SI21041A - 2,2-disubstituirani 1,3-dioksolani kot antitusične učinkovine - Google Patents
2,2-disubstituirani 1,3-dioksolani kot antitusične učinkovine Download PDFInfo
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- SI21041A SI21041A SI200120037A SI200120037A SI21041A SI 21041 A SI21041 A SI 21041A SI 200120037 A SI200120037 A SI 200120037A SI 200120037 A SI200120037 A SI 200120037A SI 21041 A SI21041 A SI 21041A
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- compounds
- phenylpiperazin
- diol
- propane
- phenyl
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- -1 2,2-disubstituted 1,3-dioxolanes Chemical class 0.000 title claims abstract description 9
- 239000003434 antitussive agent Substances 0.000 title description 3
- 229940124584 antitussives Drugs 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 16
- PTVWPYVOOKLBCG-UHFFFAOYSA-N 3-(4-phenyl-1-piperazinyl)propane-1,2-diol Chemical compound C1CN(CC(O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000543 intermediate Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 22
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 229940095064 tartrate Drugs 0.000 claims description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 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
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 150000003892 tartrate salts Chemical class 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 8
- PTVWPYVOOKLBCG-ZDUSSCGKSA-N levodropropizine Chemical compound C1CN(C[C@H](O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-ZDUSSCGKSA-N 0.000 abstract description 3
- 229960002265 levodropropizine Drugs 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 125000006091 1,3-dioxolane group Chemical class 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- ABVXMNRHZNWBJC-UHFFFAOYSA-N 3-(4-phenylpiperazin-1-yl)propane-1,1-diol Chemical compound C1CN(CCC(O)O)CCN1C1=CC=CC=C1 ABVXMNRHZNWBJC-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- MCUBFMAIIFMLDW-UHFFFAOYSA-N (4,5-dihydroxy-2-methylpent-2-en-3-yl) 4-methylbenzenesulfonate Chemical compound OCC(O)C(=C(C)C)OS(=O)(=O)C1=CC=C(C)C=C1 MCUBFMAIIFMLDW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HPPXUFCTZBZGHF-UHFFFAOYSA-N 1,4-dioxaspiro[4.4]nonan-3-ylmethyl methanesulfonate Chemical compound O1C(COS(=O)(=O)C)COC11CCCC1 HPPXUFCTZBZGHF-UHFFFAOYSA-N 0.000 description 1
- NJTGZOBLSBCVHD-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decan-3-ylmethyl methanesulfonate Chemical compound O1C(COS(=O)(=O)C)COC11CCCCC1 NJTGZOBLSBCVHD-UHFFFAOYSA-N 0.000 description 1
- FPDBQWYHIIZWPH-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decan-3-ylmethyl trifluoromethanesulfonate Chemical compound O1C(COS(=O)(=O)C(F)(F)F)COC11CCCCC1 FPDBQWYHIIZWPH-UHFFFAOYSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- YOWQWFMSQCOSBA-UHFFFAOYSA-N 2-methoxypropene Chemical compound COC(C)=C YOWQWFMSQCOSBA-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- TZBLDNXQFGCZRB-UHFFFAOYSA-N 3-(4-phenylpiperazin-1-yl)propane-1,1-diol;hydrochloride Chemical compound Cl.C1CN(CCC(O)O)CCN1C1=CC=CC=C1 TZBLDNXQFGCZRB-UHFFFAOYSA-N 0.000 description 1
- XGQRXAWHKWEULC-UHFFFAOYSA-N 3-(chloromethyl)-1,4-dioxaspiro[4.5]decane Chemical compound O1C(CCl)COC11CCCCC1 XGQRXAWHKWEULC-UHFFFAOYSA-N 0.000 description 1
- SSZWWUDQMAHNAQ-UHFFFAOYSA-N 3-chloropropane-1,2-diol Chemical compound OCC(O)CCl SSZWWUDQMAHNAQ-UHFFFAOYSA-N 0.000 description 1
- 125000001960 7 membered carbocyclic group Chemical group 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 229910006069 SO3H Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Holo Graphy (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Hydrogenated Pyridines (AREA)
- Compounds Of Alkaline-Earth Elements, Aluminum Or Rare-Earth Metals (AREA)
- Glass Compositions (AREA)
- Fats And Perfumes (AREA)
- Liquid Crystal Substances (AREA)
- Electrochromic Elements, Electrophoresis, Or Variable Reflection Or Absorption Elements (AREA)
- Secondary Cells (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
(+-) 3-(4-fenil-1-piperazinil)-1,2-propandiol ciklični acetali oz. njihove soli, postopek za njihovo optično ločevanje ter njihova uporaba kot vmesnih spojin za pripravo (-) 3-(4-fenil-1-piperazinil)-1,2-propandiola (levodropropizina).ŕ
Description
2,2-d.isubstituirani 1,3-dioksolani kot antitusične učinkovine
Predmet pričujočega izuma so (±) 3-(4-fenil-lpiperazinil)-1,2-propandiol ciklični acetali oz. njihove soli, postopek za njihovo optično ločevanje ter njihova uporaba kot vmesnih spojin za pripravo (-) 3-(4-fenil-lpiperazinil)-1,2-propandiola (levodropropizina).
