CA2446696A1 - Inhibiteurs des phosphodiesterases des nucleotides cycliques, preparation et utilisations de ces inhibiteurs - Google Patents
Inhibiteurs des phosphodiesterases des nucleotides cycliques, preparation et utilisations de ces inhibiteurs Download PDFInfo
- Publication number
- CA2446696A1 CA2446696A1 CA002446696A CA2446696A CA2446696A1 CA 2446696 A1 CA2446696 A1 CA 2446696A1 CA 002446696 A CA002446696 A CA 002446696A CA 2446696 A CA2446696 A CA 2446696A CA 2446696 A1 CA2446696 A1 CA 2446696A1
- Authority
- CA
- Canada
- Prior art keywords
- dihydro
- benzodiazepin
- dimethoxy
- phenyl
- methyl
- 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
- 238000002360 preparation method Methods 0.000 title claims description 17
- 101000909851 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) cAMP/cGMP dual specificity phosphodiesterase Rv0805 Proteins 0.000 title description 5
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 title description 3
- 239000002571 phosphodiesterase inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 164
- 238000000034 method Methods 0.000 claims abstract description 19
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims abstract description 13
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims abstract description 13
- 230000007170 pathology Effects 0.000 claims abstract description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 268
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 211
- -1 COOR' Chemical group 0.000 claims description 124
- 125000003118 aryl group Chemical group 0.000 claims description 59
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- NRGGDWGRGDCVAF-UHFFFAOYSA-N 2,3-benzodiazepin-4-one Chemical compound N1=NC(=O)C=C2C=CC=CC2=C1 NRGGDWGRGDCVAF-UHFFFAOYSA-N 0.000 claims description 44
- 125000001544 thienyl group Chemical group 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 33
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 29
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 230000002757 inflammatory effect Effects 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
- 150000001350 alkyl halides Chemical class 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 150000003857 carboxamides Chemical class 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- FVZWOEXGLBRPHR-UHFFFAOYSA-N 1-(4-hept-1-ynylphenyl)-7,8-dimethoxy-3-methyl-5h-2,3-benzodiazepin-4-one Chemical compound C1=CC(C#CCCCCC)=CC=C1C1=NN(C)C(=O)CC2=CC(OC)=C(OC)C=C12 FVZWOEXGLBRPHR-UHFFFAOYSA-N 0.000 claims description 4
- VQJSSLAQHFVHJH-UHFFFAOYSA-N 1-[4-(3-acetylphenyl)phenyl]-7,8-dimethoxy-3-methyl-5h-2,3-benzodiazepin-4-one Chemical compound C1=2C=C(OC)C(OC)=CC=2CC(=O)N(C)N=C1C(C=C1)=CC=C1C1=CC=CC(C(C)=O)=C1 VQJSSLAQHFVHJH-UHFFFAOYSA-N 0.000 claims description 4
- KPXOZBSLTVTKAJ-UHFFFAOYSA-N 3-(3-hydroxypropyl)-7,8-dimethoxy-1-phenyl-5h-2,3-benzodiazepin-4-one Chemical compound C1=2C=C(OC)C(OC)=CC=2CC(=O)N(CCCO)N=C1C1=CC=CC=C1 KPXOZBSLTVTKAJ-UHFFFAOYSA-N 0.000 claims description 4
