CA2781041C - Spiropiperidine compounds as orl-1 receptor antagonists - Google Patents
Spiropiperidine compounds as orl-1 receptor antagonists Download PDFInfo
- Publication number
- CA2781041C CA2781041C CA2781041A CA2781041A CA2781041C CA 2781041 C CA2781041 C CA 2781041C CA 2781041 A CA2781041 A CA 2781041A CA 2781041 A CA2781041 A CA 2781041A CA 2781041 C CA2781041 C CA 2781041C
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- CA
- Canada
- Prior art keywords
- methyl
- pyran
- piperidine
- pyrazol
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 108010020615 nociceptin receptor Proteins 0.000 title abstract description 31
- 239000002464 receptor antagonist Substances 0.000 title abstract description 4
- 229940044551 receptor antagonist Drugs 0.000 title abstract description 4
- JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical class C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 223
- 238000011282 treatment Methods 0.000 claims abstract description 35
- 208000008589 Obesity Diseases 0.000 claims abstract description 17
- 235000020824 obesity Nutrition 0.000 claims abstract description 17
- 206010033307 Overweight Diseases 0.000 claims abstract description 14
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 11
- 208000020401 Depressive disease Diseases 0.000 claims abstract description 8
- -1 chloro, cyano, cyanomethyl Chemical group 0.000 claims description 106
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 84
- 150000003839 salts Chemical class 0.000 claims description 49
- 125000001153 fluoro group Chemical group F* 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 14
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 150000002431 hydrogen Chemical group 0.000 claims description 10
- 206010027599 migraine Diseases 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 6
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims description 5
- DWYGLHSLUMTSPC-UHFFFAOYSA-N spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1CNCCC21C(SC=C1)=C1CCO2 DWYGLHSLUMTSPC-UHFFFAOYSA-N 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- XXTAOIPDMBHKNU-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-[2-fluoro-6-(1-methylimidazol-2-yl)phenyl]-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1C1=NC=CN1C XXTAOIPDMBHKNU-UHFFFAOYSA-N 0.000 claims description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
- JJWDJWQBHRUEIN-UHFFFAOYSA-N [4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-1-(2-fluorophenyl)pyrazol-3-yl]methanol Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(CO)=NN1C1=CC=CC=C1F JJWDJWQBHRUEIN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- PETZZCNIISAXSO-UHFFFAOYSA-N 1-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-fluorophenyl]-n-methylmethanamine Chemical compound CNCC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 PETZZCNIISAXSO-UHFFFAOYSA-N 0.000 claims 2
- ALDFBAMFJCZMRT-UHFFFAOYSA-N 1-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-fluorophenyl]ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 ALDFBAMFJCZMRT-UHFFFAOYSA-N 0.000 claims 2
- QTOTZWFQCWGMHS-UHFFFAOYSA-N 2-chloro-1'-[[1-(2,6-difluorophenyl)-3-methylpyrazol-4-yl]methyl]-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1F QTOTZWFQCWGMHS-UHFFFAOYSA-N 0.000 claims 2
- RBBAMCYZDBRGRI-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-[2-fluoro-6-(2-methylimidazol-1-yl)phenyl]-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1N1C=CN=C1C RBBAMCYZDBRGRI-UHFFFAOYSA-N 0.000 claims 2
