NO150435B - Analogifremgangsmaate for fremstilling av terapeutisk aktive fenylamino-imidazolin-derivater - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive fenylamino-imidazolin-derivater Download PDFInfo
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- NO150435B NO150435B NO792389A NO792389A NO150435B NO 150435 B NO150435 B NO 150435B NO 792389 A NO792389 A NO 792389A NO 792389 A NO792389 A NO 792389A NO 150435 B NO150435 B NO 150435B
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- Prior art keywords
- general formula
- acid
- compounds
- preparation
- phenylamino
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- 238000002360 preparation method Methods 0.000 title claims description 7
- 238000000034 method Methods 0.000 title claims description 5
- 230000001225 therapeutic effect Effects 0.000 title description 2
- SACAEVOKRBNXPN-UHFFFAOYSA-N n-phenyl-4,5-dihydroimidazol-1-amine Chemical class C1=NCCN1NC1=CC=CC=C1 SACAEVOKRBNXPN-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 claims abstract description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 150000004820 halides Chemical class 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- JCOPITWIWLFFPC-UHFFFAOYSA-N n-phenyl-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1NC1=CC=CC=C1 JCOPITWIWLFFPC-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 230000000059 bradycardiac effect Effects 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract 1
- 230000003000 nontoxic effect Effects 0.000 abstract 1
- 150000003254 radicals Chemical group 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 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
- 239000007858 starting material Substances 0.000 description 3
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-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
- 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
- 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
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000000202 analgesic 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
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012259 ether extract Substances 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
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-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
- 238000003786 synthesis reaction Methods 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
- 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
- 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
- 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
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-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
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 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
- 208000002193 Pain Diseases 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
- 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
- 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
- 239000011230 binding agent Substances 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
- 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
- 229960002896 clonidine Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 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
- 238000001990 intravenous administration 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
- 238000004519 manufacturing process Methods 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
- 206010027599 migraine Diseases 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- LLDKCOYIVPKCTE-UHFFFAOYSA-N n-(2,6-dichlorophenyl)-n-(3-methylbut-3-enyl)-4,5-dihydro-1h-imidazol-2-amine Chemical compound ClC=1C=CC=C(Cl)C=1N(CCC(=C)C)C1=NCCN1 LLDKCOYIVPKCTE-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 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
- 230000009257 reactivity Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 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
- 230000007306 turnover Effects 0.000 description 1
- 229940005605 valeric acid Drugs 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
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Denne oppfinnelse angår fremstilling av nye substituerte 2-fenylamino-imidazolin-(2)-forbindelser med den generelle formel
og deres fysiologisk forlikelige syreaddisjonssalter med verdifulle terapeutiske egenskaper.
I formel I betyr R 1 og R 2, som kan være like eller forskjellige, et hydrogenatom, et kloratom eller en metylgruppe,
1 2
idet R og R ikke samtidig kan være hydrogen.
R betyr resten - (CH2) 2~C (CH-j) =CH2 , - (CH2) 2-CH=CH2 , -0-CH2"CH=CH2 , -0- (CH2) 2~CH=CH2 , -0-CH2-C.(CH3)=CH2 aller -0-CH2-CH=CH-CH3 .
Forbindelsene med formel I fremstilles ved:
a) Omsetning av et 2-fenylimino-imidazolidin med den
generelle formel 1 2
hvor R og R har de ovenfor angitte betydninger, omsettes med et halogenid med den generelle formel
hvor Hal betyr et klor-, brom- eller jodatom, og R har den ovenfor angitte betydning; eller
b) For fremstilling av 2-[N-(substituert fenyl)-N-(substituert metoksyamino]-imidazolin-(2)-forbindelser med den
generelle formel
hvor R 1 og R 2 har den ovenfor angitte betydning, og R' representerer en av restene -CH2-CH=CH2, -CH2-C(CH3)=CH2 , -(CH2)2-CH=CH2 eller -CH2-CH=CH-CH omsettes et 2-[N-(substituert fenyl)-N-hydroksy-amino]-im.idazolin-(2) med den generelle formel 1 2 hvor R og R er som ovenfor angitt, med et halogenid med den generelle formel
hvor Hal og R' har de ovenfor angitte betydninger.
Ved alkyleringen av 2-arylimino-imidazolidinene med formel II ved fremgangsmåte a) skjer substitusjonen utelukkende på bro-nitrogenatomet. Ved omsetningen ifølge fremgangsmåte b)
og c) er konstitusjonen av sluttforbindelsene fastlagt ved syntesen. Substituentenes stilling kan foruten ved syntesen også fastslås ved NMR-spektroskopi (kfr. H. StåhleogK.H. Pook, Liebigs Ann. Chem. 751, 159 ff (1971).
Omsetningen ifølge fremgangsmåte a) og b) skjer hensikts-messig ved oppvarmning av reaksjonskomponentene, fortrinnsvis i nærvær av et polart eller upolart organisk oppløsningsmiddel,
til temperaturer på ca. 50-150°C. De spesielle reaksjons-betingelser er i sterk grad avhengig av reaktiviteten av reaksjonskomponentene. Det anbefales å anvende halogenidet i overskudd ved alkyleringen, og utføre omsetningen i nærvær av et syrebindende middel.
Utgangsforbindelsen med formel II er f.eks. beskrevet
i de belgiske patenter 623.305, 687.657 og 705.944.
Utgangsforbindelser med formlene III og VII kan fremstilles ved halogenering av de tilsvarende primære alkoholer.
Utgangsforbindelsene med formel VI får man ved oksydasjon av forbindelser med den generelle formel II med persyrer i henhold til tysk off.skrift 2.457.979.
De nye 2-fenylamino-imidazolin-(2)-forbindelser 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-amino-benzoesyre, ftalsyre, kanelsyre, salicylsyré, askorbinsyre, metansulfonsyre, 8-klorteofyllin o.l.
De nye forbindelser og deres syreaddisjonssalter har verdifulle analgetiske egenskaper og kan derfor anvendes ved behandling av forskjellige typer av smertetilstander, f.eks. migrene.. Den smertestillende virkning av de nye forbindelser ble undersøkt på mus ved vridningsprøven (Blumberg, Wolf og Dayton, Proe. soc. Exp. Biol. Med. 118, (1965) 763) og varmeplate-prøven (Woolfe og MacDonald, J. Pharmacol. Exp. Ther. 80 (1944) 300), og det viste seg da at de nye 2-fenylamino-imidazoliner har opptil 100 ganger så sterk virkning som morfin. I forhold til de N-allyl-2-fenylamino-imidazolin- (2)-forbindelser som er beskrevet
i tysk off.skrift 1.958.201, oppnås likeledes en virkningsøkning på det 100-dobbelte for de nye forbindelser.
De nye forbindelser med den generelle formel I, særlig slike som bærer en cyklopropylmety1- eller cyklobutylmetylgruppe,
og deres syreaddisjonssalter, virker dessuten meget sterkt bradykard og er derfor egnet til behandling av coronarlidelser. Innvirkningen på hjertefrekvensen ble undersøkt på kaniner og
på spinalbedøvede rotter såvel som intakte, narkotiserte rotter. Doseringen ligger ved 0,1 til 80 mg, fortrinnsvis 1 til 30 mg.
Forbindelsene med formel I og deres syreaddisjonssalter
kan også anvendes sammen med andre aktive stoffer. Egnede galeniske tilberedelsesformer er f.eks. tabletter, kapsler, stikkpiller, oppløsninger eller pulvere. For fremstilling av
slike preparater kan man anvende de vanlig anvendte galeniske hjelpestoffer, bæremidler, sprengmidler eller smøremidler eller stoffer som medfører en depot<y>irkning.
Farmakologiske sammenligningsforsøk
For de nedenfor angitte forbindelser fant man frem til den' dose som på spinalbedøvede rotter (5 dyr pr. forbindelse) senker hjertefrekvensen med 150 slag pr. minutt (D 150) ved kumulativ intravenøs administrering.
De følgende eksempler skal tjene til å illustrer opp-finnelsen ytterligere:
Eksempel 1 2-[ N-( 2, 6- diklorfenyl)- N-( 2- metyl- l- buten- 4- yl)- amino]- 2- imidazolin
6,9 g (0,03 mol) klonidin oppvarmes sammen med 5,6 g 4-brom-2-metyl-buten-(1) og 5 ml trietylamin i 25 ml toluen i 24 timer i et rør til 120°C. Efter avkjøling avdekanteres oppløsningsmidlet, og det gjenværende residuum oppløses i IN saltsyre. Efter flere gangers utetring (eterekstraktene kastes) ekstraheres fraksjonert med eter ved stigende pH-verdier (alkalisering med 2N natronlut). De tynnskiktkromatografisk enhetlige eterekstrakter samles, tørres over MgSO^, og eteren avdrives i vakuum. Utbytte 1,8 g (19,6% av det teoretiske), smeltepunkt: 117-119°C.
Analogt med det foregående eksempel ble de følgende forbindelser fremstilt. Smeltepunktene gjelder for basene med formel I med mindre saltformen er angitt.
Claims (1)
- Analogifremgangsmåte for fremstilling av terapeutisk aktive substituerte 2-fenylamino-imidazolin-(2)-forbindelser med den generelle formelhvor R 1 og R 2, som kan være like eller forskjellige, betyr et hydrogenatom, et kloratom eller en metylgruppe, idet R 1 og R<2 >ikke samtidig kan være hydrogen, og R betyr resten - (CH2)2-C(CH3)=CH2, - (CH2)2-CH=CH2, -0-CH2-CH=CH2, -0- (CH2)2~CH=CH2, -0-CH2-C (CH3) =CH,, eller -0-CH2-CH=CH-CH3og syreaddisjonssalter derav, karakterisert ved at a) et 2-fenyliminoimidazolidin med den generelle formelhvor R 1 og R 2 har de ovenfor angitte betydninger, omsettes med et halogenid med den generelle formelhvor Hal betyr et klor-, brom- eller jodatom, og R har den ovenfor angitte betydning, eller b) for fremstilling av 2-[N-(substituert fenyl)-N-(substituert metoksy-amino]-imidazolin-(2)-forbindelser med den generelle formelhvor R 1 og R 2 har den ovenfor anqitte betydning, og R' betyr -CH2-CH=CH2, -CH2-C (CH3)=CH2, - (CH2)2~CH=CH2 eller -CH2~CH=CH-CH3, omsettes et 2-[N-(substituert fenyl)-N-hydroksy-amino]-imidazolin-(2) med den generelle formelhvor R 1 og R 2 er som ovenfor angitt, med et halogenid med den generelle formelhvor Hal og R' har de ovenfor angitte betydninger,og en forbindelse fremstilt som ovenfor angitt, overføres eventuelt til et syreaddisjonssalt derav.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782831671 DE2831671A1 (de) | 1978-07-19 | 1978-07-19 | Neue substituierte 2-phenylamino-imidazoline-(2), deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO792389L NO792389L (no) | 1980-01-22 |
| NO150435B true NO150435B (no) | 1984-07-09 |
| NO150435C NO150435C (no) | 1984-10-17 |
Family
ID=6044762
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO792389A NO150435C (no) | 1978-07-19 | 1979-07-18 | Analogifremgangsmaate for fremstilling av terapeutisk aktive fenylamino-imidazolin-derivater |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4277487A (no) |
| EP (1) | EP0007438B1 (no) |
| JP (1) | JPS5515466A (no) |
| AT (1) | ATE1503T1 (no) |
| AU (1) | AU524192B2 (no) |
| CA (1) | CA1121824A (no) |
| DE (2) | DE2831671A1 (no) |
| DK (1) | DK146939C (no) |
| ES (1) | ES482581A1 (no) |
| FI (1) | FI69067C (no) |
| GR (1) | GR69931B (no) |
| IE (1) | IE48452B1 (no) |
| IL (1) | IL57834A (no) |
| NO (1) | NO150435C (no) |
| NZ (1) | NZ191052A (no) |
| PT (1) | PT69934A (no) |
| ZA (1) | ZA793636B (no) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2947563A1 (de) * | 1979-11-26 | 1981-06-04 | C.H. Boehringer Sohn, 6507 Ingelheim | Neue substituierte 2-phenylamino-imidazoline-(2), deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
| DE2950345A1 (de) * | 1979-12-14 | 1981-07-02 | C.H. Boehringer Sohn, 6507 Ingelheim | Neue substituierte 2-phenylaminoimidazoline-(2), deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
| FR2499991A1 (fr) * | 1981-02-19 | 1982-08-20 | Sandoz Sa | Nouveaux 2,1,3-benzothiadiazoles et 2,1,3-benzoxadiazoles, leur preparation et leur application comme medicaments |
| US4393077A (en) * | 1981-07-02 | 1983-07-12 | William H. Rorer, Inc. | 1-Methylene-1-phenylguanidine compounds |
| IT1211138B (it) * | 1981-12-01 | 1989-09-29 | Ausonia Farma Srl | Composto antiipertensivo procedimento per la sua preparazione e relative composizioni farmaceutiche. |
| DE3514351A1 (de) * | 1985-04-20 | 1986-11-06 | Boehringer Ingelheim KG, 6507 Ingelheim | Neue substituierte 2-(n-alkinyl-n-phenyl)amino)-imidazolinderivate, deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zu deren herstellung |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE759125A (fr) * | 1969-11-19 | 1971-05-18 | Boehringer Sohn Ingelheim | Nouvelles n-allyl-2-arylamino-imidazolines-(2) substituees et procedes pour les fabriquer |
| DE2102733A1 (en) * | 1971-01-21 | 1972-08-03 | CH. Boehringer Sohn, 6507 Ingelheim | 2-arylamino-2-imidazolines |
| US3850926A (en) * | 1971-01-21 | 1974-11-26 | Boehringer Sohn Ingelheim | 2-(n-substituted-phenylamino)-imidazolines-(2) |
| DD95843A5 (no) * | 1971-01-21 | 1973-02-20 |
-
1978
- 1978-07-19 DE DE19782831671 patent/DE2831671A1/de not_active Withdrawn
-
1979
- 1979-06-21 DE DE7979102052T patent/DE2963605D1/de not_active Expired
- 1979-06-21 EP EP79102052A patent/EP0007438B1/de not_active Expired
- 1979-06-21 AT AT79102052T patent/ATE1503T1/de not_active IP Right Cessation
- 1979-07-09 JP JP8600679A patent/JPS5515466A/ja active Pending
- 1979-07-13 GR GR59597A patent/GR69931B/el unknown
- 1979-07-17 US US06/058,165 patent/US4277487A/en not_active Expired - Lifetime
- 1979-07-18 DK DK302679A patent/DK146939C/da not_active IP Right Cessation
- 1979-07-18 NO NO792389A patent/NO150435C/no unknown
- 1979-07-18 IL IL57834A patent/IL57834A/xx unknown
- 1979-07-18 ZA ZA00793636A patent/ZA793636B/xx unknown
- 1979-07-18 FI FI792251A patent/FI69067C/fi not_active IP Right Cessation
- 1979-07-18 PT PT69934A patent/PT69934A/pt unknown
- 1979-07-18 CA CA000332040A patent/CA1121824A/en not_active Expired
- 1979-07-18 NZ NZ191052A patent/NZ191052A/xx unknown
- 1979-07-18 ES ES482581A patent/ES482581A1/es not_active Expired
- 1979-07-18 AU AU49022/79A patent/AU524192B2/en not_active Ceased
- 1979-08-08 IE IE1356/79A patent/IE48452B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5515466A (en) | 1980-02-02 |
| ES482581A1 (es) | 1980-04-01 |
| IE791356L (en) | 1980-01-19 |
| NO150435C (no) | 1984-10-17 |
| PT69934A (de) | 1979-08-01 |
| IL57834A0 (en) | 1979-11-30 |
| AU524192B2 (en) | 1982-09-02 |
| DK146939C (da) | 1984-07-30 |
| GR69931B (no) | 1982-07-21 |
| US4277487A (en) | 1981-07-07 |
| EP0007438A1 (de) | 1980-02-06 |
| NO792389L (no) | 1980-01-22 |
| DE2831671A1 (de) | 1980-02-07 |
| DK146939B (da) | 1984-02-20 |
| AU4902279A (en) | 1980-01-24 |
| CA1121824A (en) | 1982-04-13 |
| FI69067B (fi) | 1985-08-30 |
| IL57834A (en) | 1983-03-31 |
| FI792251A7 (fi) | 1980-01-20 |
| DK302679A (da) | 1980-01-20 |
| FI69067C (fi) | 1985-12-10 |
| NZ191052A (en) | 1981-02-11 |
| DE2963605D1 (en) | 1982-10-28 |
| ZA793636B (en) | 1981-03-25 |
| ATE1503T1 (de) | 1982-09-15 |
| EP0007438B1 (de) | 1982-09-01 |
| IE48452B1 (en) | 1985-01-23 |
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