NO122481B - - Google Patents
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- Publication number
- NO122481B NO122481B NO111968A NO111968A NO122481B NO 122481 B NO122481 B NO 122481B NO 111968 A NO111968 A NO 111968A NO 111968 A NO111968 A NO 111968A NO 122481 B NO122481 B NO 122481B
- Authority
- NO
- Norway
- Prior art keywords
- imidazoline
- methyl
- mixture
- mice
- reaction
- Prior art date
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- -1 2-(substituted phenoxymethyl)-2-imidazoline compounds Chemical class 0.000 claims description 51
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 22
- HVCCFMAPGCBCHZ-UHFFFAOYSA-N 2-aminoethylazanium;4-methylbenzenesulfonate Chemical compound NCCN.CC1=CC=C(S(O)(=O)=O)C=C1 HVCCFMAPGCBCHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- VLLSCJFPVSQXDM-UHFFFAOYSA-N 2-phenoxyacetonitrile Chemical compound N#CCOC1=CC=CC=C1 VLLSCJFPVSQXDM-UHFFFAOYSA-N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 82
- 239000000203 mixture Substances 0.000 description 45
- 241000699670 Mus sp. Species 0.000 description 42
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 32
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000000047 product Substances 0.000 description 26
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 24
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 23
- 239000012065 filter cake Substances 0.000 description 23
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
- 239000007789 gas Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- 238000001704 evaporation Methods 0.000 description 12
- 230000008020 evaporation Effects 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 11
- 229910021529 ammonia Inorganic materials 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 8
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 8
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 8
- 239000012458 free base Substances 0.000 description 8
- 239000007928 intraperitoneal injection Substances 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 8
- 229960003147 reserpine Drugs 0.000 description 8
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 8
- 229940025084 amphetamine Drugs 0.000 description 7
- 238000007796 conventional method Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 229910001873 dinitrogen Inorganic materials 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 5
- 229960002456 hexobarbital Drugs 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
- 239000000935 antidepressant agent Substances 0.000 description 4
- 229940005513 antidepressants Drugs 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000004622 sleep time Effects 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- LVLKWYRHTDZICQ-UHFFFAOYSA-N 2-(2,6-dichlorophenoxy)acetonitrile Chemical compound ClC1=CC=CC(Cl)=C1OCC#N LVLKWYRHTDZICQ-UHFFFAOYSA-N 0.000 description 3
- NIQAEZYNTJNSMP-UHFFFAOYSA-N 2-(3,4-dichlorophenoxy)acetonitrile Chemical compound ClC1=CC=C(OCC#N)C=C1Cl NIQAEZYNTJNSMP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 3
- 230000008485 antagonism 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
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229940049920 malate Drugs 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- IXRNQIKIVWWFBH-UHFFFAOYSA-N n-(1-phenylethenyl)acetamide Chemical compound CC(=O)NC(=C)C1=CC=CC=C1 IXRNQIKIVWWFBH-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- SSIZLKDLDKIHEV-UHFFFAOYSA-N 2,6-dibromophenol Chemical compound OC1=C(Br)C=CC=C1Br SSIZLKDLDKIHEV-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 230000037023 motor activity Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 2
- WNHOJUYNIMPNAG-UHFFFAOYSA-N 1-(2,6-dichloro-4-ethyl-3-methylphenoxy)aziridine-2,3-dione hydrochloride Chemical compound Cl.C(C)C1=C(C(=C(ON2C(C2=O)=O)C(=C1)Cl)Cl)C WNHOJUYNIMPNAG-UHFFFAOYSA-N 0.000 description 1
- ROFYLHXAHQGEED-UHFFFAOYSA-N 2-(2,6-dichloro-3-methylphenoxy)acetonitrile Chemical compound ClC1=C(OCC#N)C(=CC=C1C)Cl ROFYLHXAHQGEED-UHFFFAOYSA-N 0.000 description 1
- UPCRTXKNNYWEJV-UHFFFAOYSA-N 2-(3,4-dibromophenoxy)acetonitrile Chemical compound BrC=1C=C(OCC#N)C=CC1Br UPCRTXKNNYWEJV-UHFFFAOYSA-N 0.000 description 1
- GRMJZZBFHKTYDJ-UHFFFAOYSA-N 2-(phenoxymethyl)-4,5-dihydro-1h-imidazole Chemical class N=1CCNC=1COC1=CC=CC=C1 GRMJZZBFHKTYDJ-UHFFFAOYSA-N 0.000 description 1
- JUAMJFXZEBGJMC-UHFFFAOYSA-N 2-[(2-bromo-6-chlorophenoxy)methyl]-4,5-dihydro-1H-imidazole 4-methylbenzenesulfonic acid Chemical compound S(=O)(=O)(O)C1=CC=C(C)C=C1.BrC1=C(OCC=2NCCN2)C(=CC=C1)Cl JUAMJFXZEBGJMC-UHFFFAOYSA-N 0.000 description 1
- AOMZMOWSWJHDRD-UHFFFAOYSA-N 2-[(3,4-dichlorophenoxy)methyl]-4,5-dihydro-1h-imidazole;hydrochloride Chemical compound Cl.C1=C(Cl)C(Cl)=CC=C1OCC1=NCCN1 AOMZMOWSWJHDRD-UHFFFAOYSA-N 0.000 description 1
- WDNBURPWRNALGP-UHFFFAOYSA-N 3,4-Dichlorophenol Chemical compound OC1=CC=C(Cl)C(Cl)=C1 WDNBURPWRNALGP-UHFFFAOYSA-N 0.000 description 1
- SHZQDCSEIZEYLY-UHFFFAOYSA-N 4-(4,5-dihydro-1H-imidazol-2-ylmethoxy)-2-(trifluoromethyl)aniline Chemical compound NC1=C(C=C(OCC=2NCCN2)C=C1)C(F)(F)F SHZQDCSEIZEYLY-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-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
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- YQYKXCYFNYYJNY-UHFFFAOYSA-N S(=O)(=O)(O)C1=CC=C(C)C=C1.BrC1=C(OCC=2NCCN2)C(=CC=C1)Br Chemical compound S(=O)(=O)(O)C1=CC=C(C)C=C1.BrC1=C(OCC=2NCCN2)C(=CC=C1)Br YQYKXCYFNYYJNY-UHFFFAOYSA-N 0.000 description 1
- 206010039897 Sedation 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
- 206010044565 Tremor Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 229960000632 dexamfetamine Drugs 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 231100000324 minimal toxicity Toxicity 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000004197 pelvis Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—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
Description
Analogifremgangsmåte for fremstilling av Analogy method for the production of
terapeutisk aktive aryloksyimidazoliner. therapeutically active aryloxyimidazolines.
Oppfinnelsen vedrører fremstilling av terapeutisk aktive aryloksyimidazoliner og er spesielt rettet på 2-(fenoksymetyl)-2-imidazoliner som er substituert i fenoksygruppen, samt de fysiologisk akseptable salter av disse, med formelen: The invention relates to the production of therapeutically active aryloxyimidazolines and is particularly directed at 2-(phenoxymethyl)-2-imidazolines which are substituted in the phenoxy group, as well as the physiologically acceptable salts thereof, with the formula:
hvor Z betyr en rest som tilsvarer en av formlene: where Z means a residue corresponding to one of the formulas:
hvor X, X^ og hver, uavhengig av hverandre betyr klor eller brom, X" er klor, brom eller metyl, R er trifluormetyl, klor eller brom, og R' er hydrogen, trifluormetyl, klor eller brom. wherein X, X^ and each independently means chlorine or bromine, X" is chlorine, bromine or methyl, R is trifluoromethyl, chlorine or bromine, and R' is hydrogen, trifluoromethyl, chlorine or bromine.
Uttrykket "fysiologisk akseptabelt salt" slik det her anvendes, refererer seg til salter av de 2-(substituert fenoksymetyl)-2-imidazoliner som er i alt vesentlig ikke-toksiske i doseringsgrader forenelige med god farmakologisk virkning. Slike fysiologisk akseptable salter omfatter ikke-toksiske syreaddisjonssalter med uorganiske syrer, f.eks. saltsyre, bromhydrogensyre, svovel-syre: eller fosforsyre, eller med organiske syrer, f.eks. eddiksyre, ravsyre, eplesyre, maleinsyre, vinsyre eller sitronsyre, eller med organiske sulfonsyrer, f.eks. metansulfon- eller p-toluensulfon-syre. De 2-(substituerte fenoksymetyl)-2-imidazoliner er krystal-linske faste stoffer og oljer som har varierende grad av løselig-het i organiske oppløsningsmidler som f.eks. 1,2-diklorbenzen, 1,2-dimetoksymetan, metylenklorid og alkoholer og som bare er svakt løselige i vann. De fysiologisk akseptable salter av de 2-(substituert fenoksymetyl)-2-imidazoliner, f.eks. 2-/_(2 ,6-dibrom-fenoksy)metyl/-2-imidazolin-hydrogenklorid og 2/_( 3 ,4-diklorfenoksy) - metyl/-2-imidazolin-hydrogenklorid, er løselige i vann og svakt løselige i organiske oppløsningsmidler som f.eks. aceton, benzen og alkohqler. The term "physiologically acceptable salt" as used here refers to salts of the 2-(substituted phenoxymethyl)-2-imidazolines which are essentially non-toxic in dosage levels compatible with good pharmacological action. Such physiologically acceptable salts include non-toxic acid addition salts with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid: or phosphoric acid, or with organic acids, e.g. acetic acid, succinic acid, malic acid, maleic acid, tartaric acid or citric acid, or with organic sulphonic acids, e.g. methanesulfonic or p-toluenesulfonic acid. The 2-(substituted phenoxymethyl)-2-imidazolines are crystalline solids and oils which have varying degrees of solubility in organic solvents such as e.g. 1,2-dichlorobenzene, 1,2-dimethoxymethane, methylene chloride and alcohols and which are only slightly soluble in water. The physiologically acceptable salts of the 2-(substituted phenoxymethyl)-2-imidazolines, e.g. 2-/_(2,6-dibromo-phenoxy)methyl/-2-imidazoline hydrogen chloride and 2/_(3,4-dichlorophenoxy)-methyl/-2-imidazoline hydrogen chloride are soluble in water and slightly soluble in organic solvents such as e.g. acetone, benzene and alcohols.
