FI104901B - Nya metylenbisfosfonsyraderivat - Google Patents
Nya metylenbisfosfonsyraderivat Download PDFInfo
- Publication number
- FI104901B FI104901B FI974001A FI974001A FI104901B FI 104901 B FI104901 B FI 104901B FI 974001 A FI974001 A FI 974001A FI 974001 A FI974001 A FI 974001A FI 104901 B FI104901 B FI 104901B
- Authority
- FI
- Finland
- Prior art keywords
- dichloromethylene
- ppm
- acid
- bisphosphonate
- salt
- Prior art date
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- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical class OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 title description 14
- 229910052698 phosphorus Inorganic materials 0.000 claims description 135
- -1 (isobutyroyl) (dichloromethylene) bisphosphonic acid sodium salt Chemical compound 0.000 claims description 61
- 239000002253 acid Substances 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 26
- 150000008064 anhydrides Chemical class 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 11
- 239000002184 metal Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- ZEKKCKJNBVLJIO-UHFFFAOYSA-L [Na+].[Na+].[O-]P(=O)OC(Cl)(Cl)OP([O-])=O Chemical compound [Na+].[Na+].[O-]P(=O)OC(Cl)(Cl)OP([O-])=O ZEKKCKJNBVLJIO-UHFFFAOYSA-L 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- FALZCNWTEGSSCS-UHFFFAOYSA-N ClC([Na])([Na])Cl Chemical class ClC([Na])([Na])Cl FALZCNWTEGSSCS-UHFFFAOYSA-N 0.000 claims 2
- SDIXRDNYIMOKSG-UHFFFAOYSA-L disodium methyl arsenate Chemical compound [Na+].[Na+].C[As]([O-])([O-])=O SDIXRDNYIMOKSG-UHFFFAOYSA-L 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 238000005481 NMR spectroscopy Methods 0.000 description 63
- 239000000651 prodrug Substances 0.000 description 26
- 229940002612 prodrug Drugs 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 22
- 229940122361 Bisphosphonate Drugs 0.000 description 17
- 229960002286 clodronic acid Drugs 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 150000004663 bisphosphonates Chemical class 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000006460 hydrolysis reaction Methods 0.000 description 11
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- PFBUKDPBVNJDEW-UHFFFAOYSA-N dichlorocarbene Chemical group Cl[C]Cl PFBUKDPBVNJDEW-UHFFFAOYSA-N 0.000 description 9
- 230000007062 hydrolysis Effects 0.000 description 9
- YQZICAIMXIOFOI-UHFFFAOYSA-L [O-]P(=O)OC(Cl)(Cl)OP([O-])=O.CCCC[N+](C)(CCCC)CCCC.CCCC[N+](C)(CCCC)CCCC Chemical compound [O-]P(=O)OC(Cl)(Cl)OP([O-])=O.CCCC[N+](C)(CCCC)CCCC.CCCC[N+](C)(CCCC)CCCC YQZICAIMXIOFOI-UHFFFAOYSA-L 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 108090000445 Parathyroid hormone Proteins 0.000 description 7
- 238000010306 acid treatment Methods 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- HJHUXWBTVVFLQI-UHFFFAOYSA-N tributyl(methyl)azanium Chemical class CCCC[N+](C)(CCCC)CCCC HJHUXWBTVVFLQI-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000008363 phosphate buffer Substances 0.000 description 6
- 102100036893 Parathyroid hormone Human genes 0.000 description 5
- 238000005192 partition Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 208000006386 Bone Resorption Diseases 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- GTDPSWPPOUPBNX-UHFFFAOYSA-N ac1mqpva Chemical compound CC12C(=O)OC(=O)C1(C)C1(C)C2(C)C(=O)OC1=O GTDPSWPPOUPBNX-UHFFFAOYSA-N 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- 230000024279 bone resorption Effects 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- FPDNKWSQWXOPSC-UHFFFAOYSA-N 1-(methylamino)ethanol Chemical compound CNC(C)O FPDNKWSQWXOPSC-UHFFFAOYSA-N 0.000 description 3
- DWRVKCFZZJZSJX-UHFFFAOYSA-N 1-propan-2-ylpyridin-1-ium Chemical class CC(C)[N+]1=CC=CC=C1 DWRVKCFZZJZSJX-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 2
- 238000004679 31P NMR spectroscopy Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 208000020084 Bone disease Diseases 0.000 description 2
- YVMMMLLMHCGYCE-UHFFFAOYSA-L C[N+](CCCC)(CCCC)CCCC.P(OC(Br)(Br)OP([O-])=O)([O-])=O.C[N+](CCCC)(CCCC)CCCC Chemical compound C[N+](CCCC)(CCCC)CCCC.P(OC(Br)(Br)OP([O-])=O)([O-])=O.C[N+](CCCC)(CCCC)CCCC YVMMMLLMHCGYCE-UHFFFAOYSA-L 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- KCDFLUMSXOELGE-UHFFFAOYSA-N OP(OC(OP(O)=O)(Cl)Cl)=O Chemical compound OP(OC(OP(O)=O)(Cl)Cl)=O KCDFLUMSXOELGE-UHFFFAOYSA-N 0.000 description 2
