JP5250205B2 - トルテロジン、その組成物及び使用、及びその製造方法 - Google Patents
トルテロジン、その組成物及び使用、及びその製造方法 Download PDFInfo
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- JP5250205B2 JP5250205B2 JP2006546322A JP2006546322A JP5250205B2 JP 5250205 B2 JP5250205 B2 JP 5250205B2 JP 2006546322 A JP2006546322 A JP 2006546322A JP 2006546322 A JP2006546322 A JP 2006546322A JP 5250205 B2 JP5250205 B2 JP 5250205B2
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- Prior art keywords
- tolterodine
- formula
- grams
- phenyl
- compound
- 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.)
- Expired - Fee Related
Links
- 229960004045 tolterodine Drugs 0.000 title claims description 47
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 title claims description 47
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 title claims description 40
- 239000000203 mixture Substances 0.000 title description 14
- 238000004519 manufacturing process Methods 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 26
- 239000012458 free base Substances 0.000 claims description 19
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 13
- 239000012535 impurity Substances 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 229940095064 tartrate Drugs 0.000 claims description 7
- SUHIZPDCJOQZLN-UHFFFAOYSA-N 6-methyl-4-phenyl-3,4-dihydrochromen-2-one Chemical compound C12=CC(C)=CC=C2OC(=O)CC1C1=CC=CC=C1 SUHIZPDCJOQZLN-UHFFFAOYSA-N 0.000 claims description 5
- 229940043279 diisopropylamine Drugs 0.000 claims description 5
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000005490 tosylate group Chemical group 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000539 dimer Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- -1 3-{[3- (2-hydroxy, 5-methyl-phenyl) -3-phenyl-propyl] -isopropyl-amino} -1-phenyl-propyl Chemical group 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- YYSCJLLOWOUSHH-UHFFFAOYSA-N 4,4'-disulfanyldibutanoic acid Chemical compound OC(=O)CCCSSCCCC(O)=O YYSCJLLOWOUSHH-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 206010046543 Urinary incontinence Diseases 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229960003553 tolterodine tartrate Drugs 0.000 description 4
- OOGJQPCLVADCPB-UHFFFAOYSA-N 2-[3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-methylphenol Chemical compound C=1C(C)=CC=C(O)C=1C(CCN(C(C)C)C(C)C)C1=CC=CC=C1 OOGJQPCLVADCPB-UHFFFAOYSA-N 0.000 description 3
