NO178395B - Fenoksyfenyl-derivater - Google Patents
Fenoksyfenyl-derivater Download PDFInfo
- Publication number
- NO178395B NO178395B NO922110A NO922110A NO178395B NO 178395 B NO178395 B NO 178395B NO 922110 A NO922110 A NO 922110A NO 922110 A NO922110 A NO 922110A NO 178395 B NO178395 B NO 178395B
- Authority
- NO
- Norway
- Prior art keywords
- pharmaceutically acceptable
- phenoxyphenyl
- dihydro
- imidazole
- formula
- Prior art date
Links
- -1 Phenoxyphenyl Chemical class 0.000 title claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 2
- ZGLAVBMQKPBEQJ-UHFFFAOYSA-N 2-[2-(4-chlorophenoxy)phenyl]-4,5-dihydro-1h-imidazole Chemical group C1=CC(Cl)=CC=C1OC1=CC=CC=C1C1=NCCN1 ZGLAVBMQKPBEQJ-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- IDVLIYJREHEZQR-UHFFFAOYSA-N [2-(3,4-dichlorophenoxy)phenyl]methanamine Chemical group NCC1=CC=CC=C1OC1=CC=C(Cl)C(Cl)=C1 IDVLIYJREHEZQR-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- VMWJCFLUSKZZDX-UHFFFAOYSA-N n,n-dimethylmethanamine Chemical compound [CH2]N(C)C VMWJCFLUSKZZDX-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 5
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000725 suspension Substances 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- OAKRNCISUVTPPE-UHFFFAOYSA-N 2-(4-chlorophenoxy)benzonitrile Chemical compound C1=CC(Cl)=CC=C1OC1=CC=CC=C1C#N OAKRNCISUVTPPE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 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
- 239000011976 maleic acid Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000000697 serotonin reuptake Effects 0.000 description 3
- RUHGJWKIGJKQEW-UHFFFAOYSA-N 2-(3,4-dichlorophenoxy)benzonitrile Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1=CC=CC=C1C#N RUHGJWKIGJKQEW-UHFFFAOYSA-N 0.000 description 2
- AFMPMSCZPVNPEM-UHFFFAOYSA-N 2-bromobenzonitrile Chemical compound BrC1=CC=CC=C1C#N AFMPMSCZPVNPEM-UHFFFAOYSA-N 0.000 description 2
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical compound OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- GWOPGJKFCPWKGF-UHFFFAOYSA-N [2-(3,4-dichlorophenoxy)phenyl]methanamine;hydrochloride Chemical compound Cl.NCC1=CC=CC=C1OC1=CC=C(Cl)C(Cl)=C1 GWOPGJKFCPWKGF-UHFFFAOYSA-N 0.000 description 2
- IJXXQQMVSQDMRM-UHFFFAOYSA-N [2-(4-chlorophenoxy)phenyl]methanamine;hydrochloride Chemical compound Cl.NCC1=CC=CC=C1OC1=CC=C(Cl)C=C1 IJXXQQMVSQDMRM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000007864 aqueous solution 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000002825 dopamine reuptake Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- DJLYZQORDBVJFE-UHFFFAOYSA-N (2-phenylsulfanylphenyl)methanamine Chemical compound NCC1=CC=CC=C1SC1=CC=CC=C1 DJLYZQORDBVJFE-UHFFFAOYSA-N 0.000 description 1
- KKGWMXUVUTUJIL-BTJKTKAUSA-N (Z)-but-2-enedioic acid 1-[2-(4-chlorophenoxy)phenyl]-N,N-dimethylmethanamine Chemical compound OC(=O)\C=C/C(O)=O.CN(C)CC1=CC=CC=C1OC1=CC=C(Cl)C=C1 KKGWMXUVUTUJIL-BTJKTKAUSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- VIGSVRVTHHOPCQ-UHFFFAOYSA-N 4-[(3-carboxy-2-hydroxynaphthalen-1-yl)methyl]-3-hydroxynaphthalene-2-carboxylic acid;2-[2-(4-chlorophenoxy)phenyl]-4,5-dihydro-1h-imidazole Chemical compound C1=CC(Cl)=CC=C1OC1=CC=CC=C1C1=NCCN1.C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 VIGSVRVTHHOPCQ-UHFFFAOYSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010012335 Dependence Diseases 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