- KUFMXPZUZBPFCT-UHFFFAOYSA-N P(O)(OCOP(O)=O)=O Chemical class P(O)(OCOP(O)=O)=O KUFMXPZUZBPFCT-UHFFFAOYSA-N 0.000 description 2
- 102000003982 Parathyroid hormone Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000007073 chemical hydrolysis Effects 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- HJKBJIYDJLVSAO-UHFFFAOYSA-L clodronic acid disodium salt Chemical compound [Na+].[Na+].OP([O-])(=O)C(Cl)(Cl)P(O)([O-])=O HJKBJIYDJLVSAO-UHFFFAOYSA-L 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([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 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
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- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 210000003625 skull Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
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- RAXXELZNTBOGNW-UHFFFAOYSA-O Imidazolium Chemical compound C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
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- 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
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 description 1
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- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 125000004076 pyridyl group Chemical group 0.000 description 1
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- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 125000005624 silicic acid group Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- YPPQYORGOMWNMX-UHFFFAOYSA-L sodium phosphonate pentahydrate Chemical compound [Na+].[Na+].[O-]P([O-])=O YPPQYORGOMWNMX-UHFFFAOYSA-L 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([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
- 239000008223 sterile water Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LPWCRLGKYWVLHQ-UHFFFAOYSA-N tetradecanoyl chloride Chemical compound CCCCCCCCCCCCCC(Cl)=O LPWCRLGKYWVLHQ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- LQHJDMDQUHOTFV-UHFFFAOYSA-J tetrasodium;[dichloro(phosphonato)methyl]-dioxido-oxo-$l^{5}-phosphane Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)C(Cl)(Cl)P([O-])([O-])=O LQHJDMDQUHOTFV-UHFFFAOYSA-J 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000008281 urolithiasis Diseases 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- 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
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/409—Compounds containing the structure P(=X)-X-acyl, P(=X) -X-heteroatom, P(=X)-X-CN (X = O, S, Se)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- 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
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/409—Compounds containing the structure P(=X)-X-acyl, P(=X) -X-heteroatom, P(=X)-X-CN (X = O, S, Se)
- C07F9/4093—Compounds containing the structure P(=X)-X-C(=X)- (X = O, S, Se)
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Molecular Biology (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (4)
1. Metylenbisfosfonsyraanhydridderivat med den allmänna formeln I 5 O Y1 u Q1^ ^9—-Y2
10 -Y3 o ^ Y' i vilken formel Y1, Y2, Y3 och Y4 betecknar en grupp OR1,
15 NR2R3, OCOR1, OCNR2R3, O(CO)OR1, 0(S02)R3, 0(S02)0Rl eller OP (O) R2 (OR3) , väri R1, R2 och R3 är oberoende av varandra väte, en rak eller förgrenad, eventuellt substituerad, eventuellt omättad Cj-Cjj alkyl, en eventuellt substituerad, eventuellt omättad C3-C10 alicyklyl, heterocyklyl, 20 aryl, heteroaryl, aralkyl eller silyl SiR3, väri R betecknar en Ci-C, alkyl, fenyl, en substituerad fenyl eller kombinationer av Cj-C, alkyler och/eller fenyler, eller grupperna R2 och R3 bildar tillsammans med en intill belä-gen kväveatom en mättad, delvis mättad eller aromatisk 25 ring med 3-10 medlemmar, väri utöver kväveatomen kan fin-nas en eller tvä heteroatomer ur gruppen N, o och S, fö-rutsatt att ätminstone en av grupperna Y1, Y2, Y3 eller Y' i formeln I är nägon annan än en grupp OR1 eller NR2R3; Q1 och Q2 är oberoende av varandra väte, fluor, klor, brom 30 eller jod, inklusive föreningarnas stereoisomerer, säsom geometriska isomerer och optiskt aktiva isomerer, samt farmakologiskt godtagna salter av dessa föreningar.
2. Metylenbisfosfonsyraanhydridderivat enligt patentkrav 1, kännetecknat därav, att det är 104901 p, p'-diacetyl(diklormetylen)bisfosfonat dinatriumsalt eller fri syra, p, p'-dibutyroyl(diklormetylen)bisfosfonat dinatriumsalt eller fri syra,
5 P,P'-bis(pivaloyl)(diklormetylen)bisfosfonsyrans dinat- riumsalt eller fri syra, P,P'-bis(bensoyl)(diklormetylen)bisfosfonsyrans dinat-riumsalt eller fri syra, P,P'-bis(isobutyroyl)(diklormetylen)bisfosfonsyrans di-10 natriumsalt eller fri syra, P,P'-bis(tetradekanoyl)(diklormetylen)bisfosfonsyrans dinatr iumsalt eller fri syra, P,P'-bis(oktadekanoyl)(diklormetylen)bisfosfonsyrans dinatr iumsalt eller fri syra. 15
3. Förfarande för framstalining av metylenbisfosfonsy-raanhydridderivat enligt patentkrav 1, kännetecknat dä-rav, att 20 a) ett utgängsämne med formeIn II, väri ätminstone en av grupperna X^X4 eller alla är oberoende av varandra OH eller OM, väri M kan vara en metall- eller ammoniumgrupp, och Q1 och Q2 är väte eller halogen, selektivt omsättes med ett önskat syraderivat Z-A, vari A betecknar en grupp 25 OCOR1, OCNR2R\ OfCOJOR1, 0(S02)R!, OfSO^OR1 eller OP (o) R2 (OR3) och Z är halogen eller analog; eller O X1 30 n1 p<—-x2 \ / + Z-A ---> I Q2 ^P—-X3 l|X\ 0 ^x' 35 (II) 104901 b) ett utgängsämne med formeIn II, väri ätminstone en av grupperna X^X1 eller alla är oberoende av varandra halogen eller halogenanalog, omsättes med en vald syra eller valda syror A-OH (Z=OH) eller med dess metallsalt A-OM 5 (Z=OM), väri A och M betecknar detsamma som under punkt a), och till slut avlägsnas extra X-grupper och even-tuellt extra Y-grupper tili exempel genom att hydrolysera med vatten; eller 10 c) för framställning av tri-, di- och monopartiellanhyd-ridderivat I, hydrolyseras de ovan under punkterna a) eller b) erh&llna tetraanhydriderna selektivt.
4. Farmaceutiskt preparat, kännetecknat därav, att det 15 som aktiv ingrediens innehäller ett metylenbisfosfonsy-raanhydridderivat enligt patentkrav 1. • «
Priority Applications (19)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FI974001A FI104901B (sv) | 1997-10-20 | 1997-10-20 | Nya metylenbisfosfonsyraderivat |
HU0004386A HUP0004386A3 (en) | 1997-10-20 | 1998-10-20 | Methylenebisphosphonic acid derivatives, process for producing them and medicaments containing the same as active agent |
KR1020007004256A KR20010031269A (ko) | 1997-10-20 | 1998-10-20 | 신규한 메틸렌비스포스폰산 유도체 |
JP2000516975A JP2001520232A (ja) | 1997-10-20 | 1998-10-20 | 新規なメチレンビスホスホン酸誘導体 |
TR2000/01055T TR200001055T2 (tr) | 1997-10-20 | 1998-10-20 | Yeni metilenbifosfonik asit türevleri |
BR9813102-8A BR9813102A (pt) | 1997-10-20 | 1998-10-20 | Derivados de ácido metilenobisfosfÈnico novos |
CNB988103710A CN1147497C (zh) | 1997-10-20 | 1998-10-20 | 亚甲基双膦酸类衍生物 |
EP98949022A EP1032578A1 (en) | 1997-10-20 | 1998-10-20 | Novel methylenebisphosphonic acid derivatives |
AU95437/98A AU740355B2 (en) | 1997-10-20 | 1998-10-20 | Novel Methylenebisphosphonic Acid Derivatives |
IL13563998A IL135639A0 (en) | 1997-10-20 | 1998-10-20 | Novel methylenebisphosphonic acid derivatives |
PCT/FI1998/000814 WO1999020634A1 (en) | 1997-10-20 | 1998-10-20 | Novel methylenebisphosphonic acid derivatives |
EEP200000239A EE04061B1 (et) | 1997-10-20 | 1998-10-20 | Metüleenbisfosfoonhappe derivaadid |
RU2000112534/04A RU2205833C2 (ru) | 1997-10-20 | 1998-10-20 | Производные ангидрида метиленбисфосфоновой кислоты, способы их получения, фармацевтическая композиция |