- CCXFTVHDCYNKJH-UHFFFAOYSA-N 3-(2-methoxy-5-methylphenyl)-3-phenyl-n,n-di(propan-2-yl)propan-1-amine Chemical compound COC1=CC=C(C)C=C1C(CCN(C(C)C)C(C)C)C1=CC=CC=C1 CCXFTVHDCYNKJH-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- TWHNMSJGYKMTRB-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid;2-[3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-methylphenol Chemical compound OC(=O)C(O)C(O)C(O)=O.C=1C(C)=CC=C(O)C=1C(CCN(C(C)C)C(C)C)C1=CC=CC=C1 TWHNMSJGYKMTRB-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)N(CC[C@@](C(C)=CC=CC)c1cc(OCOc2c(C(CCN(C(C)C)*(C)C)c3ccccc3)cc(C)cc2)ccc1C)C(C)C Chemical compound CC(C)N(CC[C@@](C(C)=CC=CC)c1cc(OCOc2c(C(CCN(C(C)C)*(C)C)c3ccccc3)cc(C)cc2)ccc1C)C(C)C 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000001358 L(+)-tartaric acid Substances 0.000 description 2
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000001078 anti-cholinergic effect Effects 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 150000003461 sulfonyl halides Chemical class 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- MJPIYYRDVSLOME-UHFFFAOYSA-N 2-(3-hydroxy-1-phenylpropyl)-4-methylphenol Chemical compound CC1=CC=C(O)C(C(CCO)C=2C=CC=CC=2)=C1 MJPIYYRDVSLOME-UHFFFAOYSA-N 0.000 description 1
- FSUOGWPKKKHHHM-VEIFNGETSA-N 2-[(1r)-3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-methylphenol;hydrochloride Chemical compound Cl.C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 FSUOGWPKKKHHHM-VEIFNGETSA-N 0.000 description 1
- 102100027324 2-hydroxyacyl-CoA lyase 1 Human genes 0.000 description 1
- OCGTUTJXBDQGKL-UHFFFAOYSA-N 3-(2-methoxy-5-methylphenyl)-3-phenylpropan-1-ol Chemical compound COC1=CC=C(C)C=C1C(CCO)C1=CC=CC=C1 OCGTUTJXBDQGKL-UHFFFAOYSA-N 0.000 description 1
- DKVFUIQWDZMTOU-UHFFFAOYSA-N 3-(5-methyl-2-phenylmethoxyphenyl)-3-phenyl-n,n-di(propan-2-yl)propan-1-amine Chemical compound C=1C(C)=CC=C(OCC=2C=CC=CC=2)C=1C(CCN(C(C)C)C(C)C)C1=CC=CC=C1 DKVFUIQWDZMTOU-UHFFFAOYSA-N 0.000 description 1
- RKLIBBRRUITMAB-UHFFFAOYSA-N 3-(5-methyl-2-phenylmethoxyphenyl)-3-phenylpropan-1-ol Chemical compound C=1C=CC=CC=1C(CCO)C1=CC(C)=CC=C1OCC1=CC=CC=C1 RKLIBBRRUITMAB-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101001009252 Homo sapiens 2-hydroxyacyl-CoA lyase 1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- BJQJPTJDNINOMT-UHFFFAOYSA-N methyl 3-(2-methoxy-5-methylphenyl)-3-phenylpropanoate Chemical compound C=1C(C)=CC=C(OC)C=1C(CC(=O)OC)C1=CC=CC=C1 BJQJPTJDNINOMT-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
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Description
式(III)の中間体化合物は、適当には、ジイソプロピルアミンと、式(IV)の中間体化合物との反応によって製造することができる。
適当には、式(V)の化合物は、式(VI)の中間体化合物:
また、本明細書に開示されるように、本発明によって治療に用いられるためのトルテロジンが実質的に提供される。前記化合物及び本発明の組成物は、コリン作動性疾患、特に尿失禁の治療に有用である。
本発明は、いかなる形であれ、本発明の範囲を制限しない、以下の中間体及び実施例によって更に特定される。
(中間体1)
(6−メチル−4−フェニル−クロマン−2−オンの合成)
桂皮酸(100グラム)及びp−クレゾール(76.6mg)を、窒素雰囲気下で、汚れていない、乾燥したフラスコに入れ、撹拌した。濃硫酸をゆっくりと入れ、反応混合物を125℃〜130℃に6時間加熱した。反応完了後、混合物を約60℃に冷却し、約50mlの水及び約300mlのトルエンを撹拌しながら入れた。層を分離した。トルエン層を、炭酸水素ナトリウムの水飽和溶液及び水で洗浄した。有機層を硫酸ナトリウムで乾燥し、50℃未満の温度で減圧下で濃縮した。残渣を2×100mlのIPAで分離した。残渣を200mlのイソプロパノールに溶解し、5℃に冷却し、2時間撹拌した。得られた固体をろ過し、約60℃で4〜5時間乾燥し、約135〜137グラムの表題の生成物を得た。
(3−(2−メトキシ−5−メチルフェニル)−3−フェニルプロピオン酸メチルエステルの合成)
アセトン(200ml)及びメタノール(200ml)を乾燥フラスコに入れ、100グラムの中間体1を撹拌しながら入れた。71グラムの炭酸カリウム及び66mlの硫酸ジメチルを入れ、反応混合物を約50℃〜55℃に24時間加熱した。反応の完了後、反応塊を室温に冷却し、無機物をろ過した。透明なろ液を減圧下で濃縮し、油状の残渣を得た。該残渣を塩化メチレンに溶解し、有機層を水で洗浄した。有機層を減圧下で濃縮し、表題の化合物を油状として得た(117〜119グラム)。
(3−(2−メトキシ−5−メチル−フェニル)−3−フェニル−プロパン−1−オールの合成)
THF(200ml)及び16gの水素化ホウ素ナトリウムを、汚れていない、乾燥したフラスコに窒素雰囲気下で入れた。混合物を約−10℃に冷却し、250mlのテトラヒドロフランに溶解した100グラムの中間体2を、0℃〜−10℃の範囲の温度で2〜3時間かけてゆっくりと加えた。72mlの三フッ化ホウ素エーテルをゆっくりと3時間以上かけて入れ、0℃〜5℃の温度に維持した。添加の完了後、温度をゆっくりと25℃〜30℃に上昇させ、反応塊を2時間撹拌した。反応完了後、反応混合物を約5℃に冷却し、3M塩酸をゆっくりと加え、1〜3の間のpHに調整した。反応混合物をろ過した。透明な濾液を減圧下で濃縮し、表題の化合物を油状として得た(95グラム9.
(トルエン−4−スルホン酸−3−(2−メトキシ−5−メチル−フェニル)−3−フェニルプロピルエステルの合成)
MDC(200ml)及び中間体3(100グラム)を、汚れていない、乾燥したフラスコに窒素雰囲気下で加え、撹拌した。175mlのTEAを加え、反応混合物を約−5℃に冷却した。−5℃〜0℃で、500mlのMDC中の190グラムのp−トルエンスルホニルクロライドの溶液をゆっくりと2時間以上かけて入れた。反応混合物を3時間撹拌した。反応の完了後、10℃未満で250mlの水を加えた。有機層を分離し、150mlの2N HClで2回、及び最後に200mlの水で3回洗浄した。有機層を乾燥し、45℃未満で減圧下で濃縮し、油を得た。該油を100mlのアセトン及び600mlのn−ヘキサンの混合物に溶解し、ゆっくりと5℃に冷却し、2時間撹拌した。固体をろ過し、50℃で減圧下で4時間乾燥し、表題の化合物を得た(135〜138グラム)。
(〔3−(2−メトキシ−5−メチル−フェニル)−3−フェニル−プロピル〕−ジイソプロピルアミンの合成)
100グラムの中間体4、及び200mlのアセトニトリル中の324mlのジイソプロピルアミンの混合物を、オートクレーブに入れ、圧力をかけて120℃〜125℃で4〜5時間加熱した。反応の完了後、反応混合物を室温に冷却し、60℃未満で減圧下で、残渣にまで濃縮した。残渣をジイソプロピルエーテルに溶解した。60mlの2N NaOHを加え、層を分離した。次いで、有機層を3N HClで抽出した。次いで、水層を4N NaOHで塩基性にし、生成物をMDCに再抽出した。次いで、有機層を乾燥し、濃縮して油を得た(65グラム)。
(2−(3−ヒドロキシ−1−フェニル−プロピル)−4−メチル−フェノール)
6−メチル−4−フェニル−クロマン−2−オン、250グラムを、1.25リットルのメタノール中で、室温で撹拌した。温度を室温に維持しながら水素化ホウ素ナトリウム70グラムをゆっくりと加えた。反応混合物を18時間撹拌した。反応の完了後、酢酸を用いて、反応塊のpHをpH5に調整した。反応混合物を減圧下で濃縮し、2リットルの水を加えた。反応塊を30分間撹拌し、固体をろ過した。該固体を熱風炉中で55℃で20時間乾燥させた。重量248グラム。
