CA2560128A1 - Intermediates for the preparation of pramipexole - Google Patents
Intermediates for the preparation of pramipexole Download PDFInfo
- Publication number
- CA2560128A1 CA2560128A1 CA002560128A CA2560128A CA2560128A1 CA 2560128 A1 CA2560128 A1 CA 2560128A1 CA 002560128 A CA002560128 A CA 002560128A CA 2560128 A CA2560128 A CA 2560128A CA 2560128 A1 CA2560128 A1 CA 2560128A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- tetrahydro
- benzothiazole
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 title claims abstract description 23
- 229960003089 pramipexole Drugs 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000000543 intermediate Substances 0.000 title claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 118
- 239000000203 mixture Substances 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 125000003277 amino group Chemical group 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- -1 arylmethylamino Chemical class 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 230000000269 nucleophilic effect Effects 0.000 claims description 10
- OTLJUTZKDDNQQY-UHFFFAOYSA-N 2-acetamido-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1CC(C(O)=O)CC2=C1N=C(NC(=O)C)S2 OTLJUTZKDDNQQY-UHFFFAOYSA-N 0.000 claims description 9
- 230000002378 acidificating effect Effects 0.000 claims description 8
- 125000004442 acylamino group Chemical class 0.000 claims description 8
- OTLJUTZKDDNQQY-LURJTMIESA-N (6s)-2-acetamido-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1C[C@H](C(O)=O)CC2=C1N=C(NC(=O)C)S2 OTLJUTZKDDNQQY-LURJTMIESA-N 0.000 claims description 7
- 230000008707 rearrangement Effects 0.000 claims description 7
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 239000012948 isocyanate Substances 0.000 claims description 6
- 150000002513 isocyanates Chemical class 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 150000001340 alkali metals Chemical class 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 230000000171 quenching effect Effects 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- OTLJUTZKDDNQQY-ZCFIWIBFSA-N (6r)-2-acetamido-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1C[C@@H](C(O)=O)CC2=C1N=C(NC(=O)C)S2 OTLJUTZKDDNQQY-ZCFIWIBFSA-N 0.000 claims description 4
- 230000010933 acylation Effects 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 230000029936 alkylation Effects 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- DOOXJKFCYMFGOD-UHFFFAOYSA-N ethyl 2-(propanoylamino)-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylate Chemical compound C1C(C(=O)OCC)CCC2=C1SC(NC(=O)CC)=N2 DOOXJKFCYMFGOD-UHFFFAOYSA-N 0.000 claims description 4
- GXJCNUJEVKUQDE-UHFFFAOYSA-N ethyl 2-acetamido-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylate Chemical compound C1C(C(=O)OCC)CCC2=C1SC(NC(C)=O)=N2 GXJCNUJEVKUQDE-UHFFFAOYSA-N 0.000 claims description 4
- XZNCYDMHLCOBDH-UHFFFAOYSA-N methyl 2-(propanoylamino)-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylate Chemical compound C1CC(C(=O)OC)CC2=C1N=C(NC(=O)CC)S2 XZNCYDMHLCOBDH-UHFFFAOYSA-N 0.000 claims description 4
- QAKBICNXVCOPRS-UHFFFAOYSA-N methyl 2-acetamido-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylate Chemical compound C1C(C(=O)OC)CCC2=C1SC(NC(C)=O)=N2 QAKBICNXVCOPRS-UHFFFAOYSA-N 0.000 claims description 4
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 4
- ZUQZGPGQZDIZLK-UHFFFAOYSA-N propyl 2-(propanoylamino)-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylate Chemical compound C1C(C(=O)OCCC)CCC2=C1SC(NC(=O)CC)=N2 ZUQZGPGQZDIZLK-UHFFFAOYSA-N 0.000 claims description 4
- 238000006462 rearrangement reaction Methods 0.000 claims description 4
- HMWSDSXKIAJHFQ-ZCFIWIBFSA-N (6r)-2-(propanoylamino)-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1C[C@@H](C(O)=O)CC2=C1N=C(NC(=O)CC)S2 HMWSDSXKIAJHFQ-ZCFIWIBFSA-N 0.000 claims description 3
