NZ196172A - 6(r)-(2-(8'-acyloxy(or hydroxy)-2'-methyl-6'-methyl(or hydrogen)-polyhydronaphthyl-1')-ethyl)-4(r)-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-one derivatives;pharmaceutical compositions - Google Patents
6(r)-(2-(8'-acyloxy(or hydroxy)-2'-methyl-6'-methyl(or hydrogen)-polyhydronaphthyl-1')-ethyl)-4(r)-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-one derivatives;pharmaceutical compositionsInfo
- Publication number
- NZ196172A NZ196172A NZ196172A NZ19617281A NZ196172A NZ 196172 A NZ196172 A NZ 196172A NZ 196172 A NZ196172 A NZ 196172A NZ 19617281 A NZ19617281 A NZ 19617281A NZ 196172 A NZ196172 A NZ 196172A
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- compound
- acids
- ethyl
- phenyl
- Prior art date
Links
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 title description 6
- 229910052739 hydrogen Inorganic materials 0.000 title description 6
- 239000001257 hydrogen Substances 0.000 title description 6
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 72
- 238000002360 preparation method Methods 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 29
- 150000002148 esters Chemical class 0.000 claims description 24
- -1 phenyldimethylamino- Chemical class 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 21
- 150000007513 acids Chemical class 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 239000012298 atmosphere Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 125000005907 alkyl ester group Chemical group 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- 239000007858 starting material Substances 0.000 claims description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- 125000005059 halophenyl group Chemical group 0.000 claims description 6
- 230000020477 pH reduction Effects 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- OZJPLYNZGCXSJM-UHFFFAOYSA-N delta-Valerolactone Natural products O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 claims description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- 230000000326 anti-hypercholesterolaemic effect Effects 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 238000007273 lactonization reaction Methods 0.000 claims description 3
- 239000003586 protic polar solvent Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims 4
- 238000005917 acylation reaction Methods 0.000 claims 4
- 125000001475 halogen functional group Chemical group 0.000 claims 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 239000007903 gelatin capsule Substances 0.000 claims 1
- 239000008101 lactose Substances 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 44
- 239000000243 solution Substances 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 229910001868 water Inorganic materials 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 238000000855 fermentation Methods 0.000 description 12
- 230000004151 fermentation Effects 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 150000001298 alcohols Chemical class 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical class O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 7
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000001261 hydroxy acids Chemical group 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 235000010633 broth Nutrition 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000013587 production medium Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- VGMFHMLQOYWYHN-UHFFFAOYSA-N Compactin Natural products OCC1OC(OC2C(O)C(O)C(CO)OC2Oc3cc(O)c4C(=O)C(=COc4c3)c5ccc(O)c(O)c5)C(O)C(O)C1O VGMFHMLQOYWYHN-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 150000002009 diols Chemical class 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 4
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000011573 trace mineral Substances 0.000 description 4
- 235000013619 trace mineral Nutrition 0.000 description 4
- FHSAZOGISLHXPK-UHFFFAOYSA-N 3-hydroxyoxan-2-one Chemical compound OC1CCCOC1=O FHSAZOGISLHXPK-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000538 analytical sample Substances 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 235000011148 calcium chloride Nutrition 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 229920000151 polyglycol Polymers 0.000 description 3
- 239000010695 polyglycol Substances 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- XNAQEDQKXCHDIW-UHFFFAOYSA-N 2-ethyl-2-methylbutanoyl chloride Chemical compound CCC(C)(CC)C(Cl)=O XNAQEDQKXCHDIW-UHFFFAOYSA-N 0.000 description 2
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 239000003529 anticholesteremic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- WWSNTLOVYSRDEL-DZSDEGEFSA-N compactin diol lactone Chemical compound C([C@@H]1[C@H]2[C@@H](O)CCC=C2C=C[C@@H]1C)C[C@@H]1C[C@@H](O)CC(=O)O1 WWSNTLOVYSRDEL-DZSDEGEFSA-N 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- WWSNTLOVYSRDEL-UHFFFAOYSA-N desmethylmonacolin J Natural products CC1C=CC2=CCCC(O)C2C1CCC1CC(O)CC(=O)O1 WWSNTLOVYSRDEL-UHFFFAOYSA-N 0.000 description 2
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
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- 125000002346 iodo group Chemical group I* 0.000 description 2
- 150000002596 lactones Chemical group 0.000 description 2
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 2
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- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
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- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
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- KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical class OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 1
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- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- AZYTZQYCOBXDGY-UHFFFAOYSA-N 2-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=CC=N1 AZYTZQYCOBXDGY-UHFFFAOYSA-N 0.000 description 1
- FJNCXZZQNBKEJT-UHFFFAOYSA-N 8beta-hydroxymarrubiin Natural products O1C(=O)C2(C)CCCC3(C)C2C1CC(C)(O)C3(O)CCC=1C=COC=1 FJNCXZZQNBKEJT-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
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- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- VXDSGTRNDFHIJB-QQPOVDNESA-N [(1s,4ar)-8-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1CCC[C@@H](C21)OC(=O)[C@@H](C)CC)=CC(C)C2CC[C@@H]1C[C@@H](O)CC(=O)O1 VXDSGTRNDFHIJB-QQPOVDNESA-N 0.000 description 1
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- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- 229940041514 candida albicans extract Drugs 0.000 description 1
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- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 1
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- VXDSGTRNDFHIJB-UHFFFAOYSA-N dihydrocompactin Natural products C12C(OC(=O)C(C)CC)CCCC2C=CC(C)C1CCC1CC(O)CC(=O)O1 VXDSGTRNDFHIJB-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000000686 lactone group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
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- 229910052749 magnesium Inorganic materials 0.000 description 1
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- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
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- 210000004080 milk Anatomy 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
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- 229910052700 potassium Inorganic materials 0.000 description 1
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- 230000003389 potentiating effect Effects 0.000 description 1
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
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- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 235000015113 tomato pastes and purées Nutrition 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ200588A NZ200588A (en) | 1980-02-04 | 1982-05-12 | 6(r)-(2-(8(s)-(2,2-dimethylbutyryloxy)-2(s),6(s)-dimethyl-1,2,3,4,4a(s),5,6,7,8,8a(s)-decahydronaphthyl-1(s))-ethyl)-4(r)-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-one and pharmaceutical compositions |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11805180A | 1980-02-04 | 1980-02-04 | |
| US11804980A | 1980-02-04 | 1980-02-04 | |
| US17546080A | 1980-08-05 | 1980-08-05 | |
| US06/175,232 US4293496A (en) | 1980-02-04 | 1980-08-05 | 6(R)-[2-(8-Hydroxy-2,6-dimethylpolyhydronaphthyl-1)-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ196172A true NZ196172A (en) | 1985-01-31 |
Family
ID=27494171
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ196172A NZ196172A (en) | 1980-02-04 | 1981-02-03 | 6(r)-(2-(8'-acyloxy(or hydroxy)-2'-methyl-6'-methyl(or hydrogen)-polyhydronaphthyl-1')-ethyl)-4(r)-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-one derivatives;pharmaceutical compositions |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0033538B1 (en:Method) |
| AU (1) | AU548996B2 (en:Method) |
| CA (1) | CA1199322A (en:Method) |
| CY (1) | CY1404A (en:Method) |
| DD (1) | DD155989A5 (en:Method) |
| DE (1) | DE3173042D1 (en:Method) |
| DK (1) | DK157292C (en:Method) |
| ES (1) | ES499079A0 (en:Method) |
| FI (1) | FI78082C (en:Method) |
| GR (1) | GR74798B (en:Method) |
| HK (1) | HK16488A (en:Method) |
| IE (1) | IE51478B1 (en:Method) |
| IL (1) | IL62044A (en:Method) |
| MA (1) | MA19054A1 (en:Method) |
| MY (1) | MY8700745A (en:Method) |
| NL (1) | NL930009I2 (en:Method) |
| NO (2) | NO154229C (en:Method) |
| NZ (1) | NZ196172A (en:Method) |
| PT (1) | PT72441B (en:Method) |
| RO (1) | RO82367B (en:Method) |
| SG (1) | SG61087G (en:Method) |
| YU (1) | YU28181A (en:Method) |
Families Citing this family (54)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0692381B2 (ja) * | 1980-03-31 | 1994-11-16 | 三共株式会社 | Ｍｂ−５３０ａ誘導体 |
| US4343814A (en) * | 1980-11-17 | 1982-08-10 | Merck & Co., Inc. | Hypocholesterolemic fermentation products |
| US4432996A (en) * | 1980-11-17 | 1984-02-21 | Merck & Co., Inc. | Hypocholesterolemic fermentation products and process of preparation |
| EP0094443A1 (en) * | 1982-05-17 | 1983-11-23 | Merck & Co. Inc. | 6(R)-(2-(8(S) (2,2-dimethylbutyryloxy)-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S))ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, process for preparing and pharmaceutical composition containing the same |
| US4503072A (en) * | 1982-12-22 | 1985-03-05 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
| CA1268473A (en) * | 1983-01-24 | 1990-05-01 | Paul L. Anderson | Analogs of mevalonolactone and derivatives thereof, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals |
| EP0137445B1 (en) * | 1983-10-11 | 1990-01-03 | Merck & Co. Inc. | Process for c-methylation of 2-methylbutyrates |
| EP0137444B1 (en) * | 1983-10-11 | 1990-01-31 | Merck & Co. Inc. | Processes for preparing 6(R)-[2-[8(S)(2,2-dimethylbutyryloxy)-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-Decahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one |
| US4668699A (en) * | 1985-08-05 | 1987-05-26 | Merck & Co., Inc. | Novel HMG-CoA reductase inhibitors |
| US4833258A (en) * | 1987-02-17 | 1989-05-23 | Merck & Co., Inc. | Intermediates useful in the preparation of HMG-COA reductase inhibitors |
| US4997848A (en) | 1987-10-27 | 1991-03-05 | Sankyo Company, Limited | Octahydronaphthalene oxime derivatives for cholesterol synthesis inhibition |
| US5021451A (en) * | 1988-11-14 | 1991-06-04 | Hoffman-La Roche Inc. | Method for inhibiting hyperproliferative diseases |
| GB8915280D0 (en) * | 1989-07-04 | 1989-08-23 | British Bio Technology | Compounds |
| US5110825A (en) * | 1989-12-28 | 1992-05-05 | Shionogi & Co., Ltd. | Benzofuran derivative |
| GB9100174D0 (en) * | 1991-01-04 | 1991-02-20 | British Bio Technology | Compounds |
| NZ250609A (en) * | 1992-12-28 | 1995-07-26 | Sankyo Co | Hexahydronaphthalene esters and ring closed lactones; preparation and medicaments |
| US6642268B2 (en) | 1994-09-13 | 2003-11-04 | G.D. Searle & Co. | Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors |
| US6268392B1 (en) | 1994-09-13 | 2001-07-31 | G. D. Searle & Co. | Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors |
| NZ286920A (en) * | 1995-07-03 | 1997-06-24 | Sankyo Co | Use of combination of hmg-coa reductase inhibitors and of insulin sensitizers for the prevention/treatment of arteriosclerosis or xanthoma |
| AU7271696A (en) * | 1995-12-06 | 1997-06-27 | Antibiotic Co | Method of production of lovastatin |
| CA2185961A1 (en) | 1996-09-19 | 1998-03-20 | K.S. Keshava Murthy | Process for producing simvastatin |
| US6083497A (en) | 1997-11-05 | 2000-07-04 | Geltex Pharmaceuticals, Inc. | Method for treating hypercholesterolemia with unsubstituted polydiallylamine polymers |
| SI9800057A (sl) * | 1998-02-26 | 1999-08-31 | Krka, Tovarna Zdravil, D.D. | Postopek za pripravo simvastatina in njegovih derivatov |
| CA2240983A1 (en) | 1998-06-18 | 1999-12-18 | Yong Tao | Process to manufacture simvastatin and intermediates |
| ATE241386T1 (de) | 1998-12-23 | 2003-06-15 | Searle Llc | Kombinationen von ileumgallensäuretransports inhibitoren und cholesteryl ester transfer protein inhibitoren |
| EP1340508A1 (en) | 1998-12-23 | 2003-09-03 | G.D. Searle LLC. | Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications |
| PT1140190E (pt) | 1998-12-23 | 2003-02-28 | Searle Llc | Combinacoes de inibidores do transporte ileal dos acidos biliares e agentes sequestrantes dos acidos biliares usadas para problemas cardiovasculares |
| EP1140186B1 (en) | 1998-12-23 | 2003-06-04 | G.D. Searle LLC. | Combinations of cholesteryl ester transfer protein inhibitors and fibric acid derivatives for cardiovascular indications |
| ES2203239T3 (es) | 1998-12-23 | 2004-04-01 | G.D. Searle Llc | Combinaciones de inhibidores de la proteina de transferencia de ester de colesterilo y de agentes secuestrantes de acidos biliares para indicaciones cardiovasculares. |
| US6462091B1 (en) | 1998-12-23 | 2002-10-08 | G.D. Searle & Co. | Combinations of cholesteryl ester transfer protein inhibitors and HMG coA reductase inhibitors for cardiovascular indications |
| WO2000038727A1 (en) | 1998-12-23 | 2000-07-06 | G.D. Searle Llc | Combinations of ileal bile acid transport inhibitors and fibric acid derivatives for cardiovascular indications |
| WO2001068637A2 (en) | 2000-03-10 | 2001-09-20 | Pharmacia Corporation | Method for the preparation of tetrahydrobenzothiepines |
| HUP0302929A3 (en) | 2000-09-07 | 2004-10-28 | Kaneka Corp | Methods for crystallization of hydroxycarboxylic acids |
| BR0213501A (pt) | 2001-11-02 | 2004-08-24 | Searle Llc | Compostos de benzotiepina mono- e di-fluorada como inibidores de transporte de ácido biliar co-dependente de sódio apical (asbt) e captação de taurocolato |
| CA2471639A1 (en) | 2002-01-17 | 2003-07-31 | Pharmacia Corporation | Novel alkyl/aryl hydroxy or keto thiepines. |
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| ES2330184B1 (es) | 2008-06-03 | 2010-07-05 | Neuron Biopharma, S.A. | Uso de estatinas como anticonvulsivantes, antiepilepticos y neuroprotectores. |
| ES2343049B1 (es) | 2008-10-15 | 2011-06-10 | Neuron Biopharma, S.A. | Biosintesis de derivados de monacolina j. |
| EP2204170A1 (en) | 2008-12-01 | 2010-07-07 | LEK Pharmaceuticals D.D. | Pharmaceutical composition comprising ezetimibe and simvastatin |
| WO2010069593A1 (en) | 2008-12-19 | 2010-06-24 | Krka, D. D., Novo Mesto | Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates |
| EP2327682A1 (en) | 2009-10-29 | 2011-06-01 | KRKA, D.D., Novo Mesto | Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates |
| EP2216016A1 (en) | 2009-02-06 | 2010-08-11 | LEK Pharmaceuticals d.d. | Process for the preparation of a pharmaceutical composition comprising ezetimibe |
| EP2241561A1 (en) * | 2009-04-16 | 2010-10-20 | Neuron Biopharma, S.A. | Neuroprotective, hypocholesterolemic and antiepileptic compound |
| WO2011002424A2 (en) | 2009-07-02 | 2011-01-06 | Bilgic Mahmut | Solubility and stability enchancing pharmaceutical formulation |
| AR079336A1 (es) | 2009-12-11 | 2012-01-18 | Irm Llc | Antagonistas de la pro-proteina convertasa-subtilisina/quexina tipo 9 (pcsk9) |
| EP2368543A1 (en) | 2010-03-25 | 2011-09-28 | KRKA, tovarna zdravil, d.d., Novo mesto | Method of preparing a granulated pharmaceutical composition comprising simvastatin and/or ezetimibe |
| ES2380473B1 (es) * | 2010-10-13 | 2013-02-19 | Neuron Biopharma, S.A. | Compuesto neuroprotector, hipocolesterolémico, antiinflamatorio y antiepiléptico. |
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Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4049495A (en) * | 1974-06-07 | 1977-09-20 | Sankyo Company Limited | Physiologically active substances and fermentative process for producing the same |
| JPS5612114B2 (en:Method) * | 1974-06-07 | 1981-03-18 | ||
| DE2748825C2 (de) | 1976-11-02 | 1986-11-27 | Sankyo Co., Ltd., Tokio/Tokyo | Substituierte 3,5-Dihydroxyheptansäurederivate und diese enthaltende Arzneimittel gegen Hyperlipämie |
| JPS6026094B2 (ja) | 1978-07-04 | 1985-06-21 | 三共株式会社 | テトラヒドロｍｌ↓−２３６ｂおよびその誘導体並びにそれを有効成分とする高脂血症治療剤 |
| JPS5925599B2 (ja) * | 1979-02-20 | 1984-06-19 | 三共株式会社 | 新生理活性物質モナコリンｋおよびその製造法 |
| IL60219A (en) * | 1979-06-15 | 1985-05-31 | Merck & Co Inc | Hypocholesteremic fermentation products of the hmg-coa reductase inhibitor type,their preparation and pharmaceutical compositions containing them |
| US4231938A (en) * | 1979-06-15 | 1980-11-04 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
| PT72394B (en) | 1980-02-04 | 1982-09-06 | Merck & Co Inc | Process for preparing dihydro and tetrahydromevinoline hypocholesterolimics |
-
1981
- 1981-01-23 AU AU66573/81A patent/AU548996B2/en not_active Expired
- 1981-01-29 MA MA19255A patent/MA19054A1/fr unknown
- 1981-02-02 IL IL62044A patent/IL62044A/xx not_active IP Right Cessation
- 1981-02-02 GR GR64028A patent/GR74798B/el unknown
- 1981-02-02 FI FI810287A patent/FI78082C/fi not_active IP Right Cessation
- 1981-02-02 CY CY140481A patent/CY1404A/xx unknown
- 1981-02-02 EP EP81100729A patent/EP0033538B1/en not_active Expired
- 1981-02-02 DE DE8181100729T patent/DE3173042D1/de not_active Expired
- 1981-02-03 NO NO810358A patent/NO154229C/no unknown
- 1981-02-03 IE IE204/81A patent/IE51478B1/en not_active IP Right Cessation
- 1981-02-03 DD DD81227405A patent/DD155989A5/de unknown
- 1981-02-03 CA CA000369992A patent/CA1199322A/en not_active Expired
- 1981-02-03 DK DK046181A patent/DK157292C/da active
- 1981-02-03 NZ NZ196172A patent/NZ196172A/en unknown
- 1981-02-03 ES ES499079A patent/ES499079A0/es active Granted
- 1981-02-03 YU YU00281/81A patent/YU28181A/xx unknown
- 1981-02-03 PT PT72441A patent/PT72441B/pt unknown
- 1981-02-04 RO RO103303A patent/RO82367B/ro unknown
-
1987
- 1987-07-27 SG SG610/87A patent/SG61087G/en unknown
- 1987-12-30 MY MY745/87A patent/MY8700745A/xx unknown
-
1988
- 1988-03-03 HK HK164/88A patent/HK16488A/en not_active IP Right Cessation
-
1993
- 1993-02-09 NL NL930009C patent/NL930009I2/nl unknown
-
1994
- 1994-07-01 NO NO1994001C patent/NO1994001I1/no unknown
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