前述のようにして調製した粗製の中間体1を、700mlのトルエンに溶解し、85℃〜87℃に加熱した。透明な溶液を、徐々に室温に冷却し、30分間撹拌した。固体をろ過し、トルエンで洗浄した。該固体を熱風炉中で55℃〜60℃で乾燥させた。収量:222グラム、Mp(117〜119℃)
(3−(2−ベンジルオキシ−5−メチル−フェニル)−3−フェニル−プロパン−1−オール)
中間体6(75グラム)を750mlのアセトンに溶解した。無水炭酸カリウム(170グラム)及びヨウ化カリウム(0.75グラム)を加えた。60mlの塩化ベンジルをゆっくりと加え、反応混合物を42時間還流した。反応塊を室温に冷却してろ過した。真空下、アセトンを濃縮した。N−ヘキサン300mlを該オイルに加え、20℃で1時間撹拌した。生成物をろ過し、固体を熱風炉中で50℃〜55℃で3時間乾燥した。収量:102グラム(mp69〜71℃)
(トルエン−4−スルホン酸−3−(2−ベンジルオキシ−5−メチル−フェニル)−3−フェニルプロピルエステル)
中間体7(50グラム)を300mlの塩化メチレンに溶解した。トリエチルアミン(45.6グラム)を加えた。反応混合物を5℃に冷却し、140mlの塩化メチレンに溶解した34.3グラムのp−トルエンスルホニルクロライドを、ゆっくりと加え、反応混合物を室温で18時間撹拌した。反応混合物を100mlの水で急冷した。有機層を分離し、75mlの2N HClで洗浄した。有機層を5%炭酸水素ナトリウム溶液を用いて中性pHになるまで洗浄した。塩化メチレン層を硫酸ナトリウムで乾燥し、減圧下で濃縮して油を得た。収量:73グラム。
(〔3−(2−ベンジルオキシ−5−メチル−フェニル)−3−フェニル−プロピル〕−ジイソプロピルアミン)
中間体8(50グラム)をアセトニトリル(150ml)に溶解した。ジイソプロピルアミン(150グラム)を加え、反応塊をオートクレーブ中で100℃〜120℃で4時間加熱した。塊を室温に冷却し、減圧下で濃縮してアセトニトリルを除去し、200mlのトルエン及び150mlの水を加えた。有機層を分離し、水で洗浄し、濃縮して油を得た。収率:38グラム。
(〔3−(2−ヒドロキシ−5−メチルフェニル)−3−フェニル−プロピル〕−ジイソプロピルアミン(ラセミ体のトルテロジン遊離塩基))
中間体5(100グラム)及び107グラムのピリジンHClを、窒素雰囲気下に2リットルのRBフラスコに入れた。混合物をゆっくりと2時間かけて約210℃の温度に加熱し、この温度に1.5時間維持した。反応混合物を約120℃に冷却し、100mlのジメチルホルムアミドをゆっくりと加えた。反応混合物を更に約70℃に冷却し、500mlの氷水中で急冷した。混合物を約5℃で更に3時間撹拌した。沈殿した固体をろ過し、冷水で洗浄し、標題生成物を塩酸塩として得た。
[3−(2−ヒドロキシ−5メチルフェニル)−3−フェニルプロピル]−ジイソプロピルアミンの精製(ラセミ体トルテロジン遊離塩基)
実施例1に従って得られた粗精の塩基(80グラム)を、150mlのn−ヘキサンに、約50℃で溶解した。該透明溶液を、0℃〜5℃に3時間冷却し、かつ該沈殿固体を濾過し、乾燥して、70グラムの純粋ラセミ体トルテロジン塩基を得た(HPLC > 99.8%)。
R(+)2−(ジイソプロピルアミノ−1−フェニル−プロピル)−4−メチルフェノール酒石酸塩((+)酒石酸トルテロジン)
実施例2に従って得られた純粋なラセミ体トルテロジン遊離塩基(70グラム)を、400mlアルコールに溶解した。L(+)酒石酸45グラムを加え、該混合液を、50℃に30分間加熱し、室温に冷却して、2時間撹拌した。該混合液を、10℃にさらに冷却し、1時間撹拌した。該沈殿固体を濾過し、乾燥して、75グラムの(+)酒石酸トルテロジンを得た。
R(+)2−(ジイソプロピルアミノ−1−フェニル−プロピル)−4−メチルフェノール酒石酸塩((+)酒石酸トルテロジン)
中間体9(35グラム)を、150mlのメタノールに溶解した。10%パラジウム炭素触媒(3.5グラム)を加え、該反応塊を、オートクレーブ中、水素の50psi圧力下、50℃で3時間、水素化した。反応完了後に、該触媒を濾過し、該透明ろ液を減圧下で濃縮して、油を得た。残渣を100mlのn−ヘキサンに溶解した。該透明溶液を、0℃に冷却し、3時間撹拌した。該沈殿固体を濾過し、減圧下、室温で乾燥して、ラセミ体トルテロジン塩基を得た。該塩基を、200mlのエタノールに溶解し、L(+)酒石酸を加えた。該反応混合物を、2時間還流し、25℃に冷却し、2時間撹拌した。該生成物を濾過し、減圧下、60℃で乾燥し、(+)酒石酸トルテロジンを得た。
本発明によって提供されるように、酒石酸トルテロジンと関連する二量体不純物を、本明細書に実質的に開示したように、以下のHPCL法により測定し、本発明によって製造された酒石酸トルテロジンについて、約0.1%未満の二量体不純物レベルが測定された。
デス−イソプロピルトルテロジン: 0.68
二量体2: 1.43
二量体1: 2.39
Claims (6)
- 得られたラセミ体のトルテロジンの遊離塩基を分割して、二量体不純物が0.1%未満である(+)酒石酸トルテロジンを得ることを更に含む、請求項1記載の方法。
- 式(III)の化合物のRaが置換されていないベンジルを表わす、請求項1又は2記載の方法。
- 式(IV)の化合物のXがアリールスルホニルオキシを表す、請求項1記載の方法。
- Xがトシレート基を表す、請求項4記載の方法。
- 式(VI)の化合物が、6−メチル−4−フェニル−クロマン−2−オンから製造される、請求項1記載の方法。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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GB0330056A GB0330056D0 (en) | 2003-12-24 | 2003-12-24 | Pharmaceutical composition |
GB0330056.3 | 2003-12-24 | ||
GB0423300.3 | 2004-10-20 | ||
GB0423300A GB0423300D0 (en) | 2004-10-20 | 2004-10-20 | Compositions and uses thereof, and preparation of the same |
PCT/GB2004/005420 WO2005061432A1 (en) | 2003-12-24 | 2004-12-23 | Tolterodine, compositions and uses thereof, and preparation of the same |
Publications (2)
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JP2007517009A JP2007517009A (ja) | 2007-06-28 |
JP5250205B2 true JP5250205B2 (ja) | 2013-07-31 |
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Application Number | Title | Priority Date | Filing Date |
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JP2006546322A Expired - Fee Related JP5250205B2 (ja) | 2003-12-24 | 2004-12-23 | トルテロジン、その組成物及び使用、及びその製造方法 |
Country Status (6)
Country | Link |
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US (1) | US7538249B2 (ja) |
EP (1) | EP1701932B1 (ja) |
JP (1) | JP5250205B2 (ja) |
KR (1) | KR101154023B1 (ja) |
CA (1) | CA2551501C (ja) |
WO (1) | WO2005061432A1 (ja) |
Families Citing this family (10)
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ES2235648B1 (es) * | 2003-12-22 | 2006-11-01 | Ragactives, S.L. | Procedimiento para la obtencion de tolterodina. |
US20080045602A1 (en) * | 2004-12-24 | 2008-02-21 | Casar Renata T | Process for Preparation of 3-(2-Hydroxy-5Methylphenyl)-N, N-Disopropyl-3-Phenylpropylamine |
AR057333A1 (es) * | 2005-05-27 | 2007-11-28 | Medichem Sa | Proceso para la preparacion de 3,3-diarilpropilaminas |
KR100686351B1 (ko) * | 2006-01-12 | 2007-02-22 | 주식회사 카이로제닉스 | 톨테로딘 라세미체의 제조방법 |
WO2009019599A2 (en) | 2007-08-08 | 2009-02-12 | Themis Laboratories Private Limited | Extended release compositions comprising tolterodine |
WO2010092500A2 (en) * | 2009-02-12 | 2010-08-19 | Alembic Limited | A process for the preparation of tolterodine tartrate |
WO2010094292A1 (en) * | 2009-02-17 | 2010-08-26 | Pharmathen S.A. | Improved process for the preparation of (r)-2-(3-diisopropylamino)-1-phenylpropyl)-4methylphenol and salts thereof |
