NO159999B - Analogifremgangsmaate for fremstilling av farmakologisk aktive substituerte 2-fenyl-2-(pyridyloksy)-etylamin-derivater og isostere forbindelser. - Google Patents
Analogifremgangsmaate for fremstilling av farmakologisk aktive substituerte 2-fenyl-2-(pyridyloksy)-etylamin-derivater og isostere forbindelser. Download PDFInfo
- Publication number
- NO159999B NO159999B NO823253A NO823253A NO159999B NO 159999 B NO159999 B NO 159999B NO 823253 A NO823253 A NO 823253A NO 823253 A NO823253 A NO 823253A NO 159999 B NO159999 B NO 159999B
- Authority
- NO
- Norway
- Prior art keywords
- hydrogen
- amino
- methyl
- group
- ethylamine
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 26
- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 3
- KOTORXCUYIJTDH-UHFFFAOYSA-N 2-phenyl-2-pyridin-2-yloxyethanamine Chemical class C=1C=CC=CC=1C(CN)OC1=CC=CC=N1 KOTORXCUYIJTDH-UHFFFAOYSA-N 0.000 title description 2
- 230000000144 pharmacologic effect Effects 0.000 title description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- -1 methoxy, amino Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000007858 starting material Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 230000001430 anti-depressive effect Effects 0.000 description 5
- 239000000935 antidepressant agent Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229940005513 antidepressants Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 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
- 239000000126 substance Substances 0.000 description 3
- 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 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali 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
- USFRYJRPHFMVBZ-UHFFFAOYSA-M benzyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CC1=CC=CC=C1 USFRYJRPHFMVBZ-UHFFFAOYSA-M 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 2
- 229960003147 reserpine Drugs 0.000 description 2
- 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 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- LJHHIQDQJJALPC-UHFFFAOYSA-N 2-(4-bromophenyl)-n,n-dimethyl-2-pyridin-3-yloxyethanamine;dihydrochloride Chemical compound Cl.Cl.C=1C=C(Br)C=CC=1C(CN(C)C)OC1=CC=CN=C1 LJHHIQDQJJALPC-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 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
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- PLOZGFUTWNOXFV-UHFFFAOYSA-N OC(=O)C(O)=O.OC(=O)C(O)=O.C=1C=C(Br)C=CC=1C(CN(C)C)NC1=CC=CC=N1 Chemical compound OC(=O)C(O)=O.OC(=O)C(O)=O.C=1C=C(Br)C=CC=1C(CN(C)C)NC1=CC=CC=N1 PLOZGFUTWNOXFV-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-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
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000009835 boiling Methods 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
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 150000007925 phenylethylamine derivatives Chemical class 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
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- C07D213/68—One oxygen atom attached in position 4
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description
Denne oppfinnelse angår en analogifremgangsmåte for fremstilling av nye substituerte 2-fenyl-2-(pyridyloksy)-etyl-aminer og isostere forbindelser med den generelle formel
hvor
og R2# som kan være like eller forskjellige, betyr hydrogen, halogen, metyl, metoksy, amino eller nitro,
R^ betyr hydrogen, halogen eller metyl,
R4 og R^, som kan være like eller forskjellige, betyr hydrogen eller en alkylgruppe med 1 til 2 karbonatomer eller kan sammen med nitrogenatomet danne en pyrrolidino- eller morfolinoring, og X betyr 0, NH eller S,
og deres syreaddisjonssalter,
som kan anvendes som virkestoffer i legemidler.
De nye forbindelser fremstilles ifølge oppfinnelsen
ved at et fenyletylamin med den generelle formel
hvor R^, R^, R^ og R^ har de ovenfor angitte betydninger, og Y betyr et halogenatom eller en hydroksygruppe, eller st syreaddisjonssalt av denne forbindelse, omsettes med et pyridinderivat med den generelle formel
hver har den ovenfor angitte betydning, og Z betyr en hydroksy-, amino- eller merkaptogruppe.
