BG61295B2 - New esters of thienylcarboxylic acids with aminoalcohols,their quaternary products as well as the preparation andutilization of these compounds - Google Patents
New esters of thienylcarboxylic acids with aminoalcohols,their quaternary products as well as the preparation andutilization of these compounds Download PDFInfo
- Publication number
- BG61295B2 BG61295B2 BG098532A BG9853294A BG61295B2 BG 61295 B2 BG61295 B2 BG 61295B2 BG 098532 A BG098532 A BG 098532A BG 9853294 A BG9853294 A BG 9853294A BG 61295 B2 BG61295 B2 BG 61295B2
- Authority
- BG
- Bulgaria
- Prior art keywords
- compounds
- thienyl
- formula
- alkyl
- acid
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 50
- 150000002148 esters Chemical class 0.000 title claims description 13
- 239000002253 acid Substances 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 9
- 150000001414 amino alcohols Chemical class 0.000 title claims description 7
- 150000007513 acids Chemical class 0.000 title 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 8
- 229910052801 chlorine Chemical group 0.000 claims abstract description 7
- 239000000460 chlorine Chemical group 0.000 claims abstract description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- 150000001450 anions Chemical class 0.000 claims abstract description 5
- 239000011737 fluorine Substances 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 125000002541 furyl group Chemical group 0.000 claims abstract description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 17
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 claims description 3
- 206010040741 Sinus bradycardia Diseases 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 230000001078 anti-cholinergic effect Effects 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- -1 phenyl-2-thienylglycolic acid tropin ester Chemical class 0.000 claims description 2
- 208000023504 respiratory system disease Diseases 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- LXVSANCQXSSLPA-UHFFFAOYSA-N diethylglycolic acid Natural products CCC(O)(CC)C(O)=O LXVSANCQXSSLPA-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 238000005809 transesterification reaction Methods 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000004593 Epoxy Substances 0.000 description 7
- FVEJUHUCFCAYRP-UHFFFAOYSA-N 2-hydroxy-2,2-dithiophen-2-ylacetic acid Chemical compound C=1C=CSC=1C(O)(C(=O)O)C1=CC=CS1 FVEJUHUCFCAYRP-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- SYHWYWHVEQQDMO-UHFFFAOYSA-N methyl 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C=1C=CSC=1C(O)(C(=O)OC)C1=CC=CS1 SYHWYWHVEQQDMO-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical class OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- DXHCHIJMMKQRKR-UHFFFAOYSA-N 2-fluorothiophene Chemical group FC1=CC=CS1 DXHCHIJMMKQRKR-UHFFFAOYSA-N 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- GIWRVUADKUVEGU-UHFFFAOYSA-N 2-oxo-2-thiophen-2-ylacetic acid Chemical compound OC(=O)C(=O)C1=CC=CS1 GIWRVUADKUVEGU-UHFFFAOYSA-N 0.000 description 2
- WPAQIMRFMFRJTP-UHFFFAOYSA-N 3-fluorothiophene Chemical compound FC=1C=CSC=1 WPAQIMRFMFRJTP-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- XMLNCADGRIEXPK-KUMOIWDRSA-M chembl2146143 Chemical compound [Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N+]2(C)C)C(=O)C(CO)C1=CC=CC=C1 XMLNCADGRIEXPK-KUMOIWDRSA-M 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical class OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 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
- HTJPDOPKPWUNBX-UHFFFAOYSA-M magnesium;2h-thiophen-2-ide;bromide Chemical compound [Mg+2].[Br-].C=1C=[C-]SC=1 HTJPDOPKPWUNBX-UHFFFAOYSA-M 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 2
- 150000002902 organometallic compounds Chemical class 0.000 description 2
- FIMXSEMBHGTNKT-UPGAHCIJSA-N scopine Chemical compound C([C@@H]1N2C)C(O)C[C@@H]2[C@@H]2[C@H]1O2 FIMXSEMBHGTNKT-UPGAHCIJSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- WMCDDNAETBQBMJ-UHFFFAOYSA-N 2-bromo-5-fluorothiophene Chemical compound FC1=CC=C(Br)S1 WMCDDNAETBQBMJ-UHFFFAOYSA-N 0.000 description 1
- SHOLYXBVJFTGSH-UHFFFAOYSA-N 2-oxo-2-thiophen-3-ylacetic acid Chemical compound OC(=O)C(=O)C=1C=CSC=1 SHOLYXBVJFTGSH-UHFFFAOYSA-N 0.000 description 1
- HLBOAQSKBNNHMW-UHFFFAOYSA-N 3-(3-methoxyphenyl)pyridine Chemical compound COC1=CC=CC(C=2C=NC=CC=2)=C1 HLBOAQSKBNNHMW-UHFFFAOYSA-N 0.000 description 1
- XCMISAPCWHTVNG-UHFFFAOYSA-N 3-bromothiophene Chemical compound BrC=1C=CSC=1 XCMISAPCWHTVNG-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 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
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- XQJMXPAEFMWDOZ-PBWFPOADSA-N [(1s,5r)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] benzoate Chemical compound C([C@H]1CC[C@@H](C2)N1C)C2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-PBWFPOADSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- LDNHFZMAFBIHTC-UHFFFAOYSA-N ethene;2-hydroxyacetic acid Chemical compound C=C.C=C.OCC(O)=O LDNHFZMAFBIHTC-UHFFFAOYSA-N 0.000 description 1
- UPTVHSCRWQCIOS-UHFFFAOYSA-N ethyl 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C=1C=CSC=1C(O)(C(=O)OCC)C1=CC=CS1 UPTVHSCRWQCIOS-UHFFFAOYSA-N 0.000 description 1
- YGGQOQVOGNCEBH-UHFFFAOYSA-N ethyl 2-hydroxy-2-phenyl-2-thiophen-2-ylacetate Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC)C1=CC=CS1 YGGQOQVOGNCEBH-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- CCKXJTLFNDEZDU-UHFFFAOYSA-N furan-3-carbonyl cyanide Chemical compound N#CC(=O)C=1C=COC=1 CCKXJTLFNDEZDU-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- BIHFCPRVAAVAPP-UHFFFAOYSA-N hydroxy(phenyl)2-thienylacetic acid Chemical compound C=1C=CC=CC=1C(O)(C(=O)O)C1=CC=CS1 BIHFCPRVAAVAPP-UHFFFAOYSA-N 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960001361 ipratropium bromide Drugs 0.000 description 1
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- SNHOZPMHMQQMNI-UHFFFAOYSA-N lithium;2h-thiophen-2-ide Chemical compound [Li+].C=1C=[C-]SC=1 SNHOZPMHMQQMNI-UHFFFAOYSA-N 0.000 description 1
- 229940125386 long-acting bronchodilator Drugs 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- GFTXWCQFWLOXAT-UHFFFAOYSA-M magnesium;cyclohexane;bromide Chemical compound [Mg+2].[Br-].C1CC[CH-]CC1 GFTXWCQFWLOXAT-UHFFFAOYSA-M 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical class OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
-
- 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
- A61P11/06—Antiasthmatics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
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Abstract
Description
(54) НОВИ ЕСТЕРИ НА ТИЕНИЛКАРБОКСИЛНИ КИСЕЛИНИ С АМИНОАЛКОХОЛИ, ТЕХНИ(54) NEW THYENYL CARBOXYLIC ACIDES WITH AMINO-ALCOHOLS, THEIR
КВАТЕРНЕРНИ ПРОДУКТИ, ПОЛУЧАВАНЕ И ИЗПОЛЗВАНЕ НА ТЕЗИ СЪЕДИНЕНИЯ (57) Съединение с формулаQUARTERNAL PRODUCTS, PREPARATION AND USE OF THESE COMPOUNDS (57) Compound of Formula
R. - С - CO - ОА I в която А означава групата сн,------сн сн,------сн2 R. - C - CO - OA I in which A stands for dream group, ------ dream dream, ------ dream 2
в която Q е група c двойно свързванеin which Q is a double bond group
-сн2-сн2-, -сн2-сн2-сн2-, СН=СН-,-Sh 2 -Sh 2 -, -Sh 2 --Sh 2 --Sh 2 -, CH = CH-,
СНи R означава в даден случай заместен с халоген или хидрокси (Ц-С^-алкилов остатък, R’ - C,-C4алкилов остатък и R и R’ заедно могат да образуват С4-С6-алкилов остатък и един еквивалент от анион (X ) неутрализира положителния заряд на N-атом, R, означава тиенилов, фенилов, фурилов, циклопентилов или циклохексилов остатък, при което тези остатъци могат да бъдат заместени с метилна група, тиениловия и фениловия остатък могат да бъдат заместени също с флуор или хлор, R2 означава водород, ОН или (Ц-С^-алкокси или (Ц-С^-алкил, R означава Н, F, С1 или СНГ претенции (54) НОВИ ЕСТЕРИ НА ТИЕНИЛКАРБОКСИЛНИ КИСЕЛИНИ С АМИНОАЛКОХОЛИ, ТЕХНИ КВАТЕРНЕРНИ ПРОДУКТИ, ПОЛУЧАВАНЕ И ИЗПОЛЗВАНЕ НА ТЕЗИ СЪЕДИНЕНИЯSRI R is optionally substituted with halogen or hydroxy (C-C alkyl radical, R '- C, -C 4 alkyl radical and R and R' can together form a C 4 -C 6 alkyl radical and one equivalent of of the anion (X) neutralize the positive charge of the N atom, R 1 denotes a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl moiety, wherein these moieties may be substituted by a methyl group, the thienyl and phenyl moieties may also be replaced by fluorine or chlorine, R 2 is hydrogen, OH or (C C ^ alkoxy or (C C ^ alkyl, R denotes H, F, C1 or CH G claims (54) NEW THYENYL CARBOXYLIC ACIDES WITH AMINO-ALCOHOLS, THEIR QUATTERN PRODUCTS, THE PREPARATION AND USE OF THESE COMPOUNDS
Изобретението се отнася до нови естери на тиенил карбоксилни киселини с аминоалкохоли и техни кватернерни продукти, както и получаване на новите съединения и тяхното използване като активен компонент в лекарствени средства.The invention relates to novel thienyl carboxylic acid esters of amino alcohols and their quaternary products, and to the preparation of new compounds and their use as an active ingredient in pharmaceuticals.