- HMWSDSXKIAJHFQ-LURJTMIESA-N (6s)-2-(propanoylamino)-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1C[C@H](C(O)=O)CC2=C1N=C(NC(=O)CC)S2 HMWSDSXKIAJHFQ-LURJTMIESA-N 0.000 claims description 3
- HMWSDSXKIAJHFQ-UHFFFAOYSA-N 2-(propanoylamino)-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1CC(C(O)=O)CC2=C1N=C(NC(=O)CC)S2 HMWSDSXKIAJHFQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000005544 phthalimido group Chemical class 0.000 claims description 3
- BRLIGTUBZDEGLL-UHFFFAOYSA-N propyl 2-acetamido-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylate Chemical compound C1C(C(=O)OCCC)CCC2=C1SC(NC(C)=O)=N2 BRLIGTUBZDEGLL-UHFFFAOYSA-N 0.000 claims description 3
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 238000011084 recovery Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 239000007787 solid Substances 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 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 description 10
- 238000004090 dissolution Methods 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000006085 Schmidt reaction Methods 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- ZXYAWONOWHSQRU-UHFFFAOYSA-N ethyl 4-oxocyclohexanecarboxylate Chemical compound CCOC(=O)C1CCC(=O)CC1 ZXYAWONOWHSQRU-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- VVPFOYOFGUBZRY-LURJTMIESA-N n-[(6s)-2-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl]propanamide Chemical compound C1[C@@H](NC(=O)CC)CCC2=C1SC(N)=N2 VVPFOYOFGUBZRY-LURJTMIESA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
- DRRYZHHKWSHHFT-BYPYZUCNSA-N (6s)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine Chemical compound C1[C@@H](N)CCC2=C1SC(N)=N2 DRRYZHHKWSHHFT-BYPYZUCNSA-N 0.000 description 1
- RYYXDZDBXNUPOG-FHNDMYTFSA-N (6s)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine;dihydrochloride Chemical compound Cl.Cl.C1[C@@H](N)CCC2=C1SC(N)=N2 RYYXDZDBXNUPOG-FHNDMYTFSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 238000006105 Hofmann reaction Methods 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000006644 Lossen rearrangement reaction Methods 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- IPCRBOOJBPETMF-UHFFFAOYSA-N N-acetylthiourea Chemical compound CC(=O)NC(N)=S IPCRBOOJBPETMF-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- RRUDCFGSUDOHDG-UHFFFAOYSA-N acetohydroxamic acid Chemical compound CC(O)=NO RRUDCFGSUDOHDG-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-O benzylaminium Chemical compound [NH3+]CC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-O 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- SEWZIOVTGXEYEZ-UHFFFAOYSA-N ethyl 2-amino-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylate Chemical compound C1C(C(=O)OCC)CCC2=C1SC(N)=N2 SEWZIOVTGXEYEZ-UHFFFAOYSA-N 0.000 description 1
- GZRNKZBFDCWQTO-UHFFFAOYSA-N ethyl 2-amino-4,5,6,7-tetrahydro-1,3-benzothiazole-6-carboxylate;hydrobromide Chemical compound Br.C1C(C(=O)OCC)CCC2=C1SC(N)=N2 GZRNKZBFDCWQTO-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- YHWAAYIZIQAHRG-ILKKLZGPSA-N n-[(6s)-6-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl]acetamide;dihydrochloride Chemical compound Cl.Cl.C1C[C@H](N)CC2=C1N=C(NC(=O)C)S2 YHWAAYIZIQAHRG-ILKKLZGPSA-N 0.000 description 1
- CONNCHYOBAALSI-UHFFFAOYSA-N n-[6-[(2-acetamido-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)carbamoylamino]-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl]acetamide Chemical compound C1C=2SC(NC(=O)C)=NC=2CCC1NC(=O)NC(C1)CCC2=C1SC(NC(C)=O)=N2 CONNCHYOBAALSI-UHFFFAOYSA-N 0.000 description 1