PL98340055A PL340055A1 (en) | 1997-10-20 | 1998-10-20 | Novel derivatives of methylene biphosphonic acid |
NZ504390A NZ504390A (en) | 1997-10-20 | 1998-10-20 | Methylenebisphosphonic acid anhydride derivatives and pharmaceuticals thereof |
US09/529,826 US6326363B1 (en) | 1997-10-20 | 1998-10-20 | Methylenebisphosphonic acid derivatives |
CA002306080A CA2306080A1 (en) | 1997-10-20 | 1998-10-20 | Novel methylenebisphosphonic acid derivatives |
NO20002006A NO20002006L (no) | 1997-10-20 | 2000-04-17 | Nye metylenbisfosfonsyrederivater |
BG104452A BG104452A (en) | 1997-10-20 | 2000-05-17 | New derivatives of the methylenebisphosphonic acid |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FI974001 | 1997-10-20 | ||
FI974001A FI104901B (sv) | 1997-10-20 | 1997-10-20 | Nya metylenbisfosfonsyraderivat |
Publications (3)
Publication Number | Publication Date |
---|---|
FI974001A0 FI974001A0 (fi) | 1997-10-20 |
FI974001A FI974001A (sv) | 1999-04-21 |
FI104901B true FI104901B (sv) | 2000-04-28 |
Family
ID=8549759
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
FI974001A FI104901B (sv) | 1997-10-20 | 1997-10-20 | Nya metylenbisfosfonsyraderivat |
Country Status (19)
Country | Link |
---|---|
US (1) | US6326363B1 (sv) |
EP (1) | EP1032578A1 (sv) |
JP (1) | JP2001520232A (sv) |
KR (1) | KR20010031269A (sv) |
CN (1) | CN1147497C (sv) |
AU (1) | AU740355B2 (sv) |
BG (1) | BG104452A (sv) |
BR (1) | BR9813102A (sv) |
CA (1) | CA2306080A1 (sv) |
EE (1) | EE04061B1 (sv) |
FI (1) | FI104901B (sv) |
HU (1) | HUP0004386A3 (sv) |
IL (1) | IL135639A0 (sv) |
NO (1) | NO20002006L (sv) |
NZ (1) | NZ504390A (sv) |
PL (1) | PL340055A1 (sv) |
RU (1) | RU2205833C2 (sv) |
TR (1) | TR200001055T2 (sv) |
WO (1) | WO1999020634A1 (sv) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NO313180B1 (no) * | 2000-07-04 | 2002-08-26 | Anticancer Therapeutic Inv Sa | Bensökende alfapartikkel emitterende radiofarmasöytika |
US7862552B2 (en) | 2005-05-09 | 2011-01-04 | Boston Scientific Scimed, Inc. | Medical devices for treating urological and uterine conditions |
WO2008024169A1 (en) * | 2006-07-21 | 2008-02-28 | Glsynthesis, Inc. | Reactive pyrophosphoric and bisphosphonic acid derivatives and methods of their use |
CA2747188C (en) | 2008-11-20 | 2017-06-13 | Glsynthesis Inc. | Antithrombotic diadenosine tetraphosphates and related analogs |
CN107011380A (zh) * | 2016-01-28 | 2017-08-04 | 臧伟 | 一种二膦酸衍生物及含二膦酸衍生物的组合物治疗骨折的应用 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4447256A (en) | 1977-07-20 | 1984-05-08 | Nissan Chemical Industries, Ltd. | N-(Unsubstituted or substituted pyridyl)aminomethylene-diphosphonic acids, herbicidal compositions containing same, their use for herbicides, and process for preparing same |
DE2758580A1 (de) | 1977-12-29 | 1979-07-05 | Hoechst Ag | Verfahren zur herstellung von phosphin- und phosphonsaeure-anhydriden |
HU199151B (en) | 1987-03-10 | 1990-01-29 | Yamanouchi Pharma Co Ltd | Process for producing bis-phosphonic acid derivatives |
US4933472A (en) | 1988-04-08 | 1990-06-12 | Yamanouchi Pharmaceutical Co., Ltd. | Substituted aminomethylenebis(phosphonic acid) derivatives |
EP0356866A3 (en) | 1988-08-29 | 1991-03-27 | E.R. SQUIBB & SONS, INC. | Phosphorus-containing squalene synthetase inhibitors and method |
FI83421C (sv) | 1989-06-21 | 1991-07-10 | Huhtamaeki Oy | Förfarande för framställning av farmakologiskt användbara metylenbisfo sfonsyraderivat |