De forbindelser som tilsvarer formel IV er spesielt nyttige som antidepresserende midler. For slike anvendelser er den foretrukne form av forbindelsene hvor Z tilsvarer formel IV, et farmasøytisk akseptabelt salt av disse, og hydrogenkloridsaltene foretrekkes. Andre salter, spesielt tosylatet (p-toluensulfonat), kan også brukes ved fremstilling og rensning av forbindelsene og kan omdannes til det foretrukne hydrogenkloridsalt. Forbindelsen hvor X og X' begge er klor, foretrekkes spesielt som et antidepresserende middel og som et analgetikum. The compounds corresponding to formula IV are particularly useful as antidepressants. For such applications, the preferred form of the compounds wherein Z corresponds to formula IV is a pharmaceutically acceptable salt thereof, the hydrogen chloride salts being preferred. Other salts, especially the tosylate (p-toluenesulfonate), can also be used in the preparation and purification of the compounds and can be converted to the preferred hydrogen chloride salt. The compound wherein X and X' are both chlorine is particularly preferred as an antidepressant and as an analgesic.
De nevnte forbindelser fremstilles ved reaksjon mellom The aforementioned compounds are produced by reaction between
et substituert fenoksyacetonitril med en av formlene I-V med a substituted phenoxyacetonitrile with one of the formulas I-V with
etylendiamin-monotosylat for dannelse av et 2-(substituert fenoksy-metyl) -2-imidazolin-tosylat , med påfølgende hydrolyse av tosylatet i vandig base for å frigjøre 2-(substituert fenoksymetyl)-2-imida-zolinet i den frie baseform. Reaksjonen forløper under utvikling av ammoniakk når det substituerte fenoksyacetonitril og etyl-diamin-monotosylatet bringes i kontakt og blandes, fortrinnsvis i et inert organisk oppløsningsmiddel som reaksjonsmiljø. Representative og egnede inerte organiske oppløsningsmidler som kan anvendes som reaksjonsmiljø, omfatter xylener, alkylbenzener og halogen-benzener, fortrinnsvis 1,2-diklorbenzen. Reaksjonen utføres fortrinnsvis under inert atmosfære med en inert gass som ledes gjennom reaksjonsblåndingen for å føre vekk ammoniakk fra reaksjonen. Reaksjonen forløper lett ved temperaturer fra 140 til 180°c, og reaksjonen utføres fortrinnsvis under tilbakeløpskjøling ved reaksjons-blandingens koketemperatur. I de fleste tilfelle felles 2-(substituert fenoksymetyl)-2-imidazolin-produktet ut i reaksjonsblandingen som sitt tosylat (p-toluensulfonat), og dette salt kan utskilles ved konvensjonelle metoder, f.eks. filtrering, sentrifugering eller dekantering. Hvis det ikke danner seg noen utfelling, kan saltet utskilles ved fordampning. 2-(substituert fenoksymetyl)-2-imida-zolin-tosylatet kan renses ved konvensjonelle metoder, f.eks. rekrystallisering og vasking. 2-(substituert fenoksymetyl)-2-imida-zolin-tosylatet kan omdannes til den frie baseform ved hydrolyse i vandig base. Den frie base 2-(substituert fenoksymetyl)-2-imidazolin utskilles deretter ved ekstraksjon med et organisk oppløsningsmiddel, f.eks. metylenklorid eller kloroform, fulgt av fordampning av oppløsningsmidlet. Produktet kan renses ved konvensjonelle metoder, f.eks. rekrystallisering, eller det kan omdannes til et fysiologisk akseptabelt salt. ethylenediamine monotosylate to form a 2-(substituted phenoxymethyl)-2-imidazoline tosylate, with subsequent hydrolysis of the tosylate in aqueous base to release the 2-(substituted phenoxymethyl)-2-imidazoline in the free base form. The reaction proceeds with the evolution of ammonia when the substituted phenoxyacetonitrile and the ethyl diamine monotosylate are brought into contact and mixed, preferably in an inert organic solvent as reaction medium. Representative and suitable inert organic solvents that can be used as reaction medium include xylenes, alkylbenzenes and halogenobenzenes, preferably 1,2-dichlorobenzene. The reaction is preferably carried out under an inert atmosphere with an inert gas which is passed through the reaction mixture to remove ammonia from the reaction. The reaction proceeds easily at temperatures from 140 to 180°c, and the reaction is preferably carried out under reflux cooling at the boiling temperature of the reaction mixture. In most cases, the 2-(substituted phenoxymethyl)-2-imidazoline product precipitates in the reaction mixture as its tosylate (p-toluenesulfonate), and this salt can be isolated by conventional methods, e.g. filtration, centrifugation or decantation. If no precipitate forms, the salt can be separated by evaporation. The 2-(substituted phenoxymethyl)-2-imidazoline tosylate can be purified by conventional methods, e.g. recrystallization and washing. The 2-(substituted phenoxymethyl)-2-imidazoline tosylate can be converted to the free base form by hydrolysis in an aqueous base. The free base 2-(substituted phenoxymethyl)-2-imidazoline is then separated by extraction with an organic solvent, e.g. methylene chloride or chloroform, followed by evaporation of the solvent. The product can be cleaned by conventional methods, e.g. recrystallization, or it can be converted into a physiologically acceptable salt.
De nye forbindelser hvor Z tilsvarer formel IV og R er metyl, fremstilles ved N-metylering av de nye forbindelser hvor R er hydrogen, med metylsulfat. Reaksjonen forløper når reaksjonspartnerne bringes i kontakt og blandes, fortrinnsvis i nærvær av vann som oppløsningsmiddel. De nøyaktige mengdeforhold av reaksjonspartnerne som skal anvendes, er ikke kritiske, da noe av det ønskede produkt alltid vil danne seg ved danning av reaksjonspartnerne i vilkårlige forhold. Imidlertid forbruker reaksjonen ekvimolare mengder av reaksjonspartnerne, og disse anvendes fortrinnsvis i ekvimolare forhold. Reaksjonen forløper ved temperaturer fra ca. 25 til 75°C. Det utvikles varme ved begynnelsen av reaksjonen, og denne varme er vanligvis tilstrekkelig til å bringe reaksjonsblandingen opp på en temperatur som ligger i reaksjonstemperaturområdet . Reaksjonsblandingen holdes på en temperatur i reaksjonstemperaturområdet i opptil 2-3 timer. Ved slutten av reaksjonsperioden gjøres blandingen sterkt basisk ved tilsetning av natriumhydroksyd. Produktet ekstraheres så med et klorert hydrokarbonoppløsningsmiddel. l-metyl-2-^(3,4-dihalogenfenoksy)-metyl/7^-imidazol inproduktet kan utskilles ved konvensjonelle metoder, f.eks., fordampning av oppløsningsmidlet. Produktet kan renses ytterligere ved konvensjonelle metoder, f.eks. rekrystallisering, eller det kan omdannes til et farmasøytisk akseptabelt salt. The new compounds where Z corresponds to formula IV and R is methyl are prepared by N-methylation of the new compounds where R is hydrogen with methyl sulfate. The reaction proceeds when the reaction partners are brought into contact and mixed, preferably in the presence of water as solvent. The exact quantitative ratios of the reaction partners to be used are not critical, as some of the desired product will always form when the reaction partners are formed in arbitrary ratios. However, the reaction consumes equimolar amounts of the reaction partners, and these are preferably used in equimolar proportions. The reaction proceeds at temperatures from approx. 25 to 75°C. Heat is developed at the beginning of the reaction, and this heat is usually sufficient to bring the reaction mixture up to a temperature that is in the reaction temperature range. The reaction mixture is kept at a temperature in the reaction temperature range for up to 2-3 hours. At the end of the reaction period, the mixture is made strongly basic by the addition of sodium hydroxide. The product is then extracted with a chlorinated hydrocarbon solvent. The 1-methyl-2-(3,4-dihalophenoxy)-methyl/7-imidazole inproduct can be isolated by conventional methods, e.g., evaporation of the solvent. The product can be further purified by conventional methods, e.g. recrystallization, or it can be converted to a pharmaceutically acceptable salt.