Natančneje, predmet izuma so (±) 2,2-substituirani1,3-dioksolani po formuli (1):
kjer:
sta lahko Ra in Rb bodisi enaka ali različna, in sicer sta vodik, Ci-Cg-alkil, fenil ali pa
Ra in Rb, vzeta skupaj s C atomom, na katerega sta vezana, tvorita fakultativno substituiran 4- do 7-členi karbociklični obroč.
V spojinah s formulo (1) po izumu sta Ra in Rb prednostno alkilni skupini, vsebujoči manj kot 6 C atomov. Ra in Rb sta prednostno enaka; posebno prednostno sta Ra in Rb metil ali etil oz., vzeta skupaj s C atomom, na katerega sta vezana, tvorita obroč, vsebujoč od 5 do 6 ogljikovih atomov.
Predmet izuma so tudi enantiomerno čiste enobazne soli
2,2-substituiranih-l,3-dioksolanov s formulo (1) in farmacevtsko sprejemljivih kiralnih kislin, kot so Ljabolčna, D- in L-vinska, D- in L-mandl j eva, L- in Dkamforsulfonska kislina.
Primeri posebno prednostnih spojin po izumu so:
(±) 1,2-ciklopentiliden-3-(4-fenilpiperazin-l-il)propan-1,2-diol;
(±) 1,2-cikloheksiliden-3-(4-fenilpiperazin-l-il)propan-1,2-diol;
(±) 1,2-(2-propiliden)-3-(4-fenilpiperazin-l-il)propan-1,2-diol;
(±) 1,2-(3-pentiliden)-3-(4-fenilpiperazin-l-il)propan-1,2-diol;
S(-)-1,2-cikloheksiliden-3-(4-fenilpiperazin-l-il)propan-1,2-diol L-tartrat;
S(-)-1,2-ciklopentiliden-3-(4-fenilpiperazin-l-il)propan-1,2-diol L-tartrat.
Spojine s formulo (1) po izumu se pripravijo z reakcijo med fenilpiperazinom in (+) 1,2glicerildioksolanom s formulo (2):
kjer je X izbran iz skupine, ki vključuje Cl, Br, I in primeren sulfonski ester (R-SO3-) , medtem ko je R izbran iz skupine, ki vključuje Ci-C3-alkil (prednostno metil), trifluormetil, fenil, p-tolil in p-metoksifenil.
Dioksolani s formulo (2) so poznane spojine oz. jih je moč pripraviti po poznanih postopkih.
Sulfonski estri po formuli (2) (X= R-SO3-) se pripravijo tako, da se anhidrid ali klorid alkil- oz. arilsulfonske kisline s formulo (3)
R-SO3H (3) uporabi za estrenje (±) 2,2-substituiranega-l,3dioksolan-4-metanola s formulo (4):
kjer sta Ra in Rb taka, kot je bilo zgoraj opredeljeno.