Ved anvendelse av utgangsstoffer med den generelle
formel II hvor Y betyr en hydroksygruppe, skjer kondensasjonen med en forbindelse med den generelle formel III i et surt medium ved forhøyede temperaturer. Ved denne omsetning anvendes sterke uorganiske eller organiske syrer, f.eks. konsentrerte mineralsyrer så som saltsyre, bromhydrogensyre, svovelsyre, polyfosforsyre, og dessuten eddiksyreanhydrid, fosforpentoksyd eller trifluoreddiksyre.
Fenyletylaminer med den generelle formel II hvor Y betyr et halogenatom, omsettes fortrinnsvis under anvendelse av et basisk stoff og fortrinnsvis under fase-overførings-betingelser (dvs. under tilsetning av ett eller flere langkjedete,
tertiære aminer så som et benzyl-tributyl-ammonium-halogenid eller et tetrabutyl-ammonium-halogenid eller under tilsetning av benzyl-trifenylfosfoniumklorid) med pyridin-derivatet med den generelle formel III.
Som basiske stoffer kan f.eks. anvendes uorganiske baser
så som alkali- eller jordalkalihydroksyder eller -karbonater, organiske baser så som pyridin, piperidin, tertiære aminer eller også alkalialkoholater.
Forbindelser med den generelle formel I hvor R^ og/eller R^ betyr hydrogen, kan alkyleres på i og for seg kjent måte, f.eks. ved omsetning med et dialkylsulfat eller et alkyl-halogenid.
Utgangsmaterialene er vanlige kjemikalier som kan kjøpes eller som kan fremstilles ved vanlig kjente fremgangsmåter.
Sluttproduktene med den generelle formel I kan eventuelt overføres til sine fysiologisk godtagbare syreaddisjonssalter efter vanlige metoder.
Egnede syrer for dette formål er både uorganiske syrer
så som halogenhydrogensyrer, svovelsyre, fosforsyre og amino-sulfonsyre, og også organiske syrer så som maursyre, eddiksyre, propionsyre, melkesyre, glykolsyre, glukonsyre, maleinsyre, ravsyre, vinsyre, benzoesyre, salicylsyre, sitronsyre,
askorbinsyre, p-toluensulfonsyre eller oksyetansulfonsyre.
De nye forbindelser med den generelle formel I og deres syreaddisjonssalter representerer verdifulle farmasøytiske forbindelser. De er godt virksomme i de biokjemiske og farmakologiske testanordninger som er spesifikke for anti-depressiva. Således har de evnen til å hemme den ptose som fremkalles hos mus ved hjelp av tetrabenzain, og ED50 ligger ved størrelsesorden 1 mg/kg. Denne test tjener som standard-test på antidepressive egenskaper (International Journal of Neuropharmacology 8, 73 (1969)).
Også ved testen på reserpinantagonisme, en opphevelse
av den hypotermiske effekt som forårsakes av reserpin, ved hjelp av en antidepressiv aktiv forbindelse, har forbindelsene fremstilt ifølge oppfinnelsen vist seg å ha en særdeles gunstig virkning. Dessuten har det vist seg at de hemmer gjenopptagelsen av serotonin og adrenalin i neuronene.
De nye forbindelser er særlig verdifulle da de har en struktur som adskiller seg fra strukturen hos kjent anti-depressiva og dessuten er de likeverdige med eller bedre enn kjente handelsprodukter med hensyn til virkning og lav toksisitet.
Særlig skal fremheves slike forbindelser med den generelle formel I hvor R^ betyr et bromatom i p-stilling, X betyr et oksygenatom eller en aminogruppe, R2 betyr hydrogen, og R, og R^ betyr metylgrupper. Spesielt skal følgende forbindelser fremheves: 2-(p-bromfenyl)-2-(pyridyl-(3)-oksy)-N,N-dimetyl-etylamin, 2-(p-bromfenyl-2-(pyridyl-(2)-amino)-N,N-dimetyl-etylamin, 2-(p-bromfenyl)-2-(pyridyl-(3)-amino)-N,N-dimetyl-etylamin.
