolering får man et utbytte på 3,20 g, svarende til 13,3% av det teoretiske, sm.p.: 234-236°C, Rf-verdi 0,4
i utviklingsmiddel benzen 50, dioksan 40, etanol 5, kons. NH^OH 5. Bærer: silikagel. Farvefremkaller: UV-lys, kaliumjodplatinat.
Eksempel 2
2-( 3- brom- 4- fluor- fenylimino)- imidazolidin- hydroklorid
10,75 g 2-(4-fluor-fenylimino)-imidazolidin-base (0,06 mol) oppløses i 210 ml kloroform, og under god omrøring ved 10°C tilsettes brom dråpevis. Derved utfelles et fast stoff. Efter videre omrøring i 30 minutter ved 10°C foretas avsugning, omhyggelig vasking med eter og tørring. Da det resulterende imidazolidin-hydrobromid, sm.p.: 137-139°C, ennu er forurenset, oppløses det i 1^0, og oppløsningen ekstraheres fraksjonert med eter ved stigende pH-verdier (trinnvis alkalisering med 2N natronlut).
De kromatografisk enhetlige eterekstrakter samles, tørres over MgSO^, filtreres og tilsettes eterisk saltsyre til kongosur reaksjon. Herved utfelles det hvite hydroklorid. Det avsuges, vaskes med eter og tørres. Utbytte: 4,12 g, svarende til 2 3,3%
av det teoretiske. Sm.p.: 182,5°C, Rf-verdi: 0,7 i utviklingsmiddel benzen 50, dioksan 40, konsentrert ammoniakk 5, etanol 5. Bærer: silikagel G med lyspigment ZS.
Farvefremkaller: UV-lys og kaliumplatinat.
Claims (1)
- Analogifremgangsmåte for fremstilling av terapeutisk aktive substituerte 2-fenylimino-imidazolidiner med den generelle formel Ihvor R betyr en 3,5-dibrom-4-aminofenyl- eller 3-brom-4-fluorfenylrest,og syreaddisjonssalter derav, karakterisert ved at a) en forbindelse med den generelle formelhvor R har den ovenfor angitte betydning, og R<1> betyr et hydrogenatom eller en alkylgruppe med opptil 4 karbonatomer, eller syreaddisjonssalter derav, omsettes med etylendiamin eller syreaddisjonssalter derav;og eventuelt overføres den erholdte forbindelse med formel I til et syreaddisjonssalt.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782806775 DE2806775A1 (de) | 1978-02-17 | 1978-02-17 | Neue substituierte 2-phenylimino- imidazolidine deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO790523L NO790523L (no) | 1979-08-20 |
| NO151239B true NO151239B (no) | 1984-11-26 |
| NO151239C NO151239C (no) | 1985-03-06 |
Family
ID=6032231
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO790523A NO151239C (no) | 1978-02-17 | 1979-02-16 | Analogifremgangsmaate for fremstilling av terapeutisk aktive 2-fenyliminoimidazolidiner |
Country Status (32)
| Country | Link |
|---|---|
| US (2) | US4250186A (no) |
| JP (1) | JPS54122273A (no) |
| AT (1) | AT370093B (no) |
| AU (1) | AU519356B2 (no) |
| BE (1) | BE874252A (no) |
| CA (1) | CA1115717A (no) |
| CH (1) | CH640230A5 (no) |
| CS (2) | CS207773B2 (no) |
| DD (1) | DD142048A5 (no) |
| DE (1) | DE2806775A1 (no) |
| DK (1) | DK69479A (no) |
| ES (2) | ES477784A1 (no) |
| FI (1) | FI69301C (no) |
| FR (1) | FR2417502A1 (no) |
| GB (1) | GB2014575B (no) |
| GR (2) | GR67626B (no) |
| HU (1) | HU180430B (no) |
| IE (1) | IE48073B1 (no) |
| IL (1) | IL56678A (no) |
| IT (1) | IT1113469B (no) |
| LU (1) | LU80924A1 (no) |
| NL (1) | NL7901241A (no) |
| NO (1) | NO151239C (no) |
| NZ (1) | NZ189684A (no) |
| PH (1) | PH16188A (no) |
| PL (2) | PL116527B1 (no) |
| PT (1) | PT69239A (no) |
| RO (2) | RO81504B (no) |
| SE (1) | SE7901405L (no) |
| SU (2) | SU812175A3 (no) |
| YU (1) | YU36779A (no) |
| ZA (1) | ZA79709B (no) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2854659A1 (de) * | 1978-12-18 | 1980-07-10 | Boehringer Sohn Ingelheim | Neue 3,4-disubstituierte 2-phenylimino-imidazolidine, deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zu deren herstellung |
| DE3168754D1 (en) * | 1980-07-09 | 1985-03-21 | Beecham Group Plc | Clonidine derivatives useful in the treatment of diarrhoea |
| EP0070084A3 (en) * | 1981-04-24 | 1983-02-16 | Beecham Group Plc | Imidazoline derivatives |
| US4517199A (en) * | 1981-11-20 | 1985-05-14 | Alcon Laboratories, Inc. | Method for lowering intraocular pressure using phenylimino-imidazoles |
| US4515800A (en) * | 1981-11-20 | 1985-05-07 | Icilio Cavero | Method of lowering intraocular pressure using phenylimino-imidazoles |
| US4461904A (en) * | 1981-11-20 | 1984-07-24 | Alcon Laboratories, Inc. | 2-(Trisubstituted phenylimino)-imidazolines |
| CA1201066A (en) * | 1981-11-20 | 1986-02-25 | Alcon Laboratories, Inc. | N-¬3,5-dichloro-4-(2-imidazolidinylideneamino)- phenyl|-acetamide solutions for lowering intraocular pressure |
| US4644007A (en) * | 1981-11-20 | 1987-02-17 | Alcon Laboratories, Inc. | 3-chloro-4-(4,5-dihydro-1H-imidazo-2-yl)-amino-5-alkylbenzoic acids, esters, salts, compositions and methods |
| FR2521140A1 (fr) * | 1982-02-05 | 1983-08-12 | Synthelabo | Derives d'imidazolidine, leur preparation et leur application en therapeutique |
| GB2137191A (en) * | 1983-02-28 | 1984-10-03 | Sumitomo Chemical Co | Fungicidal N-phenylimidates |
| DE19514579A1 (de) * | 1995-04-20 | 1996-10-24 | Boehringer Ingelheim Kg | Verwendung von alpha¶1¶¶L¶-Agonisten zur Behandlung der Harninkontinenz |
| JP2003166617A (ja) | 2001-11-28 | 2003-06-13 | Honda Motor Co Ltd | トルクコンバータ付き内燃機関 |
| JP2007308392A (ja) * | 2006-05-16 | 2007-11-29 | Bayer Cropscience Ag | 殺虫性ベンズアミジン類 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2938038A (en) * | 1960-05-24 | X-dihydroxyphenylamino | ||
| US2899426A (en) * | 1959-08-11 | Synthesis of l | ||
| FR1211341A (fr) * | 1955-12-19 | 1960-03-15 | A Wander Dr | Procédé pour la préparation de 2-amino-imidazolines |
| US3595961A (en) * | 1965-10-01 | 1971-07-27 | Boehringer Sohn Ingelheim | Hypotensive compositions containing 2-(2' - halo-anilino) - 1,3 -diazacyclopentenes-(2) and methods of using the same |
| DE1670274A1 (de) * | 1966-10-31 | 1970-07-16 | Boehringer Sohn Ingelheim | Neues Verfahren zur Herstellung von 2-Arylamino-1,3-diazacycloalkenen-(2) |
| AT285599B (de) * | 1968-06-21 | 1970-11-10 | Boehringer Sohn Ingelheim | Verfahren zur Herstellung von neuen trisubstituierten 2-Arylaminoimidazolinen und ihren Salzen |