DE69023844T2 (de) | 1989-09-06 | 1996-06-20 | Merck & Co Inc | Acyloxymethylester der Bisphonsäuren als Knochenresorptions-Inhibitoren. |
FI89366C (sv) * | 1990-12-20 | 1993-09-27 | Leiras Oy | Förfarande för framställning av nya farmakologiskt användbara metylenb isfosfonsyraderivat |
FI89364C (sv) | 1990-12-20 | 1993-09-27 | Leiras Oy | Förfarande för framställning av nya, farmakologiskt användbara metylen bisfosfonsyraderivat |
FI89365C (sv) | 1990-12-20 | 1993-09-27 | Leiras Oy | Förfarande för framställning av nya farmakologiskt användbara metylenb isfosfonsyraderivat |
WO1992017488A1 (en) | 1991-04-06 | 1992-10-15 | Fisons Plc | Atp analogues |
TW237386B (sv) | 1992-04-15 | 1995-01-01 | Ciba Geigy | |
DE69406649T2 (de) * | 1993-02-10 | 1998-03-05 | Astra Pharmaceuticals Ltd., Kings Langley, Hertfordshire | N-alkyl-2-substituierte atp-analoge |
US5462932A (en) | 1994-05-17 | 1995-10-31 | Merck & Co., Inc. | Oral liquid alendronate formulations |
-
1997
- 1997-10-20 FI FI974001A patent/FI104901B/sv not_active IP Right Cessation
-
1998
- 1998-10-20 TR TR2000/01055T patent/TR200001055T2/xx unknown
- 1998-10-20 EE EEP200000239A patent/EE04061B1/xx not_active IP Right Cessation
- 1998-10-20 BR BR9813102-8A patent/BR9813102A/pt not_active IP Right Cessation
- 1998-10-20 PL PL98340055A patent/PL340055A1/xx unknown
- 1998-10-20 EP EP98949022A patent/EP1032578A1/en not_active Withdrawn
- 1998-10-20 HU HU0004386A patent/HUP0004386A3/hu unknown
- 1998-10-20 US US09/529,826 patent/US6326363B1/en not_active Expired - Lifetime
- 1998-10-20 JP JP2000516975A patent/JP2001520232A/ja not_active Withdrawn
- 1998-10-20 IL IL13563998A patent/IL135639A0/xx unknown
- 1998-10-20 RU RU2000112534/04A patent/RU2205833C2/ru not_active IP Right Cessation
- 1998-10-20 CN CNB988103710A patent/CN1147497C/zh not_active Expired - Fee Related
- 1998-10-20 CA CA002306080A patent/CA2306080A1/en not_active Abandoned
- 1998-10-20 AU AU95437/98A patent/AU740355B2/en not_active Ceased
- 1998-10-20 WO PCT/FI1998/000814 patent/WO1999020634A1/en not_active Application Discontinuation
- 1998-10-20 NZ NZ504390A patent/NZ504390A/en unknown
- 1998-10-20 KR KR1020007004256A patent/KR20010031269A/ko not_active Application Discontinuation
-
2000
- 2000-04-17 NO NO20002006A patent/NO20002006L/no not_active Application Discontinuation
- 2000-05-17 BG BG104452A patent/BG104452A/xx unknown
Also Published As
Publication number | Publication date |
---|---|
KR20010031269A (ko) | 2001-04-16 |
WO1999020634A1 (en) | 1999-04-29 |
NZ504390A (en) | 2001-10-26 |
CA2306080A1 (en) | 1999-04-29 |
HUP0004386A3 (en) | 2002-08-28 |
IL135639A0 (en) | 2001-05-20 |
BR9813102A (pt) | 2000-08-22 |
FI974001A (sv) | 1999-04-21 |
US6326363B1 (en) | 2001-12-04 |
EE04061B1 (et) | 2003-06-16 |
AU740355B2 (en) | 2001-11-01 |
HUP0004386A2 (hu) | 2001-04-28 |
PL340055A1 (en) | 2001-01-15 |
RU2205833C2 (ru) | 2003-06-10 |
BG104452A (en) | 2000-12-29 |
CN1147497C (zh) | 2004-04-28 |
FI974001A0 (fi) | 1997-10-20 |
EP1032578A1 (en) | 2000-09-06 |
NO20002006L (no) | 2000-06-15 |
AU9543798A (en) | 1999-05-10 |
CN1276793A (zh) | 2000-12-13 |
EE200000239A (et) | 2001-08-15 |
TR200001055T2 (tr) | 2000-09-21 |
NO20002006D0 (no) | 2000-04-17 |
JP2001520232A (ja) | 2001-10-30 |
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Legal Events
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MA | Patent expired |