CA2591415A1 - Nouveaux composes - Google Patents
Nouveaux composes Download PDFInfo
- Publication number
- CA2591415A1 CA2591415A1 CA002591415A CA2591415A CA2591415A1 CA 2591415 A1 CA2591415 A1 CA 2591415A1 CA 002591415 A CA002591415 A CA 002591415A CA 2591415 A CA2591415 A CA 2591415A CA 2591415 A1 CA2591415 A1 CA 2591415A1
- Authority
- CA
- Canada
- Prior art keywords
- pyrrolidin
- methyl
- propanamide
- 4alkyl
- 6alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 title claims description 56
- 229940076279 serotonin Drugs 0.000 title claims description 28
- 239000003112 inhibitor Substances 0.000 title description 11
- 230000000966 norepinephrine reuptake Effects 0.000 title description 3
- 230000000697 serotonin reuptake Effects 0.000 title description 3
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical class NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 title 1
- -1 -C(A)Y Chemical group 0.000 claims abstract description 244
- 150000001875 compounds Chemical class 0.000 claims abstract description 233
- 125000003118 aryl group Chemical group 0.000 claims abstract description 63
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 51
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 32
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 32
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 21
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 16
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 16
- 125000005843 halogen group Chemical group 0.000 claims abstract description 15
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 12
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 12
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims abstract description 10
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims abstract description 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 9
- 125000005561 phenanthryl group Chemical group 0.000 claims abstract description 9
- 125000004350 aryl cycloalkyl group Chemical group 0.000 claims abstract description 6
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 125000003003 spiro group Chemical group 0.000 claims abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 3
- 125000006621 (C3-C8) cycloalkyl-(C1-C6) alkyl group Chemical group 0.000 claims abstract 3
- 208000002193 Pain Diseases 0.000 claims description 75
- 230000036407 pain Effects 0.000 claims description 66
- 238000000034 method Methods 0.000 claims description 60
- 238000011282 treatment Methods 0.000 claims description 58
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 43
- 208000035475 disorder Diseases 0.000 claims description 36
- 239000002253 acid Substances 0.000 claims description 32
- 125000001475 halogen functional group Chemical group 0.000 claims description 30
- 229960002748 norepinephrine Drugs 0.000 claims description 30
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 28
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 19
- 230000033228 biological regulation Effects 0.000 claims description 15
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 13
- 206010046543 Urinary incontinence Diseases 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 101710164184 Synaptic vesicular amine transporter Proteins 0.000 claims description 7
- 102100034333 Synaptic vesicular amine transporter Human genes 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 6
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 5
- 208000001640 Fibromyalgia Diseases 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- 150000001266 acyl halides Chemical class 0.000 claims description 4
- 206010036596 premature ejaculation Diseases 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- RQQIFQXOKVSJMS-UHFFFAOYSA-N n-(naphthalen-2-ylmethyl)-n-piperidin-4-ylacetamide Chemical compound C=1C=C2C=CC=CC2=CC=1CN(C(=O)C)C1CCNCC1 RQQIFQXOKVSJMS-UHFFFAOYSA-N 0.000 claims description 3
- UVHJBFXDODHRJG-UHFFFAOYSA-N n-(naphthalen-2-ylmethyl)-n-piperidin-4-ylbutanamide Chemical compound C=1C=C2C=CC=CC2=CC=1CN(C(=O)CCC)C1CCNCC1 UVHJBFXDODHRJG-UHFFFAOYSA-N 0.000 claims description 3
- USUPIRYFHGUVOR-IBGZPJMESA-N 2-methyl-n-[(2-phenylphenyl)methyl]-n-[(3s)-pyrrolidin-3-yl]propanamide Chemical compound CC(C)C(=O)N([C@@H]1CNCC1)CC1=CC=CC=C1C1=CC=CC=C1 USUPIRYFHGUVOR-IBGZPJMESA-N 0.000 claims description 2
- FFWMVMYKTQEBAE-NSHDSACASA-N 2-methyl-n-[(3s)-pyrrolidin-3-yl]-n-[(2,3,4-trichlorophenyl)methyl]propanamide Chemical compound CC(C)C(=O)N([C@@H]1CNCC1)CC1=CC=C(Cl)C(Cl)=C1Cl FFWMVMYKTQEBAE-NSHDSACASA-N 0.000 claims description 2
- VGSCEHIVOAIVKK-LBPRGKRZSA-N 2-methyl-n-[(3s)-pyrrolidin-3-yl]-n-[(2,3,5-trichlorophenyl)methyl]propanamide Chemical compound CC(C)C(=O)N([C@@H]1CNCC1)CC1=CC(Cl)=CC(Cl)=C1Cl VGSCEHIVOAIVKK-LBPRGKRZSA-N 0.000 claims description 2
- FYDXJUSDGLWNFV-ZDUSSCGKSA-N 2-methyl-n-[(3s)-pyrrolidin-3-yl]-n-[[2-(trifluoromethyl)phenyl]methyl]propanamide Chemical compound CC(C)C(=O)N([C@@H]1CNCC1)CC1=CC=CC=C1C(F)(F)F FYDXJUSDGLWNFV-ZDUSSCGKSA-N 0.000 claims description 2
- XUMSWXWTJVVUOJ-UHFFFAOYSA-N 3-methyl-n-(naphthalen-1-ylmethyl)-n-piperidin-4-ylbutanamide Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C(=O)CC(C)C)C1CCNCC1 XUMSWXWTJVVUOJ-UHFFFAOYSA-N 0.000 claims description 2
- RDLDWTPNWMTWKO-FQEVSTJZSA-N 3-methyl-n-[(2-phenylphenyl)methyl]-n-[(3s)-pyrrolidin-3-yl]butanamide Chemical compound CC(C)CC(=O)N([C@@H]1CNCC1)CC1=CC=CC=C1C1=CC=CC=C1 RDLDWTPNWMTWKO-FQEVSTJZSA-N 0.000 claims description 2
- JWHFSAHLVNODKZ-UHFFFAOYSA-N OC(C(=O)N(C1CCNCC1)CC1=CC2=CC=CC=C2C=C1)C Chemical compound OC(C(=O)N(C1CCNCC1)CC1=CC2=CC=CC=C2C=C1)C JWHFSAHLVNODKZ-UHFFFAOYSA-N 0.000 claims description 2
- DWBBFNBXAKCWFH-QGZVFWFLSA-N n-(naphthalen-2-ylmethyl)-n-[(3r)-pyrrolidin-3-yl]acetamide Chemical compound C=1C=C2C=CC=CC2=CC=1CN(C(=O)C)[C@@H]1CCNC1 DWBBFNBXAKCWFH-QGZVFWFLSA-N 0.000 claims description 2
- RCMGBZYHSPTETA-QGZVFWFLSA-N n-(naphthalen-2-ylmethyl)-n-[(3r)-pyrrolidin-3-yl]propanamide Chemical compound C=1C=C2C=CC=CC2=CC=1CN(C(=O)CC)[C@@H]1CCNC1 RCMGBZYHSPTETA-QGZVFWFLSA-N 0.000 claims description 2
- DWBBFNBXAKCWFH-KRWDZBQOSA-N n-(naphthalen-2-ylmethyl)-n-[(3s)-pyrrolidin-3-yl]acetamide Chemical compound C=1C=C2C=CC=CC2=CC=1CN(C(=O)C)[C@H]1CCNC1 DWBBFNBXAKCWFH-KRWDZBQOSA-N 0.000 claims description 2
- INDDCTQFCFNYFA-UHFFFAOYSA-N n-(naphthalen-2-ylmethyl)-n-piperidin-4-ylpropanamide Chemical compound C=1C=C2C=CC=CC2=CC=1CN(C(=O)CC)C1CCNCC1 INDDCTQFCFNYFA-UHFFFAOYSA-N 0.000 claims description 2
- QQHHIEUIUNCEIF-UHFFFAOYSA-N n-[(1-methylnaphthalen-2-yl)methyl]-n-piperidin-4-ylacetamide Chemical compound C=1C=C2C=CC=CC2=C(C)C=1CN(C(=O)C)C1CCNCC1 QQHHIEUIUNCEIF-UHFFFAOYSA-N 0.000 claims description 2
- RCMVHXAYSDWNBI-GFCCVEGCSA-N n-[(2,3-dichlorophenyl)methyl]-2-methyl-n-[(3r)-pyrrolidin-3-yl]propanamide Chemical compound CC(C)C(=O)N([C@H]1CNCC1)CC1=CC=CC(Cl)=C1Cl RCMVHXAYSDWNBI-GFCCVEGCSA-N 0.000 claims description 2
- NIOAQGHNSBVJRZ-UHFFFAOYSA-N n-[(2,3-dichlorophenyl)methyl]-2-methyl-n-piperidin-4-ylpropanamide Chemical compound C1CNCCC1N(C(=O)C(C)C)CC1=CC=CC(Cl)=C1Cl NIOAQGHNSBVJRZ-UHFFFAOYSA-N 0.000 claims description 2
- YYVFHUIYCOUOCD-ZDUSSCGKSA-N n-[(2,3-dichlorophenyl)methyl]-3-methyl-n-[(3s)-pyrrolidin-3-yl]butanamide Chemical compound CC(C)CC(=O)N([C@@H]1CNCC1)CC1=CC=CC(Cl)=C1Cl YYVFHUIYCOUOCD-ZDUSSCGKSA-N 0.000 claims description 2
- YRBVTLBLPHIXQP-ZDUSSCGKSA-N n-[(2,4-dichlorophenyl)methyl]-2-methyl-n-[(3s)-pyrrolidin-3-yl]propanamide Chemical compound CC(C)C(=O)N([C@@H]1CNCC1)CC1=CC=C(Cl)C=C1Cl YRBVTLBLPHIXQP-ZDUSSCGKSA-N 0.000 claims description 2
- DINOQTNPFRDVRK-AWEZNQCLSA-N n-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-n-[(3s)-pyrrolidin-3-yl]butanamide Chemical compound CC(C)(C)CC(=O)N([C@@H]1CNCC1)CC1=CC=C(Cl)C=C1Cl DINOQTNPFRDVRK-AWEZNQCLSA-N 0.000 claims description 2
- ANVIRSRIYYSFBV-AWEZNQCLSA-N n-[(2,4-dichlorophenyl)methyl]-3-methyl-n-[(3s)-pyrrolidin-3-yl]butanamide Chemical compound CC(C)CC(=O)N([C@@H]1CNCC1)CC1=CC=C(Cl)C=C1Cl ANVIRSRIYYSFBV-AWEZNQCLSA-N 0.000 claims description 2
- BSMJJWYXCCOYNP-ZDUSSCGKSA-N n-[(2,4-dichlorophenyl)methyl]-n-[(3s)-pyrrolidin-3-yl]butanamide Chemical compound CCCC(=O)N([C@@H]1CNCC1)CC1=CC=C(Cl)C=C1Cl BSMJJWYXCCOYNP-ZDUSSCGKSA-N 0.000 claims description 2
- PXZVEYWSVBEKRN-AWEZNQCLSA-N n-[(2,4-dichlorophenyl)methyl]-n-[(3s)-pyrrolidin-3-yl]cyclobutanecarboxamide Chemical compound ClC1=CC(Cl)=CC=C1CN(C(=O)C1CCC1)[C@@H]1CNCC1 PXZVEYWSVBEKRN-AWEZNQCLSA-N 0.000 claims description 2
- ABWNRPAQIBGXIY-ZDUSSCGKSA-N n-[(2,4-dichlorophenyl)methyl]-n-[(3s)-pyrrolidin-3-yl]cyclopropanecarboxamide Chemical compound ClC1=CC(Cl)=CC=C1CN(C(=O)C1CC1)[C@@H]1CNCC1 ABWNRPAQIBGXIY-ZDUSSCGKSA-N 0.000 claims description 2
- RUCURZAOXQKURR-AWEZNQCLSA-N n-[(2,4-dichlorophenyl)methyl]-n-[(3s)-pyrrolidin-3-yl]pentanamide Chemical compound CCCCC(=O)N([C@@H]1CNCC1)CC1=CC=C(Cl)C=C1Cl RUCURZAOXQKURR-AWEZNQCLSA-N 0.000 claims description 2
- QEHHRDFKZARORR-IBGZPJMESA-N n-[(2-phenylphenyl)methyl]-n-[(3s)-pyrrolidin-3-yl]butanamide Chemical compound CCCC(=O)N([C@@H]1CNCC1)CC1=CC=CC=C1C1=CC=CC=C1 QEHHRDFKZARORR-IBGZPJMESA-N 0.000 claims description 2
- DNSFFPXOVPKGCT-SFHVURJKSA-N n-[(2-phenylphenyl)methyl]-n-[(3s)-pyrrolidin-3-yl]propanamide Chemical compound CCC(=O)N([C@@H]1CNCC1)CC1=CC=CC=C1C1=CC=CC=C1 DNSFFPXOVPKGCT-SFHVURJKSA-N 0.000 claims description 2
- YPZWAYMKJBJUMH-UHFFFAOYSA-N n-[(7-methoxy-1-methylnaphthalen-2-yl)methyl]-n-piperidin-4-ylacetamide Chemical compound CC=1C2=CC(OC)=CC=C2C=CC=1CN(C(C)=O)C1CCNCC1 YPZWAYMKJBJUMH-UHFFFAOYSA-N 0.000 claims description 2
- XJHRKLACZVPBOO-UHFFFAOYSA-N n-[(7-methoxy-1-methylnaphthalen-2-yl)methyl]-n-piperidin-4-ylpropanamide Chemical compound C=1C=C2C=CC(OC)=CC2=C(C)C=1CN(C(=O)CC)C1CCNCC1 XJHRKLACZVPBOO-UHFFFAOYSA-N 0.000 claims description 2
- ZFAZBQUXCIBGID-ZDUSSCGKSA-N n-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-methyl-n-[(3s)-pyrrolidin-3-yl]propanamide Chemical compound CC(C)C(=O)N([C@@H]1CNCC1)CC1=CC=C(C(F)(F)F)C=C1F ZFAZBQUXCIBGID-ZDUSSCGKSA-N 0.000 claims description 2
- 230000002485 urinary effect Effects 0.000 claims 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- NFXSKGKGQACNCS-AWEZNQCLSA-N 2-methyl-n-[(2-methylsulfanylphenyl)methyl]-n-[(3s)-pyrrolidin-3-yl]propanamide Chemical compound CSC1=CC=CC=C1CN(C(=O)C(C)C)[C@@H]1CNCC1 NFXSKGKGQACNCS-AWEZNQCLSA-N 0.000 claims 1
- JNLWAWMHYQYRKA-SFHVURJKSA-N 2-methyl-n-[(2-phenoxyphenyl)methyl]-n-[(3s)-pyrrolidin-3-yl]propanamide Chemical compound CC(C)C(=O)N([C@@H]1CNCC1)CC1=CC=CC=C1OC1=CC=CC=C1 JNLWAWMHYQYRKA-SFHVURJKSA-N 0.000 claims 1
- WHVWXRWHDIGHPE-UHFFFAOYSA-N n-[(1-ethylnaphthalen-2-yl)methyl]-n-piperidin-4-ylacetamide Chemical compound C1=CC2=CC=CC=C2C(CC)=C1CN(C(C)=O)C1CCNCC1 WHVWXRWHDIGHPE-UHFFFAOYSA-N 0.000 claims 1
- RCMVHXAYSDWNBI-LBPRGKRZSA-N n-[(2,3-dichlorophenyl)methyl]-2-methyl-n-[(3s)-pyrrolidin-3-yl]propanamide Chemical compound CC(C)C(=O)N([C@@H]1CNCC1)CC1=CC=CC(Cl)=C1Cl RCMVHXAYSDWNBI-LBPRGKRZSA-N 0.000 claims 1
- KSQKTWNQJCTCMA-LBPRGKRZSA-N n-[(2,4-dichlorophenyl)methyl]-n-[(3s)-pyrrolidin-3-yl]propanamide Chemical compound CCC(=O)N([C@@H]1CNCC1)CC1=CC=C(Cl)C=C1Cl KSQKTWNQJCTCMA-LBPRGKRZSA-N 0.000 claims 1
- YRGCYAJUEHMWAR-ZDUSSCGKSA-N n-[(2-chloro-4-fluorophenyl)methyl]-2-methyl-n-[(3s)-pyrrolidin-3-yl]propanamide Chemical compound CC(C)C(=O)N([C@@H]1CNCC1)CC1=CC=C(F)C=C1Cl YRGCYAJUEHMWAR-ZDUSSCGKSA-N 0.000 claims 1
- PXHGECKMKPJNDM-INIZCTEOSA-N n-[(2-cyclopropylphenyl)methyl]-2-methyl-n-[(3s)-pyrrolidin-3-yl]propanamide Chemical compound CC(C)C(=O)N([C@@H]1CNCC1)CC1=CC=CC=C1C1CC1 PXHGECKMKPJNDM-INIZCTEOSA-N 0.000 claims 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 abstract description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 92
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 76
- 238000002360 preparation method Methods 0.000 description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
- 150000001412 amines Chemical class 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 37
- 239000000203 mixture Substances 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- 241001465754 Metazoa Species 0.000 description 32
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 30
- 238000003556 assay Methods 0.000 description 30
- 150000003839 salts Chemical class 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 208000004454 Hyperalgesia Diseases 0.000 description 28
- 241000700159 Rattus Species 0.000 description 28
- 239000002904 solvent Substances 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 27
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 210000002683 foot Anatomy 0.000 description 21
- 238000012360 testing method Methods 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 206010053552 allodynia Diseases 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000010511 deprotection reaction Methods 0.000 description 18
- 230000004044 response Effects 0.000 description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 17
- 239000012528 membrane Substances 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 241000282414 Homo sapiens Species 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 239000002287 radioligand Substances 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- 208000027418 Wounds and injury Diseases 0.000 description 13
- 125000003545 alkoxy group Chemical group 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 239000007924 injection Substances 0.000 description 13
- 238000002347 injection Methods 0.000 description 13
- XZOWIJDBQIHMFC-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O.CCCC(N)=O XZOWIJDBQIHMFC-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 208000004296 neuralgia Diseases 0.000 description 12
- 208000021722 neuropathic pain Diseases 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000012453 solvate Substances 0.000 description 12
- 239000011324 bead Substances 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 208000014674 injury Diseases 0.000 description 11
- 229960001866 silicon dioxide Drugs 0.000 description 11
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- VHWJSJBTUWUEAL-UHFFFAOYSA-N propanamide;hydrochloride Chemical compound Cl.CCC(N)=O VHWJSJBTUWUEAL-UHFFFAOYSA-N 0.000 description 10
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 230000003068 static effect Effects 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 208000009935 visceral pain Diseases 0.000 description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 9
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- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical class CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229950005135 traxoprodil Drugs 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 208000002271 trichotillomania Diseases 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- ZNRGQMMCGHDTEI-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 ZNRGQMMCGHDTEI-ITGUQSILSA-N 0.000 description 1
- IYFNEFQTYQPVOC-UHFFFAOYSA-N udenafil Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)NCCC1CCCN1C IYFNEFQTYQPVOC-UHFFFAOYSA-N 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 239000000105 vanilloid receptor agonist Substances 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- 229960001255 viloxazine Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
- 229960001360 zolmitriptan Drugs 0.000 description 1
- ULSDMUVEXKOYBU-ZDUSSCGKSA-N zolmitriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1C[C@H]1COC(=O)N1 ULSDMUVEXKOYBU-ZDUSSCGKSA-N 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
