TW200526607A - Heterocyclic inhibitors of MEK and methods of use thereof - Google Patents
Heterocyclic inhibitors of MEK and methods of use thereof Download PDFInfo
- Publication number
- TW200526607A TW200526607A TW093126520A TW93126520A TW200526607A TW 200526607 A TW200526607 A TW 200526607A TW 093126520 A TW093126520 A TW 093126520A TW 93126520 A TW93126520 A TW 93126520A TW 200526607 A TW200526607 A TW 200526607A
- Authority
- TW
- Taiwan
- Prior art keywords
- aryl
- heteroaryl
- heterocyclyl
- alkyl
- groups
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 98
- 125000000623 heterocyclic group Chemical group 0.000 title claims description 202
- 239000003112 inhibitor Substances 0.000 title description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 235
- 229940002612 prodrug Drugs 0.000 claims abstract description 57
- 239000000651 prodrug Substances 0.000 claims abstract description 57
- 150000003839 salts Chemical class 0.000 claims abstract description 56
- 201000010099 disease Diseases 0.000 claims abstract description 50
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 50
- 241000124008 Mammalia Species 0.000 claims abstract description 42
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 24
- -1 trifluorofluorenyl Chemical group 0.000 claims description 283
- 125000003118 aryl group Chemical group 0.000 claims description 184
- 125000001072 heteroaryl group Chemical group 0.000 claims description 177
- 125000000217 alkyl group Chemical group 0.000 claims description 138
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 101
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 89
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 78
- 239000002253 acid Substances 0.000 claims description 76
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 66
- 239000000203 mixture Substances 0.000 claims description 60
- 125000003342 alkenyl group Chemical group 0.000 claims description 54
- 150000001412 amines Chemical class 0.000 claims description 53
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 50
- 229920006395 saturated elastomer Polymers 0.000 claims description 45
- 125000000304 alkynyl group Chemical group 0.000 claims description 43
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 41
- 229910052736 halogen Inorganic materials 0.000 claims description 39
- 150000002367 halogens Chemical class 0.000 claims description 39
- 239000001257 hydrogen Substances 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 39
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 31
- 125000002837 carbocyclic group Chemical group 0.000 claims description 29
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 26
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 26
- 125000004429 atom Chemical group 0.000 claims description 22
- 239000007789 gas Substances 0.000 claims description 21
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 claims description 20
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 claims description 20
- 125000000539 amino acid group Chemical group 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 18
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 17
- 239000012453 solvate Substances 0.000 claims description 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 229910019142 PO4 Inorganic materials 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 14
- 239000010452 phosphate Substances 0.000 claims description 14
- BPXYEYJNCXITEY-UHFFFAOYSA-N diazonio(trifluoromethoxy)azanide Chemical compound FC(F)(F)ON=[N+]=[N-] BPXYEYJNCXITEY-UHFFFAOYSA-N 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 5
- 150000001540 azides Chemical class 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 5
- 125000005647 linker group Chemical group 0.000 claims description 5
- 239000004474 valine Substances 0.000 claims description 5
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims description 4
- VEDTXTNSFWUXGQ-UHFFFAOYSA-N Carbophenothion Chemical group CCOP(=S)(OCC)SCSC1=CC=C(Cl)C=C1 VEDTXTNSFWUXGQ-UHFFFAOYSA-N 0.000 claims description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- NFMJLOPNVZKQHV-UHFFFAOYSA-N 1,2-difluoro-9h-fluorene Chemical compound C1=CC=C2CC3=C(F)C(F)=CC=C3C2=C1 NFMJLOPNVZKQHV-UHFFFAOYSA-N 0.000 claims description 2
- AMTCKRZHSPPHSE-UHFFFAOYSA-N [N-]=[N+]=NON=[N+]=[N-] Chemical compound [N-]=[N+]=NON=[N+]=[N-] AMTCKRZHSPPHSE-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 3
- 229910002651 NO3 Inorganic materials 0.000 claims 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 2
- 239000007983 Tris buffer Substances 0.000 claims 2
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 101150072608 CVC1 gene Proteins 0.000 claims 1
- YJWQZEXPWAOYLQ-UHFFFAOYSA-N FC(O[N])(F)F Chemical compound FC(O[N])(F)F YJWQZEXPWAOYLQ-UHFFFAOYSA-N 0.000 claims 1
- LXJXQRSTNIDKAZ-UHFFFAOYSA-N FOC1=CC=CC=2C3=CC=CC=C3CC12 Chemical group FOC1=CC=CC=2C3=CC=CC=C3CC12 LXJXQRSTNIDKAZ-UHFFFAOYSA-N 0.000 claims 1
- 240000003473 Grevillea banksii Species 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 239000013078 crystal Substances 0.000 claims 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 230000001419 dependent effect Effects 0.000 claims 1
- 230000001969 hypertrophic effect Effects 0.000 claims 1
- 229910052750 molybdenum Inorganic materials 0.000 claims 1
- 239000011733 molybdenum Substances 0.000 claims 1
- 150000003014 phosphoric acid esters Chemical class 0.000 claims 1
- 150000003180 prostaglandins Chemical class 0.000 claims 1
- 230000001954 sterilising effect Effects 0.000 claims 1
- 238000004659 sterilization and disinfection Methods 0.000 claims 1
- KHKSXAYMYFVLBL-UHFFFAOYSA-N tris(phosphanyl) phosphate Chemical compound POP(=O)(OP)OP KHKSXAYMYFVLBL-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 30
- 201000011510 cancer Diseases 0.000 abstract description 20
- 238000011282 treatment Methods 0.000 abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 11
- 229910052727 yttrium Inorganic materials 0.000 abstract description 8
- 229910052721 tungsten Inorganic materials 0.000 abstract description 5
- 206010061218 Inflammation Diseases 0.000 abstract description 2
- 230000004054 inflammatory process Effects 0.000 abstract description 2
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 abstract description 2
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 122
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 78
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 71
- 238000003786 synthesis reaction Methods 0.000 description 70
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 57
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 56
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 47
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 46
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 46
- 235000011152 sodium sulphate Nutrition 0.000 description 46
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 45
- 239000012267 brine Substances 0.000 description 45
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 45
- 229910052794 bromium Inorganic materials 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 36
- 238000003818 flash chromatography Methods 0.000 description 33
- 239000000725 suspension Substances 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 30
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
- 238000000746 purification Methods 0.000 description 28
- 239000007864 aqueous solution Substances 0.000 description 26
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 26
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- 238000003756 stirring Methods 0.000 description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
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- 239000007788 liquid Substances 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 19
- 238000004293 19F NMR spectroscopy Methods 0.000 description 18
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 18
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- 101150041968 CDC13 gene Proteins 0.000 description 17
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- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 230000002159 abnormal effect Effects 0.000 description 14
- 238000010168 coupling process Methods 0.000 description 14
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- AJKNNUJQFALRIK-UHFFFAOYSA-N 1,2,3-trifluorobenzene Chemical compound FC1=CC=CC(F)=C1F AJKNNUJQFALRIK-UHFFFAOYSA-N 0.000 description 13
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 13
- 238000010561 standard procedure Methods 0.000 description 13
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 12
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- 230000037361 pathway Effects 0.000 description 12
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- 230000008878 coupling Effects 0.000 description 8
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- 102000043136 MAP kinase family Human genes 0.000 description 7
- 108091054455 MAP kinase family Proteins 0.000 description 7
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 7
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 7
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- 125000003277 amino group Chemical group 0.000 description 7
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
Landscapes
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| JP4931419B2 (ja) * | 2003-09-19 | 2012-05-16 | 中外製薬株式会社 | 新規４−フェニルアミノ−ベンズアルドオキシム誘導体並びにそのｍｅｋ阻害剤としての使用 |
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| ES2330872T3 (es) * | 2004-12-01 | 2009-12-16 | Merck Serono Sa | Derivados de (1,2,4)triazolo(4,3-a)piridina para el tratamiento de enfermedades hiperproliferativas. |
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| US7666880B2 (en) * | 2005-03-21 | 2010-02-23 | S*Bio Pte Ltd. | Imidazo[1,2-A]pyridine derivatives: preparation and pharmaceutical applications |
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-
2003
- 2003-09-03 US US10/654,580 patent/US7144907B2/en not_active Expired - Fee Related
-
2004
- 2004-08-30 US US10/929,295 patent/US7230099B2/en not_active Expired - Fee Related
- 2004-09-01 CN CNA2004800326551A patent/CN1874769A/zh active Pending
- 2004-09-01 JP JP2006525449A patent/JP4131741B2/ja not_active Expired - Fee Related
- 2004-09-01 KR KR1020067004505A patent/KR20060070558A/ko not_active Withdrawn
- 2004-09-01 PT PT47830286T patent/PT1673339E/pt unknown
- 2004-09-01 RU RU2006109599/04A patent/RU2006109599A/ru not_active Application Discontinuation
- 2004-09-01 AU AU2004270699A patent/AU2004270699B2/en not_active Ceased
- 2004-09-01 CA CA002537321A patent/CA2537321A1/en not_active Abandoned
- 2004-09-01 WO PCT/US2004/028649 patent/WO2005023759A2/en not_active Ceased
- 2004-09-01 BR BRPI0414111-3A patent/BRPI0414111A/pt not_active IP Right Cessation
- 2004-09-01 MX MXPA06002466A patent/MXPA06002466A/es not_active Application Discontinuation
- 2004-09-01 ZA ZA200602581A patent/ZA200602581B/en unknown
- 2004-09-01 EP EP04783028.6A patent/EP1673339B1/en not_active Expired - Lifetime
- 2004-09-02 AR ARP040103151A patent/AR046081A1/es not_active Application Discontinuation
- 2004-09-02 TW TW093126520A patent/TW200526607A/zh unknown
-
2006
- 2006-02-26 IL IL173936A patent/IL173936A/en not_active IP Right Cessation
- 2006-03-31 IS IS8392A patent/IS8392A/is unknown
- 2006-04-03 NO NO20061506A patent/NO20061506L/no not_active Application Discontinuation
- 2006-04-24 US US11/410,336 patent/US7511058B2/en not_active Expired - Fee Related
- 2006-04-24 US US11/410,343 patent/US7271178B2/en not_active Expired - Fee Related
- 2006-04-24 US US11/410,344 patent/US20060189668A1/en not_active Abandoned
-
2012
- 2012-05-08 IL IL219670A patent/IL219670A/en not_active IP Right Cessation
- 2012-05-08 IL IL219669A patent/IL219669A0/en unknown
- 2012-05-08 IL IL219671A patent/IL219671A0/en unknown
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