- TVYHGRSGZGTTLT-UHFFFAOYSA-N 7,8-dimethoxy-1-methyl-5-(2-phenylethyl)-3h-1,4-benzodiazepin-2-one Chemical compound C1=2C=C(OC)C(OC)=CC=2N(C)C(=O)CN=C1CCC1=CC=CC=C1 TVYHGRSGZGTTLT-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- MOLLMKZLHNWYJJ-UHFFFAOYSA-N 3-[(1-ethyl-7,8-dimethoxy-2-oxo-5-phenyl-3h-1,4-benzodiazepin-3-yl)methyl]benzonitrile Chemical compound O=C1N(CC)C2=CC(OC)=C(OC)C=C2C(C=2C=CC=CC=2)=NC1CC1=CC=CC(C#N)=C1 MOLLMKZLHNWYJJ-UHFFFAOYSA-N 0.000 claims description 3
- AFYOEJRCJMPOQK-UHFFFAOYSA-N 3-[(8-ethoxy-7-methoxy-1-methyl-2-oxo-5-phenyl-3h-1,4-benzodiazepin-3-yl)methyl]benzonitrile Chemical compound N1=C(C=2C=CC=CC=2)C=2C=C(OC)C(OCC)=CC=2N(C)C(=O)C1CC1=CC=CC(C#N)=C1 AFYOEJRCJMPOQK-UHFFFAOYSA-N 0.000 claims description 3
- AALFNMGUYPJUST-UHFFFAOYSA-N 5-[3,5-bis(trifluoromethyl)phenyl]-7,8-dimethoxy-1-methyl-3h-1,4-benzodiazepin-2-one Chemical compound C1=2C=C(OC)C(OC)=CC=2N(C)C(=O)CN=C1C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 AALFNMGUYPJUST-UHFFFAOYSA-N 0.000 claims description 3
- LTCMYALFHUJZML-UHFFFAOYSA-N 7,8-dimethoxy-1-methyl-5-(2-methylphenyl)-3h-1,4-benzodiazepin-2-one Chemical compound C1=2C=C(OC)C(OC)=CC=2N(C)C(=O)CN=C1C1=CC=CC=C1C LTCMYALFHUJZML-UHFFFAOYSA-N 0.000 claims description 3
- DUMABVVGUSIGPX-UHFFFAOYSA-N 7,8-dimethoxy-5-(4-methoxyphenyl)-1-methyl-3h-1,4-benzodiazepin-2-one Chemical compound C1=CC(OC)=CC=C1C1=NCC(=O)N(C)C2=CC(OC)=C(OC)C=C12 DUMABVVGUSIGPX-UHFFFAOYSA-N 0.000 claims description 3
- PICWHVLACPHMEF-UHFFFAOYSA-N 7-ethoxy-8-methoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C1=C(OC)C(OCC)=CC2=C1NC(=O)CN=C2C1=CC=CC=C1 PICWHVLACPHMEF-UHFFFAOYSA-N 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 claims description 3
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 claims description 3
- 239000002773 nucleotide Substances 0.000 claims description 3
- 125000003729 nucleotide group Chemical group 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- WNWRPVFIEUZBNY-UHFFFAOYSA-N 1-ethyl-7,8-dimethoxy-5-[4-(3-phenylmethoxyprop-1-ynyl)phenyl]-3h-1,4-benzodiazepin-2-one Chemical compound N=1CC(=O)N(CC)C2=CC(OC)=C(OC)C=C2C=1C(C=C1)=CC=C1C#CCOCC1=CC=CC=C1 WNWRPVFIEUZBNY-UHFFFAOYSA-N 0.000 claims description 2
- DNVLRCDPCFXSAQ-UHFFFAOYSA-N 1-ethyl-7,8-dimethoxy-5-phenyl-3-[(4-phenylphenyl)methyl]-3h-1,4-benzodiazepin-2-one Chemical compound O=C1N(CC)C2=CC(OC)=C(OC)C=C2C(C=2C=CC=CC=2)=NC1CC(C=C1)=CC=C1C1=CC=CC=C1 DNVLRCDPCFXSAQ-UHFFFAOYSA-N 0.000 claims description 2
- ONANEURZGVLNCQ-UHFFFAOYSA-N 2-[(8-ethoxy-7-methoxy-1-methyl-2-oxo-5-phenyl-3h-1,4-benzodiazepin-3-yl)methyl]benzonitrile Chemical compound N1=C(C=2C=CC=CC=2)C=2C=C(OC)C(OCC)=CC=2N(C)C(=O)C1CC1=CC=CC=C1C#N ONANEURZGVLNCQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- FGMBQTNFQLFNRR-UHFFFAOYSA-N 3-[1,2-bis(4-bromophenyl)ethyl]-1-ethyl-7,8-dimethoxy-5-phenyl-3h-1,4-benzodiazepin-2-one Chemical compound O=C1N(CC)C2=CC(OC)=C(OC)C=C2C(C=2C=CC=CC=2)=NC1C(C=1C=CC(Br)=CC=1)CC1=CC=C(Br)C=C1 FGMBQTNFQLFNRR-UHFFFAOYSA-N 0.000 claims description 2
- HMGUXGCHAZNRKQ-UHFFFAOYSA-N 3-[[2-(aminomethyl)phenyl]methyl]-1-ethyl-7,8-dimethoxy-5-phenyl-3h-1,4-benzodiazepin-2-one Chemical compound O=C1N(CC)C2=CC(OC)=C(OC)C=C2C(C=2C=CC=CC=2)=NC1CC1=CC=CC=C1CN HMGUXGCHAZNRKQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- XWIOUMQHEOMYLF-UHFFFAOYSA-N C(C)N1C(C(N=C(C2=C1C=C(C(=C2)OC)OC)C2=CC=CC=C2)CC2=CC(=CC=C2)C(F)(F)F)=O.C(C)OC2=CC1=C(C(=NCC(N1C)=O)C1=CC=CC=C1)C=C2OC Chemical compound C(C)N1C(C(N=C(C2=C1C=C(C(=C2)OC)OC)C2=CC=CC=C2)CC2=CC(=CC=C2)C(F)(F)F)=O.C(C)OC2=CC1=C(C(=NCC(N1C)=O)C1=CC=CC=C1)C=C2OC XWIOUMQHEOMYLF-UHFFFAOYSA-N 0.000 claims description 2
- GJBQXRBJGJSZGQ-UHFFFAOYSA-N C(C)OC=1C(=CC2=C(C(=NCC(N2CC)=O)C2=CC=CC=C2)C1)OCC.C(C)OC=1C(=CC2=C(C(=NCC(N2C)=O)C2=CC=CC=C2)C1)OCC Chemical compound C(C)OC=1C(=CC2=C(C(=NCC(N2CC)=O)C2=CC=CC=C2)C1)OCC.C(C)OC=1C(=CC2=C(C(=NCC(N2C)=O)C2=CC=CC=C2)C1)OCC GJBQXRBJGJSZGQ-UHFFFAOYSA-N 0.000 claims description 2
- JDXBESBPFZCBKX-UHFFFAOYSA-N C(C1=CC=CC=C1)C1C(N(C2=C(C(=N1)C1=CC=CC=C1)C=C(C(=C2)OCC)OCC)CC)=O.C2(=CC(=CC=C2)CC2C(N(C1=C(C(=N2)C2=CC=CC=C2)C=C(C(=C1)OC)OC)CC)=O)C1=CC=CC=C1 Chemical compound C(C1=CC=CC=C1)C1C(N(C2=C(C(=N1)C1=CC=CC=C1)C=C(C(=C2)OCC)OCC)CC)=O.C2(=CC(=CC=C2)CC2C(N(C1=C(C(=N2)C2=CC=CC=C2)C=C(C(=C1)OC)OC)CC)=O)C1=CC=CC=C1 JDXBESBPFZCBKX-UHFFFAOYSA-N 0.000 claims description 2
- RGZATWPGZGJBNA-UHFFFAOYSA-N C(C1=CC=CC=C1)C1C(NC2=C(C(=N1)C1=CC=CC=C1)C=C(C(=C2)OC)OC)=O.COC=2C(=CC1=C(C(=NC(C(N1)=O)CC(C)C)C1=CC=CC=C1)C2)OC Chemical compound C(C1=CC=CC=C1)C1C(NC2=C(C(=N1)C1=CC=CC=C1)C=C(C(=C2)OC)OC)=O.COC=2C(=CC1=C(C(=NC(C(N1)=O)CC(C)C)C1=CC=CC=C1)C2)OC RGZATWPGZGJBNA-UHFFFAOYSA-N 0.000 claims description 2
- ALCIOTMJXMIVGN-UHFFFAOYSA-N C(C1=CC=CC=C1)C1C(NC2=C(C(=N1)C1=CC=CC=C1)C=C(C(=C2)OCC)OC)=O.C2(=CC=CC=C2)C2C(NC1=C(C(=N2)C2=CC=CC=C2)C=C(C(=C1)OCC)OC)=O Chemical compound C(C1=CC=CC=C1)C1C(NC2=C(C(=N1)C1=CC=CC=C1)C=C(C(=C2)OCC)OC)=O.C2(=CC=CC=C2)C2C(NC1=C(C(=N2)C2=CC=CC=C2)C=C(C(=C1)OCC)OC)=O ALCIOTMJXMIVGN-UHFFFAOYSA-N 0.000 claims description 2
- AYRXPZTWFJELAZ-UHFFFAOYSA-N COC1=CC2=C(C(=NCC(N2C)=O)C2=CC=CC=C2)C=C1.COC=1C=CC2=C(C(=NCC(N2C)=O)C2=CC=CC=C2)C1.COC=1C=CC2=C(C(=NCC(N2)=O)C2=CC=CC=C2)C1 Chemical compound COC1=CC2=C(C(=NCC(N2C)=O)C2=CC=CC=C2)C=C1.COC=1C=CC2=C(C(=NCC(N2C)=O)C2=CC=CC=C2)C1.COC=1C=CC2=C(C(=NCC(N2)=O)C2=CC=CC=C2)C1 AYRXPZTWFJELAZ-UHFFFAOYSA-N 0.000 claims description 2
- GXVDUWJOTLYRTG-UHFFFAOYSA-N COC=1C(=CC2=C(C(=NC(C(N2)=O)CC=2N=CNC2)C2=CC=CC=C2)C1)OC.COC=1C(=CC2=C(C(=NC(C(N2)=O)C)C2=CC=CC=C2)C1)OC Chemical compound COC=1C(=CC2=C(C(=NC(C(N2)=O)CC=2N=CNC2)C2=CC=CC=C2)C1)OC.COC=1C(=CC2=C(C(=NC(C(N2)=O)C)C2=CC=CC=C2)C1)OC GXVDUWJOTLYRTG-UHFFFAOYSA-N 0.000 claims description 2
- MIRKNYSWZBBCFK-RRABGKBLSA-N COC=1C(=CC2=C(C(=NCC(N2C)=O)C#CC2=CC=CC=C2)C1)OC.COC=1C(=CC2=C(C(=NCC(N2C)=O)\C=C\C2=CC=CC=C2)C1)OC Chemical compound COC=1C(=CC2=C(C(=NCC(N2C)=O)C#CC2=CC=CC=C2)C1)OC.COC=1C(=CC2=C(C(=NCC(N2C)=O)\C=C\C2=CC=CC=C2)C1)OC MIRKNYSWZBBCFK-RRABGKBLSA-N 0.000 claims description 2
- HKSKRDCCGFZXFW-UHFFFAOYSA-N COC=1C(=CC2=C(C(=NCC(N2C)=O)C2=CC=NC=C2)C1)OC.COC=1C(=CC2=C(C(=NCC(N2C)=O)C2=CC=C(C=C2)F)C1)OC Chemical compound COC=1C(=CC2=C(C(=NCC(N2C)=O)C2=CC=NC=C2)C1)OC.COC=1C(=CC2=C(C(=NCC(N2C)=O)C2=CC=C(C=C2)F)C1)OC HKSKRDCCGFZXFW-UHFFFAOYSA-N 0.000 claims description 2
- AGPDUKNQLNXZAI-UHFFFAOYSA-N ClC1=C(CC2C(N(C3=C(C(=N2)C2=CC=CC=C2)C=C(C(=C3)OC)OC)CC)=O)C=C(C=C1)Cl.ClC1=C(CC3C(N(C2=C(C(=N3)C3=CC=CC=C3)C=C(C(=C2)OC)OC)CC)=O)C=CC(=C1)Cl Chemical compound ClC1=C(CC2C(N(C3=C(C(=N2)C2=CC=CC=C2)C=C(C(=C3)OC)OC)CC)=O)C=C(C=C1)Cl.ClC1=C(CC3C(N(C2=C(C(=N3)C3=CC=CC=C3)C=C(C(=C2)OC)OC)CC)=O)C=CC(=C1)Cl AGPDUKNQLNXZAI-UHFFFAOYSA-N 0.000 claims description 2
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 150000002429 hydrazines Chemical class 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 230000003959 neuroinflammation Effects 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000002524 organometallic group Chemical group 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 6
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 3
- 229940126601 medicinal product Drugs 0.000 claims 3
- 230000003213 activating effect Effects 0.000 claims 2
- GZHJMAVOLIEASV-UHFFFAOYSA-N 1-(1-benzothiophen-2-yl)-7,8-diethoxy-3,5-dihydro-2,3-benzodiazepin-4-one Chemical compound C1=2C=C(OCC)C(OCC)=CC=2CC(=O)NN=C1C1=CC2=CC=CC=C2S1 GZHJMAVOLIEASV-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
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- 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
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- 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]
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/02—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (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)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Psychiatry (AREA)
- Child & Adolescent Psychology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0107458 | 2001-06-07 | ||
| FR01/07458 | 2001-06-07 | ||
| PCT/FR2002/001952 WO2002098865A2 (fr) | 2001-06-07 | 2002-06-07 | Inhibiteurs des phosphodiesterases des nucleotides cycliques, preparation et utilisations de ces inhibiteurs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2446696A1 true CA2446696A1 (fr) | 2002-12-12 |
Family
ID=8864056
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002446696A Abandoned CA2446696A1 (fr) | 2001-06-07 | 2002-06-07 | Inhibiteurs des phosphodiesterases des nucleotides cycliques, preparation et utilisations de ces inhibiteurs |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US7250410B2 (enExample) |
| EP (1) | EP1392663A2 (enExample) |
| JP (1) | JP2005503356A (enExample) |
| AU (2) | AU2002317910B2 (enExample) |
| CA (1) | CA2446696A1 (enExample) |
| IL (2) | IL159105A0 (enExample) |
| NZ (1) | NZ529582A (enExample) |
| WO (1) | WO2002098865A2 (enExample) |
| ZA (1) | ZA200400057B (enExample) |
Families Citing this family (39)
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| US20060025388A1 (en) * | 1999-04-30 | 2006-02-02 | Glick Gary D | Compositions and methods relating to novel compounds and targets thereof |
| US20050113460A1 (en) * | 1999-04-30 | 2005-05-26 | The Regents Of The University Of Michigan | Compositions and methods relating to novel compounds and targets thereof |
| US7572788B2 (en) * | 1999-04-30 | 2009-08-11 | The Regents Of The University Of Michigan | Compositions and methods relating to novel compounds and targets thereof |
| US20030119029A1 (en) * | 1999-04-30 | 2003-06-26 | Regents Of The University Of Michigan | Compositions and methods relating to novel benzodiazepine compounds and targets thereof |
| JP5127096B2 (ja) | 1999-04-30 | 2013-01-23 | ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン | アポトーシスにより誘導される自己免疫疾患を処置するためのベンゾジアゼピンの使用 |
| JP2005535710A (ja) * | 2002-08-09 | 2005-11-24 | トランス テック ファーマ,インコーポレイテッド | アリールおよびヘテロアリール化合物ならびに凝固を調節する方法 |
| NZ540167A (en) * | 2002-10-30 | 2007-06-29 | Neuro3D | Cyclic nucleotide phosphodiesterase inhibitors, preparation and uses |
| FR2846653B1 (fr) * | 2002-10-30 | 2007-04-20 | Neuro3D | Inhibiteurs des phosphodiesterases des nucleotides cycliques, preparation et utilisations |
| WO2005014532A1 (en) * | 2003-08-08 | 2005-02-17 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds, compositions and methods of use |
| US7208601B2 (en) * | 2003-08-08 | 2007-04-24 | Mjalli Adnan M M | Aryl and heteroaryl compounds, compositions, and methods of use |
| EP1548011A1 (en) * | 2003-12-23 | 2005-06-29 | Neuro3D | Benzo[1,4]diazepin-2-one derivatives as phosphodiesterase PDE2 inhibitors, preparation and therapeutic use thereof |
| US20090275099A1 (en) * | 2004-04-27 | 2009-11-05 | Regents Of The University Of Michigan | Methods and compositions for treating diseases and conditions associated with mitochondrial function |
| US20050272723A1 (en) * | 2004-04-27 | 2005-12-08 | The Regents Of The University Of Michigan | Methods and compositions for treating diseases and conditions associated with mitochondrial function |
| FR2870539B1 (fr) * | 2004-05-19 | 2006-08-04 | Greenpharma Sa Sa | Nouvelles methodes et medicaments |
| AU2005272627A1 (en) | 2004-08-13 | 2006-02-23 | Amgen Inc. | Substituted benzofused heterocycles |
| US20060052369A1 (en) * | 2004-09-07 | 2006-03-09 | The Regents Of The University Of Michigan | Compositions and methods relating to novel compounds and targets thereof |
| CA2611031A1 (en) * | 2005-06-01 | 2007-05-10 | The Regents Of The University Of Michigan | Unsolvated benzodiazepine compositions and methods |
| US20070105844A1 (en) * | 2005-10-26 | 2007-05-10 | Regents Of The University Of Michigan | Therapeutic compositions and methods |
| AU2006308655B2 (en) | 2005-11-01 | 2010-09-23 | The Regents Of The University Of Michigan | Novel 1,4-benzodiazepine-2,5-diones with therapeutic properties |
| US7759338B2 (en) * | 2006-04-27 | 2010-07-20 | The Regents Of The University Of Michigan | Soluble 1,4 benzodiazepine compounds and stable salts thereof |
| JP5264716B2 (ja) | 2006-06-09 | 2013-08-14 | ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン | 化合物およびその標的に関連する組成物および方法 |
| AU2008226532B2 (en) | 2007-03-09 | 2011-09-22 | The Regents Of The University Of Michigan | Compositions and methods relating to novel compounds and targets thereof |
| EP2146722A4 (en) * | 2007-05-10 | 2011-08-03 | Amr Technology Inc | ARYL AND HETEROARYL SUBSTITUTED TETRAHYDROBENZO-1,4-DIAZEPINES AND THEIR USE FOR BLOCKING THE RECOVERY OF NOREPINEPHRIN, DOPAMINE AND SEROTONINE |
| ES2614498T3 (es) * | 2007-09-14 | 2017-05-31 | The Regents Of The University Of Michigan | Inhibidores de ATPasa F1F0 y métodos relacionados |
| WO2009037302A1 (en) * | 2007-09-18 | 2009-03-26 | Via Pharmaceuticals, Inc. | 5-substituted-1, 4-benz0diazepines as phosphodiesterase inhibitors |
| US8188072B2 (en) | 2007-11-06 | 2012-05-29 | The Regents Of The University Of Michigan | Benzodiazepinone compounds useful in the treatment of skin conditions |
| WO2010030891A2 (en) | 2008-09-11 | 2010-03-18 | The Regents Of The University Of Michigan | Aryl guanidine f1f0-atpase inhibitors and related methods |
| US8604023B2 (en) | 2009-04-17 | 2013-12-10 | The Regents Of The University Of Michigan | 1,4-benzodiazepinone compounds and their use in treating cancer |
| JP2013505258A (ja) | 2009-09-18 | 2013-02-14 | ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン | ベンゾジアゼピノン化合物およびそれを使用する治療方法 |
| AU2010322287B2 (en) | 2009-11-17 | 2014-04-03 | The Regents Of The University Of Michigan | 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties |
| US9126978B2 (en) | 2009-11-17 | 2015-09-08 | The Regents Of The University Of Michigan | 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties |
| WO2012075456A1 (en) | 2010-12-02 | 2012-06-07 | Constellation Pharmaceuticals | Bromodomain inhibitors and uses thereof |
| AR084070A1 (es) | 2010-12-02 | 2013-04-17 | Constellation Pharmaceuticals Inc | Inhibidores del bromodominio y usos de los mismos |
| US9422292B2 (en) | 2011-05-04 | 2016-08-23 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
| US9328117B2 (en) | 2011-06-17 | 2016-05-03 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
| TWI602820B (zh) | 2012-06-06 | 2017-10-21 | 星宿藥物公司 | 溴域抑制劑及其用途 |
| WO2013184878A1 (en) | 2012-06-06 | 2013-12-12 | Constellation Pharmaceuticals, Inc. | Benzo [b] isoxazoloazepine bromodomain inhibitors and uses thereof |
| SI3157928T1 (sl) | 2014-06-20 | 2019-06-28 | Constellation Pharmaceuticals, Inc. | Kristalinične oblike 2-((4S)-6-(4-klorofenil)-1-metil-4H-benzo(C)izoksazolo(4,5-E)azepin-4-il acetamida |
| US20250313537A1 (en) * | 2022-05-13 | 2025-10-09 | University Of Cincinnati | Benzodiazepine analogs and methods of use in treating cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH411910A (de) * | 1959-12-10 | 1966-04-30 | Hoffmann La Roche | Verfahren zur Herstellung von 1,4-Benzodiazepin-Derivaten |
| NL279830A (enExample) * | 1961-06-20 | |||