Новите съединения имат обща формула в която А означава групатаThe new compounds have the general formula wherein A represents the group
R,—С-СО-ОА (I)R, -C-CO-OA (I)
където Q е група с двойно свързванеwhere Q is a double bond group
-СН2-СН2-, -СНг-СН2-СН2-, -сн=сн-,-CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH = CH-,
и R означава в даден случай заместен с халоген или зсмдрокстч С^Сд-аякмяов остатък, R1 означава С,-С4-алкилое остатък и R и R’ заедно могат да образуват С«-Св-алкмлов остатък и един еквивалент от анион (Х°) неутрализира положителния заряд на N-агом,and R is optionally substituted with halogen or zsmdrokstch C ^ -C-ayakmyaov radical, R 1 represents C, -C 4 -alkiloe residue and R and R 'together may form a "C in -alkmlov residue and one equivalent of anion (X °) neutralizes the positive charge of N-ag,
R, означава тиенилов, фенилов, фурилов, циклопентилов или циклохексилов остатък, при което тези остатъци могат да бъдат заместени с метилна група, тиениловиЯГи фениловият остатък могат да бъдат заместени също с флуор или хлор,R 1 denotes a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl moiety, wherein these moieties may be substituted by a methyl group, thienyl, and the phenyl moiety may also be substituted by fluorine or chlorine,
Rj;означава водород, ОН млн С,-С,-алкокси мли С,-С,- алкил, R, означава Н, F, CI или СН,.R 1 represents hydrogen, OH million C 1 -C 1 -alkoxy or C 1 -C 1 alkyl, R 1 represents H, F, Cl or CH.
При съединенията с формула I, за предпочитане R, е тиенил, R, за предпочитане е ОН. Групата -0А има за аредяочмтане ^конфдгурадия и сеопределя..за предпочитане например от съответните нор-съединения скопин, тропин, гранатолин или 6,7-дихидротропин. -ОА може да показва също β-конфигурация както в псевдотропин, псевдоскопин.In the compounds of formula I, preferably R is thienyl, R is preferably OH. The -OA group has a confluency and is preferably determined by, for example, the corresponding norx compounds skopin, tropin, granatoline or 6,7-dihydrotropin. -OA may also exhibit the β-configuration as in pseudotropin, pseudoscopin.
Подходящи остатъци са напримерSuitable residues are, for example
ν-<ν- <
ЗаместителятThe substitute
R за предпочитане еR is preferably
нисш алкилов остатък като СН3, С2Н5, норм-С3Н7, изо-С3Н7, R1 за предпочитане е СН3, R и R’ заедно означават например -(СН2)5-. Като халогенни заместители за R се имат предвид F или на второ място CI.a lower alkyl residue such as CH 3 , C 2 H 5 , norm-C 3 H 7 , iso-C 3 H 7 , R 1 is preferably CH 3 , R and R 'together denote, for example, - (CH 2 ) 5 -. Halogen substituents for R are F or secondarily CI.
Когато R означава халогензаместен или хидроксизаместен алкилов остатък, се имат предвид за предпочитане -CH2-CH2-F, съответно -СН2-СН2ОН. Съобразно с това групата А означава например скопинов, Nетилнорскопинов, N-изопропилнорскопинов, тропинов, Nизопропилнортропинов, 6,7-дехидротропинов, Ν-βфлуоретилнортропинов, N-изопропил-6,7-дехидронортропинов, N-метилгранатолинов като съответното кватернерно съединение, при което анионът за предпочитане е ВгсъответноWhen R is a halogen-substituted or hydroxy-substituted alkyl moiety, preferably -CH 2 -CH 2 -F, or -CH 2 -CH 2 OH, is preferred. Accordingly, group A means, for example, skopin, Netylnorskopin, N-isopropylnorskopin, tropin, Nisopropylnorthropin, 6,7-dehydrotropin, Ν-βfluoroethylnorthropin, N-isopropyl-6,7-dehydrononotropin, N-methylotinotronotropin preferably it is suitably
CH3SO3-.CH3SO3-.
Като киселинен остатъкAs an acid residue
( III ) преди всичко се имат предвид(Iii) above all are taken into account
НО—с-со—BUT - with - so -
Съединенията съгласно изобретението показват силно и продължително антихолинергично действие. При дозиране в jxg-област се достига продължително инхалационно действие от /- rn*rtW>-WltflT>~l JTTl·· .— j-jir.The compounds of the invention exhibit a strong and long-lasting anticholinergic action. By dosing in the jxg region, a long inhalation action of / - rn * rtW> -WltflT> ~ l JTTl · · .— j-jir is achieved.
най-малко 24 h . Токсичността е в същата граница както при търговския продукт ипратропиумбромид, като в същото време терапевтичната им активност е по-силна.at least 24 hours. Toxicity is in the same range as the commercial product ipratropium bromide, while at the same time their therapeutic activity is higher.
Новите съединения са подходящи поради тяхното свойство като антихолинергици, например за лечение на хронични обструктивни бронхити и (леки и среднотежки) астми, освен това за лечение на вагусно обусловената синусова брадикардия.The novel compounds are suitable for their properties as anticholinergics, for example for the treatment of chronic obstructive bronchitis and (mild to moderate) asthma, and in addition for the treatment of vagus-induced sinus bradycardia.
Докато при болестите на дихателните пътища се препоръчва главно инхалатмвно прилагане на новите активни вещества (особено на кватернерните съединени), чрез което се изключват странични действия в широки размери, прилагането при синусова брадикардия става за предпочитане интравенозно или орално. При това предимство за новите съединения е, че не повлияват стомашно-чревния мотилитет.While respiratory diseases are mainly recommended for the inhalation administration of new active substances (especially quaternary compounds), thereby eliminating wide-scale side effects, sinus bradycardia is preferably administered intravenously or orally. The advantage of the new compounds is that they do not affect the gastrointestinal motility.
От Acta Chem. Scand., Bd. 24 (1970), s.1590-6 e известно получаването на 3-тропанил-2,2‘-, съответно 3,3’-By Acta Chem. Scand., Bd. 24 (1970), s.1590-6 is known for the preparation of 3-tropanyl-2,2′-, respectively 3,3′-
дитиенилгликолат. За физиологичната активност на тези третични съединения не е казано нищо. Тропиновите естери на фенил-2-тиенилгликоловата киселина са познати от J. Chem.diethylene glycolate. Nothing is said about the physiological activity of these tertiary compounds. The tropinic esters of phenyl-2-thienylglycolic acid are known from J. Chem.
Soc. (1957), s. 3575-8.Тук е спомената също спазмолитичната активност на съединенията върху изолирано заешко черво.Soc. (1957), p. 3575-8. The spasmolytic activity of the compounds on the isolated rabbit is also mentioned here.
Указание за неочаквано силно и продължително действие като бронхолитици чрез превръщане на съединенията в съответните кватернерни съединения не е намерено.No indication of an unexpectedly strong and prolonged action as a bronchodilator by converting the compounds into the corresponding quaternary compounds was found.
N-заместеният норгранатанол-Зр-естер е описан вThe N-substituted norganatanol-3p-ester is described in
GB 955 535. Тези съединения съгласно описанието се характеризират като отлични централно действащи антихолинергици. Съгласно изобретението преди всичко продължително бронхолитично действащи съединения съгласно GB патентно описание не се препоръчват .GB 955 535. These compounds, as described, are characterized as excellent centrally acting anticholinergics. According to the invention, above all, long-acting bronchodilator compounds according to GB patent description are not recommended.
За прилагане съединенията съгласно изобретението се обработват с познати помощни средства и/или носители до обичайни галенични форми, например до разтвори за инхалация, суспензии в сгъстени газове, форми?съдържащи липозоми съответно пролипозоми, инжекционни разтвори, таблети, дражета, капсули, инхалационни прахове за прилагане в обичайните инхалационни устройства.For application, the compounds of the invention are treated with known excipients and / or carriers to conventional galenical forms, for example, to inhalation solutions, compressed gas suspensions, forms ? containing liposomes, respectively, proliposomes, injectable solutions, tablets, dragees, capsules, inhalation powders for use in conventional inhalation devices.
Примери за форми на приложение (количествата са в тегловни проценти).Examples of forms of administration (amounts are by weight).
1. Аерозол с дозиране·1. Dosing aerosol ·
Суспензията се пълни в обичайни контейнери за аерозол. За привеждане в действие се подават 50 pg суспензия.Активното вещество може по желание да се дозира в по-голямо количество (например 0,02^тегловни ).The suspension is filled into conventional aerosol containers. 50 pg of suspension are administered for actuation. The active substance may optionally be dosed in a larger amount (e.g., 0.02 wt.%).
.wuiWitwM ς*ν· ъ 'Ч-лг t*~ χ.wuiWitwM ς * ν · ''--lg t * ~ χ
2. Таблети.2. Tablets.
Компонентите се преработват на таблети по обичаен начин.The components are processed into tablets in the usual manner.
Полезните свойства на новите съединения са показани например в подтискане на бронхолизата у зайци (ацетилхолинови спазми, i.v.). След венозно прилане на новите съединения (дозиThe useful properties of the new compounds are shown, for example, in the suppression of broncholysis in rabbits (acetylcholine spasms, i.v.). After intravenous administration of new compounds (doses
настъпва максимално действие след до 40 πιίη ιmaximum action occurs after up to 40 πιίη ι
След 5 h подтискащото действие още не е спаднало наполовина, това значи, че времето на полуактивност е повече, т.е. повече от 5 h . както ясно показват по-долу представените данни за остатъчно действие след 5 h.After 5 hours the suppression action has not yet halved, this means that the half-life is longer, ie. more than 5 hours. as clearly shown by the residual action data presented after 5 hours.
Съед.Comp.
Съединения с формулаCompounds of formula
АA
—< сн3-гЛсн3 - <CH 3 -gLsn 3
ΘΘ
ВгBr
2-Тиенил2-Thienyl
З-Тиенил3-Tienyl
2-Тиенил2-Thienyl
З-Тиенил3-Tienyl
ЦиклопентилCyclopentyl
ЦиклопентилCyclopentyl
Забележки:Notes:
1. При съединенията, при които R, не е 2-тиенил .става въпрос за рацемати,1. In compounds where R is not 2-thienyl, it is a racemate,
2. Става въпрос за За-съединения .2. It is about Za-compounds.
За получаване на новите съединения се използват познати методи.Known methods are used to prepare the new compounds.
За предпочитане естер с формулаPreferably an ester of formula
R-j—С-СО—OR (IV), в която Р”означава Ст-Сд-ал килов остатък, за предпочитане метилов или етилов остатък (R,, R2 и Ra имат горните значения) се преестерифицира с аминоалкол с формулаR 1 -C-CO-OR (IV) in which P 'represents a C 1 -C 6 -alkyl residue, preferably a methyl or ethyl residue (R 2 , R 2 and R a have the above meanings) is transesterified with an amino alcohol of formula
(V) в която Q има горните значения, Q” означава -NR или -NH и 0Нгрупите са на а- или β-място, в присъствие на подходящ катализатор за преестерификация и получените съединения(V) in which Q has the above meanings, Q 'means -NR or -NH and 0H groups are in the α- or β-site, in the presence of a suitable catalyst for the esterification and the compounds obtained
а) когато Q” означава -NR, се превръщат в кватернерни съединения с реакционноспособно монопроизводноa) when Q 'is -NR, they are converted to quaternary compounds with a reactive monoproduct
Z-(CrC4-anкил) на съответните алкани (Z е отцепваща се група) илиZ- (C r C 4 -ankil) of the corresponding alkane (Z is a leaving group) or
б) когато Q” означава =NH;ce превръщат в кватернерни съединения с краен дизаместен алкан Z-(C4-C6алкилен)-г без междинно изолиране.b) when Q 'means = NH ; are converted to quaternary compounds with terminal disubstituted alkane Z- (C 4 -C 6 alkylene) -d without any intermediate isolation.
Взаимодействието се провежда при нагряване в среда от органичен разтворител, например толуен, ксилен, хептен^или при стапяне, при което се използва силна основа като натриев метилат, натриев етилат, натриев хидрид, метален натрий като катализатор. За отстраняване на освободените нисши алкохоли от равновесието се прилага намалено налягане, като алкохолът се дестилира ацеотропно. Взаимодействието протича при температури, които не надвишават 95°С. Често е по-изгодно взаимодействието да протече при стапяне.The reaction is carried out by heating in an organic solvent medium, for example toluene, xylene, heptene or melting, using a strong base such as sodium methylate, sodium ethylate, sodium hydride, sodium metal as a catalyst. A reduced pressure is applied to remove the released lower alcohols from the equilibrium, distilling the alcohol azeotropically. The reaction takes place at temperatures not exceeding 95 ° C. Often, it is more advantageous for the reaction to take place upon melting.
Присъединителна с киселина сол с третичен амин може по желание да се превърне с подходящи основни съединения по познат начин в свободна основа. Превръщането в кватернерно съединение се провежда в подходящ разтворител като ацетонитрил или ацетонитрил/метиленхлорид. за предпочитане при стайна температура. Като кватернизиращо средство за предпочитане се използва съответен алкилхалогенид, например алкилбромид. Преестерифицираният продукт със значение на Q” като NH се използва като изходен продукт за онези съединения, където R и R’ заедно означават С4. С6-алкиленова група. Превръщането в третично и след това вThe tertiary amine acid addition salt may optionally be converted to the corresponding basic compounds in a known manner in a free base. Conversion to the quaternary compound is carried out in a suitable solvent such as acetonitrile or acetonitrile / methylene chloride. preferably at room temperature. A suitable alkyl halide, for example alkyl bromide, is preferably used as quaternizing agent. The transesterified product having the meaning of Q 'as NH is used as the starting material for those compounds where R and R' together denote C 4 . With a 6- alkylene group. Tertiary conversion and then tertiary conversion
-. ·5 л «<-< * λ·...*·'· ·· ·-.; · ’ч +. »<’ ά ;., .- .?-. · 5 l «<- <* λ · ... * · '· ·· · - .; · ' H +. »<'Ά;., .-.?
четвъртично съединение се осъществява с помощта на подходящa quaternary compound is made using a suitable
1,4-, 1,5-, съответно 1,6-дихалогеналкан без междинно изолиране.1,4-, 1,5- or 1,6-dihalogenalkane without intermediate isolation.
Изходните продукти могат, по-нататък те вече няма да се описват, да се получат аналогично на известни съединения.The starting materials may, furthermore, no longer be described, be prepared analogously to known compounds.
Пример.An example.
Метилов естер на ди-(2-тиенил)гликолова киселина от диметилов естер на оксалова киселина и 2-тиенилмагнезиев бромид,Di- (2-thienyl) glycolic acid methyl ester of oxalic acid dimethyl ester and 2-thienylmagnesium bromide,
Етилов естер на ди-(2-тиенил)гликолова киселина от (2-тиенил)глиоксилова киселина и 2-тиениллитий,Di- (2-thienyl) glycolic acid ethyl ester of (2-thienyl) glyoxylic acid and 2-thienyllithium,
Етилов естер на хидроксифенил-(2-тиенил)оцетна киселина от метилов естер на фенилглиоксилова киселина и 2тиенилмагнезиев бромид или от метилов естер на (2-тиенил) глиоксилова киселина и фенилмагнезиев бромид.Hydroxyphenyl- (2-thienyl) acetic acid ethyl ester of phenylglyoxyl acid methyl ester and 2-thienylmagnesium bromide or (2-thienyl) glyoxyl acid methyl ester and phenylmagnesium bromide.
Подобно могат да взаимодействат метилов естер наSimilarly, methyl ester can interact
2-тиенилглиоксилова киселина и циклохексилмагнезиев бромид. съответно циклопентилмагнезиев бромид.2-Thienylglyoxylic acid and cyclohexylmagnesium bromide. respectively cyclopentylmagnesium bromide.
За получаването на аминоалкохоли се имат предвид също редица методи.A number of methods are also contemplated for the preparation of amino alcohols.
Псевдоскопин може да се получи съгласно M.Polonovski et al., Bull. Soc. Chim., 43, 79 (1928).Pseudoscopin can be prepared according to M. Polonovski et al., Bull. Soc. Chim., 43, 79 (1928).
Псевдотропенол може да се изолира от смес (фракционна кристализация, съответно дестилация), както е получен например от V.Nayakawa et al., J.Am.Chem.Soc., 1978, 100(6), 1786, съответно R.Noyori, J.Amer.Chem.Soc., 1974, 96(10), 3336.Pseudotropenol can be isolated from a mixture (fractional crystallization, respectively distillation), as obtained, for example, from V. Nayakawa et al., J. Am.Chem.Soc., 1978, 100 (6), 1786, respectively, R. Nooyori, J.Amer.Chem.Soc., 1974, 96 (10), 3336.
ί i ί iί and ί i
Като се излиза от 2-, съответно 3-фурилглиоксил нитрил може през получаващата се от тях 2-,съответно 3фурилглиоксилова киселина да се получи съответният метилов естер по обичаен начин. От тях може, както е описано, с металорганични производни отStarting from 2- or 3-furylglyoxyl nitrile, the corresponding methyl ester can be obtained in the usual way, via the 2- or 3-furylglyoxyl acid resulting from them. Of these, as described, with organometallic derivatives of
2-^съответно 3-бромтиофен, да се получи съответният естер на гликолова киселина.2- ^ respectively 3-bromothiophene, to give the corresponding glycolic acid ester.
Получаващите се от 2-, 3- или 4-халогенпиридин металорганични съединения взаимодействат с метилов естер на 2-, съответноThe organometallic compounds derived from 2-, 3- or 4-halogenpyridine are reacted with 2-, respectively, methyl ester
3-тиенилглиоксилова киселина до съответните естери на гликоловата киселина.3-Thienylglyoxylic acid to the corresponding glycolic acid esters.
Естерите на тиенилгликоловата киселина, при които тиофеновият пръстен съдържа флуор на 2-, съответно З-място, могат например да се получат? като се излиза от 2-флуор, съответно 3-флуортиофен| бромиране до 2-бром-З-флуор- илиThienylglycolic acid esters, in which the thiophene ring contains fluorine at the 2- or 3-position, for example, can be obtained? starting from 2-fluoro or 3-fluorothiophene | bromination to 2-bromo-3-fluoro- or
2-бром-5-флуортиофен и след превръщане в съответните металорганични съединения, взаимодействие с подходящи естери на глиоксиловата киселина до естери на гликоловата киселина.2-bromo-5-fluorothiophene and after conversion to the corresponding organometallic compounds, reaction with suitable glyoxylic acid esters to glycolic acid esters.
2-флуортиофен и 3-флуортиофен взаимодействат аналогично, Arch. Pharm, 322, 839 (1989), на съответните естери на глиоксилова киселина, които от друга страна, както вече е описано, могат да взаимодействат например с 2- или 3 тиенилови производни до естери на гликолова киселина. При подходящ избор на компоненти могат да се получат аналогично симетрично заместени естери на ди-тиенилгликоловата киселина.2-fluorothiophene and 3-fluorothiophene interact similarly, Arch. Pharm, 322, 839 (1989), of the corresponding glyoxylic acid esters, which on the other hand, as described above, may be reacted, for example, with 2- or 3-thienyl derivatives to glycolic acid esters. With the appropriate selection of components, analogously symmetrically substituted diethylene glycol acid esters can be obtained.
Друг начин се предлага аналогично на бензоинова кондензация и прегрупировка на бензинова киселина.Another method is offered analogously to benzoic condensation and regrouping of benzoic acid.
ii
Следващите примери илюстрират изобретението>без да го ограничават.The following examples illustrate the invention without limitation.
ПРИМЕР 1.EXAMPLE 1.
Скопинов естер на ди-(2-тиенил)гликолова киселина 50,87 g (0,2 mol) метилов естер на ди-(2тиенил)гликолова киселина и 31,04 g (0,2 mol) скопин се разтварят в 100 ml абсолютен толуен и взаимодействат при прибавяне на 1,65 g (0,071 граматома) натрий на няколко части при температура на банята от 90°С. При температура от 78-90°С на реакционната смес и налягане от 500 mbar полученият метанол се дестилира. След реакционно време от около 5 h реакционната смес се разбърква в смес от лед и солна киселина. Киселата фаза се отделя, алкализира се с натриев карбонат и свободната основа се екстрахира с метиленхлорид. След сушене върху натриев сулфат метиленхлоридът се отстранява под намалено налягане и остатъкът се прекристализира из ацетонитрил.Di- (2-thienyl) glycolic acid scopic ester 50.87 g (0.2 mol) of di- (2-thienyl) glycolic acid methyl ester and 31.04 g (0.2 mol) of scopin are dissolved in 100 ml of absolute toluene and reacted with the addition of 1.65 g (0.071 grams) of sodium in several parts at a bath temperature of 90 ° C. At a temperature of 78-90 ° C of the reaction mixture and a pressure of 500 mbar, the resulting methanol was distilled. After a reaction time of about 5 hours, the reaction mixture was stirred in a mixture of ice and hydrochloric acid. The acidic phase was separated, basified with sodium carbonate and the free base extracted with methylene chloride. After drying over sodium sulfate, the methylene chloride was removed under reduced pressure and the residue was recrystallized from acetonitrile.
Слабо оцветени кристали (из ацетонитрил).Lightly colored crystals (acetonitrile).
Т. на топене 149-150°С.Mp 149-150 ° C.
Добив 33,79 g (44,7 % от теоретичния).Yield 33.79 g (44.7% of theory).
ПРИМЕР 2,EXAMPLE 2,
Скопинов естер на ди-(2-тиенил)гликолова киселинаDi- (2-thienyl) glycolic acid scopic ester
12,72 g (0,05 mol) метилов естер на ди-(2-тиенил)гликолова киселина и 7,76 g (0,05 mol) скопин се стапят на нагревателна баня от 70°С под вакуум на водна струя. В тази стопилка се вкарва 2,70 g (0,05 mol) натриев метилат и се нагрява в продължение на 1 h под вакуум на водна струя, на нагревателна баня от 70°С и след взаимодействието още 1 h на нагревателна баня от 90°С. Втвърдената стопилка се разбърква в смес от 100 ml вода и 100 ml метиленхлорид при температурен контрол и метиленхлоридната фаза се екстрахира няколко пъти с вода. Метиленхлоридната фаза се екстрахира със съответно количество разредена солна киселина. От обединените водни фази, след прибавяне на съответно количество натриев карбонат, се екстрахира скопинов естер на ди-(2-тиенил)гликолова киселина с метиленхлорид и се суши над натриев сулфат. От сухия метиленхлориден разтвор по обичаен начин се получава хидрохлорид. Кристалите се филтрират, промиват се с ацетон и се сушат при 35°С под намалено налягане.12.72 g (0.05 mol) of di- (2-thienyl) glycolic acid methyl ester and 7.76 g (0.05 mol) of skopin were melted in a 70 ° C heat bath under a water jet vacuum. 2.70 g (0.05 mol) of sodium methylate are introduced into this melt and heated for 1 h under vacuum in a water jet, in a heating bath of 70 ° C, and after a further 1 h in a heating bath of 90 ° S. The solidified melt was stirred in a mixture of 100 ml of water and 100 ml of methylene chloride under temperature control and the methylene chloride phase was extracted several times with water. The methylene chloride phase is extracted with an appropriate amount of dilute hydrochloric acid. From the combined aqueous phases, after the addition of an appropriate amount of sodium carbonate, the di- (2-thienyl) glycolic acid scopic ester was extracted with methylene chloride and dried over sodium sulfate. Dry methylene chloride solution in the usual way produces hydrochloride. The crystals were filtered off, washed with acetone and dried at 35 ° C under reduced pressure.
Слабо жълти кристали (из метанол).Slightly yellow crystals (methanol).
Т. на топене 238-241°С.Mp 238-241 ° C.
Добив 10,99 g (53,1 % от теоретичния).Yield 10.99 g (53.1% of theory).
Хидрохлоридът може по обичаен начин да се превърне в основа.The hydrochloride can in the usual way become the base.
ПРИМЕР 3.EXAMPLE 3
Скопинов естер на ди-(2-тиенил)гликолова киселинаDi- (2-thienyl) glycolic acid scopic ester
38,15 g (0,15 mol) метилов естер на ди-(2-тиенил)гликолова киселина и 23,28 g (0,15 mol) скопин се разбъркват, прибавя се 0,34 g (0,015 граматома) натрий и се стапят под вакуум на водна струя, в нагревателна баня от 90°С. Взаимодействието продължава 2,5 h · След това се прибавят 100 ml абсолютен толуен и се разбърква при температура на нагряване 90сС, докато се получи разтвор. Реакционният разтвор се охлажда до стайна температура и се разбърква в охладена'с лед смес от лед и солна киселина. Кристализиралият .»-» хидрохлорид на основните естери се филтрира, промива се с малко вода и обилно с диетилов етер. Филтратите се сушат и водната фаза се екстрахира с диетилов етер. Филтрираният хидрохлорид се суспендира в киселата водна фаза и при температурен контрол и при добавяне на съответно количество натриев карбонат се превръща в основа, която се екстрахира с метиленхлорид. Обединените метиленхлоридни фази се сушат над натриев сулфат. След отдестилиране на метиленхлорида38.15 g (0.15 mol) of di- (2-thienyl) glycolic acid methyl ester and 23.28 g (0.15 mol) of scopin were stirred, 0.34 g (0.015 grams) of sodium was added and melt in a water jet in a 90 ° C heating bath. Reaction continued for 2,5 h · then added 100 ml of absolute toluene and stirred at heating temperature 90 to C until a solution was obtained. The reaction solution was cooled to room temperature and stirred in an ice-cold mixture of ice and hydrochloric acid. The crystallized »-» hydrochloride of the basic esters is filtered off, washed with a little water and copious diethyl ether. The filtrates were dried and the aqueous phase was extracted with diethyl ether. The filtered hydrochloride is suspended in the acidic aqueous phase and, under temperature control and with the addition of an appropriate amount of sodium carbonate, is converted to the base, which is extracted with methylene chloride. The combined methylene chloride phases were dried over sodium sulfate. After distilling off the methylene chloride
остава кристализат, който се пречиства чрез активен въглен и се прекристализира из ацетонитрил.crystallizate remains which is purified by activated carbon and recrystallized from acetonitrile.
Слабо жълти кристали (из ацетонитрил).Slightly yellow crystals (acetonitrile).
Т. на топене 148-149°С.Mp 148-149 ° C.
Добив 39,71 g (70,1 % от теоретичния).Yield 39.71 g (70.1% of theory).
ТАБЛИЦА 1,TABLE 1,
Съединение с формулаCompound of Formula
НО—С-СО-ОАBUT-C-CO-OA
I R1I R 1
т.т. °C т.т. °C № A R, основа HCImp ° C mp. ° C No. A R, HCI base
нортропанилnortropanil
Т.Т. °C Т.Т. °CT.T. ° C ° C
Т.Т. °C Т.Т. °CT.T. ° C ° C
Т.Т. °CT.T. ° C
Т.Т. °C ' IT.T. ° C 'I
За-(6,7-дехидро) тропай илFor (6,7-dehydro), get the silt
R,R,
2-пириоснова2-base
HCI дилHCI dil
За-тропанилOver-tapped
3-тиенил3-thienyl
За-(6,7-дехидро) тропай ил циклохексилFor - (6,7-dehydro) tropyl yl cyclohexyl
За-(6р,7р-епокси)тропанил циклохексил3- (6β, 7β-epoxy) tropanyl cyclohexyl
За-(6,7-дехидро)тропанил циклохексил3- (6,7-Dehydro) tropanyl cyclohexyl
Забележка: Всички хидрохлориди се топят при разлагане.Note: All hydrochloride melts upon decomposition.
ПРИМЕР 4.EXAMPLE 4.
Метобромид на скопинов естер на ди-(2-тиенил)гликолова киселина*Di- (2-thienyl) glycolic acid methobromide of Skopin ester *
10,0 g (0,0265 mol) скопинов естер на ди-(2-тиенил)гликолова киселина се разтваря в смес от 20 ml безводен метиленхлорид и 30 ml безводен ацетонитрил и се смесва с 12,8 g (0,1325 mol) метилбромид (като 50 %-ен разтвор в безводен ацетонитрил). ч реакционната смес се затваря плътно в реакционнен съд и се оставя да стои при стайна температура в продължение на 24 h . През това време изпадат кристали. Те се филтрират, промиват се с метиленхлорид и се сушат при10.0 g (0.0265 mol) of di- (2-thienyl) glycolic acid Skopin ester was dissolved in a mixture of 20 ml of anhydrous methylene chloride and 30 ml of anhydrous acetonitrile and mixed with 12.8 g (0.1325 mol) methyl bromide (as a 50% solution in anhydrous acetonitrile). The reaction mixture was sealed tightly in a reaction vessel and allowed to stand at room temperature for 24 hours. During this time crystals fall out. They are filtered off, washed with methylene chloride and dried at
35°С под намалено налягане.35 ° C under reduced pressure.
Бели кристали (из метанол/ацетон).White crystals (methanol / acetone).
Т. на топене 21 7-8°С (разлагане) след сушене приMp 21 7-8 ° C (decomposition) after drying at
1 1 °C под намалено налягане.1 1 ° C under reduced pressure.