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- XPFAPCMFZPIUQF-BTJKTKAUSA-N OC(=O)\C=C/C(O)=O.c1cc(Cl)ccc1Oc1ccccc1C1=NCCN1 Chemical compound OC(=O)\C=C/C(O)=O.c1cc(Cl)ccc1Oc1ccccc1C1=NCCN1 XPFAPCMFZPIUQF-BTJKTKAUSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 238000003482 Pinner synthesis reaction Methods 0.000 description 1
- 206010037213 Psychomotor retardation Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000003833 Wallach reaction Methods 0.000 description 1
- IAXVDWCOADTYIX-UHFFFAOYSA-N [2-(4-chlorophenoxy)phenyl]methanamine Chemical compound NCC1=CC=CC=C1OC1=CC=C(Cl)C=C1 IAXVDWCOADTYIX-UHFFFAOYSA-N 0.000 description 1
- WETJRTARNMHRQA-UHFFFAOYSA-N [2-(4-methoxyphenyl)sulfanylphenyl]methanamine Chemical compound C1=CC(OC)=CC=C1SC1=CC=CC=C1CN WETJRTARNMHRQA-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- MGFYSGNNHQQTJW-UHFFFAOYSA-N iodonium Chemical class [IH2+] MGFYSGNNHQQTJW-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
-
- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Description
Oppfinnelsen angår fenoksyfenyl-derivater, farmasøytiske preparater som inneholder slike og deres anvendelse for fremstilling av et medikament.
Derivater med kjemiske strukturer beslektet med fenoksyfenyl-derivatene i henhold til foreliggende oppfinnelse, er kjent fra J. Jilek et al., Collect. Czech. Commun., 54/1995 (1989), fra J. Jilek et al., ibid, 54/3294
(1989), fra Tsjekkisk patentsøknad 151.755 og fra Europeisk patentsøknad 402.097. Disse referanser beskriver fenyltiofenyl-derivater som selektive hemmere av serotonin-gjenopptak. Det har vist seg at disse tidligere forbindelsene har korte halveringstider, hvilket er en vesentlig ulempe ved deres praktiske anvendelse. Forbindelsene i henhold til oppfinnelsen har imidlertid lange halveringstider og hemmer, foruten serotonin-gjenopptak, også gjenopptaket av noradrenalin og dopamin. Hemmingen av dopamin-gjenopptak antas å føre til en hurtig hevning av stemningsleiet, hvilket gjør forbindelsene egnet for akutt lindring av depresjons-symptomer. Dette anses som en vesentlig fordel fremfor kjente antidepressiva, som for eksempel spesifikke blokkere av serotonin-gjenopptak, hvor den innsettende virkning er forsinket med 2 uker eller mer. Foreliggende forbindelser er dessuten som følge av deres blokkerende egenskaper av dopamin-gjenopptak, mindre sedative enn tidligere kjente forbindelser, og således bedre egnet ved behandling av depressive pasienter med psykomotorisk retardasjon. Forbindelsene i henhold til oppfinnelsen, kan også benyttes til behandling av Parkinsons sykdom, fedme, angst, sentral smerte, avhengighet og negative symptomer hos schizofrene pasienter.
Fenoksyfenyl-derivatene i henhold til oppfinnelsen har formelen
hvor
R er ett eller to halogenatomer; og
A er CH2NR1R2eller 4,5-dihydro-lH-imidazol, hvor R1og R2uavhengig av hverandre, er valgt fra hydrogen og lavere alkyl; eller
et farmasøytisk akseptabelt salt derav.
Foretrukne forbindelser i henhold til oppfinnelsen er fenoksyfenyl-derivater med formel I, hvor R er ett eller to kloratomer og A er CH2NH2, CH2N(CH3)2, eller 4,5-dihydro-lH-imidazol, og hvor dessuten fortrinnsvis R er én eller to klorsubstituenter, eller et farmasøytisk akseptabelt salt derav.
De mest fordelaktige fenoksyfenyl-derivater er 2-(3,4-diklorfenoksy)benzenmetanamin og 2-[2-(4-klorfenoksy)fenyl]-4,5-dihydro-lH-imidazol, eller farmasøytisk akseptable salter derav.