De fysiologisk akseptable salter av 2-(substituert fen-oksymetyl) -2 -imidazol in -forbindelsene kan fremstilles ved oppløs-ning av 2-(substituert fenoksymetyl)-2-imidazolin i en minimal mengde av alkohol og ved å tilsette en alkohokppløsning av en syre, f.eks. saltsyre, bromhydrogensyre, eplesyre, maleinsyre eller ravsyre, inntil fullstendig utfelling av det tilsvarende salt. Saltet kan renses ytterligere ved rekrystallisering eller omdannes til den frie baseform av 2-(substituert fenoksymetyl)-2-imidazolin. The physiologically acceptable salts of the 2-(substituted phenoxymethyl)-2-imidazoline compounds can be prepared by dissolving 2-(substituted phenoxymethyl)-2-imidazoline in a minimal amount of alcohol and by adding an alcoholic solution of an acid, e.g. hydrochloric acid, hydrobromic acid, malic acid, maleic acid or succinic acid, until complete precipitation of the corresponding salt. The salt can be further purified by recrystallization or converted to the free base form of 2-(substituted phenoxymethyl)-2-imidazoline.
Den frie base kan fremstilles ved hydrolyse av saltet i vandig base. Saltet blandes med en vandig oppløsning av natrium-hy±oksyd (ca. 4 n), hvoretter den frie base kan utskilles ved ekstraksjon med et klorert hydrokarbon-oppløsningsmiddel. Oppløsnings-midlet kan fjernes ved konvensjonelle metoder som f.eks. fordampning eller destillasjon, og 2-(substituert fenoksymetyl)-2-imi-dazolinet kan renses ved metoder som f.eks. rekrystallisering. The free base can be prepared by hydrolysis of the salt in an aqueous base. The salt is mixed with an aqueous solution of sodium hy±oxide (approx. 4 n), after which the free base can be separated by extraction with a chlorinated hydrocarbon solvent. The solvent can be removed by conventional methods such as e.g. evaporation or distillation, and the 2-(substituted phenoxymethyl)-2-imidazoline can be purified by methods such as e.g. recrystallization.
Ved fremstilling av forbindelsene ifølge oppfinnelsen blandes et egnet substituert fenoksyacetonitril-fenoksyacetimid-hydrogenklorid, etylendiamin-monotosylat og et inert organisk opp-løsningsmiddel, fortrinnsvis 1,2-diklorbenzen. De nøyaktige mengdeforhold av reaksjonspartnerne som skal anvendes, er ikke kritiske, da noe av det ønskede produkt alltid vil oppnås når reaksjonspartnerne blandes i vilkårlige forhold. Imidlertid forbruker reaksjonen reaksjonspartnerne i ekvimolare forhold, og det foretrekkes derfor å bruke reaksjonspartnerne i slike forhold. Nitrogen ledes gjennom blandingen og blandingen oppvarmes til en temperatur innen, reaksjonstemperaturområdet i 1 til 10 timer. Ved en bekvem fremgangsmåte ventileres reaksjonskaret til en felle som inneholder saltsyre, slik at denne kan reagere med ammoniakken fra reaksjonen. Reaksjonsblandingen avkjøles deretter og filtreres. 2-(substituert fenoksymetyl)-2-imidazolin-tosylat-filterkaken kan renses ytterligere ved rekrystallisering eller den kan omdannes til den frie base ved hydrolyse i vandig base. When preparing the compounds according to the invention, a suitable substituted phenoxyacetonitrile-phenoxyacetimide hydrogen chloride, ethylenediamine monotosylate and an inert organic solvent, preferably 1,2-dichlorobenzene, are mixed. The exact proportions of the reaction partners to be used are not critical, as some of the desired product will always be obtained when the reaction partners are mixed in arbitrary proportions. However, the reaction consumes the reaction partners in equimolar ratios, and it is therefore preferred to use the reaction partners in such ratios. Nitrogen is passed through the mixture and the mixture is heated to a temperature within the reaction temperature range for 1 to 10 hours. In a convenient method, the reaction vessel is ventilated to a trap containing hydrochloric acid, so that this can react with the ammonia from the reaction. The reaction mixture is then cooled and filtered. The 2-(substituted phenoxymethyl)-2-imidazoline tosylate filter cake can be further purified by recrystallization or it can be converted to the free base by hydrolysis in aqueous base.
Følgende eksempler belyser oppfinnelsen. The following examples illustrate the invention.
Eksempel 1 Example 1
2,6-dibromfenoksyacetonitril (58,2 g, 0,20 mol) ble blandet med el^iondiamin-monotosylat (47 g, 0,20 mol) og 200 ml 1,2-diklorbenzen. Nitrogengass ble ledet gjennom blandingen mens blandingen ble oppvarmet til en temperatur av 150°C i 1 time. Ammoniakken fra reaksjonen ble oppsamlet ved at utløpsgassene ble ledet gjennom en gass-skrubber som inneholdt fortynnet saltsyre. Re-aks jonsblandingen ble avkjølt og filtrert for oppnåelse av 2-^(2,6-dibromfenoksy)metyl/-2-imidazolin-tosylat, med en molekylvekt 506,2, som en filterkake. 2~ £_{ 2 ,6-dibromf enoksyJmetylT^-imidazo-lintosylat-f ilterkaken ble oppslemmet med en blanding av metylenklorid og vann. Oppslemmingen ble gjort basisk ved tilsetning av ca. 8 g natriumhydroksyd i vann. Det organiske sjikt ble skilt fra og inndampet i vakuum. Inndampningsresten var 2-^(2,6-dibromfen-oksy) me ty 1/-2-imidazol in med molekylvekt 334,0 og ble oppløst i ca. 100 ml isopropylalkohol. Alkoholoppløsningen ble surgjort ved tilsetning av 5 n saltsyre i isopropylalkohol inntil utfellingen var fullstendig. Blandingen ble filtrert og 2-/_( 2,6-dibromfenok-sy)metyl/-2-imidazolin-hydrogenklorid-produktet oppsamlet som en filterkake med smeltepunkt 230-231°C.' 2,6-Dibromophenoxyacetonitrile (58.2 g, 0.20 mol) was mixed with ethyl iondiamine monotosylate (47 g, 0.20 mol) and 200 mL of 1,2-dichlorobenzene. Nitrogen gas was passed through the mixture while the mixture was heated to a temperature of 150°C for 1 hour. The ammonia from the reaction was collected by passing the exhaust gases through a gas scrubber containing dilute hydrochloric acid. The reaction mixture was cooled and filtered to obtain 2-[(2,6-dibromophenoxy)methyl]-2-imidazoline tosylate, with a molecular weight of 506.2, as a filter cake. 2~ £_{ 2 ,6-dibromophenoxyJmethylT^-imidazo-lintosylate filter cake was slurried with a mixture of methylene chloride and water. The slurry was made alkaline by adding approx. 8 g sodium hydroxide in water. The organic layer was separated and evaporated in vacuo. The evaporation residue was 2-^(2,6-dibromophenoxy)methy 1/-2-imidazoline with a molecular weight of 334.0 and was dissolved in approx. 100 ml isopropyl alcohol. The alcohol solution was acidified by adding 5 N hydrochloric acid in isopropyl alcohol until precipitation was complete. The mixture was filtered and the 2-/_(2,6-dibromophenoxy)methyl/-2-imidazoline hydrogen chloride product collected as a filter cake with melting point 230-231°C.
Ved praktisk talt samme fremgangsmåte som den ovenfor beskrevne, under:anvendelse av de samme inerte organiske oppløsnings-midler, men istedenfor saltsyre en syre som er i stand til å gi et fysiologisk akseptabelt salt, ble følgende 2-^2,6-dibromfenoksy)-metyl/-2-imidazolinsalter fremstilt: 2-/_{ 2,6-dibromfenoksy)metyl/- 2-imidazolin-hydrogenbromid, 2-^/(2 ,6-dibromf enoksy) me tyl/-2-imida-zolinsulfat, 2-/_{ 2 ,6-dibromfenoksy)metyl/-2-imidazolinsuksinat, 2-/_( 2 ,6-dibromf enoksy )metyl/-2-imidazolinmaleat, 2-</(2 ,6-dibrom-fenoksy)mety1/-2-imidazolin-malat. By practically the same procedure as that described above, using the same inert organic solvents, but instead of hydrochloric acid an acid capable of giving a physiologically acceptable salt, the following 2-^2,6-dibromophenoxy) -methyl/-2-imidazoline salts prepared: 2-/_{ 2,6-dibromophenoxy)methyl/- 2-imidazoline hydrogen bromide, 2-^/(2 ,6-dibromophenoxy)methyl/-2-imidazoline sulfate , 2-/_{ 2 ,6-dibromophenoxy)methyl/-2-imidazoline succinate, 2-/_( 2 ,6-dibromophenoxy )methyl/-2-imidazoline maleate, 2-</(2 ,6-dibromo-phenoxy )methyl 1/-2-imidazoline-malate.