Fra TJS-patent 3.471.501 er det kjent forbindelser som f.eks. N,N-dimetyl-N<1->fenyl-N'-(2-pyridylmetyl)-etylendiamin. Disse forbindelser har hostestillende egenskaper. Struktur-messig er disse forbindelser vesentlig forskjellige fra forbindelsene som fremstilles ifølge oppfinnelsen. De kjente forbindelser inneholder således to tertiære aminogrupper, hvor fenylresten er bundet direkte til nitrogenatomet, mens pyridylresten er bundet over CH2. I de anti-depressivt virkende forbindelser fremstilt ifølge oppfinnelsen er derimot fenylgruppen bundet til et C-atom i etylendiamin, og pyridylresten er bundet direkte til nitrogen (hvis X er NH; når X
er 0 eller S, er forskjellen enda større), slik at de nye forbindelser da inneholder en sekundær aminogruppe.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere: E ksempel 1
2- p- bromfenyl- 2-( 3- pyridyloksy)- N, N- dimetyl- etylamin-d ihydroklorid
29,9 g 2-klor-2-p-bromf enyl-N ,N-dimetyl-etylan;in-hydroklorid (0,1 mol) og 14,3 g 3-hydroksypyridin (0,15 mol)
i 150 ml 25%ig natronlut og 150 ml toluen oppvarmes til kokning under tilbakeløpskjøling i 16 timer sammen med 0,5 g benzyltrifenylfosfoniumklorid. Efter avdestillering av oppløsningsmidlet fra den organiske fase blir tilbake et residuum som oppløses i alkohol. Med saltsyre dannes dihydrokloridet av tittelforbindelsen. For rensning behandles titelforbindelsen i cykloheksan med aktivt kull og kiselgur. Utbyttet av dihydroklorid er 20 g (44% av det teoretiske). Sm.p. 128-129°C (etanol).
Eksempel 2
2- p- bromfenyl- 2-( 2- pyridylamino)- N, N- dimety1- etylamin- dioksalat
24,5 g 2-p-bromfenyl-N,N-dimetyletanolamin (0,1 mol)
og 11 g'2-aminopyridin (0,11 mol) oppvarmes i 50 ml metan-sulfonsyre i 30 minutter til 60°C. Den ennu varme reaksjons-blanding helles på is, gjøres alkalisk med ammoniakk og ekstraheres med etylacetat. Rensningen foretas kolonne-kromatografisk over silikagel/metylenklorid-etylacetat-metanol. Ved tilsetning av alkoholisk oksalsyre dannes det krystallinske dioksalat av tittelforbindelsen.
Utbyttet utgjør 21 g (42% av det teoretiske).
Sm.p. 170-171°C.
Ifølge den ovenfor beskrevne fremgangsmåte ble de følgende forbindelser med den generelle formel I fremstilt:
Claims (4)
1. Analogifremgangsmåte for fremstilling av farmakologisk aktive substituerte 2^fenyl-2-(pyridyloksy)-etylaminer og
deres isostere forbindelser med den generelle formel
hvor
og R2/ som kan være like eller forskjellige, betyr hydrogen, halogen, metyl, metoksy, amino eller nitro, R, betyr hydrogen, halogen eller metyl,
R4 og R,-, som kan være like eller forskjellige, betyr hydrogen eller en alkylgruppe med 1 til 2 karbonatomer eller kan sammen med nitrogenatomet danne en pyrrolidino- eller morfolinoring, og X betyr 0, NH eller S,
og deres fysiologisk forlikelige syreaddisjonssalter, karakterisert ved at et fenyletylamin med
den generelle formel
hvor R^, R2, R^ og R^ har den ovenfor angitte betydning, og V betyr et halogenatom eller en hydroksygruppe, resp. et <sy>readdisjonssalt av denne forbindelse, omsettes med et pyridinderivat med den generelle formel
hvor betyr hydrogen, et halogenatom eller en metylgruppe,
og Z betyr en hydroksy-, amino- eller merkaptogruppe,
og det således oppnådde sluttprodukt overføres eventuelt til et fysiologisk forlikelig syreaddisjonssalt.
2. Fremgangsmåte ifølge krav 1 for fremstilling av 2-(p-brcmfenyl)-2-(pyridyl-(3)-oksy)-N,N-dimetyl-etylamin, karakterisert ved at det anvendes utgangs-materialer hvor R, er hydrogen, R., er p-brom, R^ er hydrogen, R4 og R^ er hver metyl, og Z er en hydroksygruppe i 3-stilling.
3. Fremgangsmåte ifølge krav 1 for fremstilling av 2-(p-bromfenyl)-2-(pyridyl-(2)-amino)-N,N-dimetyl-etylamin, karakterisert ved at det anvendes utgangs-materialer hvor R^ er hydrogen, R-, er p-brom, R^ er hydrogen, R. og R^ er hver metyl, og Z er en aminogruppe i 2-stilling.
4. Fremgangsmåte ifølge krav 1 for fremstilling av 2- (p-brcmfenyl)-2-(pyridyl-(3)-amino)-N,N-dimetyl-etylamin, karakterisert ved at det anvendes utgangs-materialer hvor R^ er hydrogen, R2 er p-brom, R^ er hydrogen, R. og Rj. er hver metyl, og Z er en aminogruppe i 3-stilling.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19813138550 DE3138550A1 (de) | 1981-09-28 | 1981-09-28 | Substituierte 2-phenyl-2-(pyridyloxy)-ethylamine und isostere verbindungen, verfahren zu ihrer herstellung und verwendung |
Publications (3)
Publication Number | Publication Date |
---|---|
NO823253L NO823253L (no) | 1983-03-29 |
NO159999B true NO159999B (no) | 1988-11-21 |
NO159999C NO159999C (no) | 1989-03-01 |
Family
ID=6142812
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO823253A NO159999C (no) | 1981-09-28 | 1982-09-27 | Analogifremgangsmaate for fremstilling av farmakologisk aktive substituerte 2-fenyl-2-(pyridyloksy)-etylamin-derivater og isostere forbindelser. |
Country Status (21)
Country | Link |
---|---|
US (1) | US4666910A (no) |
EP (1) | EP0075752B1 (no) |
JP (1) | JPS5869865A (no) |
KR (1) | KR880002705B1 (no) |
AR (1) | AR231534A1 (no) |
AT (1) | ATE18551T1 (no) |
AU (1) | AU550614B2 (no) |
CA (1) | CA1171086A (no) |
DE (2) | DE3138550A1 (no) |
DK (1) | DK156718C (no) |
ES (1) | ES8308543A1 (no) |
FI (1) | FI78074C (no) |
GB (1) | GB2106902B (no) |
GR (1) | GR77657B (no) |
IE (1) | IE53959B1 (no) |
IL (1) | IL66870A (no) |
NO (1) | NO159999C (no) |
NZ (1) | NZ202015A (no) |
PH (1) | PH23219A (no) |
PT (1) | PT75611B (no) |
ZA (1) | ZA827055B (no) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
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GB8320699D0 (en) * | 1983-08-01 | 1983-09-01 | Wellcome Found | Ethylenediamines |
GB0004151D0 (en) * | 2000-02-23 | 2000-04-12 | Astrazeneca Uk Ltd | Novel use |
GB0004153D0 (en) * | 2000-02-23 | 2000-04-12 | Astrazeneca Uk Ltd | Novel use |
GB0004152D0 (en) | 2000-02-23 | 2000-04-12 | Astrazeneca Uk Ltd | Novel compounds |
AR035700A1 (es) * | 2001-05-08 | 2004-06-23 | Astrazeneca Ab | Derivados de arilheteroalquilamina, composicion farmaceutica, usos de estos derivados para la fabricacion de medicamentos, metodos de tratamiento, y proceso para la preparacion de estos derivados |
SE0102641D0 (sv) * | 2001-07-31 | 2001-07-31 | Astrazeneca Ab | Novel compounds |
SE0102640D0 (sv) * | 2001-07-31 | 2001-07-31 | Astrazeneca Ab | Novel compounds |
SE0102639D0 (sv) * | 2001-07-31 | 2001-07-31 | Astrazeneca Ab | Novel compounds |
GB0219154D0 (en) * | 2002-08-16 | 2002-09-25 | Pfizer Ltd | Diaryl compounds |
US6800652B2 (en) | 2002-08-16 | 2004-10-05 | Pfizer Inc. | Diaryl compounds |
SE0203304D0 (sv) * | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Coumpounds |
KR20060110288A (ko) * | 2003-10-09 | 2006-10-24 | 밀레니엄 파머슈티컬스 인코퍼레이티드 | 인자 xa 의 저해제로서의 티오에테르-치환 벤즈아미드 |
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US2734846A (en) * | 1956-02-14 | Aqueous suspension of procaine penicil- | ||
US2734845A (en) * | 1956-02-14 | Aqueous suspension of procaine penicil- | ||
FR1511398A (fr) * | 1966-02-16 | 1968-01-26 | Takeda Chemical Industries Ltd | Procédé de préparation de nouveaux dérivés de picoline |
BE790592A (no) * | 1971-10-28 | 1973-04-26 | Oreal | |
US4011324A (en) * | 1976-01-20 | 1977-03-08 | Pfizer Inc. | Esters and amides of pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylic acids as antiulcer agents |
JPS53141271A (en) * | 1977-05-13 | 1978-12-08 | Yamanouchi Pharmaceut Co Ltd | Heterocyclic compounds and process for their preparation |
-
1981
- 1981-09-28 DE DE19813138550 patent/DE3138550A1/de not_active Withdrawn
-
1982
- 1982-09-06 EP EP82108196A patent/EP0075752B1/de not_active Expired
- 1982-09-06 AT AT82108196T patent/ATE18551T1/de not_active IP Right Cessation
- 1982-09-06 DE DE8282108196T patent/DE3269839D1/de not_active Expired
- 1982-09-22 FI FI823246A patent/FI78074C/fi not_active IP Right Cessation
- 1982-09-24 AR AR290759A patent/AR231534A1/es active
- 1982-09-24 IL IL66870A patent/IL66870A/xx unknown
- 1982-09-27 ZA ZA827055A patent/ZA827055B/xx unknown
- 1982-09-27 NZ NZ202015A patent/NZ202015A/en unknown
- 1982-09-27 NO NO823253A patent/NO159999C/no unknown
- 1982-09-27 AU AU88738/82A patent/AU550614B2/en not_active Ceased
- 1982-09-27 ES ES515972A patent/ES8308543A1/es not_active Expired
- 1982-09-27 IE IE2330/82A patent/IE53959B1/en not_active IP Right Cessation
- 1982-09-27 JP JP57168221A patent/JPS5869865A/ja active Granted
- 1982-09-27 PT PT75611A patent/PT75611B/pt not_active IP Right Cessation
- 1982-09-27 DK DK428582A patent/DK156718C/da not_active IP Right Cessation
- 1982-09-27 KR KR8204342A patent/KR880002705B1/ko active
- 1982-09-27 CA CA000412268A patent/CA1171086A/en not_active Expired
- 1982-09-27 GB GB08227449A patent/GB2106902B/en not_active Expired
- 1982-09-28 GR GR69383A patent/GR77657B/el unknown
-
1984
- 1984-08-28 US US06/645,007 patent/US4666910A/en not_active Expired - Fee Related
-
1985
- 1985-03-07 PH PH31952A patent/PH23219A/en unknown
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