PL143322B1 - Process for preparing novel phenyl substituted pyrido/1,4/benzodiazepines - Google Patents
Process for preparing novel phenyl substituted pyrido/1,4/benzodiazepines Download PDFInfo
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- PL143322B1 PL143322B1 PL1981253540A PL25354081A PL143322B1 PL 143322 B1 PL143322 B1 PL 143322B1 PL 1981253540 A PL1981253540 A PL 1981253540A PL 25354081 A PL25354081 A PL 25354081A PL 143322 B1 PL143322 B1 PL 143322B1
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- mol
- phenyl
- pyrido
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims description 10
- 229940049706 benzodiazepine Drugs 0.000 title description 15
- 150000001557 benzodiazepines Chemical class 0.000 title description 13
- 238000004519 manufacturing process Methods 0.000 title 1
- 239000000203 mixture Substances 0.000 claims description 80
- 229910001868 water Inorganic materials 0.000 claims description 53
- 150000001875 compounds Chemical class 0.000 claims description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- 239000000047 product Substances 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 17
- -1 phenyl-substituted pyrido [1,4] benzodiazepines Chemical class 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 238000007363 ring formation reaction Methods 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 239000007795 chemical reaction product Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 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 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 125000005265 dialkylamine group Chemical group 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 101100490437 Mus musculus Acvrl1 gene Proteins 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 238000010586 diagram Methods 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 174
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 54
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 239000000243 solution Substances 0.000 description 43
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 35
- 239000011541 reaction mixture Substances 0.000 description 34
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 28
- 238000002844 melting Methods 0.000 description 27
- 230000008018 melting Effects 0.000 description 27
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 27
- 238000000921 elemental analysis Methods 0.000 description 26
- 239000000284 extract Substances 0.000 description 25
- 239000000725 suspension Substances 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 229910000104 sodium hydride Inorganic materials 0.000 description 21
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 20
- 239000012312 sodium hydride Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000001914 filtration Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000012458 free base Substances 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 239000012299 nitrogen atmosphere Substances 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 14
- 239000002480 mineral oil Substances 0.000 description 12
- 235000010446 mineral oil Nutrition 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- LJQNMDZRCXJETK-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine;hydron;chloride Chemical compound Cl.CN(C)CCCCl LJQNMDZRCXJETK-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 10
- 239000001530 fumaric acid Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000007858 starting material Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical class N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- CJHKJXZMFZKGHI-UHFFFAOYSA-N 1h-pyrido[2,3-i][1,2]benzodiazepine Chemical class N1N=CC=CC2=CC=C(N=CC=C3)C3=C12 CJHKJXZMFZKGHI-UHFFFAOYSA-N 0.000 description 4
- TXHIDIHEXDFONW-UHFFFAOYSA-N benzene;propan-2-one Chemical compound CC(C)=O.C1=CC=CC=C1 TXHIDIHEXDFONW-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- SAALQYKUFCIMHR-UHFFFAOYSA-N propan-2-ol;2-propan-2-yloxypropane Chemical compound CC(C)O.CC(C)OC(C)C SAALQYKUFCIMHR-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical class NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 description 3
- MEQBJJUWDCYIAB-UHFFFAOYSA-N 2-chloropyridin-3-amine Chemical compound NC1=CC=CN=C1Cl MEQBJJUWDCYIAB-UHFFFAOYSA-N 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- WUFWBVLAMURTLR-UHFFFAOYSA-N 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine Chemical class N=1C2=CC=CN=C2NC2=CC=CC=C2C=1C1=CC=CC=C1 WUFWBVLAMURTLR-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 3
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- LQLJZSJKRYTKTP-UHFFFAOYSA-N 2-dimethylaminoethyl chloride hydrochloride Chemical compound Cl.CN(C)CCCl LQLJZSJKRYTKTP-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000006286 aqueous extract Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- UWQIEDGNGUIPKS-UHFFFAOYSA-N benzene 2,2,4-trimethylpentane Chemical compound C1=CC=CC=C1.CC(C)CC(C)(C)C UWQIEDGNGUIPKS-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000008533 dibenzodiazepines Chemical group 0.000 description 2
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- UUBJKHVFGWGJKX-UHFFFAOYSA-N hydrate tetrahydrochloride Chemical compound O.Cl.Cl.Cl.Cl UUBJKHVFGWGJKX-UHFFFAOYSA-N 0.000 description 2
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960005333 tetrabenazine Drugs 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- PELAWRHVRDOWQT-UHFFFAOYSA-N (2-amino-4-chlorophenyl)-phenylmethanone Chemical compound NC1=CC(Cl)=CC=C1C(=O)C1=CC=CC=C1 PELAWRHVRDOWQT-UHFFFAOYSA-N 0.000 description 1
- GFHWOKUXKUUKQJ-UHFFFAOYSA-N (2-amino-4-methoxyphenyl)-phenylmethanone Chemical compound NC1=CC(OC)=CC=C1C(=O)C1=CC=CC=C1 GFHWOKUXKUUKQJ-UHFFFAOYSA-N 0.000 description 1
- ZUWXHHBROGLWNH-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-phenylmethanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 ZUWXHHBROGLWNH-UHFFFAOYSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- USQAILMOWHOBTK-WLHGVMLRSA-N (e)-but-2-enedioic acid;n,n-dimethyl-3-(6-phenylpyrido[2,3-b][1,4]benzodiazepin-11-yl)propan-1-amine Chemical compound OC(=O)\C=C\C(O)=O.N=1C2=CC=CN=C2N(CCCN(C)C)C2=CC=CC=C2C=1C1=CC=CC=C1 USQAILMOWHOBTK-WLHGVMLRSA-N 0.000 description 1
- OBOBUDMMFXRNDO-UHFFFAOYSA-N 1-(3-chloropropyl)piperidine;hydron;chloride Chemical compound Cl.ClCCCN1CCCCC1 OBOBUDMMFXRNDO-UHFFFAOYSA-N 0.000 description 1
- RYCQVMPEIVZMII-UHFFFAOYSA-N 11h-pyrido[2,3-b][1,4]benzodiazepine Chemical class C1=NC2=CC=CN=C2NC2=CC=CC=C21 RYCQVMPEIVZMII-UHFFFAOYSA-N 0.000 description 1
- OPACCTXYZFTUOQ-UHFFFAOYSA-N 1h-pyrido[2,3-i][1,4]benzodiazepine Chemical compound N1C=CN=CC2=CC=C(N=CC=C3)C3=C12 OPACCTXYZFTUOQ-UHFFFAOYSA-N 0.000 description 1
- VKJCJJYNVIYVQR-UHFFFAOYSA-N 2-(3-bromopropyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCBr)C(=O)C2=C1 VKJCJJYNVIYVQR-UHFFFAOYSA-N 0.000 description 1
- XNCXMCJPXNTROP-UHFFFAOYSA-N 2-[3-(6-phenylpyrido[2,3-b][1,4]benzodiazepin-11-yl)propyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CCCN(C1=NC=CC=C1N=1)C2=CC=CC=C2C=1C1=CC=CC=C1 XNCXMCJPXNTROP-UHFFFAOYSA-N 0.000 description 1
- YFQVSTNNJZZYLY-UHFFFAOYSA-N 2-amino-4,6-diphenylpyridine-3-carbonitrile Chemical compound N#CC=1C(N)=NC(C=2C=CC=CC=2)=CC=1C1=CC=CC=C1 YFQVSTNNJZZYLY-UHFFFAOYSA-N 0.000 description 1
- 150000005801 3-amino-2-chloropyridine Chemical class 0.000 description 1
- PQECODMSWJOUAT-UHFFFAOYSA-N 4-(3-chloropropyl)morpholine;hydrochloride Chemical compound [Cl-].ClCCC[NH+]1CCOCC1 PQECODMSWJOUAT-UHFFFAOYSA-N 0.000 description 1
- RBHLFWNKEWLHBP-UHFFFAOYSA-N 4-(4-aminophenyl)butanoic acid Chemical compound NC1=CC=C(CCCC(O)=O)C=C1 RBHLFWNKEWLHBP-UHFFFAOYSA-N 0.000 description 1
- AVLLMVWZBRQLLV-UHFFFAOYSA-N 6-(2-fluorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine Chemical compound FC1=CC=CC=C1C1=NC2=CC=CN=C2NC2=CC=CC=C12 AVLLMVWZBRQLLV-UHFFFAOYSA-N 0.000 description 1
- ONTPLJNFNFUZDH-UHFFFAOYSA-N 6-(3-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine Chemical compound ClC1=CC=CC(C=2C3=CC=CC=C3NC3=NC=CC=C3N=2)=C1 ONTPLJNFNFUZDH-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 101150070189 CIN3 gene Proteins 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical class O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
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- 240000007472 Leucaena leucocephala Species 0.000 description 1
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- 235000019483 Peanut oil Nutrition 0.000 description 1
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- 229930006000 Sucrose Natural products 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000002804 anti-anaphylactic effect Effects 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
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- 239000011260 aqueous acid Substances 0.000 description 1
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- 230000000903 blocking effect Effects 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000000451 chemical ionisation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical class CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- IFYLVUHLOOCYBG-UHFFFAOYSA-N eticyclidine Chemical compound C=1C=CC=CC=1C1(NCC)CCCCC1 IFYLVUHLOOCYBG-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000000752 ionisation method Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- WRHGGQFJPWBBTG-UHFFFAOYSA-N n,n-dimethyl-3-(6-phenylpyrido[2,3-b][1,4]benzodiazepin-11-yl)propan-1-amine Chemical compound N=1C2=CC=CN=C2N(CCCN(C)C)C2=CC=CC=C2C=1C1=CC=CC=C1 WRHGGQFJPWBBTG-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- AAZYNPCMLRQUHI-UHFFFAOYSA-N propan-2-one;2-propan-2-yloxypropane Chemical compound CC(C)=O.CC(C)OC(C)C AAZYNPCMLRQUHI-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- 230000001528 ptotic effect Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005303 weighing 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
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
-
- 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- 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
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30508081A | 1981-09-24 | 1981-09-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PL143322B1 true PL143322B1 (en) | 1988-02-29 |
Family
ID=23179241
Family Applications (6)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL1981253540A PL143322B1 (en) | 1981-09-24 | 1981-12-23 | Process for preparing novel phenyl substituted pyrido/1,4/benzodiazepines |
| PL1981241410A PL137068B1 (en) | 1981-09-24 | 1981-12-23 | Method of obtaining novel /2-/(aminopyridinylo/amino/phenyl arylmetanones |
| PL1981234426A PL138859B1 (en) | 1981-09-24 | 1981-12-23 | Method of obtaining novel phenyl substituted pyrido /1,4/ benzosiazepins |
| PL1981253539A PL143597B1 (en) | 1981-09-24 | 1981-12-23 | Process for preparing novel phenyl substituted pyrido (1,4) benzodiazepines |
| PL1981241409A PL139381B1 (en) | 1981-09-24 | 1981-12-23 | Process for preparing novel,phenyl-substituted pyrido-/1,4/benzodiazepins |
| PL1981253538A PL143596B1 (en) | 1981-09-24 | 1981-12-23 | Process for preparing novel phenyl substituted pyrido (1,4) benzodiazepin |
Family Applications After (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL1981241410A PL137068B1 (en) | 1981-09-24 | 1981-12-23 | Method of obtaining novel /2-/(aminopyridinylo/amino/phenyl arylmetanones |
| PL1981234426A PL138859B1 (en) | 1981-09-24 | 1981-12-23 | Method of obtaining novel phenyl substituted pyrido /1,4/ benzosiazepins |
| PL1981253539A PL143597B1 (en) | 1981-09-24 | 1981-12-23 | Process for preparing novel phenyl substituted pyrido (1,4) benzodiazepines |
| PL1981241409A PL139381B1 (en) | 1981-09-24 | 1981-12-23 | Process for preparing novel,phenyl-substituted pyrido-/1,4/benzodiazepins |
| PL1981253538A PL143596B1 (en) | 1981-09-24 | 1981-12-23 | Process for preparing novel phenyl substituted pyrido (1,4) benzodiazepin |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS5865290A (es) |
| KR (1) | KR890000764B1 (es) |
| BE (1) | BE891666A (es) |
| CA (1) | CA1199324A (es) |
| CH (1) | CH651833A5 (es) |
| DE (1) | DE3150522A1 (es) |
| DK (3) | DK186282A (es) |
| EG (1) | EG15904A (es) |
| ES (6) | ES507971A0 (es) |
| FI (1) | FI71935C (es) |
| FR (1) | FR2515183B1 (es) |
| GR (1) | GR78473B (es) |
| HU (2) | HU189426B (es) |
| IE (1) | IE52493B1 (es) |
| IL (1) | IL64284A (es) |
| IN (1) | IN156080B (es) |
| IT (1) | IT1146728B (es) |
| LU (1) | LU83865A1 (es) |
| NL (1) | NL8200549A (es) |
| NO (1) | NO157700C (es) |
| NZ (1) | NZ198999A (es) |
| PH (2) | PH17847A (es) |
| PL (6) | PL143322B1 (es) |
| PT (1) | PT74286B (es) |
| SE (2) | SE448629B (es) |
| YU (1) | YU46128B (es) |
| ZA (1) | ZA817866B (es) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3825549A (en) * | 1972-10-24 | 1974-07-23 | Squibb & Sons Inc | Certain dihydropyrido(2,1-b)(1,3)benzodi-azepines and benzodiazocines |
| DE2424811C3 (de) * | 1974-05-22 | 1981-08-20 | Dr. Karl Thomae Gmbh, 7950 Biberach | Pyrido-benzodiazepinone, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel |
| SE422799B (sv) * | 1975-05-28 | 1982-03-29 | Merck & Co Inc | Analogiforfarande for framstellning av 1,3-dihydroimidazo (4,5-b)pyridin-2-oner |
-
1981
- 1981-11-05 SE SE8106573A patent/SE448629B/sv not_active IP Right Cessation
- 1981-11-12 NO NO813839A patent/NO157700C/no unknown
- 1981-11-12 ZA ZA817866A patent/ZA817866B/xx unknown
- 1981-11-13 IN IN1261/CAL/81A patent/IN156080B/en unknown
- 1981-11-13 IL IL64284A patent/IL64284A/xx unknown
- 1981-11-17 GR GR66553A patent/GR78473B/el unknown
- 1981-11-18 PH PH26507A patent/PH17847A/en unknown
- 1981-11-25 IE IE2769/81A patent/IE52493B1/en unknown
- 1981-12-09 IT IT68605/81A patent/IT1146728B/it active
- 1981-12-10 FI FI813976A patent/FI71935C/fi not_active IP Right Cessation
- 1981-12-15 HU HU843212A patent/HU189426B/hu not_active IP Right Cessation
- 1981-12-15 HU HU813777A patent/HU187393B/hu not_active IP Right Cessation
- 1981-12-15 ES ES507971A patent/ES507971A0/es active Granted
- 1981-12-21 DE DE19813150522 patent/DE3150522A1/de not_active Withdrawn
- 1981-12-23 PL PL1981253540A patent/PL143322B1/pl unknown
- 1981-12-23 PL PL1981241410A patent/PL137068B1/pl unknown
- 1981-12-23 PL PL1981234426A patent/PL138859B1/pl unknown
- 1981-12-23 PL PL1981253539A patent/PL143597B1/pl unknown
- 1981-12-23 PL PL1981241409A patent/PL139381B1/pl unknown
- 1981-12-23 PL PL1981253538A patent/PL143596B1/pl unknown
- 1981-12-23 FR FR8124111A patent/FR2515183B1/fr not_active Expired
- 1981-12-30 BE BE0/206969A patent/BE891666A/fr not_active IP Right Cessation
-
1982
- 1982-01-05 LU LU83865A patent/LU83865A1/fr unknown
- 1982-01-12 EG EG11/82A patent/EG15904A/xx active
- 1982-01-14 JP JP57004813A patent/JPS5865290A/ja active Pending
- 1982-01-15 PT PT74286A patent/PT74286B/pt unknown
- 1982-01-18 CA CA000394367A patent/CA1199324A/en not_active Expired
- 1982-02-02 KR KR8200420A patent/KR890000764B1/ko not_active Expired
- 1982-02-12 NL NL8200549A patent/NL8200549A/nl not_active Application Discontinuation
- 1982-02-18 NZ NZ198999A patent/NZ198999A/en unknown
- 1982-03-23 YU YU62582A patent/YU46128B/sh unknown
- 1982-04-15 CH CH2288/82A patent/CH651833A5/fr not_active IP Right Cessation
- 1982-04-26 DK DK186282A patent/DK186282A/da not_active Application Discontinuation
- 1982-09-29 ES ES516052A patent/ES516052A0/es active Granted
- 1982-09-29 ES ES516051A patent/ES516051A0/es active Granted
-
1983
- 1983-10-19 ES ES526563A patent/ES8604531A1/es not_active Expired
- 1983-10-19 ES ES526562A patent/ES8504148A1/es not_active Expired
-
1984
- 1984-08-17 PH PH31120A patent/PH20536A/en unknown
-
1985
- 1985-05-21 ES ES543328A patent/ES8607726A1/es not_active Expired
-
1986
- 1986-02-17 SE SE8600688A patent/SE455305B/sv not_active IP Right Cessation
-
1987
- 1987-08-03 DK DK403387A patent/DK403387A/da not_active Application Discontinuation
- 1987-08-03 DK DK403487A patent/DK403487D0/da not_active Application Discontinuation
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