- 229960004496 zotepine Drugs 0.000 description 1
- HDOZVRUNCMBHFH-UHFFFAOYSA-N zotepine Chemical compound CN(C)CCOC1=CC2=CC=CC=C2SC2=CC=C(Cl)C=C12 HDOZVRUNCMBHFH-UHFFFAOYSA-N 0.000 description 1
- 210000002517 zygapophyseal joint Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Reproductive Health (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Psychiatry (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0427618.4 | 2004-12-16 | ||
GB0427618A GB0427618D0 (en) | 2004-12-16 | 2004-12-16 | Novel compounds |
US64783905P | 2005-01-27 | 2005-01-27 | |
US60/647,839 | 2005-01-27 | ||
US69523805P | 2005-06-28 | 2005-06-28 | |
US60/695,238 | 2005-06-28 | ||
PCT/IB2005/003791 WO2006064351A2 (fr) | 2004-12-16 | 2005-12-08 | Nouveaux composes |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2591415A1 true CA2591415A1 (fr) | 2006-06-22 |
Family
ID=35840463
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002591415A Abandoned CA2591415A1 (fr) | 2004-12-16 | 2005-12-08 | Nouveaux composes |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1828122A2 (fr) |
JP (1) | JP2008524200A (fr) |
CA (1) | CA2591415A1 (fr) |
WO (1) | WO2006064351A2 (fr) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2008029924A1 (ja) | 2006-09-08 | 2010-01-21 | 大日本住友製薬株式会社 | 環状アミノアルキルカルボキサミド誘導体 |
US10512644B2 (en) | 2007-03-12 | 2019-12-24 | Inheris Pharmaceuticals, Inc. | Oligomer-opioid agonist conjugates |
US8173666B2 (en) | 2007-03-12 | 2012-05-08 | Nektar Therapeutics | Oligomer-opioid agonist conjugates |
JP2011102241A (ja) * | 2008-03-04 | 2011-05-26 | Dainippon Sumitomo Pharma Co Ltd | 新規1−アミノカルボニルピペリジン誘導体 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3577440A (en) * | 1968-12-23 | 1971-05-04 | Robins Co Inc A H | 1-substituted-3-amido-pyrrolidines |
US3963745A (en) * | 1972-04-03 | 1976-06-15 | A. H. Robins Company, Incorporated | Method for controlling emesis with N-(1-substituted-3-pyrrolidinyl)benzamides and thiobenzamides |
US4002757A (en) * | 1974-12-26 | 1977-01-11 | A. H. Robins Company, Incorporated | N-(1-substituted-3-pyrrolidinyl)-4-quinolinecarboxamides |
KR20010100965A (ko) * | 1998-11-02 | 2001-11-14 | 가마꾸라 아끼오 | 피롤리딘 화합물 및 이것의 의약 용도 |
CA2490397A1 (fr) * | 2002-06-24 | 2003-12-31 | Acadia Pharmaceuticals Inc. | Derives de piperidine substitues en n en tant qu'agents recepteurs de la serotonine |
-
2005
- 2005-12-08 WO PCT/IB2005/003791 patent/WO2006064351A2/fr active Application Filing
- 2005-12-08 CA CA002591415A patent/CA2591415A1/fr not_active Abandoned
- 2005-12-08 EP EP05811385A patent/EP1828122A2/fr not_active Withdrawn
- 2005-12-08 JP JP2007546219A patent/JP2008524200A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
WO2006064351A3 (fr) | 2006-10-12 |
JP2008524200A (ja) | 2008-07-10 |
WO2006064351A2 (fr) | 2006-06-22 |
EP1828122A2 (fr) | 2007-09-05 |
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Legal Events
Date | Code | Title | Description |
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EEER | Examination request | ||
FZDE | Dead |