WO2012098044A1 (en) | 2011-01-17 | 2012-07-26 | Cambrex Profarmaco Milano S.R.L. | Process for the preparation of n,n-diisopropyl-3-(2-hydroxy-5-methylphenyl)- 3-phenyl propylamine and its salts starting from a novel intermediate |
EP2476665A1 (en) | 2011-01-17 | 2012-07-18 | Cambrex Profarmaco Milano S.r.l. | Process for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)- 3-phenyl propylamine and its salts starting from a novel intermediate |
GB201402556D0 (en) | 2014-02-13 | 2014-04-02 | Crystec Ltd | Improvements relating to inhalable particles |
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SE8800207D0 (sv) * | 1988-01-22 | 1988-01-22 | Kabivitrum Ab | Nya aminer, deras anvendning och framstellning |
US5382600A (en) | 1988-01-22 | 1995-01-17 | Pharmacia Aktiebolag | 3,3-diphenylpropylamines and pharmaceutical compositions thereof |
SE9203318D0 (sv) * | 1992-11-06 | 1992-11-06 | Kabi Pharmacia Ab | Novel 3,3-diphenylpropylamines, their use and preparation |
KR20000057548A (ko) | 1996-12-13 | 2000-09-25 | 알프레드 엘. 미첼슨 | 광학적 전송물질 및 결합재 |
JP3981357B2 (ja) * | 2001-10-26 | 2007-09-26 | ファルマシア・アンド・アップジョン・カンパニー・エルエルシー | 第4級アンモニウム化合物および抗ムスカリン剤としてのそれらの使用 |
CN1364757A (zh) | 2001-10-30 | 2002-08-21 | 华东理工大学 | N,n-二异丙基-3-(2-羟基-5-甲基苯基)-3-苯丙胺的制备方法 |
US7005449B2 (en) * | 2002-04-23 | 2006-02-28 | Pharmacia & Upjohn Company | Tolterodine salts |
-
2004
- 2004-12-23 WO PCT/GB2004/005420 patent/WO2005061432A1/en active Search and Examination
- 2004-12-23 JP JP2006546322A patent/JP5250205B2/ja not_active Expired - Fee Related
- 2004-12-23 EP EP04820622A patent/EP1701932B1/en not_active Not-in-force
- 2004-12-23 KR KR1020067014516A patent/KR101154023B1/ko not_active IP Right Cessation
- 2004-12-23 CA CA2551501A patent/CA2551501C/en not_active Expired - Fee Related
- 2004-12-23 US US10/596,767 patent/US7538249B2/en not_active Expired - Fee Related
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Publication number | Publication date |
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US20070142479A1 (en) | 2007-06-21 |
JP2007517009A (ja) | 2007-06-28 |
WO2005061432A1 (en) | 2005-07-07 |
CA2551501A1 (en) | 2005-07-07 |
EP1701932B1 (en) | 2012-07-18 |
US7538249B2 (en) | 2009-05-26 |
CA2551501C (en) | 2012-05-29 |
KR101154023B1 (ko) | 2012-06-07 |
KR20060132873A (ko) | 2006-12-22 |
EP1701932A1 (en) | 2006-09-20 |
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