- CONNCHYOBAALSI-PXYINDEMSA-N n-[6-[[(6s)-2-acetamido-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl]carbamoylamino]-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl]acetamide Chemical compound C([C@@H](C1)NC(=O)NC2CCC=3N=C(SC=3C2)NC(=O)C)CC2=C1SC(NC(C)=O)=N2 CONNCHYOBAALSI-PXYINDEMSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- ABXXLDZOCMBGIL-VIFPVBQESA-N propan-2-yl n-[(6s)-2-acetamido-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl]carbamate Chemical compound C1[C@@H](NC(=O)OC(C)C)CCC2=C1SC(NC(C)=O)=N2 ABXXLDZOCMBGIL-VIFPVBQESA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000007017 scission 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
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI20040531 ITMI20040531A1 (it) | 2004-03-19 | 2004-03-19 | Intermedi per la preparazione di pramipexolo |
| ITMI2004A000531 | 2004-03-19 | ||
| ITMI20050126 ITMI20050126A1 (it) | 2005-01-28 | 2005-01-28 | Intermedi per la preparazione di pramipexolo |
| ITMI2005A000126 | 2005-01-28 | ||
| PCT/EP2005/002641 WO2005092871A2 (en) | 2004-03-19 | 2005-03-11 | Intermediates for the preparation of pramipexole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2560128A1 true CA2560128A1 (en) | 2005-10-06 |
Family
ID=34963371
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002560128A Abandoned CA2560128A1 (en) | 2004-03-19 | 2005-03-11 | Intermediates for the preparation of pramipexole |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US7741490B2 (enExample) |
| EP (2) | EP2289885A1 (enExample) |
| JP (1) | JP2007529446A (enExample) |
| AT (1) | ATE496036T1 (enExample) |
| CA (1) | CA2560128A1 (enExample) |
| DE (1) | DE602005025988D1 (enExample) |
| IL (1) | IL178156A0 (enExample) |
| WO (1) | WO2005092871A2 (enExample) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL378587A1 (pl) * | 2005-12-29 | 2007-07-09 | Instytut Farmaceutyczny | Sposób wytwarzania (S)-(-)-2-amino-6-n-propyloamino-4,5,6,7-tetrahydrobenzotiazolu i/lub jego soli |
| ITMI20060044A1 (it) | 2006-01-13 | 2007-07-14 | Dipharma Spa | Sintesi di intermedi pr la preparazione di pramipexolo |
| US8518926B2 (en) * | 2006-04-10 | 2013-08-27 | Knopp Neurosciences, Inc. | Compositions and methods of using (R)-pramipexole |
| ES2379117T3 (es) | 2006-05-16 | 2012-04-20 | Knopp Neurosciences, Inc. | Composiciones de R(+) y S(-) pramipexol y métodos de utilización de las mismas |
| EP1878731B1 (en) * | 2006-06-26 | 2008-08-20 | Helm AG | Process for producing pramipexole |
| US8524695B2 (en) | 2006-12-14 | 2013-09-03 | Knopp Neurosciences, Inc. | Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same |
| WO2008113056A2 (en) | 2007-03-14 | 2008-09-18 | Knopp Neurosciences, Inc. | Synthesis of chirally purified substituted benzothiazole diamines |
| GB0721332D0 (en) * | 2007-10-31 | 2007-12-12 | Motac Neuroscience Ltd | Medicaments |
| GB0721333D0 (en) * | 2007-10-31 | 2007-12-12 | Motac Neuroscience Ltd | Medicaments |
| CN102186350A (zh) * | 2008-08-19 | 2011-09-14 | 诺普神经科学股份有限公司 | 使用(r)-普拉克索的组合物与方法 |
| CN101676272A (zh) * | 2008-09-17 | 2010-03-24 | 北京德众万全药物技术开发有限公司 | 一种普拉克索的制备方法 |
| WO2011021214A2 (en) * | 2009-08-07 | 2011-02-24 | Msn Laboratories Limited | Improved process for the preparation of (s)-2-amino-4,5,6,7-tetrahydro-6 - (propylamino) benzothiazole and its pharmaceutically acceptable salts |
| ITMI20101998A1 (it) * | 2010-10-27 | 2012-04-28 | Dipharma Francis Srl | Procedimento per la racemizzazione di acidi carbossilici |
| CN102442972B (zh) * | 2011-10-18 | 2014-06-25 | 济南富创医药科技有限公司 | 一种普拉克索及其二盐酸盐一水合物的工业化制备方法 |
| WO2013096816A1 (en) | 2011-12-22 | 2013-06-27 | Biogen Idec Ma Inc. | Improved synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds |
| CN103183650A (zh) * | 2011-12-31 | 2013-07-03 | 天津药物研究院 | (s)-(-)2-氨基-6-丙氨基-4,5,6,7-四氢苯并噻唑的制备方法 |
| CN103183649A (zh) * | 2011-12-31 | 2013-07-03 | 天津药物研究院 | 2-氨基-6-丙氨基-4,5,6,7-四氢苯并噻唑的制备方法 |
| US9662313B2 (en) | 2013-02-28 | 2017-05-30 | Knopp Biosciences Llc | Compositions and methods for treating amyotrophic lateral sclerosis in responders |
| US9468630B2 (en) | 2013-07-12 | 2016-10-18 | Knopp Biosciences Llc | Compositions and methods for treating conditions related to increased eosinophils |
| SMT202100119T1 (it) | 2013-07-12 | 2021-05-07 | Knopp Biosciences Llc | Trattamento dei livelli elevati di eosinofili e/o basofili |
| EP3038467B1 (en) | 2013-08-13 | 2020-07-29 | Knopp Biosciences LLC | Compositions and methods for treating plasma cell disorders and b-cell prolymphocytic disorders |
| AU2014306597B2 (en) | 2013-08-13 | 2018-05-17 | Knopp Biosciences Llc | Compositions and methods for treating chronic urticaria |
| KR20230067604A (ko) * | 2020-08-05 | 2023-05-16 | 아레테이아 테라퓨틱스, 인코포레이티드 | 중등도 내지 중증 천식의 치료를 위한 덱스프라미펙솔의 용도 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3447075A1 (de) * | 1984-12-22 | 1986-07-03 | Dr. Karl Thomae Gmbh, 7950 Biberach | Tetrahydro-benzthiazole, deren herstellung und deren verwendung als zwischenprodukte oder als arzneimittel |
| ATE45735T1 (de) | 1984-12-22 | 1989-09-15 | Thomae Gmbh Dr K | Tetrahydro-benzthiazole, deren herstellung und deren verwendung als zwischenprodukte oder als arnzneimittel. |
| ZA864626B (en) | 1985-06-24 | 1988-02-24 | Lilly Co Eli | Dialkylaminotetrahydrobenzothiazoles and oxazoles |
| US4988699A (en) * | 1989-03-14 | 1991-01-29 | Warner-Lambert Company | Substituted tetrahydrobenzothiazoles as dopaminergic agents |
| PL341356A1 (en) * | 1997-12-22 | 2001-04-09 | Bayer Ag | Raf kinase inhibition employing aryl- and heteroaryl-substituted heterocyclic ureas |
| JP2000119226A (ja) * | 1998-10-13 | 2000-04-25 | Banyu Pharmaceut Co Ltd | クルチウス転移反応を固相合成に利用した新規な芳香族アミン類又は芳香族複素環アミン類の製造方法 |
| ES2187249B1 (es) | 2000-09-18 | 2004-09-16 | Synthon Bv | Procedimiento para la preparacion de 2-amino-6-(alquil)amino-4,5,6,7-tetrahidrobenzotiazoles. |
| JP2002173476A (ja) * | 2000-12-07 | 2002-06-21 | Sumitomo Pharmaceut Co Ltd | １，４−フェニレンジアミン誘導体及びその製造法 |
| CL2004000553A1 (es) * | 2003-03-20 | 2005-02-04 | Actelion Pharmaceuticals Ltd | Uso de compuestos derivados de guanidina como antagonistas del receptor de neuropeptido ff; compuestos derivados de guanidina; procedimientos de preparacion; y composicion farmaceutica que los comprende. |
| EP1640369A4 (en) * | 2003-06-27 | 2007-10-31 | Dainippon Sumitomo Pharma Co | THIAZOLIMINE COMPOUND AND OXAZOLIMINE COMPOUND |
-
2005
- 2005-03-11 EP EP10180254A patent/EP2289885A1/en not_active Withdrawn
- 2005-03-11 EP EP05728706A patent/EP1730129B1/en not_active Expired - Lifetime
- 2005-03-11 CA CA002560128A patent/CA2560128A1/en not_active Abandoned
- 2005-03-11 WO PCT/EP2005/002641 patent/WO2005092871A2/en not_active Ceased
- 2005-03-11 JP JP2007503255A patent/JP2007529446A/ja active Pending
- 2005-03-11 AT AT05728706T patent/ATE496036T1/de not_active IP Right Cessation
- 2005-03-11 DE DE602005025988T patent/DE602005025988D1/de not_active Expired - Lifetime
- 2005-03-11 US US10/593,269 patent/US7741490B2/en not_active Expired - Fee Related
-
2006
- 2006-09-18 IL IL178156A patent/IL178156A0/en unknown
-
2010
- 2010-05-10 US US12/776,588 patent/US8203002B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP1730129B1 (en) | 2011-01-19 |
| EP1730129A2 (en) | 2006-12-13 |
| US20100222595A1 (en) | 2010-09-02 |
| ATE496036T1 (de) | 2011-02-15 |
| WO2005092871A2 (en) | 2005-10-06 |
| IL178156A0 (en) | 2006-12-31 |
| US20070191439A1 (en) | 2007-08-16 |
| JP2007529446A (ja) | 2007-10-25 |
| US8203002B2 (en) | 2012-06-19 |
| DE602005025988D1 (de) | 2011-03-03 |
| EP2289885A1 (en) | 2011-03-02 |
| US7741490B2 (en) | 2010-06-22 |
| WO2005092871A3 (en) | 2005-12-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |