JP4527408B2 - ムスカリン性アンタゴニスト - Google Patents
ムスカリン性アンタゴニスト Download PDFInfo
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- JP4527408B2 JP4527408B2 JP2003587783A JP2003587783A JP4527408B2 JP 4527408 B2 JP4527408 B2 JP 4527408B2 JP 2003587783 A JP2003587783 A JP 2003587783A JP 2003587783 A JP2003587783 A JP 2003587783A JP 4527408 B2 JP4527408 B2 JP 4527408B2
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- 229940121948 Muscarinic receptor antagonist Drugs 0.000 title description 5
- 239000003149 muscarinic antagonist Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 119
- 238000000034 method Methods 0.000 abstract description 22
- 238000002360 preparation method Methods 0.000 abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 11
- 239000000544 cholinesterase inhibitor Substances 0.000 abstract description 9
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 abstract description 8
- 229910052740 iodine Inorganic materials 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- 125000000217 alkyl group Chemical group 0.000 description 55
- -1 1,4-disubstituted piperidines Chemical class 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 125000003118 aryl group Chemical group 0.000 description 25
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 150000003839 salts Chemical class 0.000 description 24
- 239000000460 chlorine Substances 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000012453 solvate Substances 0.000 description 17
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 16
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- 125000003710 aryl alkyl group Chemical group 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 230000037396 body weight Effects 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 12
- 125000000753 cycloalkyl group Chemical group 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 125000003545 alkoxy group Chemical group 0.000 description 11
- 230000027455 binding Effects 0.000 description 11
- 208000010877 cognitive disease Diseases 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 239000003937 drug carrier Substances 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 230000001149 cognitive effect Effects 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 230000004770 neurodegeneration Effects 0.000 description 7
- 208000015122 neurodegenerative disease Diseases 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- 125000002877 alkyl aryl group Chemical group 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 125000006413 ring segment Chemical group 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 208000024827 Alzheimer disease Diseases 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 4
- 208000028698 Cognitive impairment Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000001447 alkali salts Chemical class 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000008043 acidic salts Chemical class 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 3
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 3
- 125000005110 aryl thio group Chemical group 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 125000002915 carbonyl group Chemical class [*:2]C([*:1])=O 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 2
- LWUAMROXVQLJKA-UHFFFAOYSA-N 2-amino-3-chlorobenzoic acid Chemical compound NC1=C(Cl)C=CC=C1C(O)=O LWUAMROXVQLJKA-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 125000005018 aryl alkenyl group Chemical group 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 125000005135 aryl sulfinyl group Chemical group 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 150000001602 bicycloalkyls Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 239000006210 lotion Substances 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
- 239000002609 medium Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- MYMSJFSOOQERIO-UHFFFAOYSA-N 1-bromodecane Chemical compound CCCCCCCCCCBr MYMSJFSOOQERIO-UHFFFAOYSA-N 0.000 description 1
- PBLNBZIONSLZBU-UHFFFAOYSA-N 1-bromododecane Chemical compound CCCCCCCCCCCCBr PBLNBZIONSLZBU-UHFFFAOYSA-N 0.000 description 1
- WSULSMOGMLRGKU-UHFFFAOYSA-N 1-bromooctadecane Chemical compound CCCCCCCCCCCCCCCCCCBr WSULSMOGMLRGKU-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- KOFZTCSTGIWCQG-UHFFFAOYSA-N 1-bromotetradecane Chemical compound CCCCCCCCCCCCCCBr KOFZTCSTGIWCQG-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- ZTEHOZMYMCEYRM-UHFFFAOYSA-N 1-chlorodecane Chemical compound CCCCCCCCCCCl ZTEHOZMYMCEYRM-UHFFFAOYSA-N 0.000 description 1
- YAYNEUUHHLGGAH-UHFFFAOYSA-N 1-chlorododecane Chemical compound CCCCCCCCCCCCCl YAYNEUUHHLGGAH-UHFFFAOYSA-N 0.000 description 1
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical compound CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-UHFFFAOYSA-N 0.000 description 1
- RNHWYOLIEJIAMV-UHFFFAOYSA-N 1-chlorotetradecane Chemical compound CCCCCCCCCCCCCCCl RNHWYOLIEJIAMV-UHFFFAOYSA-N 0.000 description 1
- SKIDNYUZJPMKFC-UHFFFAOYSA-N 1-iododecane Chemical compound CCCCCCCCCCI SKIDNYUZJPMKFC-UHFFFAOYSA-N 0.000 description 1
- GCDPERPXPREHJF-UHFFFAOYSA-N 1-iodododecane Chemical compound CCCCCCCCCCCCI GCDPERPXPREHJF-UHFFFAOYSA-N 0.000 description 1
- ZNJOCVLVYVOUGB-UHFFFAOYSA-N 1-iodooctadecane Chemical compound CCCCCCCCCCCCCCCCCCI ZNJOCVLVYVOUGB-UHFFFAOYSA-N 0.000 description 1
- FHQCFGPKNSSISL-UHFFFAOYSA-N 1-iodotetradecane Chemical compound CCCCCCCCCCCCCCI FHQCFGPKNSSISL-UHFFFAOYSA-N 0.000 description 1
- QAOJBHRZQQDFHA-UHFFFAOYSA-N 2,3-dichlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1Cl QAOJBHRZQQDFHA-UHFFFAOYSA-N 0.000 description 1
- WNAJXPYVTFYEST-UHFFFAOYSA-N 2-Amino-3-methylbenzoate Chemical compound CC1=CC=CC(C(O)=O)=C1N WNAJXPYVTFYEST-UHFFFAOYSA-N 0.000 description 1
- LWOKLXMNGXXORN-UHFFFAOYSA-N 2-chloro-3-methylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1Cl LWOKLXMNGXXORN-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- HXGHMCLCSPQMOR-UHFFFAOYSA-N 3-chloro-2-methylbenzoic acid Chemical compound CC1=C(Cl)C=CC=C1C(O)=O HXGHMCLCSPQMOR-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- NCOFQZRLIYPMNJ-UHFFFAOYSA-N 3-ethoxy-4-phenylmethoxybenzaldehyde Chemical compound CCOC1=CC(C=O)=CC=C1OCC1=CC=CC=C1 NCOFQZRLIYPMNJ-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- DEWIOKQDRWFLFW-UHFFFAOYSA-N 4-fluoronaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=C(F)C2=C1 DEWIOKQDRWFLFW-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
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- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- 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
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Description
本出願は、米国仮出願第60/376,093号(2002年4月26日出願)に対する優先権を主張する。
本発明は、認知障害の処置において有用な1,4−ジ置換ピペリジン、これらの化合物を含む薬学的組成物、これらの化合物を用いた処置方法、およびアセチルコリンエステラーゼインヒビターと組み合わせたこれらの化合物の使用に関する。
アルツハイマー病および他の認知障害は、最近、多くの注目を受けているが、これらの疾患の処置は未だになお、大いに成功したというわけではない。Melchiorreら(J.Med.Chem.(1993),36,3734−3737)によれば、M2ムスカリン性レセプターを選択的に拮抗する化合物(特に、M1ムスカリン性レセプターに関して)は、認知障害に対する活性を保有するに違いない。Baumgoldら(Eur.J.of Pharmacol.,251(1994)315−317)は、3−α−クロロインペリアリンを高度に選択的なM2ムスカリン性アンタゴニストとして開示する。
本発明は、ムスカリン性レセプターのアンタゴニストとしての新規クラスの化合物、このような化合物を調製する方法、1以上のこのような化合物を含む薬学的組成物、1以上のこのような化合物を含む薬学的処方物を調製する方法、およびムスカリン性レセプターに関連した1以上の疾患の処置、予防または改善の方法を提供する。1つの実施形態では、本願は、式Iに示す一般式を有する化合物:
pは0〜4であり;
mは0〜4であり;
nは0〜4であり;
R3は、H、アルキル、ハロ、アルコキシ、ヒドロキシ、ニトロ、アミノアルキル、およびアシルからなる群より選択され、ここで、mが2〜4である場合、R3は同じであっても異なっていてもよく、そして独立して選択され;
R4およびR5は、同じであっても異なっていてもよく、Hおよびハロゲンからなる群より各々独立して選択され;
R6は、H、ハロ、アルキル、ヒドロキシ、ヒドロキシアルキル、アリールアルキル、アミノアルキル、ハロアルキル、およびチオアルキルからなる群より選択され、ここで、nが2〜4である場合、R6は同じであっても異なっていてもよく、そして独立して選択され;
R7は、水素、アシル、アルキル、アルコキシ、アルケニル、シクロアルキル、同じであっても異なっていてもよく独立して選択される0〜2個のアルキル基で置換されたシクロアルキル、シクロアルケニル、ビシクロアルキル、アリールアルケニルおよびアリールアルキルからなる群より選択され;
R8は、H、アルキル、アリール、ヘテロアリール、ハロ、およびシクロアルキルからなる群より選択され;
R9は、H、アルキル、アリール、ハロ、ヒドロキシおよびシクロアルキルからなる群より選択され、ここで、(p)が2〜4である場合、R9は同じであっても異なっていてもよく、そして独立して選択されるか、または2つのR9基が一緒に連結して基−(CH2)r−を形成し得、ここで、ここで、rは1〜6であり;
R10は、置換または非置換のアルキル、置換または非置換のアリール、および置換または非置換のヘテロアリールからなる群より選択されるが、ただし、R10が、置換または非置換のヘテロアリールである場合、Mに対する結合は、R10基中の炭素原子からであり;
Zは、NまたはC−R1であり;
Xは、−O−、−S−、−S(O)−、−S(O)2−、−C(O)−、−アルキレン−、−C(S)−、−C(アルキル)2−および−C(H)(アルキル)−からなる群より選択され;そして
Mは、−S(O)2−または−C(O)−である。
本発明は、ムスカリン性レセプター(M2および/またはM4)のアンタゴニストとしての新規クラスの化合物、このような化合物を調製する方法、1以上のこのような化合物を含む薬学的組成物、1以上のこのような化合物を含む薬学的処方物を調製する方法、およびムスカリン性レセプターに関連する1以上の疾患を処置、予防または改善する方法を提供する。
「シクロアルキル」とは、3〜24個の炭素原子、好ましくは5〜10個の炭素原子を含む、非芳香族の単環式系または多環式縮合環系を意味する。好ましいシクロアルキル環は、5〜7個の環原子、より好ましくは6個の環原子を含む。このシクロアルキルは、同じであっても異なっていてもよく、上記で定義されるとおりである、1以上の「環系置換基」で必要に応じて置換され得る。適切な単環式シクロアルキルの非限定的な例としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルなどが挙げられる。適切な多環式シクロアルキルの非限定的な例としては、ビシクロアルキル(例えば、デカリニル、ノルボルネニルなど)、トリシクロアルキルおよびテトラシクロアルキルが挙げられる。
水性(aq)、トリフルオロ酢酸無水物(TFAA)、トリフルオロ酢酸(TFA)、4−ジメチルアミノピリジン(DMAP)、1−(3−ジメチルアミノプロピル−3−エチルカルボジイミド(EDCI)mおよび臭化テトラブチルアンモニウム(TBAB)。
方法の一般的説明:
目的の化合物を、クローニングされたヒトM1ムスカリン性レセプターサブタイプ、ヒトM2ムスカリン性レセプターサブタイプ、ヒトM3ムスカリン性レセプターサブタイプ、ヒトM4ムスカリン性レセプターサブタイプおよびヒトM5ムスカリン性レセプターサブタイプに対する結合を阻害する能力について試験した。これらの研究におけるレセプターの供給源は、これらのレセプター型の各々を発現する安定にトランスフェクトされたCHO細胞株由来の膜であった。増殖後、細胞をペレット化し、続いて50容積の冷10mM Na/Kリン酸緩衝液(pH7.4)(緩衝液B)中でPolytronを用いてホモジナイズした。ホモジネートを、40,000×gにて4℃にて20分間遠心分離した。得られた上清を捨て、そしてペレットを20mg湿組織/mlの最終濃度にて緩衝液B中に再懸濁した。これらの膜を、以下に記載の結合アッセイにおいて利用するまで、−80℃で保存した。
Claims (5)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US37609302P | 2002-04-26 | 2002-04-26 | |
PCT/US2003/012694 WO2003091220A1 (en) | 2002-04-26 | 2003-04-24 | Muscarinic antagonists |
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JP4527408B2 true JP4527408B2 (ja) | 2010-08-18 |
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JP2009285736A Withdrawn JP2010059213A (ja) | 2002-04-26 | 2009-12-16 | ムスカリン性アンタゴニスト |
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US (1) | US6890936B2 (ja) |
EP (1) | EP1499596B1 (ja) |
JP (2) | JP4527408B2 (ja) |
CN (1) | CN1649845A (ja) |
AT (1) | ATE413388T1 (ja) |
AU (1) | AU2003228674A1 (ja) |
CA (1) | CA2484217A1 (ja) |
DE (1) | DE60324544D1 (ja) |
ES (1) | ES2315494T3 (ja) |
HK (1) | HK1068136A1 (ja) |
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PL3461819T3 (pl) | 2017-09-29 | 2020-11-30 | Probiodrug Ag | Inhibitory cyklazy glutaminylowej |
EP3732163A4 (en) * | 2017-12-20 | 2021-07-14 | Vanderbilt University | MUSCARINIAN ACETYLCHOLINE RECEPTOR ANTAGONISTS M4 |
TWI767148B (zh) * | 2018-10-10 | 2022-06-11 | 美商弗瑪治療公司 | 抑制脂肪酸合成酶(fasn) |
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JPH04225953A (ja) * | 1990-05-07 | 1992-08-14 | Shionogi & Co Ltd | スピロ ジベンゾスベラン誘導体 |
GB9309422D0 (en) * | 1993-05-07 | 1993-06-23 | Res Inst Medicine Chem | Chemical compounds |
WO1999032489A1 (en) * | 1997-12-23 | 1999-07-01 | Alcon Laboratories, Inc. | Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions |
EP1386920A4 (en) * | 2001-04-20 | 2005-09-14 | Banyu Pharma Co Ltd | DERIVATIVES OF BENZIMIDAZOLONE |
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2003
- 2003-04-24 CA CA002484217A patent/CA2484217A1/en not_active Abandoned
- 2003-04-24 EP EP03726436A patent/EP1499596B1/en not_active Expired - Lifetime
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- 2003-04-24 WO PCT/US2003/012694 patent/WO2003091220A1/en active Application Filing
- 2003-04-24 AU AU2003228674A patent/AU2003228674A1/en not_active Abandoned
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- 2003-04-24 JP JP2003587783A patent/JP4527408B2/ja not_active Expired - Fee Related
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Also Published As
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HK1068136A1 (en) | 2005-04-22 |
DE60324544D1 (de) | 2008-12-18 |
JP2010059213A (ja) | 2010-03-18 |
US6890936B2 (en) | 2005-05-10 |
CN1649845A (zh) | 2005-08-03 |
AU2003228674A1 (en) | 2003-11-10 |
WO2003091220A1 (en) | 2003-11-06 |
EP1499596A1 (en) | 2005-01-26 |
CA2484217A1 (en) | 2003-11-06 |
US20040067972A1 (en) | 2004-04-08 |
ATE413388T1 (de) | 2008-11-15 |
EP1499596B1 (en) | 2008-11-05 |
ES2315494T3 (es) | 2009-04-01 |
JP2006507220A (ja) | 2006-03-02 |
MXPA04010552A (es) | 2005-01-25 |
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