Betegnelsen lavere alkyl, benyttet i definisjonen av fenoksyfenyl-derivater med formel I, står for en forgrenet eller uforgrenet alkylgruppe som fortrinnsvis har 1-6 karbonatomer, så som metyl, etyl, propyl, isopropyl, butyl, tert-butyl, pentyl, heksyl og lignende. Foretrukne alkylgrupper har 1-4 karbonatomer, og særlig er metylgruppen foretrukket.
Betegnelsen halogen, benyttet i definisjonen av formel I, står for fluor, klor, brom eller jod. Klor er det foretrukne halogen.
De nye forbindelsene med formel I kan isoleres fra en reaksjonsblanding i form av et farmasøytisk akseptabelt salt. De farmasøytisk akseptable saltene kan også oppnås ved å behandle den frie base I med en organisk eller uorganisk syre, som HC1, HBr, HI, H2S04, H3P04, eddiksyre, propionsyre, glykolsyre, maleinsyre, malonsyre, metansulfonsyre, fumarsyre, ravsyre, vinsyre, sitronsyre, benzosyre, pamosyre eller ascorbinsyre.
Fenoksyfenyl-derivatene i henhold til foreliggende oppfinnelse, kan fremstilles etter fremgangsmåter kjent for analoge forbindelser.
En egnet metode for fremstilling består i en kondensajon av et nitril med formel
hvor R har den tidligere angitte betydning, med 1,2-etandiamin, eventuelt etterfulgt av omdannelse til et farmasøytisk akseptabelt salt; eller en reduksjon av nitrilet med formel II, eventuelt etterfulgt av alkylering og/eller omdannelse til et farmasøytisk akseptabelt salt. Nitrilet med formel II kan fremstilles ved kondensasjon av 2-halogenbenzonitril og fortrinnsvis 2-brombenzonitril, med en mono- eller dihalogensubstituert fenol under alkaliske betingelser. Nitrilet kan også fremstilles ved kondensasjon av 2-hydroksybenzonitril og et bis[mono- eller dihalogenbenzen]jodoniumsalt, som kan oppnås fra mono- eller dihalogenbenzen, jod og en blanding av svovelsyre og salpetersyre. Fenoksyfenyl-derivatene med formel I, hvor A er CH2NR1R2, hvor R1og R2har de tidligere angitte betydninger, kan også fremstilles ved reduksjon av et amid med formel
hvor R har den tidligere angitte betydning og R' er NR^R2, hvor R1og R2har de tidligere angitte betydninger.
Forbindelser med formel I, hvor A er 4,5-dihydro-lH- imidazol, kan også fremstilles fra et nitril som har formel II, gjennom en Pinner-reaksjon, som fører til en iminoester som kan omdannes til 4,5-dihydro-lH-imidazolet med 1,2-etandiamin.
Kondensasjon av 1,2-etandiamin med syrer eller estere med formel III, hvor R har den tidligere angitte betydning og R' er hydroksy, eller metoksy, eller en annen lavere alkoksy, gir også det ønskede fenoksyfenyl-derivat hvor A er 4,5-dihydro-lH-imidazol. Lavere alkoksy vil si en alkoksygruppe hvor alkoksydelen er en lavere alkylgruppe i henhold til tidligere definisjon.
Fenoksyfenyl-derivater med formel I, hvor A er CH2N<R>1R2, kan fremstilles fra syrer eller estere med formel III, ved reduksjon til den tilsvarende alkohol, omdannelse av hydroksygruppen til en passende utgående gruppe, så som klor eller brom, og kondensasjon med et amin som har formel HNR^R2, hvor R.^og R2har de tidligere angitte betydninger.
Det er mulig å omdanne produktene oppnådd etter en av de tidligere nevnte fremgangsmåter til et annet produkt i henhold til oppfinnelsen. Ved å benytte alminnelig kjente fremgangsmåter, er det for eksempel mulig å omdanne forbindelser hvor R1og/eller R2er hydrogen, f.eks. ved en Leukart-Wallach-reaksjon, til forbindelser hvor R1og/eller R2er alkyl.