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DE3931041C2 (en) | 1989-09-16 | 2000-04-06 | Boehringer Ingelheim Kg | Esters of thienyl carboxylic acids with amino alcohols, their quaternization products, processes for their preparation and medicaments containing them |
DE4108393A1 (en) * | 1991-03-15 | 1992-09-17 | Boehringer Ingelheim Kg | NEW ESTERS BI-AND TRICYCLIC AMINO ALCOHOLS, THEIR PREPARATION AND THEIR USE IN MEDICINAL PRODUCTS |
US5770738A (en) * | 1992-03-05 | 1998-06-23 | Boehringer Ingelheim Kg | Esters of bi- and tricyclic amino alcohols, their preparation and their use in pharmaceutical compositions |
DE19921693A1 (en) | 1999-05-12 | 2000-11-16 | Boehringer Ingelheim Pharma | Pharmaceutical composition for treating respiratory disorders, e.g. asthma, comprises combination of anticholinergic and beta-mimetic agents having synergistic bronchospasmolytic activity and reduced side-effects |
US7214687B2 (en) | 1999-07-14 | 2007-05-08 | Almirall Ag | Quinuclidine derivatives and medicinal compositions containing the same |
ES2165768B1 (en) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | NEW DERIVATIVES OF QUINUCLIDINE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
GB0009583D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Respiratory formulations |
GB0009606D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Therapeutic combinations |
GB0009592D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Respiratory combinations |
GB0009605D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Medicaments |
US6858593B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
US6787532B2 (en) | 2000-08-05 | 2004-09-07 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivatives |
US6750210B2 (en) | 2000-08-05 | 2004-06-15 | Smithkline Beecham Corporation | Formulation containing novel anti-inflammatory androstane derivative |
US6777400B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
US6759398B2 (en) | 2000-08-05 | 2004-07-06 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative |
US6858596B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivative |
GB0019172D0 (en) | 2000-08-05 | 2000-09-27 | Glaxo Group Ltd | Novel compounds |
US6777399B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
CA2417825C (en) | 2000-08-05 | 2008-07-22 | Glaxo Group Limited | 6.alpha., 9.alpha.-difluoro-17.alpha.-`(2-furanylcarboxyl)oxy!-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-androst-1,4,-diene-17-carbothioic acid s-fluoromethyl ester as an anti-inflammatory agent |
UA72014C2 (en) | 2000-10-12 | 2005-01-17 | Boehringer Ingelheim Pharma | Tiotropium-containing powdery preparations for inhalations intended for treating asthma and chronic obstructive pulmonary disease (variants), method for their production and capsule |
US6908928B2 (en) | 2000-10-12 | 2005-06-21 | Bi Pharma Kg. | Crystalline tiotropium bromide monohydrate, processes for the preparation thereof, and pharmaceutical compositions |
DK1326862T3 (en) * | 2000-10-12 | 2004-11-22 | Boehringer Ingelheim Pharma | Crystalline monohydrate of tiotropium bromide, process for its preparation and use thereof for the manufacture of a drug |
SI1333819T1 (en) * | 2000-10-31 | 2007-12-31 | Boehringer Ingelheim Pharma | Inhalative solution formulation containing a tiotropium salt |
DE10064816A1 (en) * | 2000-12-22 | 2002-06-27 | Boehringer Ingelheim Pharma | Production of tiotropium bromide useful as an anticholinergic comprises oxidation of di-(2-thienyl)-glycolic acid tropenol ester and subsequent quaternisation |
ATE334128T1 (en) | 2000-12-28 | 2006-08-15 | Almirall Prodesfarma Ag | NEW QUINUCLIDENE DERIVATIVES AND MEDICINAL COMPOSITIONS CONTAINING THESE COMPOUNDS |
US6506900B1 (en) | 2001-01-31 | 2003-01-14 | Boehringer Ingelheim Pharma Ag | Process for preparing a scopine ester intermediate |
UA77656C2 (en) | 2001-04-07 | 2007-01-15 | Glaxo Group Ltd | S-fluoromethyl ester of 6-alpha, 9-alpha-difluoro-17-alpha-[(2-furanylcarbonyl)oxy]-11-beta-hydroxy-16- alpha-methyl-3-oxoandrosta-1,4-dien-17-beta-carbothioacid as anti-inflammatory agent |
US7291608B2 (en) | 2001-04-30 | 2007-11-06 | Glaxo Group Limited | Anti-inflammatory 17.β.-carbothioate ester derivatives of androstane with a cyclic ester group in position 17.α |
DE10126924A1 (en) * | 2001-06-01 | 2002-12-05 | Boehringer Ingelheim Pharma | Inhalation capsule contains powdered mixture of tiotropium and auxiliary, for treating asthma or chronic obstructive pulmonary disease, having capsule material of low moisture content to improve stability |
KR100971616B1 (en) * | 2001-06-22 | 2010-07-22 | 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 | Crystalline anticholinergic method for its production and pharmaceutical composition comprising the same |
US6608055B2 (en) | 2001-06-22 | 2003-08-19 | Boehringer Ingelheim Pharma Kg | Crystalline anticholinergic, processes for preparing it and its use for preparing a pharmaceutical composition |
US6610849B2 (en) * | 2001-06-28 | 2003-08-26 | Boehringer Ingelheim Pharma Kg | Process for the manufacture of tropenol |
DE10141377A1 (en) | 2001-08-23 | 2003-03-13 | Boehringer Ingelheim Pharma | Scattering process for the production of powder formulations |
MXPA04003865A (en) | 2001-10-26 | 2004-07-08 | Upjohn Co | Quarternary ammonium compounds and their use as antimuscarinic agents. |
DE10200943A1 (en) * | 2002-01-12 | 2003-07-24 | Boehringer Ingelheim Pharma | Process for the preparation of scopine esters |
DE10203749A1 (en) * | 2002-01-31 | 2003-08-14 | Boehringer Ingelheim Pharma | New anticholinergics, process for their preparation and their use as medicines |
US6696462B2 (en) | 2002-01-31 | 2004-02-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Anticholinergics, processes for the preparation thereof, and pharmaceutical compositions |
GB0202635D0 (en) * | 2002-02-05 | 2002-03-20 | Glaxo Wellcome Mfg Pte Ltd | Formulation containing novel anti-inflammatory androstane derivative |
GB0203193D0 (en) * | 2002-02-11 | 2002-03-27 | Pfizer Ltd | Nicotinamide derivatives useful as pde4 inhibitors |
AU2003201745A1 (en) * | 2002-02-11 | 2003-09-04 | Pfizer Limited | Nicotinamide derivatives and a tiotropium salt in combination for the treatment of e.g. inflammatory, allergic and respiratory diseases |
DE10212264A1 (en) | 2002-03-20 | 2003-10-02 | Boehringer Ingelheim Pharma | Crystalline micronisate, process for its preparation and its use for the manufacture of a medicament |
US7309707B2 (en) * | 2002-03-20 | 2007-12-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Crystalline micronisate, process for the manufacture thereof and use thereof for the preparation of a medicament |
DE10214264A1 (en) * | 2002-03-28 | 2003-10-16 | Boehringer Ingelheim Pharma | HFA suspension formulations of an anhydrate |
US7244415B2 (en) | 2002-03-28 | 2007-07-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | HFA suspension formulations of an anhydrate |
UA80123C2 (en) | 2002-04-09 | 2007-08-27 | Boehringer Ingelheim Pharma | Inhalation kit comprising inhalable powder of tiotropium |
DE10216036A1 (en) | 2002-04-11 | 2003-10-23 | Boehringer Ingelheim Pharma | Aerosol formulation for inhalation containing a tiotropium salt |
DE10224091A1 (en) * | 2002-05-31 | 2003-12-11 | Boehringer Ingelheim Pharma | Technical process for the production of tropenol |
GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
US7763280B2 (en) | 2002-11-28 | 2010-07-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Tiotropium containing powder formulation for inhalation |
EP1589968A4 (en) * | 2003-01-16 | 2009-05-06 | Univ Rochester | Quaternary antimuscarinic compounds for the treatment of bladder diseases |
US20040226556A1 (en) | 2003-05-13 | 2004-11-18 | Deem Mark E. | Apparatus for treating asthma using neurotoxin |
JP4616264B2 (en) | 2003-05-28 | 2011-01-19 | セラヴァンス, インコーポレーテッド | Azabicycloalkane compounds as muscarinic receptor antagonists |
CN1875020B (en) | 2003-11-03 | 2010-04-28 | 贝林格尔.英格海姆国际有限公司 | Novel tiotropium salts, methods for the production thereof, and pharmaceutical formulations containing the same |
DE502004010602D1 (en) * | 2003-11-03 | 2010-02-11 | Boehringer Ingelheim Pharma | NEW CRYSTALLINE ANHYDRATE WITH ANTICHOLINERGER EFFICACY |
WO2005042526A1 (en) | 2003-11-03 | 2005-05-12 | Boehringer Ingelheim International Gmbh | Method for producing tiotropium salts, tiotropium salts and pharmaceutical formulations, containing the same |
US7968717B2 (en) | 2003-11-03 | 2011-06-28 | Boehringer Ingelhein International Gmbh | Crystalline anhydrate with anticholinergic efficacy |
SE0303570L (en) | 2003-12-03 | 2005-06-04 | Microdrug Ag | Moisture-sensitive medical product |
US20080027094A1 (en) * | 2004-08-30 | 2008-01-31 | Ono Pharmaceutical Co., Ltd. | Tropane Compounds and Pharmaceutical Compositions Comprising the Same as an Active Ingredient |
CA2606549A1 (en) | 2005-05-02 | 2006-11-09 | Boehringer Ingelheim International Gmbh | Crystalline forms of tiotropium bromide |
RU2007144531A (en) * | 2005-05-02 | 2009-06-10 | БЕРИНГЕР ИНГЕЛЬХАЙМ ИНТЕРНАЦИОНАЛЬ ГмбХ (DE) | NEW CRYSTAL FORMS OF THIOTROPYBROMIDE |
DE102005035112A1 (en) | 2005-07-27 | 2007-02-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | A new process for the preparation of tiotropium salts using N-methylscopinium salts soluble in organic solvents |
BRPI0614290A2 (en) | 2005-08-08 | 2011-03-22 | Argenta Discovery Ltd | bicyclo [2.2.1] hept-7-ylamine derivatives and their uses |
US20070088030A1 (en) | 2005-10-10 | 2007-04-19 | Barbara Niklaus-Humke | Aerosol formulations for the inhalation of beta-agonists |
DE102005059602A1 (en) * | 2005-12-14 | 2007-06-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Micronization process |
US20070167480A1 (en) * | 2005-12-19 | 2007-07-19 | Sicor Inc. | Pure and stable tiotropium bromide |
US9108962B2 (en) | 2005-12-19 | 2015-08-18 | Sicor, Inc. | Forms of tiotropium bromide and processes for preparation thereof |
JP5086267B2 (en) | 2005-12-19 | 2012-11-28 | シコール インコーポレイティド | Novel form of tiotropium bromide and process for producing it |
PT1971332E (en) * | 2006-01-04 | 2011-03-18 | Boehringer Ingelheim Int | Use of tiotropium salts in the treatment of moderate persistent asthma |
ES2298049B1 (en) | 2006-07-21 | 2009-10-20 | Laboratorios Almirall S.A. | PROCEDURE FOR MANUFACTURING BROMIDE OF 3 (R) - (2-HIDROXI-2,2-DITIEN-2-ILACETOXI) -1- (3-PHENOXIPROPIL) -1-AZONIABICICLO (2.2.2) OCTANO. |
WO2008015416A1 (en) | 2006-08-01 | 2008-02-07 | Glaxo Group Limited | Pyrazolo[3,4-b]pyridine compounds, and their use as pde4 inhibitors |
EP1923393A1 (en) * | 2006-11-17 | 2008-05-21 | Boehringer Ingelheim Pharma GmbH & Co. KG | Crystalline form of tiotropium bromide and urea |
EP1925295A1 (en) * | 2006-11-22 | 2008-05-28 | Boehringer Ingelheim Pharma GmbH & Co. KG | Stable powder formulation containing a new antichinolinergic agent |
GB0716026D0 (en) | 2007-08-16 | 2007-09-26 | Norton Healthcare Ltd | An inhalable medicament |
CA2608561A1 (en) * | 2007-10-29 | 2009-04-29 | Carl Paluszkiewicz | Motorcycle wind deflector accessory support |
WO2009087419A1 (en) * | 2008-01-10 | 2009-07-16 | Generics [Uk] Limited | Novel process for the preparation of scopine esters |
US8483831B1 (en) | 2008-02-15 | 2013-07-09 | Holaira, Inc. | System and method for bronchial dilation |
EP2100599A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
EP2100598A1 (en) * | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
KR101719824B1 (en) | 2008-05-09 | 2017-04-04 | 호라이라 인코포레이티드 | Systems, assemblies, and methods for treating a bronchial tree |
EP2172190A1 (en) | 2008-10-02 | 2010-04-07 | Laboratorios Liconsa, S.A. | Inhalable particles comprising tiotropium |
EP2403851B1 (en) | 2009-03-06 | 2015-06-17 | Mahmut Bilgic | New crystalline forms of tiotropium bromide |
US8815258B2 (en) | 2009-05-29 | 2014-08-26 | Pearl Therapeutics, Inc. | Compositions, methods and systems for respiratory delivery of two or more active agents |
EP2435024B1 (en) | 2009-05-29 | 2016-07-06 | Pearl Therapeutics, Inc. | Compositions for respiratory delivery of active agents and associated methods and systems |
WO2011015883A1 (en) | 2009-08-07 | 2011-02-10 | Generics [Uk] Limited | Dichloromethane solvate of tiotropium bromide and its use |
CN102639531B (en) * | 2009-08-07 | 2016-01-20 | 基因里克斯(英国)有限公司 | The anhydrate of tiotropium bromide |
WO2011015884A1 (en) | 2009-08-07 | 2011-02-10 | Generics [Uk] Limited | Process to prepare scopine esters |
TR200907237A2 (en) | 2009-09-23 | 2011-04-21 | Bi̇lgi̇ç Mahmut | Tiotropium dry powder combination |
TR200907236A2 (en) | 2009-09-23 | 2011-04-21 | Bi̇lgi̇ç Mahmut | Transport of Tiotropium dry powder formulation in blister pack. |
EP2926757B1 (en) | 2009-10-27 | 2023-01-25 | Nuvaira, Inc. | Delivery devices with coolable energy emitting assemblies |
AU2010319477A1 (en) | 2009-11-11 | 2012-05-24 | Holaira, Inc. | Systems, apparatuses, and methods for treating tissue and controlling stenosis |
US8911439B2 (en) | 2009-11-11 | 2014-12-16 | Holaira, Inc. | Non-invasive and minimally invasive denervation methods and systems for performing the same |
TR201000679A2 (en) * | 2010-01-29 | 2011-08-22 | B�Lg�� Mahmut | Dry powder formulations containing a pharmaceutical combination. |
WO2011093813A1 (en) | 2010-01-28 | 2011-08-04 | Mahmut Bilgic | Dry powder pharmaceutical composition comprising tiotropium and fluticasone |
TR201000681A2 (en) * | 2010-01-29 | 2011-08-22 | B�Lg�� Mahmut | Dry powder formulations inhaled. |
WO2011093812A2 (en) | 2010-01-28 | 2011-08-04 | Mahmut Bilgic | Pharmaceutical formulation comprising tiotropium and budesonide in dry powder form |
WO2011093809A2 (en) | 2010-01-28 | 2011-08-04 | Mahmut Bilgic | Dry powder pharmaceutical composition comprising tiotropium and ciclesonide |
TR200909790A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Combination of dry powder containing a combination of tiotropium, formoterol and a chromoglycic acid derivative. |
WO2011093810A2 (en) | 2010-01-28 | 2011-08-04 | Bilgic Mahmut | Dry powder pharmaceutical composition comprising tiotropium and mometasone |
TR200909788A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Dry powder formulation suitable for inhalation with tiotropium |
TR200909789A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Dry powder combination containing tiotropium, budesonide and a chromoglycic acid derivative combination |
TR200909793A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Combination of dry powder containing a combination of tiotropium, mometasone and a chromoglycic acid derivative. |
TR200909792A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Dry powder combination containing tiotropium, corticosteroid and a combination of chromoglycic acid derivative |
US8834931B2 (en) | 2009-12-25 | 2014-09-16 | Mahmut Bilgic | Dry powder formulation containing tiotropium for inhalation |
TR201000733A2 (en) | 2010-02-02 | 2011-08-22 | Bi̇lgi̇ç Mahmut | Pharmaceutical compositions comprising fluticasone, tiotropium and sodium chromoglycate. |
TR201005221A2 (en) | 2010-04-01 | 2012-01-23 | Bi̇lgi̇ç Mahmut | Improved synthesis method. |
TR201002520A2 (en) | 2010-04-01 | 2010-05-21 | Bi̇lgi̇ç Mahmut | Tiotropium bromide manufacturing method. |
TR201005222A2 (en) | 2010-04-01 | 2011-10-21 | Bi̇lgi̇ç Mahmut | Tiotropium bromide synthesis method |
US8957209B2 (en) | 2010-04-01 | 2015-02-17 | Mahmut Bilgic | Methods for the synthesis of tiotropium bromide |
TR201007108A2 (en) | 2010-08-25 | 2012-03-21 | B�Lg�� Mahmut | New tiotropium bromide crystal and production method. |
TR201101897A2 (en) | 2011-02-28 | 2012-09-21 | Bi̇lgi̇ç Mahmut | Crystal material containing tiotropium bromide |
TR201111589A2 (en) | 2011-03-03 | 2012-09-21 | Bi̇lgi̇ç Mahmut | Tiotropium bromide anhydrous crystal form. |
TR201102068A2 (en) | 2011-03-03 | 2012-09-21 | Bi̇lgi̇ç Mahmut | Crystalline substances containing tiotropium bromide |
EP2510928A1 (en) | 2011-04-15 | 2012-10-17 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
ITRM20110508A1 (en) * | 2011-09-27 | 2013-03-28 | Lusochimica Spa | PROCESS FOR THE PREPARATION OF SCOPINA'S ESTERS. |
US8680297B2 (en) | 2011-10-06 | 2014-03-25 | Drug Process Licensing Assoc., LLC | Manufacturing process for tiotropium bromide |
CZ304368B6 (en) | 2011-11-28 | 2014-04-02 | Zentiva, K.S. | Tiotropium bromide mixed solvate and process for preparing thereof |
GB201200525D0 (en) | 2011-12-19 | 2012-02-29 | Teva Branded Pharmaceutical Prod R & D Inc | An inhalable medicament |
SI2607351T1 (en) * | 2011-12-22 | 2017-07-31 | Cerbios-Pharma S.A. | Continuous process for the alkylation of cyclic tertiary amines |
EP2804591A2 (en) | 2012-01-16 | 2014-11-26 | Mahmut Bilgic | Preparation of dry powder formulations comprising tiotropium |
CZ201241A3 (en) | 2012-01-20 | 2013-07-31 | Zentiva, K.S. | Novel polymorphous forms of thiotropium iodide and process for preparing thereof |
US20150165038A1 (en) | 2012-02-10 | 2015-06-18 | Arven llac Sanayi Ve Ticaret A.S. | Compositions comprising muscarinic receptor antagonist and sorbitol |
PT106142B (en) * | 2012-02-10 | 2014-07-18 | Hovione Farmaci Ncia S A | PROCESS FOR THE PREPARATION OF TIOTROPE BROMIDE |
JP6335798B2 (en) | 2012-02-28 | 2018-05-30 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | New propellant-containing tiotropium formulation |
CZ304808B6 (en) * | 2012-03-16 | 2014-11-05 | Zentiva, K.S. | Process for preparing scopine ester of di-(2- thienyl)glycolic acid, an intermediate in the synthesis of tiotropium bromide and a new form thereof |
CZ305012B6 (en) | 2012-03-30 | 2015-03-25 | Zentiva, K.S. | Process for preparing scopine ester of di-(2-thienyl)glycolic acid, an intermediate in the synthesis of tiotropium bromide |
WO2014007769A1 (en) | 2012-07-05 | 2014-01-09 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Compositions comprising muscarinic receptor antagonist and glucose anhydrous |
US10105316B2 (en) | 2012-07-05 | 2018-10-23 | Arven llac Sanayi Ve Ticaret A.S. | Inhalation compositions comprising muscarinic receptor antagonist |
EP2705838A1 (en) | 2012-09-06 | 2014-03-12 | Xspray Microparticles Ab | Tiotropium preparations |
DK2914593T3 (en) | 2012-11-05 | 2017-04-18 | Zentiva Ks | STABILIZATION OF TIOTROPIUM SOLVATES |
US9398933B2 (en) | 2012-12-27 | 2016-07-26 | Holaira, Inc. | Methods for improving drug efficacy including a combination of drug administration and nerve modulation |
KR102391332B1 (en) | 2013-03-15 | 2022-04-26 | 펄 테라퓨틱스 인코포레이티드 | Methods and systems for conditioning of particulate crystalline materials |
KR20150135328A (en) | 2013-04-01 | 2015-12-02 | 풀매트릭스 인코퍼레이티드 | Tiotropium dry powders |
EP2913332A1 (en) | 2014-02-27 | 2015-09-02 | Euticals S.P.A. | Crystalline form of tiotropium bromide with lactose |
US10034866B2 (en) | 2014-06-19 | 2018-07-31 | Teva Branded Pharmaceutical Products R&D, Inc. | Inhalable medicament comprising tiotropium |
CN107995861A (en) | 2015-05-18 | 2018-05-04 | 格兰马克专业公司 | The black tropine inhalation solution of Thailand for atomization |
US9987260B2 (en) | 2015-05-18 | 2018-06-05 | Glenmark Specialty S.A. | Tiotropium inhalation solution for nebulization |
US10653683B2 (en) | 2015-05-18 | 2020-05-19 | Glenmark Specialty S.A. | Tiotropium inhalation solution for nebulization |
KR101748796B1 (en) | 2015-09-30 | 2017-06-19 | 한미약품 주식회사 | Inhalation capsule with enhanced delivery rate of active ingredients |
CA3002300A1 (en) | 2015-10-23 | 2017-04-27 | Arven Ilac Sanayi Ve Ticaret A.S. | Blister for inhalable formulation of tiotropium bromide |
WO2017068119A1 (en) | 2015-10-23 | 2017-04-27 | Arven Ilac Sanayi Ve Ticaret A.S. | Blister for tiotropium bromide inhalable formulation |
WO2017138896A1 (en) | 2016-02-11 | 2017-08-17 | Sima Patent Ve Lisanslama Hizmetleri Ltd. Şti | Crystalline form of tiotropium bromide anhydrate |
CN106467535A (en) * | 2016-08-28 | 2017-03-01 | 杭州百诚医药科技股份有限公司 | One kind prepares the purifying process of 2,2 pairs of (2 thienyl) glycolic Rhizoma Scopoliae Japonicae esters |
WO2018055642A1 (en) * | 2016-09-23 | 2018-03-29 | Gbr Laboratories Pvt. Ltd. | A process for preparing tiotropium bromide and intermediates thereof |
WO2018069887A1 (en) | 2016-10-14 | 2018-04-19 | Glenmark Specialty S.A. | Nebulizable compositions of tiotropium and formoterol |
EA201990606A1 (en) | 2016-11-16 | 2019-10-31 | SPRAYED THIOTROPY | |
US20200215051A1 (en) | 2019-01-03 | 2020-07-09 | Glenmark Specialty S.A. | Nebulization composition comprising tiotropium and indacaterol |
US20240252440A1 (en) | 2021-07-09 | 2024-08-01 | Astrazeneca Pharmaceuticals Lp | Compositions, methods and systems for aerosol drug delivery |
CN114213408B (en) * | 2021-12-15 | 2023-03-31 | 台州仙琚药业有限公司 | Preparation method of tiotropium bromide |
WO2023119093A1 (en) | 2021-12-20 | 2023-06-29 | Astrazeneca Ab | Compositions, methods and systems for aerosol drug delivery |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB845056A (en) | 1957-07-05 | 1960-08-17 | Egyt Gyogyszervegyeszeti Gyar | Improvements in or relating to tropane derivatives |
DE1166787B (en) * | 1960-07-09 | 1964-04-02 | Boehringer & Soehne Gmbh | Process for the production of new garnetanol (3ª ‰) esters and their hydrohalides |
GB955535A (en) * | 1962-10-22 | 1964-04-15 | Boehringer & Soehne Gmbh | New n-substituted norgranatanol-(3ª‰)-esters |
DE2046659A1 (en) | 1970-01-28 | 1972-03-23 | ||
US3808263A (en) * | 1970-05-12 | 1974-04-30 | Tanabe Seiyaku Co | 6,6-dimethyl-9-alkyl-9-azabicyclo(3.3.1)nonan-3-ols |
US3673195A (en) * | 1970-05-25 | 1972-06-27 | Tanabe Seiyaku Co | Derivatives of 6,6,9-tri-lower alkyl-9-azabicyclo(3.3.1) nonan-3{60 -or 3{62 -ol |
US4353922A (en) * | 1981-03-13 | 1982-10-12 | Syntex (U.S.A.) Inc. | Anticholinergic bronchodilators |
DE3546218A1 (en) | 1985-12-27 | 1987-07-02 | Madaus & Co Dr | AZONIA SPIRONORTROPANOLESTER, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENT |
DE3931041C2 (en) | 1989-09-16 | 2000-04-06 | Boehringer Ingelheim Kg | Esters of thienyl carboxylic acids with amino alcohols, their quaternization products, processes for their preparation and medicaments containing them |
-
1989
- 1989-09-16 DE DE3931041A patent/DE3931041C2/en not_active Expired - Lifetime
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