Spojine s formulo (4) so poznane. Racemati s formulo (4) se celo uporabljajo kot substrati za fermentacijske ločevalne postopke [US Pat. 5.190.8,67 (02.03.1993)].
Priprava dl-izopropilidenglicerola (Merck 12.5232; Beil 19.65) iz glicerola je opisana v III. zvezku Org. Synth. Coli.
4-halometildioksolani po formuli (2), v kateri je X Cl, Br ali I, se lahko pripravijo iz ustreznih sulfonatov s formulo (2) (X = RSO3-, kjer je R tak, kot je bilo zgoraj opredeljeno) z reakcijo s halidom alkalije ali zemeljske alkalije v inertnem topilu, izbranem iz skupine, ki vključuje aceton, metiletilketon, tetrahidrofuran, dioksan, dimetilsulfoksid, acetonitril, C1-C4-alkohol in njihove mešanice. Prednostna metoda za sintezo navedenih spojin vključuje dioksolaniranje ustreznih 3-halo-l,2propandiolov, kot je podano v patentu EP 0930311 (21.07.1999). Posebno prednosten pri tem je 3-klorpropan1,2-diol; prednostni acetalizacijski agensi so formaldehid, acetaldehid in benzaldehid, aceton, dietilketon, benzofenon, cikloheksanon ter njihovi acetali oz. enoletri, kot so npr. 2,2-dimetoksipropan, 2,2-dimetoksietan, 2metoksipropen.
Alternativno je moč dioksolane po formuli (2) (X - Cl ali Br) pridobiti tudi z acetaliziranjem epikiorhidrinov ali epibromhidrinov s cikloalkanonom po postopkih, opisanih za pripravo (+) 2-klormetil-l,4-dioksaspiro[4,5]-dekana v patentu FR 1522153 ali v besedilih FF Blickeja in sodelavcev, objavljenih v J. A. C. S., 74, 1735 (1972) in prav tam, 76, 1226 (1954).
Alkiliranje fenilpiperazina z 1,2-glicerildioksolanom po formuli (2) se izvaja v reakcijskih pogojih, ki se običajno uporabljajo za konverzijo sekundarnega amina v terciarnega, pri čemer se za vsak mol alkilacijskega agensa po formuli (2) uporabi najmanj en mol· ali neznaten molski prebitek fenilpiperazina v prisotnosti najmanj enega mola protibaze. Protibaza se uporabi v vsaj enakovrednih molskih količinah kot alkilacijski agens po formuli (2), izbere pa se iz skupine, ki vključuje fino ločene anorganske baze, kot so npr. karbonati oz. bikarbonati alkalij ali zemeljskih alkalij (Na, K, Mg, Ca) ali Ca oz. Mg oksidi ali terciarni amini, kot so trietilamin, dimetil- ali dietilanilin, aromatski amini, kot so piridin, pikolin in kolidin ter po želji tudi sam fenilpiperazin, ki ga je moč zatem reciklirati za naslednji proizvodni cikel·.
Alkiliranje se lahko izvaja s segrevanjem, po želji v prisotnosti inertnih topil, kot sta toluen ali ksilen, ki ugodno skrajšata reakcijske čase, ko delujeta pri vreliščni temperaturi topila.
Po zaključenem alkiliranju se morebitne netopne snovi odstranijo s filtriranjem ali centrifugiranjem, nakar se organske faze večkrat sperejo z vodo, s čimer se zlahka odstranijo nečistoče in stranski produkti, topilo pa se odstrani z destiliranjem, kar nam z visokimi izkoristki da ostanek, ki sestoji iz v bistvu čistega 1,3-dioksolana s formulo (1) po izumu, katerega dobimo bodisi z neposredno kristalizacijo ali pa po nevtralizaciji z molskim ekvivalentom karboksilne kisline.
Spojine (1) in njihove soli s presenetljivo lahkoto
-•A· kristalizirajo iz običajnih topil: zato postopek po izumu skrajno zmanjša tveganje, da bi prišlo do kontaminacij e zaradi prisotnosti sledov glicidolov in/ali epihalohidrinov kot potencialnih nečistoč.