Eksempel 2 Example 2
2,6-diklorfenoksyacetonitril (80,8 g, 0,40 mol) ble blandet med etylendiamin-monotosylat (94 g, 0,40 mol) og 200 ml 1,2-diklorbenzen. Nitrogengass ble ledet gjennom blandingen mens blandingen ble oppvarmet ved en temperatur på 140-145°C i 2 timer. Ammoniakken fra reaksjonen ble oppsamlet ved å lede utløpsgassene 2,6-Dichlorophenoxyacetonitrile (80.8 g, 0.40 mol) was mixed with ethylenediamine monotosylate (94 g, 0.40 mol) and 200 mL of 1,2-dichlorobenzene. Nitrogen gas was passed through the mixture while the mixture was heated at a temperature of 140-145°C for 2 hours. The ammonia from the reaction was collected by passing the off-gases
gjennom en gass-skrubber som inneholdt fortynnet saltsyre. Reaksjon sbl åndingen ble avkjølt og filtrert, og filterkaken var 2-/_{ 2 ,6-diklorfenoksy)metyl/-2-imidazolin-tosylat, med molekylvekt 417,3, som ble oppløst i vann. Oppløsningen ble gjort basisk ved tilsetning av ca. 16 g natriumhydroksyd i vandig oppløsning. Blandingen ble ekstrahert med metylenklorid og det organiske sjikt skilt fra og inndampet i vakuum. Inndampningsresten var 2-/_(2 ,6-diklorfenoksy)metyl7-2-imidazolin med molekylvekt 245,1 og ble oppløst i 100 ml isopropylalkohol. Alkoholoppløsningen ble surgjort ved tilsetning av 5 n saltsyre i isopropylalkohol til utfellingen var fullstendig. Blandingen ble filtrert og 2-/_( 2,6-diklorfenoksy)metyl/- 2-imidazolin-hydrogenklorid-produktet ble oppsamlet som en filterkake med smeltepunkt 221-222°C. Produktets struktur ble fastslått ved magnetisk kjerneresonnans-spektroskopi. through a gas scrubber containing dilute hydrochloric acid. The reaction mixture was cooled and filtered, and the filter cake was 2-/_{ 2,6-dichlorophenoxy)methyl/-2-imidazoline tosylate, with a molecular weight of 417.3, which was dissolved in water. The solution was made basic by adding approx. 16 g sodium hydroxide in aqueous solution. The mixture was extracted with methylene chloride and the organic layer separated and evaporated in vacuo. The evaporation residue was 2-(2,6-dichlorophenoxy)methyl7-2-imidazoline with a molecular weight of 245.1 and was dissolved in 100 ml of isopropyl alcohol. The alcohol solution was acidified by adding 5 N hydrochloric acid in isopropyl alcohol until precipitation was complete. The mixture was filtered and the 2-(2,6-dichlorophenoxy)methyl/-2-imidazoline hydrogen chloride product was collected as a filter cake, mp 221-222°C. The structure of the product was determined by nuclear magnetic resonance spectroscopy.
På praktisk talt samme måte som beskrevet ovenfor, under anvendelse av samme inerte organiske oppløsningsmidler, men ved å erstatte saltsyre med en syre som er i stand til å danne et fysiologisk akseptabelt salt, ble følgende 2-/_ (2 ,6-diklorfenoksy)metyl/- 2-imidazolinsalter fremstilt: 2-^(2,6-diklor fenoksy)metyl/2-imidazolin-hydrogenbromid, 2-/J2 ,6-diklorfenoksy)metyl7r-2-imidazolinsulfat, 2-^(2 ,6-diklorfenoksy) metyl/-2-imidazolinsuksinat, 2-/_{ 2 ,6-diklor f enoksy )metyl/-2-imidazolinmaleat, 2~ l_{ 2 ,6-diklorfenoksy)metyl7-2-imidazolinmalat • In practically the same manner as described above, using the same inert organic solvents, but replacing hydrochloric acid with an acid capable of forming a physiologically acceptable salt, the following 2-/_ (2,6-dichlorophenoxy) methyl/- 2-imidazoline salts prepared: 2-^(2,6-dichlorophenoxy)methyl/2-imidazoline hydrogen bromide, 2-/J2 ,6-dichlorophenoxy)methyl7r-2-imidazoline sulfate, 2-^(2 ,6- dichlorophenoxy) methyl/-2-imidazoline succinate, 2-/_{ 2 ,6-dichloro f enoxy )methyl/-2-imidazoline maleate, 2~ l_{ 2 ,6-dichlorophenoxy)methyl7-2-imidazoline malate •
Eksempel 3 Example 3
2-brom-6-klorfenoksyacetonitril (74 g, 0,30 mol) ble blandet med etylendiamin-monotosylat (70,5 g, 0,30 mol) og 200 2-Bromo-6-chlorophenoxyacetonitrile (74 g, 0.30 mol) was mixed with ethylenediamine monotosylate (70.5 g, 0.30 mol) and 200
ml 1,2-diklorbenzen. Nitrogengass ble ledet gjennom blandingen mens blandingen ble oppvarmet ved en temperatur på ca. 180°C i 60 minutter. Ammoniakken fra reaksjonen ble oppsamlet ved å lede ut-løpsgassene gjennom en gass-skrubber som inneholdt fortynnet saltsyre. Reaksjonsblandingen ble avkjølt og filtrert for oppnåelse av 2-^(2-brom-6-klorfenoksy)metyl/-2-imidazolin-tosylat med en molekylvekt 461,8 som en filterkake, som ble oppslemmet med en blanding av metylenklorid og vann. Oppslemmingen ble gjort basisk ved tilsetning av ca. 12 g natriumhydroksyd i vann. Det organiske sjikt ble skilt fra og fordampet i vakuum<*> Inndampningsresten var 2-^(2-brom-6-klor-fenoksy)metyl7-2-imidazolin med molekylvekt 289,6 og ble oppløst i ca. 100 ml isopropylalkohol. Alkoholopp-løsningen ble surgjort ved tilsetning av 5 n saltsyre i isopropyl- ml of 1,2-dichlorobenzene. Nitrogen gas was passed through the mixture while the mixture was heated to a temperature of approx. 180°C for 60 minutes. The ammonia from the reaction was collected by passing the off-gases through a gas scrubber containing dilute hydrochloric acid. The reaction mixture was cooled and filtered to obtain 2-[(2-bromo-6-chlorophenoxy)methyl]-2-imidazoline tosylate with a molecular weight of 461.8 as a filter cake, which was slurried with a mixture of methylene chloride and water. The slurry was made alkaline by adding approx. 12 g sodium hydroxide in water. The organic layer was separated and evaporated in vacuo<*> The evaporation residue was 2-^(2-bromo-6-chloro-phenoxy)methyl7-2-imidazoline with a molecular weight of 289.6 and was dissolved in approx. 100 ml isopropyl alcohol. The alcohol solution was acidified by adding 5 N hydrochloric acid in isopropyl
alkohol inntil utfellingen var fullstendig. Blandhgen ble filtrert, alcohol until precipitation was complete. The mixture was filtered,
og 2-^(2-brom-6-klorfenoksy)metyl/-2-imidazolin-hydrogenklorid-produktet ble oppsamlet som en filterkake med smeltepunkt 214-215°C. Produktets struktur ble fastslått ved magnetisk kjerneresonans-spektroskopi. and the 2-^(2-bromo-6-chlorophenoxy)methyl/-2-imidazoline hydrogen chloride product was collected as a filter cake mp 214-215°C. The structure of the product was determined by nuclear magnetic resonance spectroscopy.
Ved vesentlig samme fremgangsmåte og ved anvendelse av By substantially the same procedure and by application of
de samme inerte organiske oppløsningsmidler ble 2-/_(4-acetamid-2,6-dibrom-fenoksy)metyl/-2-imidazolin-hydrogenklorid med et smeltepunkt 235-236°C fremstilt ved å blande ekvimolare mengder av 4-acetamid-2,6-dibromfenoksyacetonitril og etylendiamin-monotosylat, utskilling av tosylatet, frigjøring av den frie base ved behandling med natriumhydroksyd og fremstilling av hydrogenkloridet ved behandling med alkoholisk saltsyre. the same inert organic solvents, 2-/_(4-acetamide-2,6-dibromo-phenoxy)methyl/-2-imidazoline hydrogen chloride with a melting point of 235-236°C was prepared by mixing equimolar amounts of 4-acetamide- 2,6-dibromophenoxyacetonitrile and ethylenediamine monotosylate, separation of the tosylate, liberation of the free base by treatment with sodium hydroxide and preparation of the hydrogen chloride by treatment with alcoholic hydrochloric acid.
2-^(4-acetamid-2,6-diklorfenoksy)metyl/-2-imidazolin-hydrogenklorid fremstilles på lignende måte. 2-[(4-acetamide-2,6-dichlorophenoxy)methyl]-2-imidazoline hydrogen chloride is prepared in a similar manner.
Eksempel 4 Example 4
2-^(4-acetamid-2,6-dibromfenoksy)metyl/-2-imidazolin-hydrogenklorid (34,2 g, 0,08 mol) ble oppløst i 100 ml vandig 5 n saltsyre. Oppløsningen ble oppvarmet på dampbad i ca. 2,5 timer hvorved det dannet seg en utfelling. Blandingen ble avkjølt og filtrert og filterkaken vasket med 5 n saltsyre. Filterkaken ble tørket, og 2-^(4-amin-2,6-dibromfenoksy)metyl/-2-imidazolin-hydro-genklorid-produktet viste seg å smelte ved 2 35-236°C. Produktets struktur ble fastslått ved magnetisk kjerneresonans-spektroskopi. 2-(4-acetamide-2,6-dibromophenoxy)methyl-(2-imidazoline)hydrochloride (34.2 g, 0.08 mol) was dissolved in 100 mL of aqueous 5 N hydrochloric acid. The solution was heated on a steam bath for approx. 2.5 hours during which a precipitate formed. The mixture was cooled and filtered and the filter cake washed with 5 N hydrochloric acid. The filter cake was dried and the 2-(4-amino-2,6-dibromophenoxy)methyl/-2-imidazoline hydrogen chloride product was found to melt at 235-236°C. The structure of the product was determined by nuclear magnetic resonance spectroscopy.
De nye forbindelser som tilsvarer formel I, hvor Z tilsvarer en av formlene II, III eller V, er nyttige som analgetika. Grupper av mus ble administrert med en av testforbindelsene i varierende doseringsgrad. Musene ble deretter provosert ved intra-peritonal injeksjon av 0,1 % saltsyre i en doseringsgrad av 0,01 ml pr. g. Musene ble deretter plasert i klare plastbur og iakttatt. The new compounds corresponding to formula I, where Z corresponds to one of formulas II, III or V, are useful as analgesics. Groups of mice were administered one of the test compounds in varying doses. The mice were then provoked by intra-peritoneal injection of 0.1% hydrochloric acid in a dosage rate of 0.01 ml per g. The mice were then placed in clear plastic cages and observed.
Hos ubehandlede mus følges den intraperitoneale injeksjon av denne dose saltsyre av karakteristisk vridningssyndrom hos musene, dvs. utflating av buken mot gulvet i buret, ledsaget av rotering av ryggraden og bekkenet. Doseringen av hvert 2-(substituert fenok-symetyl) -2-imidazolin-hydrogenklorid som var effektiv for hindring av vridningssyndrom hos 50 % av musene (ED 50) ble beregnet. ED 50-verdiene for de testede forbindelser og administreringsmåten er oppført i følgende tabell. In untreated mice, the intraperitoneal injection of this dose of hydrochloric acid is followed by characteristic writhing syndrome in the mice, i.e. flattening of the abdomen against the floor of the cage, accompanied by rotation of the spine and pelvis. The dosage of each 2-(substituted phenoxymethyl)-2-imidazoline hydrochloride effective in preventing writhing syndrome in 50% of mice (ED 50 ) was calculated. The ED 50 values of the compounds tested and the route of administration are listed in the following table.
Ved lignende forsøk ble representative forbindelser ifølge oppfinnelsen administrert til mus i doseringskonsentrasjoner av 1, 2,5 eller 25 mg/kg. For sammenligningens skyld ble andre 2-(substituert fenoksymetyl)-2-imidazolin-forbindelser administrert til separate grupper av mus i en doseringsgrad av 10 mg/kg. Musene ble deretter provosert med saltsyre som ovenfor beskrevet. Doseringsgraden for hver forbindelse og prosent mus i hver gruppe som blir beskyt-tet mot vridningssyndrom, er oppført i tabell II. In similar experiments, representative compounds according to the invention were administered to mice in dosage concentrations of 1, 2.5 or 25 mg/kg. For comparison, other 2-(substituted phenoxymethyl)-2-imidazoline compounds were administered to separate groups of mice at a dosage level of 10 mg/kg. The mice were then provoked with hydrochloric acid as described above. The dosage level for each compound and the percentage of mice in each group that are protected against writhing syndrome are listed in Table II.
Det etyl-2,6-dihalogen-3-metylfenoksyacetimid-hydrogen-klorid som ble anvendt som utgangsmateriale her, kan fremstilles i henhold til kjente prosesser. I et representativt forsøk ble 0,07 mol 2,6-diklor-3-metylfenoksyacetonitril, 4,4 ml etanol og 250 ml dietyleter blandet sammen. Blandingen ble mettet med saltsyre i ca. 1 time ved 0 til 5°C. Blandingen ble konsentrert ved inndamp-ning og filtrert, og etyl-2,6-diklor-3-metylfenoksyacetimid-hydrogenkloridet ble oppsamlet som en filterkake. De substituerte fenoksyacetonitriler som ble anvendt som utgangsmaterialer, fremstilles likeledes ved konvensjonelle metoder. I et representativt forsøk ble 2,6-dibromfenol (101 g, 0,40 mol) blandet med 55 g (0,40 mol) vannfritt kaliumkarbonat og 200 ml dimetylsulfoksyd. Blandingen ble omrørt ved 70°C mens kloracetonitril (32 g, 0,42 mol) ble tilsatt dråpevis i løpet av 15 minutter. Blandingen ble holdt ved en temperatur på 75°C i 3 timer, hvoretter den ble avkjølt og filtrert. Filtratet ble destillert og 2,6-diklorfenoksyacetonitril,produktet ble oppsamlet som en fraksjon med kokepunkt 135-138°C under et trykk på 2-3 mm Hg. Produktet ble rekrystallisert fra cykloheksan, og 2,6-diklorfenoksyacetonitrilproduktet hadde smp. 63-63,5°C. The ethyl-2,6-dihalo-3-methylphenoxyacetimide hydrogen chloride which was used as starting material here can be prepared according to known processes. In a representative experiment, 0.07 mol of 2,6-dichloro-3-methylphenoxyacetonitrile, 4.4 ml of ethanol and 250 ml of diethyl ether were mixed together. The mixture was saturated with hydrochloric acid for approx. 1 hour at 0 to 5°C. The mixture was concentrated by evaporation and filtered, and the ethyl 2,6-dichloro-3-methylphenoxyacetimide hydrogen chloride was collected as a filter cake. The substituted phenoxyacetonitrile which were used as starting materials are likewise prepared by conventional methods. In a representative experiment, 2,6-dibromophenol (101 g, 0.40 mol) was mixed with 55 g (0.40 mol) of anhydrous potassium carbonate and 200 mL of dimethyl sulfoxide. The mixture was stirred at 70°C while chloroacetonitrile (32 g, 0.42 mol) was added dropwise over 15 minutes. The mixture was kept at a temperature of 75°C for 3 hours, after which it was cooled and filtered. The filtrate was distilled and the 2,6-dichlorophenoxyacetonitrile product was collected as a fraction boiling at 135-138°C under a pressure of 2-3 mm Hg. The product was recrystallized from cyclohexane, and the 2,6-dichlorophenoxyacetonitrile product had m.p. 63-63.5°C.
Eksempel 5 Example 5
4-acetamid-3,5-diklorfenoksyacetonitril (22 g, 0,10 mol) blandes med etylendiamin-p-toluensulfonat (23,5 g, 0,10 mol) og 100 ml 1,2-diklorbenzen. Nitrogen ledes gjennom blandingen mens blandingen oppvarmes ved koketemperatur under tilbakeløpskjøling i ca. 2 timer. Ammoniakken fra reaksjonen oppsamles ved å lede ut-løpsgassene gjennom en gass-skrubber som inneholder fortynnet saltsyre. Reaksjonsblandingen avkjøles og filtreres for oppnåelse av 2-£(4-acetamid-3,5-diklorfenoksy)mety1/-2-imidazolin-p-toluensulfonat som en filterkake. Filterkaken blandes med vann og blandingen gjøres basisk ved tilsetning av 3,2 g natriumhydroksyd i vandig oppløsning. Blandingen ekstraheres deretter med metylenklorid, og det organiske sjikt inndampes i vakuum hvorved man som rest oppnår 2-^(4-acetamid-3,5-diklorfenoksy)metyl/-2-imidazolin som oppløses i ca. 100 ml isopropylalkohol, og overskudd av alkoholisk saltsyre tilsettes til utfellingen er fullstendig. Blandingen filtreres, og 2-^(4-acetamid-3,5-diklorfenoksy)metyl/-2-imida-zolin-hydrogenkloridproduktet oppsamles som en filterkake. 4-acetamide-3,5-dichlorophenoxyacetonitrile (22 g, 0.10 mol) is mixed with ethylenediamine-p-toluenesulfonate (23.5 g, 0.10 mol) and 100 ml of 1,2-dichlorobenzene. Nitrogen is passed through the mixture while the mixture is heated at boiling temperature under reflux for approx. 2 hours. The ammonia from the reaction is collected by passing the exhaust gases through a gas scrubber containing dilute hydrochloric acid. The reaction mixture is cooled and filtered to obtain 2-[(4-acetamide-3,5-dichlorophenoxy)methyl]-2-imidazoline-p-toluenesulfonate as a filter cake. The filter cake is mixed with water and the mixture is made basic by adding 3.2 g of sodium hydroxide in aqueous solution. The mixture is then extracted with methylene chloride, and the organic layer is evaporated in vacuo, whereby 2-^(4-acetamide-3,5-dichlorophenoxy)methyl/-2-imidazoline is dissolved in approx. 100 ml of isopropyl alcohol, and an excess of alcoholic hydrochloric acid is added until precipitation is complete. The mixture is filtered, and the 2-(4-acetamide-3,5-dichlorophenoxy)methyl/-2-imidazoline hydrogen chloride product is collected as a filter cake.
2-^(4-acetamid-3,5-diklorfenoksy)metyl/-2-imidazolin-hydrogenkloridet oppløses i ca. 100 ml 5 n saltsyre. Blandingen oppvarmes på dampbad i ca. 2,5 timer. Blandingen avkjøles og filtreres, filterkaken vaskes med saltsyre og tørkes. 2-(/(4-amin-3,5-diklorfenoksy)metyl/-2-imidazolin-dihydrogenklorid-produktet smelter ved 232-234°C. The 2-^(4-acetamide-3,5-dichlorophenoxy)methyl/-2-imidazoline hydrogen chloride is dissolved in approx. 100 ml 5 N hydrochloric acid. The mixture is heated in a steam bath for approx. 2.5 hours. The mixture is cooled and filtered, the filter cake is washed with hydrochloric acid and dried. The 2-(/(4-amino-3,5-dichlorophenoxy)methyl/-2-imidazoline dihydrogen chloride product melts at 232-234°C.
Eksempel 6 Example 6
4-acetamid-3-trifluormetylfenoksyacetonitril (21,9 g, 4-acetamide-3-trifluoromethylphenoxyacetonitrile (21.9 g,
0,1 mol) blandes med etylendiamin-p-toluensulfonat (23,5 g, 0,1 mol) 0.1 mol) is mixed with ethylenediamine-p-toluenesulfonate (23.5 g, 0.1 mol)
og ca. 100 ml 1,2-diklorbenzen. Nitrogen ledes gjennom blandingen mens blandingen oppvarmes ved koketemperatur under tilbakeløpskjø-ling i ca. 2 timer. Ammoniakken fra reaksjonen oppsamles ved å le-de utløpsgassene gjennom en gass-skrubber som inneholder fortynnet saltsyre. Reaksjonsblandingen avkjøles og filtreres for oppnåelse av 2~[_(4-acetamid-3-trifluormetylfenoksy)mety 1/-2-imidazolin-p-toluensulfonat som en filterkake. Filterkaken oppløses i vann, og opp-løsningen gjøres basisk ved tilsetning av 20 ml vandig 5 n natriumhydroksyd. Blandingen ekstraheres med metylenklorid og ekstrakten inndampes i vakuum. Inndampningsresten er 2-/_(4-acetamid-3-tri-fluormetylfenoksy)metyl/-2-imidazolin, og denne oppløses i ca. 100 ml isopropanol , og en isopropanol-oppløsning av saltsyre tilsettes inntil utfellingen er fullstendig. Blandingen filtreres, og 2-l_ (4-a:cetamid-3-tri f luorme tyl f enoksy )metyl/-2-imidazol in -hy drogen - kloridproduktet samles som en filterkake. and approx. 100 ml of 1,2-dichlorobenzene. Nitrogen is passed through the mixture while the mixture is heated at boiling temperature under reflux cooling for approx. 2 hours. The ammonia from the reaction is collected by passing the exhaust gases through a gas scrubber containing diluted hydrochloric acid. The reaction mixture is cooled and filtered to obtain 2-[_(4-acetamide-3-trifluoromethylphenoxy)methyl 1 H -imidazoline-p-toluenesulfonate as a filter cake. The filter cake is dissolved in water, and the solution is made basic by adding 20 ml of aqueous 5 N sodium hydroxide. The mixture is extracted with methylene chloride and the extract is evaporated in vacuo. The evaporation residue is 2-/_(4-acetamide-3-trifluoromethylphenoxy)methyl/-2-imidazoline, and this dissolves in approx. 100 ml of isopropanol and an isopropanol solution of hydrochloric acid are added until precipitation is complete. The mixture is filtered, and the 2-1-(4-a:acetamide-3-trifluoromethylphenoxy)methyl/-2-imidazole in hydrogen chloride product is collected as a filter cake.
2~ l_ (4-acet amid-3-trifluormetyl fenoksy)metyl/-2-imidazo-lin-hydrogenkloridet oppløses i ca. 100 ml 5 n saltsyre. Blandingen oppvarmes på dampbad i ca. 2,5 timer. Blandingen avkjøles, og vandig natriumhydroksyd tilsettes for å bringe pH-verdien i den endelige blanding opp på ca. 13. Blandingen ekstraheres med metylenklorid, og metylenklorid-ekstrakten inndampes i vakuum, hvorved produktet utgjør inndampningsresten. 2-^/(4-amin-3-trifluormetylfen-oksy) mety l/-2-imidazolin-produktet smelter ved 73-75°C. The 2~1_ (4-acetamide-3-trifluoromethylphenoxy)methyl/-2-imidazoline hydrogen chloride is dissolved in approx. 100 ml 5 N hydrochloric acid. The mixture is heated in a steam bath for approx. 2.5 hours. The mixture is cooled, and aqueous sodium hydroxide is added to bring the pH of the final mixture to about 13. The mixture is extracted with methylene chloride, and the methylene chloride extract is evaporated in vacuo, whereby the product constitutes the evaporation residue. The 2-[(4-amino-3-trifluoromethylphenoxy)methyl]-2-imidazoline product melts at 73-75°C.
Antidepresserende aktivitet av de nye forbindelser ble indikert ved omvending av reserpin-indusert depresjon hos mus. Antidepressant activity of the new compounds was indicated by reversal of reserpine-induced depression in mice.
Ved representative forsøk ble separate halogenfenoksymetylimidazolin-forbindelser administrert til separate grupper av mus i varierende doseringsgrader ved intraperitoneal injeksjon. 1 time etter doseringen av halogenfenoksymetylimidazolin-forbindelsen ble reserpin administrert til hver mus i en doseringsgrad av 5 mg/kg ved intraperitoneal injeksjon. Administreringen av 5 mg/kg reserpin intraperitonealt til mus resulterer i en progresjon av symptomer som starter med at øyelokkene henger ned (ptosis) og at håre-ne reiser seg, og kulminerer i en generell depresjon med nedsatt spontan motorisk aWivitet og nedsatt responsivitet overfor addi-tive eller tactile stimuli. In representative experiments, separate halophenoxymethylimidazoline compounds were administered to separate groups of mice at varying dosage levels by intraperitoneal injection. 1 hour after the dosing of the halogenophenoxymethylimidazoline compound, reserpine was administered to each mouse at a dosage rate of 5 mg/kg by intraperitoneal injection. The administration of 5 mg/kg reserpine intraperitoneally to mice results in a progression of symptoms starting with drooping of the eyelids (ptosis) and hair standing up, and culminating in a general depression with reduced spontaneous motor activity and reduced responsiveness to addi -tive or tactile stimuli.
Etter administreringen av reserpinet ble forsøksdyrene observert med hensyn på de ovennevnte symptomer på depresjon. En omvending av reserpin-depresjonen ble indikert, da musene ble observert å oppvise øket spontan motorisk aktivitet og øket responsivitet overfor stimuli. Doseringen av representative halogenfenoksymetylimidazolin-forbindelser som er viksomme med hensyn til å omvende reserpin-depresjon hos 50 % av musene (ED 50) ble beregnet. After the administration of the reserpine, the experimental animals were observed for the above symptoms of depression. A reversal of the reserpine depression was indicated, as the mice were observed to exhibit increased spontaneous motor activity and increased responsiveness to stimuli. The dosage of representative halophenoxymethylimidazoline compounds effective in reversing reserpine depression in 50% of mice (ED 50 ) was calculated.
Eksempel 7 Example 7
3,4-diklorfenoksyacetonitril (20,2 g, 0,10 mol) ble blandet med etylendiamin-monotosylat (23,5 g, 0,10 mol) og 75 ml 1,2-diklorbenzen. Nitrogengass ble ledet gjennom blandingen mens blandingen ble oppvarmet ved koketemperaturen under tilbakeløpskjøling i 3 timer. Ammoniakken fra reaksjonen ble oppsamlet ved å lede ut-løpsgassene gjennom en gass-skrubber som inneholdt fortynnet saltsyre. Reaksjonsblandingen ble avkjølt og filtrert for oppnåelse av 2-/(3 ,4-diklorfenoksy)metyl/-2-imidazolin-tosylat som en filterkake som ble oppslemmet med en blanding av metylenklorid og vann, og oppslemmingen ble gjort basisk ved tilsetning av ca. 0,10 mol natriumhydroksyd i vandig oppløsning. Det organiske sjikt ble skilt fra og inndampet i vakuum. 2-/(3,4-diklorfenoksy)metyl/-2-imidazolin utgjorde inndampningsresten, og denne ble oppløst i 100 ml isopropylalkohol. Alkoholoppløsningen ble surgjort ved tilsetning av 5 n saltsyre i isopropylalkohol til utfellingen var fullstendig. Blandingen ble filtrert og 2-[_(3 ,4-diklorfenoksy)metyl/- 2-imidazolin-hydrogenklorid-produktet ble oppsamlet i form av en filterkake som smeltet ved 244-245°C. Produktet hadde en nøytral vekt på 280, sammenlignet med den beregnede ekvivalentvekt 281,5 for den nevnte struktur. Produktets struktur ble fastslått ved magnetisk kjerneresonans-spektroskopi. 3,4-Dichlorophenoxyacetonitrile (20.2 g, 0.10 mol) was mixed with ethylenediamine monotosylate (23.5 g, 0.10 mol) and 75 mL of 1,2-dichlorobenzene. Nitrogen gas was passed through the mixture while the mixture was heated at the reflux temperature for 3 hours. The ammonia from the reaction was collected by passing the off-gases through a gas scrubber containing dilute hydrochloric acid. The reaction mixture was cooled and filtered to obtain 2-/(3,4-dichlorophenoxy)methyl/-2-imidazoline tosylate as a filter cake which was slurried with a mixture of methylene chloride and water, and the slurry was made basic by adding approx. 0.10 mol sodium hydroxide in aqueous solution. The organic layer was separated and evaporated in vacuo. 2-/(3,4-dichlorophenoxy)methyl/-2-imidazoline constituted the evaporation residue, and this was dissolved in 100 ml of isopropyl alcohol. The alcohol solution was acidified by adding 5 N hydrochloric acid in isopropyl alcohol until precipitation was complete. The mixture was filtered and the 2-[_(3,4-dichlorophenoxy)methyl/-2-imidazoline hydrogen chloride product was collected in the form of a filter cake melting at 244-245°C. The product had a neutral weight of 280, compared to the calculated equivalent weight of 281.5 for the aforementioned structure. The structure of the product was determined by nuclear magnetic resonance spectroscopy.
På praktisk talt samme måte som beskrevet ovenfor, under anvendelse av de samme inerte organiske oppløsningsmidler og ved å erstatte saltsyren med en syre som er i stand til å danne et farmasøytisk akseptabelt salt, ble følgende 2-j/( 3 ,4-diklorfenoksy) - metyl/-2-imidazolin-salter fremstilt: 2-/(3 ,4-dikl or f enoksy) me ty 1/-2-imidazol in-hy drogenbromid, 2-/(3 ,4-diklorfenoksy)metyl/-2-imidazolin-sulfat, 2-/(3 ,4-diklorfenoksy) metyl/-2-imidazolin-suksinat , 2-/(3,4-diklorfenoksy)metyl/- 2-imidazolin-maleat, 2-/(3,4-diklorfenoksy)metyl/-2-imidazolin-malat. In substantially the same manner as described above, using the same inert organic solvents and replacing the hydrochloric acid with an acid capable of forming a pharmaceutically acceptable salt, the following 2-j/(3,4-dichlorophenoxy) - methyl/-2-imidazoline salts prepared: 2-/(3 ,4-dichlorophenoxy) methyl 1/-2-imidazole in hydrogen bromide, 2-/(3 ,4-dichlorophenoxy)methyl/- 2-Imidazoline sulfate, 2-/(3 ,4-dichlorophenoxy) methyl/-2-imidazoline succinate , 2-/(3,4-dichlorophenoxy)methyl/- 2-imidazoline maleate, 2-/(3, 4-Dichlorophenoxy)methyl/-2-imidazoline-malate.
Eksempel 8 Example 8
3,4-dibromfenoksyacetonitril (0,1 mol) ble blandet med etylendiamin-monotosylat (0,1 mol) og 100 ml 1,2-diklorbenzen. Nitrogengass ble ledet gjennom blandingen mens blandingen ble oppvarmet ved en temperatur på ca. 180°C i ca. 3 timer. Ammoniakken 3,4-Dibromophenoxyacetonitrile (0.1 mol) was mixed with ethylenediamine monotosylate (0.1 mol) and 100 ml of 1,2-dichlorobenzene. Nitrogen gas was passed through the mixture while the mixture was heated to a temperature of approx. 180°C for approx. 3 hours. The ammonia
fra reaksjonen ble oppsamlet ved å lede utløpsgassene gjennom en gass-skrubber som inneholdt fortynnet saltsyre. Reaksjonsblandingen ble avkjølt og filtrert for oppnåelse av 2-/( 3,4-dibromfenoksy)-metyl/-2-imidazolin-tosylat som en filterkake, som ble oppslemmet med en blanding av metylenklorid og vann, og oppslemmingen ble gjort basisk ved tilsetning av ca. 0,10 mol natriumhydroksyd i vandig oppløsning. Det organiske sjikt ble skilt fra og inndampet i vakuum. Inndampningsresten var 2-/_(3 ,4-dibromfenoksy)metyl/- 2-imidazolin og ble oppløst i ca. 100 ml isopropylalkohol. Alko-holoppløsningen ble surgjort ved tilsetning av 5 n saltsyre i isopropylalkohol til fullstendig utfelling. Blandingen ble filtrert, og 2-/(3,4-dibromfenoksy)metyl/-2-imidazolin-hydrogenkloridproduk-tet ble oppsamlet i form av en filterkake som smeltet ved 262-263°C. from the reaction was collected by passing the off-gases through a gas scrubber containing dilute hydrochloric acid. The reaction mixture was cooled and filtered to obtain 2-(3,4-dibromophenoxy)-methyl/-2-imidazoline tosylate as a filter cake, which was slurried with a mixture of methylene chloride and water, and the slurry was made basic by adding about. 0.10 mol sodium hydroxide in aqueous solution. The organic layer was separated and evaporated in vacuo. The evaporation residue was 2-/_(3,4-dibromophenoxy)methyl/- 2-imidazoline and was dissolved in approx. 100 ml isopropyl alcohol. The alcoholic solution was acidified by adding 5 N hydrochloric acid in isopropyl alcohol until complete precipitation. The mixture was filtered, and the 2-(3,4-dibromophenoxy)methyl/-2-imidazoline hydrogen chloride product was collected in the form of a filter cake which melted at 262-263°C.
På vesentlig samme måte som beskrevet ovenfor, under anvendelse av de samme inerte organiske oppløsningsmidler, ble 2-/(3-brom-4-klorfenoksy)metyl/-2-imidazolin-hydrogenklorid fremstilt. In substantially the same manner as described above, using the same inert organic solvents, 2-[(3-bromo-4-chlorophenoxy)methyl]-2-imidazoline hydrogen chloride was prepared.
De nye 2-/(3,4-dihalogenfenoksy)metyl/-2-imidazolin-forbindelser er nyttige som antidepresserende midler som indikeres ved sin antagonisme overfor barbiturat-fremkalt sedasjon hos små-gnagere. Denne aktivitet ble indikert ved deres effektivitet med hensyn til å nedsette den heksobarbitale sovetid hos mus. For sammenligningens skyld ble også andre aryloksyimidazoliner testet. Ved disse bestemmelser mottok separate grupper av mus en dose av The new 2-(3,4-dihalophenoxy)methyl/-2-imidazoline compounds are useful as antidepressants as indicated by their antagonism to barbiturate-induced sedation in small rodents. This activity was indicated by their effectiveness in reducing the hexobarbital sleep time in mice. For the sake of comparison, other aryloxyimidazolines were also tested. In these determinations, separate groups of mice received a dose of
én av forbindelsene i konsentrasjoner av 1, 5 eller 25 mg/kg 1 time før intraperitoneal administrering av heksobarbital i en doseringsgrad av 100 mg/kg. Separate grupper av ubehandlede mus ble likeledes injisert med heksobarbital i en doseringsgrad av 100 mg/kg for kontroll. Heksobarbital-injeksjonene fremkalte søvn hos musene. Alle dyrene ble deretter plasert på ryggen, og den tid det tok før hver mus snudde seg og rettet seg opp, ble re-gistrert som sovetid. Forholdet mellom gjennomsnittlig sovetid for de behandlede mus og for de ubehandlede mus er uttrykt som heksobarbital sovetidsforhold i følgende tabell. one of the compounds at concentrations of 1, 5 or 25 mg/kg 1 hour before intraperitoneal administration of hexobarbital at a dosage level of 100 mg/kg. Separate groups of untreated mice were likewise injected with hexobarbital at a dosage level of 100 mg/kg for control. The hexobarbital injections induced sleep in the mice. All animals were then placed on their backs, and the time it took for each mouse to turn around and straighten up was recorded as sleep time. The ratio between the average sleep time for the treated mice and for the untreated mice is expressed as hexobarbital sleep time ratio in the following table.
2-/(3,4-diklorfenoksy)metyl/-2-imidazolin har også sentralnervesystem-aktivitet, noe som indikeres ved dets effektivitet med hensyn på å øke virkningen av d-amfetamin hos mus. Ved disse for-søke ble grupper av mus administrert med 2-/(3,4-diklorfenoksy)metyl/-2-imidazolin-hydrogenklorid med en doseringsgrad av 25 mg/kg ved intraperitoneal injeksjon. Ca. 45 minutter etter administreringen av testforbindelsen ble musene administrert med 20 mg/kg av d-amfetaminsulfat ved intraperitoneal injeksjon. Øyeblikkelig etter administreringen av amfetamin ble musene samlet ved å sperre dem inne i et byr som var lite nok til å holde musene i tett nærhet av hverandre. Lignende grupper av mus ble administrert på samme måte med kjente aryloksyimidazolinforbindelser i doseringsgrader av 10 eller 25 mg/kg, likeledes ble de behandlet med amfetamin og samlet sammen for sammenligning. En separat gruppe av mus som ikke var forhåndsbehandlet med en aryloksyimidazolin-forbindelse ble likeledes behandlet med amfetamin og samlet sammen for kontroll. Administreringen av 20 mg/kg amfetamin til mus som ikke var forhåndsbehandlet med en forbindelse med sentralnervesystem-aktivitet, resulterer normalt i hyperopphisselse, skjelvinger og slåssing blant de samlede mus, etterfulgt av døden hos musene i løpet av ca. 3 timer. Forholdet mellom antall mus som overlever i 3 timer, og det totale antall mus som er behandlet med en aryloksyimidazolin-forbindelse er uttrykt som % amfetamin-antagonisme i tabell IV. 2-(3,4-Dichlorophenoxy)methyl/-2-imidazoline also has central nervous system activity as indicated by its effectiveness in enhancing the action of d-amphetamine in mice. In these experiments, groups of mice were administered 2-/(3,4-dichlorophenoxy)methyl/-2-imidazoline hydrogen chloride at a dosage level of 25 mg/kg by intraperitoneal injection. About. 45 minutes after the administration of the test compound, the mice were administered 20 mg/kg of d-amphetamine sulfate by intraperitoneal injection. Immediately after the administration of amphetamine, the mice were collected by confining them in a cage small enough to keep the mice in close proximity to each other. Similar groups of mice were similarly administered with known aryloxyimidazoline compounds at dosage levels of 10 or 25 mg/kg, likewise treated with amphetamine and pooled together for comparison. A separate group of mice not pretreated with an aryloxyimidazoline compound was likewise treated with amphetamine and pooled together for control. The administration of 20 mg/kg amphetamine to mice that have not been pretreated with a compound with central nervous system activity normally results in hyperarousal, tremors, and fighting among the pooled mice, followed by death of the mice within approx. 3 hours. The ratio of the number of mice surviving for 3 hours to the total number of mice treated with an aryloxyimidazoline compound is expressed as % amphetamine antagonism in Table IV.
x Musene som var administrert med 2-/(3,4-diklorfenoksy)mety1/-2-imidazolin-hydrogenklorid, overlevde i et meget kortere tidsrom enn kontrollmusene, noe som indikerer at 2-/(3,4-diklorfenoksy)-metyl/-2-imidazolinhydrogenklorid forbedret effekten av amfetamin. x The mice administered 2-/(3,4-dichlorophenoxy)methyl/-2-imidazoline hydrogen chloride survived for a much shorter period of time than the control mice, indicating that 2-/(3,4-dichlorophenoxy)-methyl /-2-imidazoline hydrogen chloride enhanced the effect of amphetamine.
Ved lignende forsøk ble en gruppe på 10 mus (A) samtidig administrert med 2-/T3 ,4-diklorfenoksy)metyl/-2-imidazolin-hydro-genklorid i en doseringsgrad av 25 mg/kg og d-amfetaminsulfat i en doseringsgrad av 5 mg/kg ved intraperitoneal injeksjon. En lignende gruppe mus (B) ble administrert med d-amfetaminsulfat alene i en doseringsgrad av 5 mg/kg.. Denne doseringsgrad av amfetamin er normalt av minimal toksisitet hos ubehandlede mus. To andre grupper på 10 mus (C) og (D) ble hver administrert med henholdsvis 31 In a similar experiment, a group of 10 mice (A) was simultaneously administered with 2-(T3,4-dichlorophenoxy)methyl/-2-imidazoline hydrogen chloride in a dosage level of 25 mg/kg and d-amphetamine sulfate in a dosage level of 5 mg/kg by intraperitoneal injection. A similar group of mice (B) was administered d-amphetamine sulfate alone at a dosage level of 5 mg/kg. This dosage level of amphetamine is normally of minimal toxicity in untreated mice. Two other groups of 10 mice (C) and (D) were each administered with 31, respectively
og 40 mg/kg av 2-/(3,4-diklorfenoksy)metyl/-2-imidazolin-hydrogen-klorid. De 4 gruppene av mus ble samlet sammen i små bur i alt vesentlig som beskrevet ovenfor. Prosent dødsfall i hver gruppe mus er uttrykt som prosent mortalitet i tabell V. and 40 mg/kg of 2-[(3,4-dichlorophenoxy)methyl]-2-imidazoline hydrogen chloride. The 4 groups of mice were collected together in small cages essentially as described above. Percent death in each group of mice is expressed as percent mortality in Table V.
Ved andre forsøk ble det beregnet den intraperiotoneale dose av representative 2-/(3,4-dihalogenfenoksy)metyl/-2-imidazo-linforbindelser som er effektive med hensyn på å omvende antagonis-men av de anti-konvulsive virkninger av difenylhydantoin ved hjelp av reserpin hos 50 % av de undersøkte mus (ED 50). Ed 50-verdien for omvending av virkningen av reserpin ved hjelp av 2-/(3,4-diklorfenoksy)metyl/-2-imidazolin-hydrogenklorid ble bestemt til 0,49 mg/kg. ED 50 for 2-/(3,4-dibromfenoksy)metyl/-2-imidazo-lin-hydrogenklorid ble bestemt til 23 mg/kg. ED 50 for 1-metyl-2-/(3,4-diklorfenoksy)metyl/-2-imidazolinhydrogenklorid var 8,2 mg/kg. In other experiments, the intraperitoneal dose of representative 2-(3,4-dihalophenoxy)methyl/-2-imidazoline compounds effective in reversing the antagonism of the anticonvulsant effects of diphenylhydantoin was calculated by of reserpine in 50% of the mice examined (ED 50). The Ed 50 value for reversal of the action of reserpine by 2-(3,4-dichlorophenoxy)methyl/-2-imidazoline hydrogen chloride was determined to be 0.49 mg/kg. The ED 50 for 2-(3,4-dibromophenoxy)methyl/-2-imidazoline hydrogen chloride was determined to be 23 mg/kg. The ED 50 for 1-methyl-2-(3,4-dichlorophenoxy)methyl/-2-imidazoline hydrogen chloride was 8.2 mg/kg.
Ved andre forsøk bestemte man de 50 % effektive doser In other trials, the 50% effective doses were determined
(ED 50) av 2-/(3,4-diklorfenoksy)metyl/-2-imidazolin-hydrogenklo-rid for beskyttelse mot det karakteristiske vridningssyndrom fremkalt ved den intraperitoneale injeksjon av 0,01 ml/g av 0,1 % saltsyre. Resultatene ble 11,7 mg/kg ved subkutan injeksjon og 31,5 mg/kg ved oral administrering. (ED 50) of 2-(3,4-dichlorophenoxy)methyl/-2-imidazoline hydrogen chloride for protection against the characteristic writhing syndrome induced by the intraperitoneal injection of 0.01 ml/g of 0.1% hydrochloric acid. The results were 11.7 mg/kg by subcutaneous injection and 31.5 mg/kg by oral administration.
3,4-diklorfenoksyacetonitrilet som ble anvendt som utgangsmateriale her, fremstilles ved kjente metoder. I et represen- The 3,4-dichlorophenoxyacetonitrile that was used as starting material here is prepared by known methods. In a representation
tativt forsøk ble 3,4-diklorfenol (81,5 g, 0,50 mol) blandet med 40 g kloracetonitril, 98 g vannfritt kaliumkarbonat og 100 ml dimetylsulfoksyd. Blandingen ble holdt ved en temperatur av 75°C test, 3,4-dichlorophenol (81.5 g, 0.50 mol) was mixed with 40 g of chloroacetonitrile, 98 g of anhydrous potassium carbonate and 100 ml of dimethyl sulfoxide. The mixture was maintained at a temperature of 75°C
i 3 timer, hvoretter den ble avkjølt og fortynnet ved tilsetning av ca. 2 1 vann. Det dannet seg et utfellingsprodukt etter tilsetning av vann, og blandingen ble filtrert og filtratet kassert. Filterkaken ble rekrystallisert ut fra cykloheksan, og det oppnådde 3,4-diklorfenoksyacetonitrilprodukt smeltet ved 61-62°C. for 3 hours, after which it was cooled and diluted by adding approx. 2 1 water. A precipitate formed after addition of water, and the mixture was filtered and the filtrate discarded. The filter cake was recrystallized from cyclohexane, and the 3,4-dichlorophenoxyacetonitrile product melted at 61-62°C was obtained.
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US62830167A | 1967-04-04 | 1967-04-04 | |
US62830267A | 1967-04-04 | 1967-04-04 | |
US62830367A | 1967-04-04 | 1967-04-04 |
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NO122481B true NO122481B (en) | 1971-07-05 |
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DE (1) | DE1770104C3 (en) |
DK (1) | DK135452B (en) |
FI (1) | FI49613C (en) |
FR (2) | FR1579552A (en) |
GB (1) | GB1180862A (en) |
IL (1) | IL29692A (en) |
NL (1) | NL160255C (en) |
NO (1) | NO122481B (en) |
SE (1) | SE342626B (en) |
YU (1) | YU33690B (en) |
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DE3842798A1 (en) * | 1988-12-20 | 1990-06-21 | Hoechst Ag | IMIDAZOLIN DERIVATIVES CONTAINING AGENTS FOR THE ECONOMIC CONTROL OF ECTOPARASITES AND NEW IMIDAZOLINE DERIVATIVES |
-
1968
- 1968-03-22 NO NO111968A patent/NO122481B/no unknown
- 1968-03-26 IL IL2969268A patent/IL29692A/en unknown
- 1968-04-01 DE DE19681770104 patent/DE1770104C3/en not_active Expired
- 1968-04-01 SE SE428068A patent/SE342626B/xx unknown
- 1968-04-03 DK DK146768A patent/DK135452B/en not_active IP Right Cessation
- 1968-04-03 NL NL6804672A patent/NL160255C/en not_active IP Right Cessation
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- 1968-04-03 FR FR1579552D patent/FR1579552A/fr not_active Expired
- 1968-04-03 YU YU76568A patent/YU33690B/en unknown
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FI49613C (en) | 1975-08-11 |
FR7668M (en) | 1970-02-09 |
DE1770104C3 (en) | 1979-08-23 |
DK135452B (en) | 1977-05-02 |
YU33690B (en) | 1978-02-28 |
YU76568A (en) | 1977-08-31 |
SE342626B (en) | 1972-02-14 |
DE1770104B2 (en) | 1978-11-23 |
IL29692A (en) | 1971-08-25 |
NL160255B (en) | 1979-05-15 |
DK135452C (en) | 1977-10-17 |
DE1770104A1 (en) | 1971-09-23 |
NL160255C (en) | 1979-10-15 |
GB1180862A (en) | 1970-02-11 |
FI49613B (en) | 1975-04-30 |
FR1579552A (en) | 1969-08-29 |
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