NO852822L - Fremgangsmaate for fremstilling av organiske fosfonatderivater. - Google Patents
Fremgangsmaate for fremstilling av organiske fosfonatderivater.Info
- Publication number
- NO852822L NO852822L NO852822A NO852822A NO852822L NO 852822 L NO852822 L NO 852822L NO 852822 A NO852822 A NO 852822A NO 852822 A NO852822 A NO 852822A NO 852822 L NO852822 L NO 852822L
- Authority
- NO
- Norway
- Prior art keywords
- doublet
- formula
- solution
- diphosphonates
- sodium
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 40
- 238000002360 preparation method Methods 0.000 title claims description 17
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 93
- 239000000203 mixture Substances 0.000 claims description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 29
- -1 Cf^ CE^ OCH^ Chemical group 0.000 claims description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- 239000012312 sodium hydride Substances 0.000 claims description 13
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical class 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 150000000185 1,3-diols Chemical class 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 150000001340 alkali metals Chemical group 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 2
- 229960002887 deanol Drugs 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 229910021645 metal ion Inorganic materials 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 2
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 claims 1
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 1
- 238000011065 in-situ storage Methods 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims 1
- 229910000103 lithium hydride Inorganic materials 0.000 claims 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims 1
- 229910000105 potassium hydride Inorganic materials 0.000 claims 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims 1
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 3
- 229920000166 polytrimethylene carbonate Polymers 0.000 abstract description 3
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical group OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 abstract description 3
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical class BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 100
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 72
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
- 238000004821 distillation Methods 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 22
- 229960005425 nitrendipine Drugs 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 230000000694 effects Effects 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 239000000725 suspension Substances 0.000 description 17
- 230000027455 binding Effects 0.000 description 16
- 239000011575 calcium Substances 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 15
- 230000008020 evaporation Effects 0.000 description 15
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 14
- 229940127291 Calcium channel antagonist Drugs 0.000 description 13
- 229910010082 LiAlH Inorganic materials 0.000 description 12
- 230000001077 hypotensive effect Effects 0.000 description 12
- 241000700159 Rattus Species 0.000 description 11
- VPWICVVYUCSKCN-UHFFFAOYSA-N sodium;dibutyl phosphite Chemical compound [Na+].CCCCOP([O-])OCCCC VPWICVVYUCSKCN-UHFFFAOYSA-N 0.000 description 11
- KJDXLXSXIVFIIB-UHFFFAOYSA-N P1(=O)OC(CC)OP(O1)=O Chemical compound P1(=O)OC(CC)OP(O1)=O KJDXLXSXIVFIIB-UHFFFAOYSA-N 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 108091006146 Channels Proteins 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 8
- 206010020772 Hypertension Diseases 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 230000008602 contraction Effects 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- BYMVZHORNHZYPQ-UHFFFAOYSA-N sodium;diethyl phosphite Chemical compound [Na+].CCOP([O-])OCC BYMVZHORNHZYPQ-UHFFFAOYSA-N 0.000 description 8
- 229960001722 verapamil Drugs 0.000 description 8
- LODRGECCKZZTEQ-UHFFFAOYSA-N 2-benzylpropane-1,3-diol Chemical compound OCC(CO)CC1=CC=CC=C1 LODRGECCKZZTEQ-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 6
- YNUXDWWNKONUFB-UHFFFAOYSA-N 2-(3-phenylpropyl)propane-1,3-diol Chemical compound OCC(CO)CCCC1=CC=CC=C1 YNUXDWWNKONUFB-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 108090000312 Calcium Channels Proteins 0.000 description 6
- 102000003922 Calcium Channels Human genes 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- XFUUFBLWGWFPHO-UHFFFAOYSA-N [3-bromo-2-(bromomethyl)propyl]benzene Chemical compound BrCC(CBr)CC1=CC=CC=C1 XFUUFBLWGWFPHO-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 6
- 229960004166 diltiazem Drugs 0.000 description 6
- 150000002009 diols Chemical class 0.000 description 6
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 6
- 229960001597 nifedipine Drugs 0.000 description 6
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 210000003437 trachea Anatomy 0.000 description 6
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 5
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 5
- IFFPICMESYHZPQ-UHFFFAOYSA-N Prenylamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)CCNC(C)CC1=CC=CC=C1 IFFPICMESYHZPQ-UHFFFAOYSA-N 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 230000001746 atrial effect Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- LXQXGFPPYLKKSD-UHFFFAOYSA-L disodium;2,2-diethylpropanedioate Chemical compound [Na+].[Na+].CCC(CC)(C([O-])=O)C([O-])=O LXQXGFPPYLKKSD-UHFFFAOYSA-L 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000001030 gas--liquid chromatography Methods 0.000 description 5
- 210000002837 heart atrium Anatomy 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000010626 work up procedure Methods 0.000 description 5
- 206010002383 Angina Pectoris Diseases 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 229910004298 SiO 2 Inorganic materials 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- SMANXXCATUTDDT-QPJJXVBHSA-N flunarizine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCN(C\C=C\C=2C=CC=CC=2)CC1 SMANXXCATUTDDT-QPJJXVBHSA-N 0.000 description 4
- 229960000326 flunarizine Drugs 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 229960001989 prenylamine Drugs 0.000 description 4
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- KVCGISUBCHHTDD-UHFFFAOYSA-M sodium;4-methylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1 KVCGISUBCHHTDD-UHFFFAOYSA-M 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 3
- IVFGIXMLURJXBZ-UHFFFAOYSA-N 1-phosphonopropylphosphonic acid Chemical compound CCC(P(O)(O)=O)P(O)(O)=O IVFGIXMLURJXBZ-UHFFFAOYSA-N 0.000 description 3
- DLYVTIZXOVFVMZ-UHFFFAOYSA-N 2-(2-phenoxyethyl)propane-1,3-diol Chemical compound OCC(CO)CCOC1=CC=CC=C1 DLYVTIZXOVFVMZ-UHFFFAOYSA-N 0.000 description 3
- LSMBUUGOVWEWQQ-UHFFFAOYSA-N 2-(naphthalen-1-ylmethyl)propane-1,3-diol Chemical compound C1=CC=C2C(CC(CO)CO)=CC=CC2=C1 LSMBUUGOVWEWQQ-UHFFFAOYSA-N 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 208000001953 Hypotension Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 3
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- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/28—Phosphorus compounds with one or more P—C bonds
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- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F9/58—Pyridine rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C—CHEMISTRY; METALLURGY
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- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/6533—Six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicines Containing Plant Substances (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH3488/84A CH664158A5 (fr) | 1984-07-18 | 1984-07-18 | Derives propylidenediphosphonates-1,3 substitues en position 2, leur procede de preparation et compositions pharmaceutiques les contenant. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO852822L true NO852822L (no) | 1986-01-20 |
Family
ID=4257079
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO852822A NO852822L (no) | 1984-07-18 | 1985-07-15 | Fremgangsmaate for fremstilling av organiske fosfonatderivater. |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US4696920A (da) |
| EP (1) | EP0173041B1 (da) |
| JP (1) | JPS6140294A (da) |
| KR (1) | KR930005390B1 (da) |
| AT (1) | ATE38991T1 (da) |
| AU (1) | AU581442B2 (da) |
| CA (1) | CA1284320C (da) |
| CH (1) | CH664158A5 (da) |
| CS (1) | CS262421B2 (da) |
| DE (2) | DE3566545D1 (da) |
| DK (1) | DK324185A (da) |
| ES (1) | ES8702427A1 (da) |
| FI (1) | FI79327C (da) |
| GR (1) | GR851767B (da) |
| HU (1) | HU193791B (da) |
| IL (1) | IL75807A (da) |
| NO (1) | NO852822L (da) |
| NZ (1) | NZ212768A (da) |
| PT (1) | PT80820B (da) |
| SU (1) | SU1375141A3 (da) |
| YU (1) | YU117185A (da) |
| ZA (1) | ZA855357B (da) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4639338A (en) * | 1984-08-06 | 1987-01-27 | Ciba-Geigy Corporation | Preparation of crystalline disodium 3-amino-1-hydroxypropane-1,1-diphosphonate pentahydrate |
| IL77243A (en) * | 1984-12-21 | 1996-11-14 | Procter & Gamble | Pharmaceutical compositions containing geminal diphosphonic acid compounds and certain such novel compounds |
| US5071840A (en) * | 1986-12-19 | 1991-12-10 | Norwich Eaton Pharmaceuticals, Inc. | Certain heterocyclic substituted diphosphonate compounds pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism |
| NZ226378A (en) * | 1987-10-08 | 1989-12-21 | Colgate Palmolive Co | Packaged dental cream containing polyoxyethylene/polyoxypropylene block copolymer |
| CH675422A5 (da) * | 1988-03-31 | 1990-09-28 | Symphar Sa | |
| US5332743A (en) * | 1992-06-12 | 1994-07-26 | Mcneilab, Inc. | Benzyl and benzhydryl alcohols |
| JPH08502287A (ja) * | 1992-10-09 | 1996-03-12 | ジ・アップジョン・カンパニー | 抗炎症剤としてのピリミジンビスホスホン酸エステルおよび（アルコキシメチルホスフィニル）アルキルホスホン酸 |
| DE19902924A1 (de) * | 1999-01-26 | 2000-08-03 | Hassan Jomaa | Verwendung von phosphororganischen Verbindungen zur prophylaktischen und therapeutischen Behandlung von Infektionen |
| US7442689B2 (en) * | 2000-02-29 | 2008-10-28 | Medicure International Inc. | Cardioprotective phosphonates and malonates |
| PT1268498E (pt) | 2000-02-29 | 2005-07-29 | Medicure Int Inc | Fosfonatos cardioprotectores |
| US6548519B1 (en) | 2001-07-06 | 2003-04-15 | Medicure International Inc. | Pyridoxine and pyridoxal analogues: novel uses |
| US6897228B2 (en) * | 2000-07-07 | 2005-05-24 | Medicure International Inc. | Pyridoxine and pyridoxal analogues: new uses |
| ATE364595T1 (de) | 2000-07-07 | 2007-07-15 | Medicure Int Inc | Pyridoxin- und pyridoxalanaloga als cardiovasculäre therapeutika |
| US20040186077A1 (en) * | 2003-03-17 | 2004-09-23 | Medicure International Inc. | Novel heteroaryl phosphonates as cardioprotective agents |
| CA2570048A1 (en) * | 2004-07-07 | 2006-01-12 | Medicure International Inc. | Combination therapies employing platelet aggregation drugs |
| US7459468B2 (en) * | 2004-10-28 | 2008-12-02 | Medicure International, Inc. | Aryl sulfonic pyridoxines as antiplatelet agents |
| WO2006050598A1 (en) * | 2004-10-28 | 2006-05-18 | Medicure International Inc. | Dual antiplatelet/anticoagulant pyridoxine analogs |
| US20060094749A1 (en) * | 2004-10-28 | 2006-05-04 | Medicure International Inc. | Substituted pyridoxines as anti-platelet agents |
| AU2006317440A1 (en) * | 2005-11-28 | 2007-05-31 | Medicure International Inc. | Selected dosage for the treatment of cardiovascular and related pathologies |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3256370A (en) * | 1962-12-13 | 1966-06-14 | Monsanto Co | Process for preparing alkylene-diphosphonates |
| CA770642A (en) * | 1965-12-02 | 1967-10-31 | Union Carbide Corporation | Phosphine oxides |
| DE2535685A1 (de) * | 1975-08-09 | 1977-02-17 | Bayer Ag | Verfahren zur herstellung von propan-1,3-bis-phosphonyl-verbindungen |
| DE2621604A1 (de) * | 1976-05-14 | 1977-12-01 | Bayer Ag | Substituierte propan-1,3-diphosphonsaeuren und -phosphinsaeuren |
| GB2043072B (en) * | 1979-02-13 | 1983-11-23 | Symphar Sa | Diphosphonate compounds |
| US4416877A (en) * | 1979-02-13 | 1983-11-22 | Symphar S.A. | Anti-atherosclerotic pharmaceutical compositions containing diphosphonate compounds |
| DE3065878D1 (en) * | 1979-07-09 | 1984-01-19 | Elf Aquitaine | Diphosphonic and triphosphonic acid esters, their preparation and applications |
| GB2079285B (en) * | 1980-07-09 | 1984-05-23 | Symphar Sa | Dipthosphonate derivatives and pahrmaceutical compositions containing them |
| US4639338A (en) * | 1984-08-06 | 1987-01-27 | Ciba-Geigy Corporation | Preparation of crystalline disodium 3-amino-1-hydroxypropane-1,1-diphosphonate pentahydrate |
-
1984
- 1984-07-18 CH CH3488/84A patent/CH664158A5/fr not_active IP Right Cessation
-
1985
- 1985-07-11 EP EP85108670A patent/EP0173041B1/en not_active Expired
- 1985-07-11 DE DE8585108670T patent/DE3566545D1/de not_active Expired
- 1985-07-11 DE DE198585108670T patent/DE173041T1/de active Pending
- 1985-07-11 AT AT85108670T patent/ATE38991T1/de active
- 1985-07-15 NO NO852822A patent/NO852822L/no unknown
- 1985-07-15 HU HU852714A patent/HU193791B/hu unknown
- 1985-07-15 IL IL75807A patent/IL75807A/xx unknown
- 1985-07-16 GR GR851767A patent/GR851767B/el unknown
- 1985-07-16 ZA ZA855357A patent/ZA855357B/xx unknown
- 1985-07-16 US US06/755,712 patent/US4696920A/en not_active Expired - Fee Related
- 1985-07-17 ES ES545330A patent/ES8702427A1/es not_active Expired
- 1985-07-17 NZ NZ212768A patent/NZ212768A/xx unknown
- 1985-07-17 PT PT80820A patent/PT80820B/pt not_active IP Right Cessation
- 1985-07-17 CA CA000486929A patent/CA1284320C/en not_active Expired - Fee Related
- 1985-07-17 FI FI852806A patent/FI79327C/fi not_active IP Right Cessation
- 1985-07-17 SU SU853926752A patent/SU1375141A3/ru active
- 1985-07-17 CS CS855305A patent/CS262421B2/cs unknown
- 1985-07-17 YU YU01171/85A patent/YU117185A/xx unknown
- 1985-07-17 DK DK324185A patent/DK324185A/da not_active Application Discontinuation
- 1985-07-17 AU AU45114/85A patent/AU581442B2/en not_active Ceased
- 1985-07-18 JP JP15708185A patent/JPS6140294A/ja active Pending
- 1985-07-18 KR KR1019850005129A patent/KR930005390B1/ko active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| CS530585A2 (en) | 1988-07-15 |
| PT80820B (pt) | 1988-04-21 |
| EP0173041A1 (en) | 1986-03-05 |
| ATE38991T1 (de) | 1988-12-15 |
| GR851767B (da) | 1985-11-26 |
| NZ212768A (en) | 1988-06-30 |
| JPS6140294A (ja) | 1986-02-26 |
| EP0173041B1 (en) | 1988-11-30 |
| FI852806A0 (fi) | 1985-07-17 |
| FI79327C (fi) | 1989-12-11 |
| PT80820A (en) | 1985-08-01 |
| SU1375141A3 (ru) | 1988-02-15 |
| DE173041T1 (de) | 1986-06-12 |
| ES8702427A1 (es) | 1986-12-16 |
| YU117185A (en) | 1987-10-31 |
| DK324185D0 (da) | 1985-07-17 |
| KR930005390B1 (ko) | 1993-06-19 |
| ZA855357B (en) | 1986-02-26 |
| CS262421B2 (en) | 1989-03-14 |
| IL75807A0 (en) | 1985-11-29 |
| AU4511485A (en) | 1986-01-23 |
| KR860001117A (ko) | 1986-02-22 |
| DE3566545D1 (en) | 1989-01-05 |
| FI852806L (fi) | 1986-01-19 |
| CH664158A5 (fr) | 1988-02-15 |
| ES545330A0 (es) | 1986-12-16 |
| HU193791B (en) | 1987-11-30 |
| FI79327B (fi) | 1989-08-31 |
| AU581442B2 (en) | 1989-02-23 |
| US4696920A (en) | 1987-09-29 |
| IL75807A (en) | 1989-09-10 |
| DK324185A (da) | 1986-01-19 |
| CA1284320C (en) | 1991-05-21 |
| HUT38950A (en) | 1986-07-28 |
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