NO122530B - - Google Patents
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- Publication number
- NO122530B NO122530B NO60868A NO60868A NO122530B NO 122530 B NO122530 B NO 122530B NO 60868 A NO60868 A NO 60868A NO 60868 A NO60868 A NO 60868A NO 122530 B NO122530 B NO 122530B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- ethylenediamine
- lower alkyl
- residue
- ammonia
- Prior art date
Links
- 239000002253 acid Substances 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 25
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 18
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 18
- 150000002462 imidazolines Chemical class 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 229940083254 peripheral vasodilators imidazoline derivative Drugs 0.000 claims description 10
- 229910021529 ammonia Inorganic materials 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- -1 alkyl radical Chemical class 0.000 description 15
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- 238000009835 boiling 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
- 150000002148 esters Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 239000005526 vasoconstrictor agent Substances 0.000 description 3
- MBVIMYRMRHPFKN-UHFFFAOYSA-N 2-phenoxypropanenitrile Chemical compound N#CC(C)OC1=CC=CC=C1 MBVIMYRMRHPFKN-UHFFFAOYSA-N 0.000 description 2
- UFQDKRWQSFLPQY-UHFFFAOYSA-N 4,5-dihydro-1h-imidazol-3-ium;chloride Chemical compound Cl.C1CN=CN1 UFQDKRWQSFLPQY-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
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-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
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000000739 antihistaminic agent Substances 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
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000002048 spasmolytic effect Effects 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- DWWHMKBNNNZGHF-UHFFFAOYSA-N 2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1h-imidazole;hydron;chloride Chemical compound Cl.N=1CCNC=1C(C)OC1=C(Cl)C=CC=C1Cl DWWHMKBNNNZGHF-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-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
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000004133 Sodium thiosulphate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 206010062119 Sympathomimetic effect Diseases 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
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 230000036772 blood pressure 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
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 229960001867 guaiacol Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000003589 local anesthetic agent 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
- 238000004519 manufacturing process Methods 0.000 description 1
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 150000007519 polyprotic acids Polymers 0.000 description 1
- 239000002244 precipitate Substances 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
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000002227 vasoactive effect Effects 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
- C07D233/20—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 substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D233/22—Radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Analogifremgangsmåte til fremstilling av nye, terapeutisk aktive imidazolinderivater og deres syreaddisjonssalter. Analogy process for the preparation of new, therapeutically active imidazoline derivatives and their acid addition salts.
Man kjenner en rekke imidazolin-derivater som i 2-stilling er substituert med aryloksy-alkylgrupper med uforgrenet al-kylgruppe. Disse forbindelser utmerker seg ved overveiende vasokonstriktoriske, spasmolytiske og antihistamin-virkninger. A number of imidazoline derivatives are known which are substituted in the 2-position with aryloxyalkyl groups with an unbranched alkyl group. These compounds are distinguished by predominantly vasoconstrictor, spasmolytic and antihistamine effects.
Oppfinnelsen vedrører nå én analogifremgangsmåte til fremstilling av nye aryloksy-isoalkyl-imidazoliner med den generelle formel I The invention now relates to one analogous process for the preparation of new aryloxy-isoalkyl-imidazolines with the general formula I
hvori Ar betyr en eventuelt med en metylendioksyrest en eller flere lavere alkyl- og/eller lavere alkenyl- og/eller lavere alkoksyrester, en eller flere trifluormetylgrupper og/eller en eller flere halogenatomer substituert fenylrest, R-^ betyr en lavere alkylrest med 1 til 4 C-atomer og R^ betyr hydrogen eller en lavere alkylrest med 1 til 4 G-atomer, samt deres syreaddisjonssalter. Disse forbindelser utmerker seg ved nye farmakologiske egenskaper som ikke var å forutse. Forbindelsen ifølge oppfinnelsen vil finne anvendelse som farma-søyt ika. in which Ar means a phenyl residue optionally substituted with a methylenediioic acid residue, one or more lower alkyl and/or lower alkenyl and/or lower alkoxy acid residues, one or more trifluoromethyl groups and/or one or more halogen atoms, R-^ means a lower alkyl residue with 1 to 4 C atoms and R 1 means hydrogen or a lower alkyl radical with 1 to 4 G atoms, as well as their acid addition salts. These compounds are distinguished by new pharmacological properties that were not foreseen. The compound according to the invention will find use as a pharmaceutical.
På grunn av deres gode egenskaper foretrekkes de forbindelser med generell formel I hvor betegner hydrogen og n fortrinnsvis er 0. Due to their good properties, the compounds of general formula I where denotes hydrogen and n is preferably 0 are preferred.
Videre på grunn av. deres gode egenskaper er slike forbindelser foretrukket hvor Ar betegner en fenylrest som er substituert med en eller flere lavalkyl- og/eller lavalkoksy-rester, en eller flere trifluormetyl-grupper og/eller en eller flere halogenatomer, fortrinnsvis kloratomer, R^ betegner en lavalkylrest med en til fire karbonatomer og R^ betegner hydrogen eller en lavalkylrest med en til fire karbonatomer. Furthermore, because of. their good properties, such compounds are preferred where Ar denotes a phenyl radical which is substituted by one or more lower alkyl and/or lower alkoxy radicals, one or more trifluoromethyl groups and/or one or more halogen atoms, preferably chlorine atoms, R^ denotes a lower alkyl radical with one to four carbon atoms and R^ denotes hydrogen or a lower alkyl radical with one to four carbon atoms.
Ganske spesielt foretrukket er nye forbindelser med ' den generelle formel I, hvor Ar betegner en fenylrest som er substituert med en lavalkyl-, lavalkoksy- og/eller trifluormetylrest og/eller et halogenatom, fortrinnsvis et klortaom, R^ betegner en lavalkylrest med en til fire karbonatomer, R^ betegner hydrogen eller en lavalkylrest med en til fire karbonatomer, n betegner 0 og R^ er hydrogen. Quite particularly preferred are new compounds of the general formula I, where Ar denotes a phenyl radical which is substituted by a lower alkyl, lower alkoxy and/or trifluoromethyl radical and/or a halogen atom, preferably a chlorine atom, R^ denotes a lower alkyl radical with one more four carbon atoms, R₂ denotes hydrogen or a lower alkyl radical with one to four carbon atoms, n denotes 0 and R₂ is hydrogen.
Fremgangsmåten til fremstilling av de nye forbindelser og deres syreaddisjonssalter, særlig salter med fysiologisk godtagbare syrer, karakterisert ved at man omsetter en aryloksy-karboksylsyre med den generelle formel The process for the preparation of the new compounds and their acid addition salts, in particular salts with physiologically acceptable acids, characterized by reacting an aryloxycarboxylic acid with the general formula
hvori Ar, R-^ og R,-, har samme betydning som ovenfor, eller et funksjon-elt derivat herav med etylendiamin eller med et raaktivt N-derivat av etylendiamin eller med ammoniakk eller en ammoniakkavgivende forbindelse og en forbindelse som ved omsetning med ammoniakk er overførbar in which Ar, R-^ and R,-, have the same meaning as above, or a functional derivative thereof with ethylenediamine or with a reactive N-derivative of ethylenediamine or with ammonia or an ammonia-releasing compound and a compound which by reaction with ammonia is transferable
i etylendiamin under direkte eller trinnvis dannelse av imidazolin-derivater med formel I. in ethylenediamine during direct or stepwise formation of imidazoline derivatives of formula I.
Som funksjonelle syrederivater kan man f.eks. bruke estere, ortoestere, syrehalogenider, fortrinnsvis syreklorider, amider, -tioamider, amidiner, imidsyreestere, tioimidsyreestere, iminohalogen-ider eller nitriler av de tilsvarende aryloksy-isoalkylkarbonsyrer. Herved kan man også velge reaksjonsbetingelsene slik at de funksjonelle syrederivater først dannes under reaksjonen. As functional acid derivatives, one can e.g. use esters, orthoesters, acid halides, preferably acid chlorides, amides, -thioamides, amidines, imidic acid esters, thioimidic acid esters, iminohalides or nitriles of the corresponding aryloxy-isoalkylcarboxylic acids. Hereby, the reaction conditions can also be chosen so that the functional acid derivatives are first formed during the reaction.
Ved siden av etylendiaminet selv kan man også bruke N-derivater av etylendiamin. Dette er spesielt etylendiamin-derivater som ved omsetning med karbonsyrer eller disses funksjonelle derivater gir imidazoliner. Forbindelser av denne type er f.eks. N-acyletylen-diamin, N, N'-diacyletylendiamin eller etylenurea. In addition to ethylenediamine itself, N-derivatives of ethylenediamine can also be used. These are especially ethylenediamine derivatives which, when reacted with carboxylic acids or their functional derivatives, give imidazolines. Connections of this type are e.g. N-acylethylenediamine, N,N'-diacylethylenediamine or ethylene urea.
Forbindelser som kan overføres til etylendiamin med ammoniakk, eller til N-mono-substituerte etylendiaminer ved behandling med aminer med formel R^NHg, er f.eks. amnoetanol og dennes estere, (3-halogenetylaminer, som p-kloretylaminer, etylendihalogenider, som 1,2-dikloretan eller etylenklorhydrin. Etylendiamin eller dennes derivater kan enten brukes som frie baser eller i form av mono- eller di-salter i en støkiometrisk mengde på 0,8 til 1,2. F.eks. kan man bruke etylendiamin som mono-p-toluensulfonsurt salt. Compounds which can be transferred to ethylenediamine with ammonia, or to N-mono-substituted ethylenediamines by treatment with amines of the formula R^NHg, are e.g. amnoethanol and its esters, (3-halogenethylamines, such as p-chloroethylamines, ethylene dihalides, such as 1,2-dichloroethane or ethylene chlorohydrin. Ethylenediamine or its derivatives can be used either as free bases or in the form of mono- or di-salts in a stoichiometric amount of 0.8 to 1.2 For example, ethylenediamine can be used as mono-p-toluenesulfonic acid salt.
Hvis man som utgangsstoff bruker nitrilet av den tilsvarende aryloksy-isoalkyl-karbonsyre og omsetter denne med etylendiamin eller et -derivat, er det en fordel å utføre omsetningen i nærvær av hydrogensulfid henholdsvis hydrogensulfidavgivende midler som f.eks. karbondisulfid. If one uses the nitrile of the corresponding aryloxy-isoalkyl-carboxylic acid as starting material and reacts this with ethylenediamine or a derivative, it is advantageous to carry out the reaction in the presence of hydrogen sulphide or hydrogen sulphide releasing agents such as e.g. carbon disulfide.
De nevnte omsetninger og reaksjoner kan føre til imidazolin-derivater med formel I direkte eller trinnvis. Således kan det f.eks. som mellomprodukt dannes en forbindelse med formel IV The aforementioned conversions and reactions can lead to imidazoline derivatives of formula I directly or stepwise. Thus, it can e.g. as an intermediate, a compound of formula IV is formed
hvor X-L = 0H, SH eller NH^ og Y-^ = H eller acyl. Fra forbindelser av denne type, henholdsvis fra dennes tautomere former, kan substituent-ene X-^ og Y-j^ avspaltes som X-^ på forøvrig kjente måter. F.eks. kan man fra en forbindelse med formel IV hvor X-^ = 0H og Y-^ = H avs palt e where X-L = OH, SH or NH^ and Y-^ = H or acyl. From compounds of this type, respectively from its tautomeric forms, the substituents X-^ and Y-j^ can be split off as X-^ in otherwise known ways. E.g. can be obtained from a compound of formula IV where X-^ = 0H and Y-^ = H avs palt e
vann under anvendelse av kalsiumoksyd som dehydratiseringsmiddel. Herved får man i godt utbytte det tilsvarende imidazolin-derivat med formel I. water using calcium oxide as dehydrating agent. In this way, the corresponding imidazoline derivative of formula I is obtained in good yield.
Som mellomprodukt kan man videre danne en forbindelse med formel V As an intermediate, a compound of formula V can further be formed
hvor Yp angir en rest som kan substitueres med en amino-gruppe. Ut fra en slik forbindelse eller dennes tautomere forbindelse kan man avspalte gruppen Y^ i form av HY,, under dannelse av imidazolinringen. Mellomprodukter av denne type er relativt ustabile forbindelser som allerede ved koking i et egnet inert oppløsningsmiddel går over i den ønskede imidazolinforbindelse med formel I under avspaltning av HY^. Særlig glatt forløper avspaltningsæaksjonen når Y^ = halogen. Omset-ningene skjer også med godt utbytte når Y^ = OH og det arbeides under vanntUtrekkende omgivelser. Som andre mellomprodukter ved den trinnvise dannelse av imidazolin-derivater av formel I skal nevnes forbindelser med formel VI where Yp denotes a residue that can be substituted with an amino group. From such a compound or its tautomeric compound, the group Y^ can be cleaved in the form of HY, while forming the imidazoline ring. Intermediate products of this type are relatively unstable compounds which, already upon boiling in a suitable inert solvent, turn into the desired imidazoline compound of formula I during cleavage of HY^. The cleavage reaction proceeds particularly smoothly when Y^ = halogen. The conversions also occur with good yield when Y^ = OH and work is carried out under water-extracting environments. As other intermediates in the stepwise formation of imidazoline derivatives of formula I, compounds of formula VI should be mentioned
hvori Y^ og Y^ er like eller forskjellige og betyr en rest som kan wherein Y^ and Y^ are the same or different and mean a residue which can
substitueres med en amino-gruppe, f.eks. halogen. Når man behandler en forbindelse av denne type eller en tautomer form av forbindelsen med ammoniakk eller ammoniakkavgivende midler, eventuelt aminer med den generelle formel R^NHg, får man imidazolin-derivater med formel I. Omsetningen forløper særlig glatt når Y^ og Y^ betegner halogen, særlig klor. is substituted with an amino group, e.g. halogen. When a compound of this type or a tautomeric form of the compound is treated with ammonia or ammonia-releasing agents, possibly amines of the general formula R^NHg, imidazoline derivatives of formula I are obtained. The reaction proceeds particularly smoothly when Y^ and Y^ represent halogen, especially chlorine.
Man får de nye imidaaolin-derivater som frie baser eller i form av syreaddisjonssalter• Fra de frie baser kan man ved .behandling med syrer fremstille de forskjellige syreaddisjonssalter etter vanlige metoder. For fremstilling av slike salter anvendes syrer som gir fysiologisk godtagbare syreaddisjonssalter, som f.eks. hydrogenhalogenidsyrer, s/ovelsyre, ortofosforsyre, alkankarbonsyrer som eddiksyre eller propionsyre, flerbasiske syrer som f.eks. oksal-syre, vinsyre, ravsyre, maleinsyre, askorbinsyre eller sitronsyre, sulfonsyrer som metansulfonsyre, etansulfonsyre, benzensulfonsyre eller p-toluensylfonsyre, aromatiske karbonsyrer som benzoayre, sali-cylsyre eller p-aminosalicylsyre. The new imidaaolin derivatives are obtained as free bases or in the form of acid addition salts• From the free bases, by treatment with acids, the various acid addition salts can be prepared by usual methods. For the production of such salts, acids are used which give physiologically acceptable acid addition salts, such as e.g. hydrogen halide acids, sulfuric acid, orthophosphoric acid, alkanecarboxylic acids such as acetic acid or propionic acid, polybasic acids such as e.g. oxalic acid, tartaric acid, succinic acid, maleic acid, ascorbic acid or citric acid, sulphonic acids such as methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or p-toluenesulphonic acid, aromatic carboxylic acids such as benzoic acid, salicylic acid or p-aminosalicylic acid.
Be fremstilte imidazolin-derivater'ifølge oppfinnelsen samt deres syreaddisjonssalter lar seg forarbeide til alle farmasøytiske former, eventuelt under anvendelse av de vanlige hjelpestoffer. The imidazoline derivatives produced according to the invention as well as their acid addition salts can be processed into all pharmaceutical forms, possibly using the usual excipients.
De nye imidazolin-derivater har bland annet ved siden av denne stoffgruppes kjente egenskaper som antihistaminika og spas-molytika, lokalanestetiske og sympatomimetiske virkninger med spesi-fikk hjertevirkning. Spesielt er forbindelsene vasoaktive og lar seg anvende dels som antihypertonika, dels som vasokonstriktorer i form av nesedråper eller nesespray. De følgende eksempler skal belyse fremstillingen av de nye forbindelser med formel I: The new imidazoline derivatives have, among other things, alongside the well-known properties of this substance group such as antihistamines and spasmolytics, local anesthetic and sympathomimetic effects with specific cardiac effects. In particular, the compounds are vasoactive and can be used partly as antihypertensives, partly as vasoconstrictors in the form of nasal drops or nasal sprays. The following examples will illustrate the preparation of the new compounds of formula I:
Eksempel 1: Example 1:
a) oc- f enoksypropionitril a) oc-f enoxypropionitrile
19 g fenol, 26 g vannfritt finpiverisert kaliumkarbonat 19 g phenol, 26 g anhydrous finely divided potassium carbonate
°g 0»5 g kaliumjodid tilsettes 100 ml tørretylmetylketon. I løpet av 11/2 time tildryppes en oppløsning av 29,5 6 a-brompropionitril i 20 ml absolutt etylmetylketon til den kraftig omrørte suspensjon som °g 0»5 g of potassium iodide is added to 100 ml of dry ethyl methyl ketone. In the course of 11/2 hours, a solution of 29.5 6 a-bromopropionitrile in 20 ml of absolute ethyl methyl ketone is added dropwise to the vigorously stirred suspension which
kokes under tilbakeløp. Etter ferdig tilsetning oppvarmes ennå en time ved tilbakeløp, etter avkjøling frafiltreres uoppløselig stoff, residuet vaskes med etylmetylketon og filtratet inndampes i vakuum. Den oljeaktige rest tilsettes eter, den eteriske oppløsning vaskes for å fjerne overskytende fenol tre ganger med hver gang 50 ml 10%-ig natronlut og derpå for å fjerne jod med 50 ml 5$-ig natrumtiosulfatopp-løsning, og deretter med vann til nøytral reaksjon, og stoffet tørkes over vannfritt natriumsulfat. Etter avdampning av oppløsningsmiddel gav fraksjonering av den gjenværende olje i høyvakuum 21 g a-fenoksypropionitril . boil under reflux. After the addition is complete, it is heated for another hour at reflux, after cooling, insoluble material is filtered off, the residue is washed with ethyl methyl ketone and the filtrate is evaporated in vacuo. The oily residue is added to ether, the ethereal solution is washed to remove excess phenol three times with each time 50 ml of 10% caustic soda and then to remove iodine with 50 ml of 5% sodium thiosulphate solution, and then with water until neutral reaction, and the substance is dried over anhydrous sodium sulfate. After evaporation of solvent, fractionation of the remaining oil in high vacuum gave 21 g of α-phenoxypropionitrile.
Utbytte: 71»5% av teoretisk. Yield: 71»5% of theoretical.
Farveløs væske med KpQ Q1: <5>0-53°C, n|5 : 1,5052. Colorless liquid with KpQ Q1: <5>0-53°C, n|5 : 1.5052.
Analyseverdier: CgHgNO (147,2). Analytical values: CgHgNO (147.2).
Beregnet: C 73,45 H 6,l6 N 9,52. Calculated: C 73.45 H 6.16 N 9.52.
Funnet : C 73,35 H 6,32 N 9,68. Found : C 73.35 H 6.32 N 9.68.
b) a-( fenoksy)- propioimidsyreetylester- hydroklorid b) a-(phenoxy)- propioimidic acid ethyl ester hydrochloride
44 g a-fenoksypropionitril tilsettes 11,5 ml absolutt 44 g of α-phenoxypropionitrile is added to 11.5 ml absolute
etanol, samt 100 ml kloroform tørket over fosforpentoksyd, og man innleder langsomt under omrøring og avkjøling med is/koksalt 11,5 g omhyggelig tørket hydrogenklorid. Deretter avdestilleres kloroformen og overskytende hydrogenklorid i vakuum ved værelsestemperatur, idet alt vesentlige, og residuet tilsettes tørr eter inntil man oppnår full-stendig kvantitativ felling av imidsyreester-hydrokloridet. Ved gjentatt oppløsning i liten mengde absolutt etanol uten oppvarming og utfelling med eter, kan a-(fenoksy)-propionimidsyreetylester-hydrokloridet fremstilles i form av hvite, sterkt hygroskopiske krystaller, ethanol, as well as 100 ml of chloroform dried over phosphorus pentoxide, and 11.5 g of carefully dried hydrogen chloride are introduced slowly while stirring and cooling with ice/common salt. The chloroform and excess hydrogen chloride are then distilled off in a vacuum at room temperature, all essential, and the residue is added to dry ether until complete quantitative precipitation of the imidic acid ester hydrochloride is achieved. By repeated dissolution in a small amount of absolute ethanol without heating and precipitation with ether, the α-(phenoxy)-propionimidic acid ethyl ester hydrochloride can be prepared in the form of white, strongly hygroscopic crystals,
og meget rent. and very clean.
Smeltepunkt: 83-85°C. Melting point: 83-85°C.
Utbytte: 60 g (87,5$ av teoretisk). Yield: 60 g ($87.5 of theoretical).
Analyseverdier: ^H-^CINO,, (229,7). Analytical values: ^H-^CINO,, (229.7).
Beregnet: N 6,10 Gl 15,44. Calculated: N 6.10 Gl 15.44.
Funnet : N 6,47 Cl 15,44. Found : N 6.47 Cl 15.44.
Råproduktet a-(fenoksy)-propioimidsyreetylester-hydrokloridet er også uten ovenstående utfelling med eter rent nok for videre omsetning. The crude product α-(phenoxy)-propioimidic acid ethyl ester hydrochloride is also without the above precipitation with ether pure enough for further reaction.
c) 2-/a-(fenoksy)-etyl7-Z^ -imidazolin-hydroklorid c) 2-[α-(phenoxy)-ethyl 7-Z 2 -imidazoline hydrochloride
23 g a-(fenoksy)-propionimidsyreetylester-hydroklorid tilsettes por-sjonsvis til en omrørt og isavkjølt oppløsning av 6 g vannfritt etylendiamin i 90 ml absolutt etanol, så langsomt at temperaturen ikke overstiger 0 til 5°G• Deretter fjernes kjølebadet og reaksjonsblandingen oppvarmes i løpet av en time på vannbad til ca. 70°C' Etter fornyet avkjøling blir uomsatt etylendiamin nøytralisert i en kulde-blanding med absolutt etanolisk saltsyre, deretter frafiltreres etan-oluoppløselige bestanddeler og ca. 2/3 av oppløsningemidlet avdampes i vannstrålevakuum. Ved forsiktig tilsetning av etylmetylketon felles den resterende mengde etylendiamindihydroklorid fraksjonert ut, og deretter utskilles imidazolin-hydrokloridet ved tilsetning av tørr eter. Etter omkrystallisering fra en liten mengde etylmetylketon får man produktet 2-/oe-(fenoksy)-etyl/-A -imidazolin-hydroklorid i form av små hvite nåler med smeltepunkt 144,5 - 146°C. 23 g of a-(phenoxy)-propionimidic acid ethyl ester hydrochloride is added in portions to a stirred and ice-cooled solution of 6 g of anhydrous ethylenediamine in 90 ml of absolute ethanol, so slowly that the temperature does not exceed 0 to 5°G • The cooling bath is then removed and the reaction mixture is heated within an hour in a water bath for approx. 70°C' After renewed cooling, unreacted ethylenediamine is neutralized in a cold mixture with absolute ethanolic hydrochloric acid, then ethanol-soluble components are filtered off and approx. 2/3 of the solvent is evaporated in a water jet vacuum. By careful addition of ethyl methyl ketone, the remaining quantity of ethylenediamine dihydrochloride precipitates fractionally, and then the imidazoline hydrochloride is separated by addition of dry ether. After recrystallization from a small amount of ethyl methyl ketone, the product 2-/oe-(phenoxy)-ethyl/-A-imidazoline hydrochloride is obtained in the form of small white needles with a melting point of 144.5 - 146°C.
Utbytte: 18,5 g (77% av teoretisk). Yield: 18.5 g (77% of theoretical).
Analysedata: C^H^ClNgO (226,7). Analytical data: C^H^ClNgO (226.7).
Beregnet: C 58,28 H 6,67 N 12,36. Calculated: C 58.28 H 6.67 N 12.36.
Funnet : G 58,33 H 6,72 N 12,66. Found : G 58.33 H 6.72 N 12.66.
Eksempel 2: Example 2:
17,7 g a-(o-metoksyfenoksy)-propionitril (fremstilt ved omsetning av guajacol med oc-brompropionitril i nærvær av kaliumkarbonat; vannklar væske, kokepunkt Q g=98,5-100,5°, n^2^;1,51IO) og 23,2 g etylendia-minmono-p-toluensulfonat slås sammen og oppvarmes i en time ved 225-230°C. Herved avspaltes NH^. Etter avkjøling av reaksjonsblandingen innstilles alkalisk med ca. 10%-ig lut og den frie base ekstraheres med kloroform. Den rest som blir igjen elter avdampning av oppløs-ningsmidlet gav etter omkrystalliseång fra petroleum-bensin (IOO/14O) 15>8 g (72% av teoretisk) 2-/a-(o-metoksy-fenoksy)etyl/-<^ -imidazolin. Smeltepunkt 94,5-95°C. 17.7 g a-(o-methoxyphenoxy)-propionitrile (prepared by reacting guaiacol with o-bromopropionitrile in the presence of potassium carbonate; water-clear liquid, boiling point Q g=98.5-100.5°, n^2^;1 .51IO) and 23.2 g of ethylene diamine mono-p-toluenesulfonate are combined and heated for one hour at 225-230°C. NH^ is thereby split off. After cooling the reaction mixture, it is adjusted alkaline with approx. 10% lye and the free base are extracted with chloroform. The residue which remains after evaporation of the solvent gave after recrystallization steam from petroleum petrol (100/14O) 15>8 g (72% of theoretical) 2-/a-(o-methoxy-phenoxy)ethyl/-<^ -imidazoline. Melting point 94.5-95°C.
Analyseverdier:' ci2<H>l6<N>2°2 (<2>20>3) Analytical values:' ci2<H>l6<N>2°2 (<2>20>3)
Beregnet: C 65,42 H 7,32 N 12,72. Calculated: C 65.42 H 7.32 N 12.72.
Funnet : C 65,37 H 7,36 N 12,86. Found : C 65.37 H 7.36 N 12.86.
Den frie base kan på kjent måte overføres i hydrokloridet, idet det etter omkrystallisering fra etanol/etylmetylketon fåes 15>7 g (85,5%) 2-/a-(o-metoksyf enoksy) -etyl/-^2-imidazolin-hydroklorid. Hvite, sterkt hygroskopiske krystaller med smeltepunkt: I36 - 137°C. Analyseverdier: C-^H-^CIN^ (256,8). The free base can be transferred in a known manner into the hydrochloride, whereby after recrystallization from ethanol/ethyl methyl ketone 15>7 g (85.5%) of 2-/a-(o-methoxy enoxy)-ethyl/-^2-imidazoline- hydrochloride. White, strongly hygroscopic crystals with melting point: I36 - 137°C. Analytical values: C-^H-^CIN^ (256.8).
Beregnet: N 10,91 Dl 13,8l. Calculated: N 10.91 Dl 13.8l.
Funnet : N 10,95 Cl 14,10. Found : N 10.95 Cl 14.10.
Eksempel 3: Example 3:
17,7 g cx-(p-metoksyf enoksy)-propionitril (fremstilt ved omsetning av hydrokinonmonometyleter med cx-brompropionitril i nærvær av kaliumkarbonat; vannklar væske med q smeltepunkt ved Q ' 01-84 86°C ' n2D5-l 5109) 6 g etylendiamin og 0,5 cm-5 karbondisulfid has sammen og oppvarmes i 48 timer ved ca. 100°C. Etterpå unnviker NH^. Det stivnede reaksjons-produkt omkrystalliseres etter avkjøling fra petroleumbensin (100/140), 17.7 g of c-(p-methoxy enoxy)-propionitrile (prepared by reacting hydroquinone monomethyl ether with cx-bromopropionitrile in the presence of potassium carbonate; clear liquid with q melting point at Q ' 01-84 86°C ' n2D5-l 5109) 6 g ethylenediamine and 0.5 cm-5 carbon disulphide are combined and heated for 48 hours at approx. 100°C. Afterwards, NH^ evades. The solidified reaction product is recrystallized after cooling from petroleum petrol (100/140),
idet man får 14,7 g (67% av teoretisk) 2-/a-(p-metoksyfenoksy)-etyl/- ^ ? -imidazolin med smeltepunkt 113,5-114,5 oC. whereby 14.7 g (67% of theoretical) of 2-/a-(p-methoxyphenoxy)-ethyl/- ^ ? -imidazoline with melting point 113.5-114.5 oC.
Analyseverdier: c±2UlS^ 2°2 (220,3). Analytical values: c±2UlS^ 2°2 (220.3).
Beregnet: C 65,42 H 7,32 N 12,72. Calculated: C 65.42 H 7.32 N 12.72.
Funnet : C 65,28 H 7,47 N 12,70. Found : C 65.28 H 7.47 N 12.70.
Eksempel 4: Example 4:
57j5 S a-(2,6-diklorfenoksy)-propionitril (fremstilt som beskrevet i eksempel la fra 2,6-deklorfenol og a-brompropionitril; hvite nåler med smeltepunkt 28-2°/°C) overføres til a-(2,6-diklorf enoksy) -propionimid-syreetulester-hydroklorid, som angitt i eksempel lb med 10,4 cm^ absolutt etanol og 10,4 g tørr saltsyregass, og denne forbindelse om-settes videre uten rensning, som angitt i eksempel lc med 29,5 g vannfri etylendiamin til 2-/a-(2,6-diklorfenoksy)-etyl/- -imidazolin-hydroklorid. Etter gjentatt omkrystallisering fra etanol/eter får man hvite krystaller med smeltepunkt 221-223°C. 57j5 S a-(2,6-dichlorophenoxy)-propionitrile (prepared as described in example la from 2,6-dechlorophenol and a-bromopropionitrile; white needles with melting point 28-2°/°C) is transferred to a-(2, 6-dichloroethoxy)-propionimide acid ethyl ester hydrochloride, as indicated in Example 1b with 10.4 cm 3 of absolute ethanol and 10.4 g of dry hydrochloric acid gas, and this compound is further reacted without purification, as indicated in Example 1c with 29 .5 g of anhydrous ethylenediamine to 2-[α-(2,6-dichlorophenoxy)-ethyl]--imidazoline hydrochloride. After repeated recrystallization from ethanol/ether, white crystals with a melting point of 221-223°C are obtained.
Analyseverdier: C-^H-j^Cl^O (295,6). Analytical values: C-^H-j^Cl^O (295.6).
Beregnet: N 9,48 Gl 35,99- Calculated: N 9.48 Gl 35.99-
Funnet : N 9,46 Cl 36,01. Found : N 9.46 Cl 36.01.
Eksempel 5: Example 5:
39,9 g a~(2,3-dimetylfenoksy)-propionitril (fremstilt som i eksempel la fra vie.-o-xylenol og a-brompropionitril; vannklar væske, kokepunkt q Qg:62°C, n^: 1,5108) blir som angitt i eksempel lb overført til a-(2,3-dimetylfenoksy)-propionimidsyreetylester-hydroklorid med 8,5 cm^ absolutt etylalkohol og 8,5 g tørr hydrogenkloridgass, og stoffet blir uten videre rensing omsatt og opparbeidet som angitt under eksempel lc. Råproduktet opptas for rensing i 10%-ig natronlut og overføres derved til den frie imidazolin-base (smeltepunkt 106,5°C), og etter utrysting med eter, tørking og avdampning av oppløsnings-midlet, oppløsning i absolutt alkohol og tilsetning av absolutt eter, igjen omsatt til hydroklorider ved innledning av minst den ekvivalente mengde tørr hydrogenkloridgass. Produktet 2-/a-(2,3-dimetylfenoksy)-etyl/- p-imidazolin-hydroklorid får man etter en enkelt omkrystallisering fra alkohol/eter analyserent som hvite krystaller med smeltepunkt 183°C. 39.9 g a~(2,3-dimethylphenoxy)-propionitrile (prepared as in example la from vie.-o-xylenol and a-bromopropionitrile; water-clear liquid, boiling point q Qg:62°C, n^: 1.5108) is, as indicated in example 1b, transferred to α-(2,3-dimethylphenoxy)-propionimidic acid ethyl ester hydrochloride with 8.5 cm^ of absolute ethyl alcohol and 8.5 g of dry hydrogen chloride gas, and the substance is reacted without further purification and worked up as indicated under example lc. The crude product is taken up for purification in 10% caustic soda and thereby transferred to the free imidazoline base (melting point 106.5°C), and after shaking out with ether, drying and evaporation of the solvent, dissolution in absolute alcohol and addition of absolute ether, again converted to hydrochlorides by introducing at least the equivalent amount of dry hydrogen chloride gas. The product 2-/α-(2,3-dimethylphenoxy)-ethyl/- p-imidazoline hydrochloride is obtained after a single recrystallization from alcohol/ether analytically pure as white crystals with a melting point of 183°C.
Analyseverdier: ClqHlgClN20 (254,8). Analytical values: ClqHlgClN2O (254.8).
Beregnet: N 11,00 Cl 13,91. Calculated: N 11.00 Cl 13.91.
Funnet : N 10,78 Cl 14,02. Found : N 10.78 Cl 14.02.
Den følgende tabell 1 angir andre imidazoliner og deres salter fremstilt ifølge oppfinnelsens fremgangsmåte. The following table 1 indicates other imidazolines and their salts prepared according to the method of the invention.
(1) Den vasokonstriktoriske Wrikkomponent av prøvestoffet ble fastslått på isolerte kaninører ifølge Krakow-Pissemski, (1) The vasoconstrictor Wrik component of the test substance was determined on isolated rabbit ears according to Krakow-Pissemski,
Ther. Pharm. Meth. 193 (I949). Ther. Pharm. Meth. 193 (I949).
(2) Blodtrykksregistrering på de med uretan (1,5 g/kg i.p.) narkotiserte rotter resp. katter (kanylering av carotisarterie, overføring på Statham-elementer). (3) Prøvestoffet i angitte konsentrasjoner i 0,9% NaCl-oppløsning ble applisert ved hjelp av jontoforese (0,5 mA, 2 min.) over en 3,7 cm 2 stor elektrode pa o underarmen av frivillige forsøkspersoner. Vurderingen av den etterfølgende anemi-reaksjon foregikk semikvanti-tativt. (2) Blood pressure recording in the rats anesthetized with urethane (1.5 g/kg i.p.) or cats (carotid artery cannulation, transfer on Statham elements). (3) The test substance in specified concentrations in 0.9% NaCl solution was applied by means of iontophoresis (0.5 mA, 2 min.) over a 3.7 cm 2 electrode on the forearm of volunteer subjects. The assessment of the subsequent anemia reaction took place semi-quantitatively.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEN0030055 | 1967-02-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO122530B true NO122530B (en) | 1971-07-12 |
Family
ID=7345361
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO60868A NO122530B (en) | 1967-02-23 | 1968-02-17 |
Country Status (15)
Country | Link |
---|---|
AT (1) | AT280277B (en) |
BE (1) | BE711062A (en) |
CH (1) | CH529766A (en) |
DK (1) | DK127331B (en) |
ES (1) | ES350523A1 (en) |
FI (1) | FI49612C (en) |
FR (2) | FR7361M (en) |
GB (1) | GB1181356A (en) |
IL (1) | IL29445A (en) |
IT (1) | IT1062055B (en) |
LU (1) | LU55443A1 (en) |
NL (1) | NL156691B (en) |
NO (1) | NO122530B (en) |
SE (1) | SE341631B (en) |
YU (1) | YU32924B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH642821A5 (en) * | 1976-12-20 | 1984-05-15 | Wellcome Found | Pesticidal preparations containing imidazolines, and their use for controlling pests |
US4226876A (en) * | 1976-12-20 | 1980-10-07 | Burroughs Wellcome Co. | Arthropodicidal imidazoline derivatives |
ZA787351B (en) * | 1978-06-19 | 1980-08-27 | Wellcome Found | Imidazolines,their preparation,intermediates therefor,and pesticidal formulations and use of the imidazolines |
EP0011596B1 (en) | 1978-10-09 | 1981-12-30 | Ciba-Geigy Ag | 2-(alpha-phenoxy-alkyl)-imidazolines and their salts, their preparation and use, and agents against phytoparasitic and zooparasitic mites containing them |
CA2691082A1 (en) * | 2007-07-02 | 2009-01-08 | F. Hoffmann-La Roche Ag | 2 -imidazolines having a good affinity to the trace amine associated receptors (taars) |
-
1968
- 1968-02-07 CH CH178368A patent/CH529766A/en not_active IP Right Cessation
- 1968-02-08 SE SE165668A patent/SE341631B/xx unknown
- 1968-02-09 LU LU55443D patent/LU55443A1/xx unknown
- 1968-02-09 IL IL2944568A patent/IL29445A/en unknown
- 1968-02-14 AT AT140068A patent/AT280277B/en not_active IP Right Cessation
- 1968-02-15 ES ES350523A patent/ES350523A1/en not_active Expired
- 1968-02-17 NO NO60868A patent/NO122530B/no unknown
- 1968-02-20 YU YU38368A patent/YU32924B/en unknown
- 1968-02-20 FI FI44768A patent/FI49612C/en active
- 1968-02-21 BE BE711062D patent/BE711062A/xx not_active IP Right Cessation
- 1968-02-22 IT IT1308368A patent/IT1062055B/en active
- 1968-02-22 DK DK69668A patent/DK127331B/en not_active IP Right Cessation
- 1968-02-23 NL NL6802611A patent/NL156691B/en unknown
- 1968-02-23 FR FR141118A patent/FR7361M/fr not_active Expired
- 1968-02-23 FR FR1555168D patent/FR1555168A/fr not_active Expired
- 1968-02-23 GB GB887568A patent/GB1181356A/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
NL156691B (en) | 1978-05-16 |
DK127331B (en) | 1973-10-22 |
YU38368A (en) | 1975-06-30 |
FR7361M (en) | 1969-10-20 |
FI49612B (en) | 1975-04-30 |
NL6802611A (en) | 1968-08-26 |
FI49612C (en) | 1975-08-11 |
LU55443A1 (en) | 1968-04-16 |
GB1181356A (en) | 1970-02-18 |
ES350523A1 (en) | 1969-05-01 |
FR1555168A (en) | 1969-01-24 |
BE711062A (en) | 1968-07-01 |
IL29445A (en) | 1971-08-25 |
YU32924B (en) | 1975-12-31 |
AT280277B (en) | 1970-04-10 |
IT1062055B (en) | 1983-06-25 |
CH529766A (en) | 1972-10-31 |
SE341631B (en) | 1972-01-10 |
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