- DHSXGJLFQNUKJV-UHFFFAOYSA-N [4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-1-(2,6-difluorophenyl)pyrazol-3-yl]methanol Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(CO)=NN1C1=C(F)C=CC=C1F DHSXGJLFQNUKJV-UHFFFAOYSA-N 0.000 claims 2
- GXZGKGSYYNKMCY-UHFFFAOYSA-N 1'-[[1-(2,6-difluorophenyl)-3-methylpyrazol-4-yl]methyl]-2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(F)=CC=2CCO3)C(C)=NN1C1=C(F)C=CC=C1F GXZGKGSYYNKMCY-UHFFFAOYSA-N 0.000 claims 1
- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 claims 1
- DJNPTQOCOKRPIG-UHFFFAOYSA-N 1-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-fluorophenyl]-n,n-dimethylcyclopropan-1-amine Chemical compound C=1C=CC(F)=C(N2N=C(C)C(CN3CCC4(CC3)C=3SC(Cl)=CC=3C(F)(F)CO4)=C2)C=1C1(N(C)C)CC1 DJNPTQOCOKRPIG-UHFFFAOYSA-N 0.000 claims 1
- NNOVVEMYYNWICL-UHFFFAOYSA-N 1-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-fluorophenyl]-n,n-dimethylmethanamine Chemical compound CN(C)CC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 NNOVVEMYYNWICL-UHFFFAOYSA-N 0.000 claims 1
- PUNBGDJMUIOGAT-UHFFFAOYSA-N 1-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-fluorophenyl]-n-(2-methoxyethyl)methanimine Chemical compound COCCN=CC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 PUNBGDJMUIOGAT-UHFFFAOYSA-N 0.000 claims 1
- VPCRVDXLPCCHMH-UHFFFAOYSA-N 1-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-fluorophenyl]cyclopropan-1-amine Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1C1(N)CC1 VPCRVDXLPCCHMH-UHFFFAOYSA-N 0.000 claims 1
- WODKTBZTGZUTGA-UHFFFAOYSA-N 1-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-methoxyphenyl]-n-methylmethanamine Chemical compound CNCC1=CC=CC(OC)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 WODKTBZTGZUTGA-UHFFFAOYSA-N 0.000 claims 1
- PDEMHIUPQTYTHT-UHFFFAOYSA-N 1-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]phenyl]-n,n-dimethylmethanamine Chemical compound CN(C)CC1=CC=CC=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 PDEMHIUPQTYTHT-UHFFFAOYSA-N 0.000 claims 1
- SIZQFZXBQDZRFS-UHFFFAOYSA-N 1-[2-[4-[(2-chlorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-fluorophenyl]-n,n-dimethylmethanamine Chemical compound CN(C)CC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2CCO3)=C1 SIZQFZXBQDZRFS-UHFFFAOYSA-N 0.000 claims 1
- ISBKYMUNIZSTJH-UHFFFAOYSA-N 1-[3-fluoro-2-[3-methyl-4-[(2,4,4-trifluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]pyrazol-1-yl]phenyl]-n,n-dimethylmethanamine Chemical compound CN(C)CC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(F)=CC=2C(F)(F)CO3)=C1 ISBKYMUNIZSTJH-UHFFFAOYSA-N 0.000 claims 1
- NGMSOYNACKKJSG-UHFFFAOYSA-N 1-[3-fluoro-2-[4-[(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]phenyl]-n,n-dimethylmethanamine Chemical compound CN(C)CC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(F)=CC=2CCO3)=C1 NGMSOYNACKKJSG-UHFFFAOYSA-N 0.000 claims 1
- DNFFHKWWGDTOTR-UHFFFAOYSA-N 2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-fluorobenzamide Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1C(N)=O DNFFHKWWGDTOTR-UHFFFAOYSA-N 0.000 claims 1
- RWQIMVHTRMFTQT-UHFFFAOYSA-N 2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]pyrazol-1-yl]-3-fluorobenzonitrile Chemical compound FC1=CC=CC(C#N)=C1N1N=CC(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 RWQIMVHTRMFTQT-UHFFFAOYSA-N 0.000 claims 1
- HJAQEBQKDAJQRY-UHFFFAOYSA-N 2-[[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-fluorophenyl]methylamino]ethanol Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1CNCCO HJAQEBQKDAJQRY-UHFFFAOYSA-N 0.000 claims 1
- XZPLGWDRMOMJEQ-UHFFFAOYSA-N 2-chloro-1'-[[1-(2,6-dimethylphenyl)-3-methylpyrazol-4-yl]methyl]-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(C)C=CC=C1C XZPLGWDRMOMJEQ-UHFFFAOYSA-N 0.000 claims 1
- XAFJTURCXWMRCN-UHFFFAOYSA-N 2-chloro-1'-[[1-(2-chlorophenyl)-3-methylpyrazol-4-yl]methyl]-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=CC=CC=C1Cl XAFJTURCXWMRCN-UHFFFAOYSA-N 0.000 claims 1
- FSXBLXIMZAECJS-UHFFFAOYSA-N 2-chloro-1'-[[1-[2-[(3,3-difluoroazetidin-1-yl)methyl]-6-fluorophenyl]-3-methylpyrazol-4-yl]methyl]-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1CN1CC(F)(F)C1 FSXBLXIMZAECJS-UHFFFAOYSA-N 0.000 claims 1
- JLCAIALDXIOVBP-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-(2-fluoro-6-imidazol-1-ylphenyl)-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1N1C=CN=C1 JLCAIALDXIOVBP-UHFFFAOYSA-N 0.000 claims 1
- KERMYBOLEOCRHH-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-(2-fluorophenyl)-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=CC=CC=C1F KERMYBOLEOCRHH-UHFFFAOYSA-N 0.000 claims 1
- FYTMHTRGHFVDOR-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-[2-(methoxymethyl)phenyl]-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound COCC1=CC=CC=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 FYTMHTRGHFVDOR-UHFFFAOYSA-N 0.000 claims 1
- NDESORITPQFVQC-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-[2-fluoro-6-(1h-1,2,4-triazol-5-yl)phenyl]-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1C=1N=CNN=1 NDESORITPQFVQC-UHFFFAOYSA-N 0.000 claims 1
- XURGFEMCAFOAGU-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-[2-fluoro-6-(methoxymethyl)phenyl]-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound COCC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 XURGFEMCAFOAGU-UHFFFAOYSA-N 0.000 claims 1
- GISSRLYHLGOHOP-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-[2-fluoro-6-(morpholin-4-ylmethyl)phenyl]-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1CN1CCOCC1 GISSRLYHLGOHOP-UHFFFAOYSA-N 0.000 claims 1
- HHYDBXOSCWQNSA-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-[2-fluoro-6-(pyrrolidin-1-ylmethyl)phenyl]-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1CN1CCCC1 HHYDBXOSCWQNSA-UHFFFAOYSA-N 0.000 claims 1
- LFJUFKLBEDBJPR-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[3-methyl-1-(2-methylphenyl)pyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=CC=CC=C1C LFJUFKLBEDBJPR-UHFFFAOYSA-N 0.000 claims 1
- KBYSWQYPSJYVMO-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[3-methyl-1-(2-propan-2-ylphenyl)pyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound CC(C)C1=CC=CC=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 KBYSWQYPSJYVMO-UHFFFAOYSA-N 0.000 claims 1
- NQZXVSMRXPKINR-UHFFFAOYSA-N 3-chloro-2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]benzamide Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(Cl)C=CC=C1C(N)=O NQZXVSMRXPKINR-UHFFFAOYSA-N 0.000 claims 1
- VZCOGBUVJRVDEH-UHFFFAOYSA-N 3-fluoro-2-[3-methyl-4-[(2,4,4-trifluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]pyrazol-1-yl]benzamide Chemical compound C1=C(CN2CCC3(CC2)C=2SC(F)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1C(N)=O VZCOGBUVJRVDEH-UHFFFAOYSA-N 0.000 claims 1
- KTXNEMDXEFXYKX-UHFFFAOYSA-N 3-fluoro-2-[4-[(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(F)=CC=2CCO3)=C1 KTXNEMDXEFXYKX-UHFFFAOYSA-N 0.000 claims 1
- DFXWFQJIJYLWBM-UHFFFAOYSA-N 3-fluoro-2-[4-[(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]benzamide Chemical compound C1=C(CN2CCC3(CC2)C=2SC(F)=CC=2CCO3)C(C)=NN1C1=C(F)C=CC=C1C(N)=O DFXWFQJIJYLWBM-UHFFFAOYSA-N 0.000 claims 1
- LTVCWBVBPFSYRV-UHFFFAOYSA-N 3-fluoro-2-[4-[(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]benzonitrile Chemical compound C1=C(CN2CCC3(CC2)C=2SC(F)=CC=2CCO3)C(C)=NN1C1=C(F)C=CC=C1C#N LTVCWBVBPFSYRV-UHFFFAOYSA-N 0.000 claims 1
- IUHPYGXCRJAKHC-UHFFFAOYSA-N 3-fluoro-2-[4-[(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]pyrazol-1-yl]benzamide Chemical compound NC(=O)C1=CC=CC(F)=C1N1N=CC(CN2CCC3(CC2)C=2SC(F)=CC=2CCO3)=C1 IUHPYGXCRJAKHC-UHFFFAOYSA-N 0.000 claims 1
- GBNUMIAMFXWHBQ-UHFFFAOYSA-N [2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-cyclopropylphenyl]methanol Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(CO)C=CC=C1C1CC1 GBNUMIAMFXWHBQ-UHFFFAOYSA-N 0.000 claims 1
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- ANYSGBYRTLOUPO-UHFFFAOYSA-N lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 description 1
- JCIVHYBIFRUGKO-UHFFFAOYSA-N lithium;2,2,6,6-tetramethylpiperidine Chemical compound [Li].CC1(C)CCCC(C)(C)N1 JCIVHYBIFRUGKO-UHFFFAOYSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
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- 239000012038 nucleophile Substances 0.000 description 1
- 231100000822 oral exposure Toxicity 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000020825 overweight Nutrition 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 102000014187 peptide receptors Human genes 0.000 description 1
- 108010011903 peptide receptors Proteins 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
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- 210000004761 scalp Anatomy 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000862 serotonergic effect Effects 0.000 description 1
- 239000002485 serotonin 2C agonist Substances 0.000 description 1
- 239000000952 serotonin receptor agonist Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
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- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- ACTRVOBWPAIOHC-XIXRPRMCSA-N succimer Chemical compound OC(=O)[C@@H](S)[C@@H](S)C(O)=O ACTRVOBWPAIOHC-XIXRPRMCSA-N 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- KERQCWFBKHNJDL-UHFFFAOYSA-N tert-butyl 2-bromo-4-hydroxyspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-cyclohexane]-1'-carboxylate Chemical compound C1CC(C(=O)OC(C)(C)C)CCC21C(SC(Br)=C1)=C1C(O)CO2 KERQCWFBKHNJDL-UHFFFAOYSA-N 0.000 description 1
- UIYDGRPWECFCLH-UHFFFAOYSA-N tert-butyl 2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate 2,2,6,6-tetramethylpiperidine Chemical compound CC1(NC(CCC1)(C)C)C.FC1=CC2=C(C3(OCC2)CCN(CC3)C(=O)OC(C)(C)C)S1 UIYDGRPWECFCLH-UHFFFAOYSA-N 0.000 description 1
- JKUYRAMKJLMYLO-UHFFFAOYSA-N tert-butyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OC(C)(C)C JKUYRAMKJLMYLO-UHFFFAOYSA-N 0.000 description 1
- OTFQSEYOEXRUEB-UHFFFAOYSA-N tert-butyl n-cyclopropyl-n-[[3-fluoro-2-[4-(hydroxymethyl)-3-methylpyrazol-1-yl]phenyl]methyl]carbamate Chemical compound C1=C(CO)C(C)=NN1C1=C(F)C=CC=C1CN(C(=O)OC(C)(C)C)C1CC1 OTFQSEYOEXRUEB-UHFFFAOYSA-N 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
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- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/20—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Child & Adolescent Psychology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09382245.0 | 2009-11-16 | ||
| EP09382245 | 2009-11-16 | ||
| US29862810P | 2010-01-27 | 2010-01-27 | |
| US61/298,628 | 2010-01-27 | ||
| PCT/US2010/056449 WO2011060217A1 (en) | 2009-11-16 | 2010-11-12 | Spiropiperidine compounds as orl-1 receptor antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2781041A1 CA2781041A1 (en) | 2011-05-19 |
| CA2781041C true CA2781041C (en) | 2015-01-06 |
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| Application Number | Title | Priority Date | Filing Date |
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| CA2781041A Expired - Fee Related CA2781041C (en) | 2009-11-16 | 2010-11-12 | Spiropiperidine compounds as orl-1 receptor antagonists |
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| Country | Link |
|---|---|
| US (1) | US20120214784A1 (https=) |
| EP (1) | EP2501704B1 (https=) |
| JP (1) | JP5723381B2 (https=) |
| KR (1) | KR101368130B1 (https=) |
| CN (1) | CN102666550B (https=) |
| AU (1) | AU2010319400B2 (https=) |
| BR (1) | BR112012011710A2 (https=) |
| CA (1) | CA2781041C (https=) |
| DK (1) | DK2501704T3 (https=) |
| EA (1) | EA020391B1 (https=) |
| ES (1) | ES2436241T3 (https=) |
| HR (1) | HRP20130969T1 (https=) |
| MX (1) | MX2012005690A (https=) |
| PL (1) | PL2501704T3 (https=) |
| PT (1) | PT2501704E (https=) |
| RS (1) | RS53017B (https=) |
| SI (1) | SI2501704T1 (https=) |
| WO (1) | WO2011060217A1 (https=) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG10201510665WA (en) | 2009-12-04 | 2016-01-28 | Sunovion Pharmaceuticals Inc | Multicycle Compounds And Pharmaceutical Compositions Useful For The Treatment Of Neurological Disorders |
| TWI582096B (zh) * | 2011-12-06 | 2017-05-11 | 美國禮來大藥廠 | 用於酒精依賴及濫用處理之４',５'－二氫螺［哌啶－４,７'－噻吩并[２，３－c]哌喃］化合物 |
| TW201416370A (zh) | 2012-07-31 | 2014-05-01 | Lilly Co Eli | 用於治療焦慮之ｏｒｌ－１受體拮抗劑 |
| US20140206667A1 (en) | 2012-11-14 | 2014-07-24 | Michela Gallagher | Methods and compositions for treating schizophrenia |
| JO3638B1 (ar) * | 2015-09-09 | 2020-08-27 | Lilly Co Eli | مركبات مفيدة في تثبيط ror - جاما- t |
| MA45795A (fr) | 2016-07-29 | 2019-06-05 | Sunovion Pharmaceuticals Inc | Composés et compositions, et utilisations associées |
| PT3494119T (pt) | 2016-07-29 | 2024-12-10 | Pgi Drug Discovery Llc | Compostos e composições e seus usos |
| ES2858093T3 (es) | 2016-08-10 | 2021-09-29 | Bayer Cropscience Ag | 2-Heterociclil-imidazolil-carboxamidas sustituidas como pesticidas |
| MX390141B (es) | 2017-02-16 | 2025-03-20 | Sunovion Pharmaceuticals Inc | Metodos para tratar esquizofrenia |
| US10603320B2 (en) * | 2017-03-02 | 2020-03-31 | Eli Lilly And Company | Compounds useful for inhibiting ROR-gamma-t |
| HUE054483T2 (hu) | 2017-03-02 | 2021-09-28 | Lilly Co Eli | ROR-gamma-T gátlására alkalmas vegyületek |
| CA3070993C (en) | 2017-08-02 | 2025-05-20 | Sunovion Pharmaceuticals Inc. | ISOCHROMANE COMPOUNDS AND THEIR USES |
| UA130249C2 (uk) | 2018-02-16 | 2025-12-31 | Сумітомо Фарма Америка, Інк. | Солі, кристалічні форми і способи їх отримання |
| US11618746B2 (en) | 2018-12-17 | 2023-04-04 | Vertex Pharmaceuticals Incorporated | Inhibitors of APOL1 and methods of using same |
| EP3938045A1 (en) | 2019-03-14 | 2022-01-19 | Sunovion Pharmaceuticals Inc. | Salts of a isochromanyl compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof |
| EP3766879A1 (en) | 2019-07-19 | 2021-01-20 | Basf Se | Pesticidal pyrazole derivatives |
| CA3180115A1 (en) | 2020-04-14 | 2021-10-21 | Sunovion Pharmaceuticals Inc. | (s)-(4,5-dihydro-7h-thieno[2,3-c]pyran-7-yl)-n-methylmethanamine for treating neurological and psychiatric disorders |
| CN115867543A (zh) | 2020-06-12 | 2023-03-28 | 弗特克斯药品有限公司 | Apol1抑制剂的固体形式及其使用方法 |
| CN116547287B (zh) | 2020-08-26 | 2025-09-26 | 弗特克斯药品有限公司 | Apol1的抑制剂及其使用方法 |
| CA3251050A1 (en) * | 2022-02-08 | 2023-08-17 | Vertex Pharmaceuticals Incorporated | 2-METHYL-4',5'-DIHYDROSPIRO[PIPERIDINE-4,7'-THIENO[2,3-C]PYRAN] DERIVATIVES USED AS APOL1 INHIBITORS AND THEIR METHODS OF USE |
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| WO2003095427A1 (en) | 2002-05-10 | 2003-11-20 | Taisho Pharmaceutical Co.,Ltd. | Spiro-ring compound |
| WO2005016913A1 (en) * | 2003-08-19 | 2005-02-24 | Pfizer Japan, Inc. | Tetrahydroisoquinoline or isochroman compounds as orl-1 receptor ligands for the treatment of pain and cns disorders |
| DE10360792A1 (de) * | 2003-12-23 | 2005-07-28 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| US7354925B2 (en) * | 2004-03-29 | 2008-04-08 | Pfizer Inc. | Alpha aryl or heteroaryl methyl beta piperidino propanamide compounds as ORL1-receptor antagonists |
| DE102004039382A1 (de) * | 2004-08-13 | 2006-02-23 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| WO2006130416A2 (en) * | 2005-06-02 | 2006-12-07 | Janssen Pharmaceutica, N.V. | Novel 3-spirocyclic indolyl derivatives useful as orl-1 receptor modulators |
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2010
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- 2010-11-12 DK DK10782486.4T patent/DK2501704T3/da active
- 2010-11-12 PL PL10782486T patent/PL2501704T3/pl unknown
- 2010-11-12 PT PT107824864T patent/PT2501704E/pt unknown
- 2010-11-12 US US13/504,176 patent/US20120214784A1/en not_active Abandoned
- 2010-11-12 EA EA201290355A patent/EA020391B1/ru not_active IP Right Cessation
- 2010-11-12 CN CN201080051845.3A patent/CN102666550B/zh not_active Expired - Fee Related
- 2010-11-12 HR HRP20130969AT patent/HRP20130969T1/hr unknown
- 2010-11-12 EP EP10782486.4A patent/EP2501704B1/en active Active
- 2010-11-12 BR BR112012011710A patent/BR112012011710A2/pt active Search and Examination
- 2010-11-12 MX MX2012005690A patent/MX2012005690A/es active IP Right Grant
- 2010-11-12 CA CA2781041A patent/CA2781041C/en not_active Expired - Fee Related
- 2010-11-12 WO PCT/US2010/056449 patent/WO2011060217A1/en not_active Ceased
- 2010-11-12 RS RS20130484A patent/RS53017B/sr unknown
- 2010-11-12 JP JP2012538997A patent/JP5723381B2/ja active Active
- 2010-11-12 ES ES10782486T patent/ES2436241T3/es active Active
- 2010-11-12 SI SI201030389T patent/SI2501704T1/sl unknown
- 2010-11-12 KR KR1020127012503A patent/KR101368130B1/ko not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| MX2012005690A (es) | 2012-06-13 |
| KR101368130B1 (ko) | 2014-02-27 |
| BR112012011710A2 (pt) | 2016-03-01 |
| EA201290355A1 (ru) | 2012-10-30 |
| RS53017B (sr) | 2014-04-30 |
| JP5723381B2 (ja) | 2015-05-27 |
| AU2010319400B2 (en) | 2013-12-19 |
| EP2501704A1 (en) | 2012-09-26 |
| JP2013510870A (ja) | 2013-03-28 |
| ES2436241T3 (es) | 2013-12-27 |
| HRP20130969T1 (hr) | 2013-11-22 |
| US20120214784A1 (en) | 2012-08-23 |
| PT2501704E (pt) | 2013-12-05 |
| CN102666550B (zh) | 2015-07-15 |
| DK2501704T3 (da) | 2013-10-14 |
| WO2011060217A1 (en) | 2011-05-19 |
| PL2501704T3 (pl) | 2014-02-28 |
| SI2501704T1 (sl) | 2013-11-29 |
| AU2010319400A1 (en) | 2012-06-07 |
| EA020391B1 (ru) | 2014-10-30 |
| EP2501704B1 (en) | 2013-09-18 |
| CN102666550A (zh) | 2012-09-12 |
| CA2781041A1 (en) | 2011-05-19 |
| KR20120082927A (ko) | 2012-07-24 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20201112 |