Enobazne soli spojin po formuli (1) se pridobivajo z uporabo poznanih metod, kot so nevtralizacija z ekvimolekularnimi količinami želene kisline v primernem topilu, ki ji sledi kristalizacija dobljene soli.
Kot se je izkazalo, predstavlja nevtralizacija spojin (1) s kiralnimi kislinami, zlasti z L-vinsko kislino, učinkovito optično ločevalno metodo za pridobivanje Senantiomerov spojin (1) z visokimi izkoristki.
Navedeni (S) (-) enantiomeri in njihove soli so uporabni kot antitusične učinkovine ali kot vmesne spojine za sintezo (-) 3-(4-fenil-l-piperazinil)-1,2-propandiola (levodropropizina) z vročo hidrolizo vodnih raztopin (-)
1,3-dioksolanov po formuli (1), katalizirano z molskim prebitkom razredčene vodne raztopine mineralne, npr. solne kisline, ali karboksilne kisline, kot so ocetna, malonska ali citronska kislina.
Spodaj navedeni primeri podrobneje ilustrirajo izum.
1. primer
V raztopino 11,98 g (±) 2,3-0-(3-pentiliden)-glicerol tosilata v n-butanolu (70 ml) se med močnim mešanjem doda 4,5 g fino ločenega natrijevega karbonata, zatem pa še 6 ml fenilpiperazina. Mešanica se med vrenjem meša in pusti reagirati 20 h pri temperaturi vrelišča. Butanol se nato odpari pri zmanjšanem tlaku, ostanek pa se razredči z vodo in večkrat ekstrahira z etilacetatom. Kombinirani organski fazi se posušita in prefiltrirata, nakar se topilo odpari v vakuumu, dobljeni ostanek pa se kristalizira iz vodne raztopine metanola, kar nam da 8,95 g (±) 1,2-(3pentiliden)-3-(4-fenilpiperazin-l-il)-propan-1,2-diola, znanega tudi pod imenom 4-fenilpiperazin, 1-(2,2-dietil1,3-dioksolan-4-il-metil).
2. primer
Po postopku, opisanem v 1. primeru, se iz (±) 2,3-0(2-propiliden)-glicerol tosilata dobi (±) 1,2-(2propiliden)-3-(4-fenilpiperazin-l-il)-propan-1,2-diol, znan tudi pod imenom 4-fenilpiperazin, 1-(2,2-dimetil-l,3dioksolan-4-il-metil).
3. primer
Raztopini 3,28 g (±) 1,4-dioksaspiro-[4.5]dekan-2metilklorida v toluenu (16 ml) se v inertni plinski atmosferi doda 5,45 ml fenilpiperazina. Mešanica zatem vre, dokler se reakcija ne zaključi (približno 8 ur). Reakcijska mešanica se ohladi na okrog 50° C, nakar se vanjo doda 10 ml vode in se vsaj 10 minut močno meša. Fazi se ločita in organska faza se večkrat spere z vodo. Topilo se odpari, da nastane gosto olje, to pa se raztopi v vročem izopropanolu (15 ml). Izhodna raztopina se počasi ohladi, da se izloči (±) 1,2-cikloheksiliden-3-(4-fenilpiperazin-l-il)-propan1.2- diol kot kristalna trdnina s tališčem pri 58-61° C.
XH NMR δ 7,26 (t, 2H, J=7,4 Hz); δ 6,95 (d, 2H, J=8,9 Hz); δ 6,85 (t, IH, J=7,28 Hz); δ 4,3 (m, IH, J=6,1 Hz); δ
4,1 (dd, IH, Ji=8,0 Hz, J2=6,l Hz); δ 3,65 (dd, IH, Ji=8,0, J2=7,l Hz); δ 3,2 (t, 4H, J=5,05 Hz); δ 2,9-2,55 (m, 6H) : δ 1,7-1,3 (m, 10H)
4. primer
Po postopku, opisanem v 1. in 3. primeru, se z reakcijo med fenilpiperazinom in 1,3-dioksolanom, izbranim iz skupine, vključujoče:
(±) 1,4-dioksaspiro[4.4]nonan-2-metanol mesilat;
(±) 1,4-dioksaspiro[4.4]nonan-2-metilklorid;
(+) 1,4-dioksaspiro[4.5]dekan-2-metanol trifluormetansulfonat;
(±) 1,4-dioksaspiro[4.5]dekan-2-metanol mesilat;
(±) 1,3-dioksolan-4-klormetil-2,2-dimetil;
(±) 1,3-dioksolan-4-brommetil-2,2-dimetil; dobijo naslednje spojine:
(±) 1,2-ciklopentiliden-3-(4-fenilpiperazin-l-il)propan-1,2-diol;
(±) 1,2-cikloheksiliden-3-(4-fenilpiperazin-l-il)propan-1,2-diol;
(±) 1,2- (2-propiliden)-3-(4-fenilpiperazin-l-il)propan-1,2-diol.
5. primer g L-vinske kisline se med mešanjem dodaja raztopini (±) 1,2-cikloheksiliden-3-(4-fenilpiperazin-l-il)-propan1.2- diola (6,32 g) v čistem etanolu (70 ml). Mešanica se meša do popolne raztopitve, nakar se ohladi na 5-8° C. Dobi se 4,05 g kristalne trdnine, ki se kristalizira iz čistega
-8- 8 etanola, kar nam da 3,82 g S(-)-1,2-cikloheksiliden-3-(4fenilpiperazin-l-il)-propan-1,2-diol L-tartrata, tališče 131-132° C, [a]D=-9,6° (c=l%; MeOH);
XH NMR δ 7,5 (dd, 2H, Jx=8,7, J2=7,3); δ 7,2 (m, 3H) ; δ 4,8 (m, IH); δ 4,4 (s, 2H) ; δ 4,35 (dd, IH, Ji=8,9 Hz,
J2=6,7 Hz); δ 3,86 (dd, IH, Jx=8,9 Hz, J2=5,8 Hz); δ 3,6-3,4 (m, 10H); δ 1,8-1,48 (m, 10H) .
6. primer
Vodna raztopina 2,4 g S(-)-1,2-cikloheksiliden-3-(4fenilpiperazin-l-il)-propan-1,2-diol L-tartrata se naalkali (pH=8) z dodajanjem 2N NaOH, nakar se temeljito ekstrahira z etilacetatom. Kombinirani organski fazi se spereta z 10odstotno raztopino enobaznega natrijevega fosfata, nakar se posušita na natrijevem sulfatu in odparita do suhega ter zatem kristalizirata v izopropanolu, kar nam da 1,5 g S(-)1,2-cikloheksiliden-3-(4-fenilpiperazin-l-il)-propan-1,2diola, tališče 63-64° C, [a]D=-7,8° (1% MeOH).
XH NMR δ 7,26 (t, 2H, J=7,4 Hz); δ 6,95 (d, 2H, J=8,9 Hz); δ 6,85 (t, IH, J=7,28 Hz); δ 4,3 (m, IH, J=6,1 Hz); δ 4,1 (dd, IH, Ji=8,0 Hz, J2=6, 1 Hz); δ 3,65 (dd, IH, Jx=8,0, J2=7,l Hz); δ 3,2 (t, 4H, J=5,05 Hz); δ 2,9+2,55 (m, 6H); δ 1,7+1,3 (m, 10H).
7. primer
Z nevtralizacijo po postopkih iz primerov 1-4 pripravljenega 1,3-dioksolana z L-vinsko kislino ter s frakcijsko rekristalizacij o izhodnih soli so bile pripravljene naslednje spojine:
S(-)-1,2-ciklopentiliden-3-(4-fenilpiperazin-l-il)propan-1,2-diol L-tartrat;
S(-)-1,2-(2-propiliden)-3-(4-fenilpiperazin-l-il)propan-1,2-diol L-tartrat;
S (-)-1,2-(3-pentiliden)-3- (4-fenilpiperazin-l-il)propan-1,2-diol L-tartrat;
ki smo jih kasneje nevtralizirali po postopku v 6. primeru, kar nam je dalo ustrezne proste baze.
8. primer
Suspenzija 2,8 g S (-)-1,2-ciklopentiliden-3-(4fenilpiperazin-l-il)-propan-1,2-diola v 70 ml vodne raztopine ocetne kisline (10% utežno/prostorninsko) se pusti vreti 2 h, nakar se prepiha s parnimi mehurčki, da se z destilacijo odstrani ciklopentanon, ki se izloči. Vodna faza se z dodajanjem 10-odstotne raztopine NaOH nevtralizira na pH 7,5, nato pa se ohladi na 5-10° C, kar nam da 1,97 g (-) 3-(4-fenilpiperazin-l-il)-propandiola, tališče 102-103° C, [α]D=-23,5° (2,8% CH2C12) .
9. primer
Alternativno se 0,35 molskega ekvivalenta enega izmed derivatov 1,3-dioksolana, opisanih v primerih 6 in 7, se pravi S(-)-1,2 - (2-propiliden)-3-(4-fenilpiperazin-l-il)propan-1,2-diola; S (-)-1,2-ciklopentiliden-3-(4fenilpiperazin-l-il)-propan-1,2-diola; S (-)-1,2cikloheksiliden-3-(4-fenilpiperazin-l-il)-propan-1,2-diola; med mešanjem postopno dodaja 36-odstotni raztopini solne kisline (36 ml) v 45 ml vode; suspenzija se segreje na 80° C in dobi se bistra raztopina, ki se ohranja pri tej temperaturi še 30 minut, nakar se ohladi na 20-25° C, vodna faza pa se nato večkrat ekstrahira z diklormetanom (3 * 15 ml), nakar se ji doda n-butanol (0,5 1). Dvofazno mešanico vremo, da se z destiliranj em izloči vodni n-butanol azeotrop, kar nam da okrog 300 ml destilata, ki se nato ohladi, da se spodbudi kristalizacija (-) 3—(4— fenilpiperazin-l-il)-propandiol hidroklorida (85 g).
-1010
Raztopina hidroklorida v 125 mi vode se razbarva s 15minutnim segrevanjem pri 50° C s pomočjo aktivnega oglja (2,2 g), nakar se prefiltrira in nevtralizira z dodajanjem vodne raztopine amonijevega hidroksida (30% utežno/utežno). Po krajšem segrevanju na 50° C se z dodajanjem kristalov (-) 3-(4-fenilpiperazin-l-il)-propandiola sproži kristalizacija. Počaka se, da se suspenzija sama od sebe ohladi, nakar se drži 2 uri pri +2 do +4° C, nazadnje pa se prefiltrira, pri čemer se dobi 70-72 g (-) 3-(4fenilpiperazin-1-il)-1,2-propandiola .
Claims (11)
1. Spojine po formuli (1) k j er:
sta lahko Ra in Rb bodisi enaka ali različna, in sicer sta vodik, Ci-Cg-alkil, fenil ali pa
Ra in Rb, vzeta skupaj s C atomom, na katerega sta vezana, tvorita fakultativno substituiran 4- do 7-členi
(±) 1,
2-ciklopentiliden-
3-(
4-fenilpiperazin-l-il)propan-1,2-diola;
(±) 1,2-cikloheksiliden-3-(4-fenilpiperazin-l-il)propan-1,2-diola;
(±) 1,2-(2-propiliden)-3-(4-fenilpiperazin-l-il)-propan1,2-diola;
(±) 1,2-(3-pentiliden)-3-(4-fenilpiperazin-l-il)-propan1,2-diola;
S (-)-1,2-cikloheksiliden-3-(4-fenilpiperazin-l-il)propan-1,2-diol L-tartrata;
-1212
S (-)-1,2-ciklopentiliden-3-(4-fenilpiperazin-l-il)propan-1,2-diol L-tartrata.
5. Postopek za pripravo spojin med fenilpiperazinom in ( + ) formuli (2):
po formuli (1) z reakcijo 1,2-glicerildioksolanom po (2) ki vključuje Cl, Br, I in kjer je X izbran iz skupine, primeren sulfonski ester (R-SO3-) , pri čemer je R izbran iz skupine, ki vključuje Ci~C3-alkil (prednostno metil), trifluormetil, fenil, p-tolil in p-metoksifenil.
6. Postopek po zahtevku 5, pri katerem reakcija poteka v prisotnosti baze in ob uporabi toluena ali ksilena kot topila.
7. Postopek za optično ločevanje spojin po zahtevkih 1-4 z nevtralizacijo z L-vinsko kislino.
8. Uporaba spojin po zahtevkih 1-4 kot vmesnih spojin pri sintezi ustreznih (S) enantiomerov.
9. Postopek za sintezo (-) 3-(4-fenil-l-piperazinil)-1, 2propandiola, pri katerem se tartrati spojin (1) optično ločijo, tako da se dobijo S (-)-enantiomeri, ki se nato hidroliziraj o s pomočjo molskega prebitka razredčene vodne raztopine mineralne kisline kot katalizatorja.
10. Postopek po zahtevku 1, pri katerem je mineralna kislina solna, ocetna, malonska ali citronska kislina.
11. Uporaba spojin po zahtevkih 1-4 kot vmesnih spojin za pripravo (-) 3-(4-fenil-l-piperazinil)-1,2-propandiola.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2000MI001735A IT1318651B1 (it) | 2000-07-28 | 2000-07-28 | Sintesi di (+-)1,3-diossolani e loro risoluzione ottica. |
| PCT/EP2001/008305 WO2002010150A1 (en) | 2000-07-28 | 2001-07-18 | 2,2-disubstituted 1,3-dioxolanes as antitussive agents |
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| US4049660A (en) * | 1971-06-18 | 1977-09-20 | Delalande S.A. | N-substituted derivatives of 4 (N-piperazinylmethyl) spiro dibenzocycloheptadi- (or tri-) ene-5, 2-dioxolane (1,3) their method of preparation and their application in therapeutics |
| IT1210639B (it) * | 1981-02-25 | 1989-09-14 | Menarini Sas | Prodotto: 3(4-fenil1piperazinio-1-il)-1,2-propandiolo 3(teofillin-7-il)-1propansolfonato,utilizzabile in terapia,e relativo procedimento di fabbricazione |
| IT1203721B (it) * | 1983-12-29 | 1989-02-23 | Dompe Farmaceutici Spa | Composti otticamente attivi ad attivita' antitosse e sedativa centrale,procedimento per la preparazione e composizioni che li contengono |
| SE449516B (sv) * | 1984-10-16 | 1987-05-04 | Skf Nova Ab | Klemring med reglerbar halomkrets |
| IT1254452B (it) * | 1992-02-14 | 1995-09-25 | Dompe Farmaceutici Spa | N-ossidi ed n,n'-diossidi di 3-(piperazin-1-il)-propan-1,2-dioli |
| IL111730A (en) * | 1993-11-29 | 1998-12-06 | Fujisawa Pharmaceutical Co | Piperazine derivatives, processes for their preparation and pharmaceutical preparations containing them |
| IT1318650B1 (it) * | 2000-07-28 | 2003-08-27 | Dompe Spa | 1,3-diossolani ad attivita' antitosse. |
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- 2001-07-18 IL IL15350201A patent/IL153502A0/xx active IP Right Grant
- 2001-07-18 EE EEP200300035A patent/EE05159B1/xx not_active IP Right Cessation
- 2001-07-18 JP JP2002515881A patent/JP5015403B2/ja not_active Expired - Fee Related
- 2001-07-18 PT PT01960513T patent/PT1307440E/pt unknown
- 2001-07-18 ES ES01960513T patent/ES2237589T3/es not_active Expired - Lifetime
- 2001-07-18 DE DE60109299T patent/DE60109299T2/de not_active Expired - Lifetime
- 2001-07-18 WO PCT/EP2001/008305 patent/WO2002010150A1/en active IP Right Grant
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2002
- 2002-12-17 IL IL153502A patent/IL153502A/en not_active IP Right Cessation
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2004
- 2004-03-05 HK HK04101654A patent/HK1058798A1/xx not_active IP Right Cessation
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