Forbindelsene i henhold til oppfinnelsen kan administreres enteralt eller parenteralt, og ved human-anvendelse fortrinnsvis i en døgndose på 0,001-10 mg/kg legemsvekt. Blandet med farmasøytisk passende hjelpestoffer, f.eks. som beskrevet i standard-referansen Chase et al., Remington's Pharmaceutical Sciences, kan forbindelsene presses til doseringsenheter i fast form, så som piller eller tabletter, eller tilberedes som kapsler eller suppositorier. Ved hjelp av farmasøytisk egnede væsker kan forbindelsene også administreres som et injeksjonspreparat i form av en oppløsning, suspensjon, emulsjon eller som en spray, f.eks. en nesespray.
Oppfinnelsen illustreres ytterligere gjennom de følgende
eksempler.
Eksempel 1
2-( 4- klorfenoksy) benzenmetanamin- hvdroklorid
En oppløsning av 51,4 g 4-klorfenol i 500 ml tørr N,N-dimetylformamid (DMF) ble tilsatt til en suspensjon av 20 g 60% natriumhydrid i 800 ml tørr DMF under nitrogen. Etter 30 min. ved 25°C ble 1 g 18-krone-6 tilsatt. Etter tilsetning av 73 g 2-brombenzonitril i 500 ml tørr DMF, ble blandingen oppvarmet til 100°C i 16 timer. Etter konsentrering i vakuum ble 2N natriumhydroksyd og etylacetat tilsatt. Det organiske laget ble fraskilt, vasket med 2N natriumhydroksyd og vann, tørket over magnesiumsulfat og inndampet til tørrhet. Residuet ble omkrystallisert fra metanol for i 60% utbytte å gi 2-(4-klorfenoksy)benzonitril.
Til en suspensjon av 6 g litiumaluminiumhydrid i 100 ml tørr tetrahydrofuran (THF), ble det under nitrogen tilsatt 20 g 2-(4-klorfenoksy)benzonitril. Blandingen ble kokt under tilbakeløpskjøling i 3 timer, avkjølt og dråpevis tilsatt 25 ml IN natriumhydroksyd. Det oppståtte bunnfall ble frafiltrert og vasket med dietyleter. Filtratet ble inndampet til tørrhet, oppløst i etylacetat og surgjort med en mettet oppløsning av hydrogenklorid i etanol. Bunnfallet ble oppsamlet og omkrystallisert fra etanol for i 95% utbytte å gi 2-(4-klorfenoksy)benzenmetanamin-hydroklorid. Smp. 253°C.
Eksempel 2
2-( 3. 4- diklorfenoksy) benzenmetanamin- hydroklorid
Til en kraftig omrørt oppløsning av 12,7 g jod i 13 ml 60% røkende svovelsyre og 33 ml konsentrert svovelsyre ble det dråpevis tilsatt en oppløsning av 7,5 ml 9 0% røkende salpetersyre,1,9 ml 60% røkende svovelsyre og 5,5 ml konsentrert svovelsyre. Blandingen ble omrørt i 2 timer ved 70-80°C. Etter avkjøling til 0°C, ble en oppløsning av 28,2 ml 1,2-diklorbenzen tilsatt under kraftig omrøring. Reaksjonsblandingen ble holdt ved 45°C i 2 timer, avkjølt til 0°C og tilsatt 100 ml kaldt vann i én porsjon. Det vandige laget ble avdekantert og residuet, oppløst i metanol, tilsatt 5 ml konsentrert saltsyre. Bunnfallet ble tørket etter filtrering og vasking med metanol, og 24,4 g av bunnfallet tilsatt til en oppløsning av 5,6 g 2-hydroksybenzonitril og 2,2 g natriumhydroksyd i 440 ml vann. Etter 22 timers tilbakeløpsbehandling, ble blandingen avkjølt og ekstrahert med dietyleter. Det organiske laget ble vasket med 2N natriumhydroksyd, tørket over magnesiumsulfat og inndampet til tørrhet. Residuet ble omkrystallisert fra dietyleter, for i 80% utbytte, å gi 2-(3,4-diklorfenoksy)benzonitril.
En oppløsning av 10 g vannfritt aluminiumklorid i 150 ml tørr dietyleter ble under nitrogen dråpevis tilsatt til en suspensjon av 3,1 g litiumaluminiumhydrid i 150 ml tørr dietyleter, hvoretter blandingen ble avkjølt til 0°C. Etter 30 minutter ved 0°C, ble en oppløsning av 5,0 g 2-(3,4-diklorfenoksy)benzonitril i 150 ml tørr dietyleter, langsomt tilsatt. Blandingen ble omrørt i 24 timer ved 25°C og tilsatt en konsentrert vandig oppløsning av natriumhydrogenkarbonat. Bunnfallet ble frafiltrert, filtratet inndampet til tørrhet, oppløst i etylacetat og surgjort med en konsentrert oppløsning av hydrogenklorid i etanol. Bunnfallet ble oppsamlet og omkrystallisert fra en blanding av etanol og dietyleter, for i 75% utbytte, å gi 2-(3,4-diklorfenoksy)benzenmetanamin-hydroklorid. Smp. 213°C.
Eksempel 3
Ved tilsetning av en vandig oppløsning av dinatriumsaltet av pamosyre til en oppløsning av forbindelsen fra Eksempel 2 i etanol, ble det fremstillet 2-(3,4-diklorfenoksy)-benzenmetanamin-4,4'-metylenbis[3-hydroksy-2-naftalenkarboksylsyre]
(2:1) salt. Smp. 230°C.
Eksempel 4
2- f4- klorfenoksy)- N. N- dimetylbenzenmetanamin
( Z)- 2- butendioat
En blanding av 5 g 2-(4-klorfenoksy)benzenmetanamin (Eksempel 1), 50 ml maursyre og 50 ml av en 37% oppløsning av formaldehyd i vann ble oppvarmet til 100°C i 3 timer. Oppløsningen ble avkjølt, gjort alkalisk med natriumhydroksyd og ekstrahert med diklormetan. Det organiske laget ble vasket med saltvann, tørket over magnesiumsulfat og inndampet til tørrhet. Residuet ble oppløst i etanol og tilsatt maleinsyre. Etter fortynning med dietyleter, ble bunnfallet oppsamlet, vasket med dietyleter og tørket, for i 80% utbytte, å gi 2-(4-klorfenoksy)-N,N-dimetylbenzenmetanamin (Z)-2-butendioat. Smp. 118°C.
Eksempel 5
2 -\ 2 -( 4- klorfenoksy) fenyl]- 4, 5- dihydro- lH- imidazol fZ)- 2- butendioat
En oppløsning av 20 g 2-(4-klorfenoksy)benzonitril (Eksempel 1) i 80 ml 1,2-etandiamin ble mettet med hydrogensulfid i løpet av 30 minutter ved 0°C. Blandingen ble omrørt ved 25°C i 4 dager og deretter konsentrert og tilsatt etylacetat. Det organiske laget ble vasket med 2N natriumhydroksyd, tørket over magnesiumsulfat og inndampet til tørrhet. Residuet ble oppløst i etanol, behandlet med maleinsyre og omkrystallisert fra etanol, for i 80% utbytte, å gi 2-[2-(4-klorfenoksy)fenyl]-4,5-dihydro-lH-imidazol (Z)-2-butendioat. Smp. 207°C.
Eksempel 6
Analogt med beskrivelsen i Eksempel 5, ble det fremstillet: a. 2-[2-(3,4-diklorfenoksy)fenyl]-4,5-dihydro-lH-imidazol
(Z)-2-butendioat. Smp. 123°C.
b. 2-[2-(4-klorfenoksy)fenyl]-4,5-dihydro-lH-imidazol 4,4'-metylenbis[3-hydroksy-2-naftalenkarboksylsyre] (2:1) salt. Smp. >250°C.
Eksempel 7
De biologiske halveringstidene for fenoksyfenyl-derivatene ble bestemt med henblikk på "sleep-wake" oppførsel hos rotter og sammenlignet med halveringstider for tidligere kjente forbindelser.
kjente forbindelser: 2-(fenyltio)benzenmetanamin 0,5 2-[(4-metoksyfenyl)tio]benzenmetanamin <0,5
Claims (7)
1. Fenoksyfenyl-derivat,karakterisert vedformelen
hvor
R er ett eller to halogenatomer; og
A er CH2NR1R2eller 4,5-dihydro-lH-imidazol, hvor R^^ og R2uavhengig av hverandre, er valgt fra hydrogen og lavere alkyl; eller
et farmasøytisk akseptabelt salt derav.
2. Fenoksyfenyl-derivat ifølge krav 1,karakterisert vedat R er ett eller to kloratomer, og A er CH2NH2, CH2N(CH3)2eller 4,5-dihydro-lH-imidazol, eller et farmasøytisk akseptabelt salt derav.
3. Fenoksyfenyl-derivat ifølge et av kravene 1-2, karaterisert ved at det er 2-(3,4-diklorfenoksy)-benzenmetanamin eller et farmasøytisk akseptabelt salt derav.
4. Fenoksyfenyl-derivat ifølge et av kravene 1-2, karaterisert ved at det er 2-[2-(4-klorfenoksy)-fenyl]-4,5-dihydro-lH-imidazol eller et farmasøytisk akseptabelt salt derav.
5. Fenoksyfenyl-derivat for terapeutisk anvendelse, karaterisert ved at det har den i krav I angitte formel.
6. Farmasøytisk preparat,
karaterisert ved at det inneholder fenoksyfenyl-derivatet ifølge krav 1, i blanding med farmasøytisk akseptable hjelpestoffer.
7. Bruk av fenoksyfenyl-derivatet ifølge krav 1, for fremstilling av et medikament med lang halveringstid og virkning mot depresjon.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP91201288 | 1991-05-29 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO922110D0 NO922110D0 (no) | 1992-05-27 |
| NO922110L NO922110L (no) | 1992-11-30 |
| NO178395B true NO178395B (no) | 1995-12-11 |
| NO178395C NO178395C (no) | 1996-03-20 |
Family
ID=8207675
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO922110A NO178395C (no) | 1991-05-29 | 1992-05-27 | Fenoksyfenyl-derivater |
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| EP (1) | EP0516234B1 (no) |
| JP (1) | JPH05148197A (no) |
| KR (1) | KR920021493A (no) |
| AT (1) | ATE127777T1 (no) |
| AU (1) | AU650136B2 (no) |
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| FI (1) | FI922433A (no) |
| GR (1) | GR3018357T3 (no) |
| IE (1) | IE67144B1 (no) |
| NO (1) | NO178395C (no) |
| ZA (1) | ZA923283B (no) |
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| GB0007884D0 (en) * | 2000-03-31 | 2000-05-17 | Pfizer Ltd | Diphenyl ether compounds useful in therapy |
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| EP1184372B1 (en) * | 2000-08-31 | 2006-04-26 | Pfizer Limited | Phenoxyphenylheterocycle derivatives as selective serotonin reuptake inhibitors (SSRIs) |
| US6630504B2 (en) | 2000-08-31 | 2003-10-07 | Pfizer Inc. | Phenoxyphenylheterocyclyl derivatives as SSRIs |
| EE200300084A (et) * | 2000-08-31 | 2005-02-15 | Pfizer Inc. | Fenoksübensüülamiini derivaadid kui selektiivsed serotoniini tagasihaarde inhibiitorid |
| US6436938B1 (en) * | 2001-01-22 | 2002-08-20 | Pfizer Inc. | Combination treatment for depression |
| US20020165217A1 (en) * | 2001-05-01 | 2002-11-07 | Pfizer Inc. | Combination treatment for anxiety and depression |
| EP1260221A3 (en) * | 2001-05-23 | 2002-12-18 | Pfizer Products Inc. | Combination treatment for depression and anxiety |
| EP1262196A3 (en) * | 2001-05-23 | 2002-12-18 | Pfizer Products Inc. | Combination of a monoamine reuptake inhibitor and an opioid antagonist for use in alcoholism and alcohol dependence |
| US20020183306A1 (en) * | 2001-05-30 | 2002-12-05 | Pfizer Inc. | Combination treatment for sleep disorders including sleep apnea |
| JP2006511606A (ja) | 2002-12-13 | 2006-04-06 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | 下部尿路症状を治療するα−２−δリガンド |
| WO2007036781A1 (en) * | 2005-09-30 | 2007-04-05 | Pfizer Products Inc. | Diphenyl ether monoamine reuptake inhibitor |
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| JPS55104240A (en) * | 1979-02-07 | 1980-08-09 | Idemitsu Kosan Co Ltd | N-(alpha,alpha-dimethylbenzyl)-acetamide derivative and herbicide containing the same |
| JPS56108752A (en) * | 1980-01-28 | 1981-08-28 | Sumitomo Chem Co Ltd | N-substituted benzylphenylacetamide derivative, its preparation and herbicide containing the same as active constituent |
| US5149714A (en) * | 1987-08-14 | 1992-09-22 | Merrell Dow Pharmaceuticals Inc. | Antidepressants |
| JPH0791249B2 (ja) * | 1988-11-10 | 1995-10-04 | 北興化学工業株式会社 | メタアリールオキシアラルキルアミン誘導体および除草剤 |
| JPH07103079B2 (ja) * | 1988-11-21 | 1995-11-08 | 北興化学工業株式会社 | パラアリールオキシアラルキルアミン誘導体および殺虫・殺ダニ剤 |
| ZA899033B (en) * | 1988-12-01 | 1990-09-26 | Merrell Dow Pharma | Phenoxy and phenylthio,amino substituted benzocycloalkane derivatives in the treatment and prevention of drug-resistant protozoal infections |
| ZA923283B (en) * | 1991-05-29 | 1993-01-27 | Akzo Nv | Phenoxyphenyl derivatives |
-
1992
- 1992-05-06 ZA ZA923283A patent/ZA923283B/xx unknown
- 1992-05-11 CA CA002068373A patent/CA2068373A1/en not_active Abandoned
- 1992-05-22 AU AU17104/92A patent/AU650136B2/en not_active Ceased
- 1992-05-25 DK DK92201484.0T patent/DK0516234T3/da active
- 1992-05-25 AT AT92201484T patent/ATE127777T1/de active
- 1992-05-25 EP EP92201484A patent/EP0516234B1/en not_active Expired - Lifetime
- 1992-05-25 ES ES92201484T patent/ES2079783T3/es not_active Expired - Lifetime
- 1992-05-25 DE DE69204743T patent/DE69204743T2/de not_active Expired - Fee Related
- 1992-05-27 NO NO922110A patent/NO178395C/no unknown
- 1992-05-27 FI FI922433A patent/FI922433A/fi not_active Application Discontinuation
- 1992-05-28 JP JP4137276A patent/JPH05148197A/ja active Pending
- 1992-05-28 KR KR1019920009092A patent/KR920021493A/ko not_active Application Discontinuation
- 1992-05-29 US US07/891,545 patent/US5190965A/en not_active Expired - Fee Related
- 1992-07-01 IE IE921422A patent/IE67144B1/en not_active IP Right Cessation
-
1993
- 1993-02-03 US US08/012,700 patent/US5430063A/en not_active Expired - Fee Related
-
1995
- 1995-12-11 GR GR950403478T patent/GR3018357T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI922433A (fi) | 1992-11-30 |
| GR3018357T3 (en) | 1996-03-31 |
| DE69204743T2 (de) | 1996-04-04 |
| ZA923283B (en) | 1993-01-27 |
| US5190965A (en) | 1993-03-02 |
| EP0516234A1 (en) | 1992-12-02 |
| IE921422A1 (en) | 1992-12-02 |
| US5430063A (en) | 1995-07-04 |
| CA2068373A1 (en) | 1992-11-30 |
| AU1710492A (en) | 1992-12-03 |
| ATE127777T1 (de) | 1995-09-15 |
| AU650136B2 (en) | 1994-06-09 |
| IE67144B1 (en) | 1996-03-06 |
| JPH05148197A (ja) | 1993-06-15 |
| DK0516234T3 (da) | 1996-01-29 |
| KR920021493A (ko) | 1992-12-18 |
| NO922110D0 (no) | 1992-05-27 |
| EP0516234B1 (en) | 1995-09-13 |
| ES2079783T3 (es) | 1996-01-16 |
| DE69204743D1 (de) | 1995-10-19 |
| FI922433A0 (fi) | 1992-05-27 |
| NO922110L (no) | 1992-11-30 |
| NO178395C (no) | 1996-03-20 |
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