| DE2446758C3 (de) * | 1974-10-01 | 1979-01-04 | C.H. Boehringer Sohn, 6507 Ingelheim | 2-(2-Fluor-6-trifluormethylphenylimino)-imidazolidin, dessen Säureadditionssalze, Verfahren zur Herstellung dieser Verbindungen und deren Verwendung bei der Bekämpfung der Hypertonie |
| DE2523103C3 (de) * | 1975-05-24 | 1979-11-29 | C.H. Boehringer Sohn, 6507 Ingelheim | Substituierte 2-[N-Progargyl-N-(2-chlorphenyl)amino] -imidazoline-^), deren Säureadditionssalze, Verfahren zu ihrer Herstellung und deren Verwendung |
| 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 |
-
1978
- 1978-02-17 DE DE19782806775 patent/DE2806775A1/de not_active Withdrawn
-
1979
- 1979-02-09 SU SU792721602A patent/SU812175A3/ru active
- 1979-02-12 AT AT0101579A patent/AT370093B/de not_active IP Right Cessation
- 1979-02-12 GR GR58340A patent/GR67626B/el unknown
- 1979-02-13 RO RO103172A patent/RO81504B/ro unknown
- 1979-02-14 CH CH142879A patent/CH640230A5/de not_active IP Right Cessation
- 1979-02-15 DD DD79211044A patent/DD142048A5/de unknown
- 1979-02-15 HU HU79BO1764A patent/HU180430B/hu unknown
- 1979-02-15 IT IT48010/79A patent/IT1113469B/it active
- 1979-02-15 FI FI790510A patent/FI69301C/fi not_active IP Right Cessation
- 1979-02-15 LU LU80924A patent/LU80924A1/de unknown
- 1979-02-15 YU YU00367/79A patent/YU36779A/xx unknown
- 1979-02-15 IL IL56678A patent/IL56678A/xx unknown
- 1979-02-15 PT PT7969239A patent/PT69239A/pt unknown
- 1979-02-16 GB GB7905506A patent/GB2014575B/en not_active Expired
- 1979-02-16 DK DK69479A patent/DK69479A/da not_active Application Discontinuation
- 1979-02-16 NO NO790523A patent/NO151239C/no unknown
- 1979-02-16 ES ES477784A patent/ES477784A1/es not_active Expired
- 1979-02-16 JP JP1715679A patent/JPS54122273A/ja active Pending
- 1979-02-16 NL NL7901241A patent/NL7901241A/xx not_active Application Discontinuation
- 1979-02-16 ZA ZA79709A patent/ZA79709B/xx unknown
- 1979-02-16 SE SE7901405A patent/SE7901405L/xx not_active Application Discontinuation
- 1979-02-16 IE IE311/79A patent/IE48073B1/en unknown
- 1979-02-16 PL PL1979221508A patent/PL116527B1/pl unknown
- 1979-02-16 FR FR7904052A patent/FR2417502A1/fr active Granted
- 1979-02-16 NZ NZ189684A patent/NZ189684A/xx unknown
- 1979-02-16 US US06/012,650 patent/US4250186A/en not_active Expired - Lifetime
- 1979-02-16 PL PL1979213475A patent/PL115759B1/pl unknown
- 1979-02-16 AU AU44325/79A patent/AU519356B2/en not_active Ceased
- 1979-02-16 CA CA321,805A patent/CA1115717A/en not_active Expired
- 1979-02-16 BE BE0/193531A patent/BE874252A/xx not_active IP Right Cessation
- 1979-02-17 RO RO7996602A patent/RO76799A/ro unknown
- 1979-02-19 CS CS791092A patent/CS207773B2/cs unknown
- 1979-02-19 CS CS798500A patent/CS207774B2/cs unknown
- 1979-06-18 GR GR59371A patent/GR69232B/el unknown
- 1979-10-16 ES ES485043A patent/ES485043A1/es not_active Expired
-
1980
- 1980-01-30 SU SU802874805A patent/SU828964A3/ru active
- 1980-08-20 US US06/179,839 patent/US4293564A/en not_active Expired - Lifetime
- 1980-09-08 PH PH24546A patent/PH16188A/en unknown
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