| US3182067A (en) * | 1964-04-09 | 1965-05-04 | Hoffmann La Roche | Benzodiazepine compounds |
| FR1497456A (fr) * | 1964-06-15 | 1967-10-13 | Clin Byla Ets | Ortho-amino aryl cétimines, composés hétérocycliques qui s'y rattachent et prépaation de ces divers corps |
| IL29988A0 (en) * | 1967-06-23 | 1968-07-25 | American Cyanamid Co | Novel 7-trifluoromethoxybenzo-1,4-diazepines |
| US3631029A (en) * | 1967-12-01 | 1971-12-28 | Sumitomo Chemical Co | Process for producing benzodiazepine derivatives |
| FR2085645A1 (en) * | 1970-04-22 | 1971-12-31 | Chimidrog | 1-phenyl-2,3-benzodiazepin-4-ones - as tranquillizers |
| US3801569A (en) * | 1973-01-15 | 1974-04-02 | Hoffmann La Roche | 7-(1,1-difluoroalkyl)-1,4-benzodiazepines |
| DE3119874A1 (de) | 1981-05-19 | 1982-12-09 | Dr. Karl Thomae Gmbh, 7950 Biberach | "benzazepinderivate, ihre herstellung und ihre verwendung als arzneimittel" |
| IL93401A (en) * | 1989-03-08 | 1994-08-26 | Kali Chemie Pharma Gmbh | H1 - Indole - 2 - Carboxylic acid 1, 7 - Consolidated N -) 1, 4 - Benzodiazepine - 3 - Il (amides, their preparation and drugs containing them |
| TW221687B (enExample) * | 1992-01-24 | 1994-03-11 | Hoffmann La Roche | |
| DE19604920A1 (de) | 1996-02-01 | 1997-08-07 | Schering Ag | Neue 2,3-Benzodiazepinderivate, deren Herstellung und Verwendung als Arzneimittel |
| US5891871A (en) * | 1996-03-21 | 1999-04-06 | Cocensys, Inc. | Substituted 2,3-benzodiazepin-4-ones and the use thereof |
| WO2000079263A2 (en) * | 1999-06-18 | 2000-12-28 | Synt:Em S.A. | Identifying active molecules using physico-chemical parameters |
| WO2002051232A2 (en) | 2000-12-27 | 2002-07-04 | Actelion Pharmaceuticals Ltd. | Novel benzazepines and related heterocyclic derivatives |
-
2002
- 2002-06-07 AU AU2002317910A patent/AU2002317910B2/en not_active Ceased
- 2002-06-07 WO PCT/FR2002/001952 patent/WO2002098865A2/fr not_active Ceased
- 2002-06-07 US US10/479,000 patent/US7250410B2/en not_active Expired - Fee Related
- 2002-06-07 EP EP02747514A patent/EP1392663A2/fr not_active Withdrawn
- 2002-06-07 IL IL15910502A patent/IL159105A0/xx unknown
- 2002-06-07 CA CA002446696A patent/CA2446696A1/fr not_active Abandoned
- 2002-06-07 NZ NZ529582A patent/NZ529582A/en unknown
- 2002-06-07 JP JP2003501989A patent/JP2005503356A/ja active Pending
-
2003
- 2003-11-27 IL IL159105A patent/IL159105A/en not_active IP Right Cessation
-
2004
- 2004-01-06 ZA ZA200400057A patent/ZA200400057B/en unknown
-
2008
- 2008-09-18 AU AU2008221554A patent/AU2008221554A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002098865A2 (fr) | 2002-12-12 |
| IL159105A0 (en) | 2004-05-12 |
| IL159105A (en) | 2009-05-04 |
| EP1392663A2 (fr) | 2004-03-03 |
| AU2002317910B2 (en) | 2008-06-19 |
| AU2008221554A1 (en) | 2008-10-09 |
| ZA200400057B (en) | 2005-02-21 |
| US7250410B2 (en) | 2007-07-31 |
| WO2002098865A3 (fr) | 2003-02-27 |
| NZ529582A (en) | 2006-10-27 |
| US20040152888A1 (en) | 2004-08-05 |
| JP2005503356A (ja) | 2005-02-03 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |