HRP980368A2 - 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives - Google Patents
4-bromo or 4-iodo phenylamino benzhydroxamic acid derivativesInfo
- Publication number
- HRP980368A2 HRP980368A2 HR60/051,440A HRP980368A HRP980368A2 HR P980368 A2 HRP980368 A2 HR P980368A2 HR P980368 A HRP980368 A HR P980368A HR P980368 A2 HRP980368 A2 HR P980368A2
- Authority
- HR
- Croatia
- Prior art keywords
- phenylamino
- benzamide
- iodo
- difluoro
- methyl
- Prior art date
Links
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 title description 4
- QAMBBWKIAJFFRF-UHFFFAOYSA-N n-hydroxy-2-(4-iodoanilino)benzamide Chemical class ONC(=O)C1=CC=CC=C1NC1=CC=C(I)C=C1 QAMBBWKIAJFFRF-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 94
- -1 5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-[5-(3-methoxy-phenyl)-3-methyl-pent-2-ene-4-ynyloxy ]-benzamide Chemical compound 0.000 claims description 57
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 claims description 28
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 claims description 28
- 206010028980 Neoplasm Diseases 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 241000124008 Mammalia Species 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 230000002062 proliferating effect Effects 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 239000011737 fluorine Substances 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 201000004681 Psoriasis Diseases 0.000 claims description 8
- 208000037803 restenosis Diseases 0.000 claims description 8
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- HSDBAZASWXUUHX-UHFFFAOYSA-N 4-fluoro-n-hydroxy-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NO HSDBAZASWXUUHX-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- GFMMXOIFOQCCGU-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CC1 GFMMXOIFOQCCGU-UHFFFAOYSA-N 0.000 claims description 4
- LUAWFZQWIXYGPQ-UHFFFAOYSA-N 5-bromo-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC(Br)=C(F)C(F)=C1NC1=CC=C(I)C=C1F LUAWFZQWIXYGPQ-UHFFFAOYSA-N 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- BZSLAYDTMNXEOY-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1Cl BZSLAYDTMNXEOY-UHFFFAOYSA-N 0.000 claims description 3
- VJNZMSLGVUSPCF-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-n-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C1CC1CONC(=O)C=1C=C(Br)C(F)=C(F)C=1NC1=CC=C(I)C=C1Cl VJNZMSLGVUSPCF-UHFFFAOYSA-N 0.000 claims description 3
- AAVSAALNWBQXSB-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-n-[2-(dimethylamino)ethoxy]-3,4-difluorobenzamide;hydrochloride Chemical compound Cl.CN(C)CCONC(=O)C1=CC(Br)=C(F)C(F)=C1NC1=CC=C(I)C=C1Cl AAVSAALNWBQXSB-UHFFFAOYSA-N 0.000 claims description 3
- YOURVUHYTAPYOX-UHFFFAOYSA-N 5-bromo-n-(cyclohexylmethoxy)-3,4-difluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C(=O)NOCC1CCCCC1 YOURVUHYTAPYOX-UHFFFAOYSA-N 0.000 claims description 3
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 3
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 3
- 201000004983 autoimmune atherosclerosis Diseases 0.000 claims description 3
- BZJWSLFAFFNFIW-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-3,4-difluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1Br BZJWSLFAFFNFIW-UHFFFAOYSA-N 0.000 claims description 2
- XYYUOXLXTADKMW-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-4-fluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1Br XYYUOXLXTADKMW-UHFFFAOYSA-N 0.000 claims description 2
- AVIWCXSGNKPKKK-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-5-chloro-3,4-difluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC(Cl)=C(F)C(F)=C1NC1=CC=C(I)C=C1Br AVIWCXSGNKPKKK-UHFFFAOYSA-N 0.000 claims description 2
- JHBIWAOIBNORTA-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-3,4,5-trifluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC(F)=C(F)C(F)=C1NC1=CC=C(I)C=C1Cl JHBIWAOIBNORTA-UHFFFAOYSA-N 0.000 claims description 2
- NXUSIIDZHWMSCV-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-3,4-difluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1Cl NXUSIIDZHWMSCV-UHFFFAOYSA-N 0.000 claims description 2
- ROCRLSIAQQGIPN-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-n-(cyclobutylmethoxy)-3,4-difluorobenzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CCC1 ROCRLSIAQQGIPN-UHFFFAOYSA-N 0.000 claims description 2
- SHNRDYXLGNJCOC-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-n-hydroxy-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NO)C(NC=2C(=CC(I)=CC=2)Cl)=C1 SHNRDYXLGNJCOC-UHFFFAOYSA-N 0.000 claims description 2
- UOPHVVWHOCFXFI-UHFFFAOYSA-N 2-(2-fluoro-4-iodoanilino)-n-hydroxy-4-nitrobenzamide Chemical compound ONC(=O)C1=CC=C([N+]([O-])=O)C=C1NC1=CC=C(I)C=C1F UOPHVVWHOCFXFI-UHFFFAOYSA-N 0.000 claims description 2
- PYEBOHZEONEOFB-UHFFFAOYSA-N 3,4,5-trifluoro-2-(2-fluoro-4-iodoanilino)-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC(F)=C(F)C(F)=C1NC1=CC=C(I)C=C1F PYEBOHZEONEOFB-UHFFFAOYSA-N 0.000 claims description 2
- OEDQBUOUDGINPB-UHFFFAOYSA-N 4-fluoro-2-(2-fluoro-4-iodoanilino)-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1F OEDQBUOUDGINPB-UHFFFAOYSA-N 0.000 claims description 2
- RPWNJSYAWBWAFW-UHFFFAOYSA-N 5-bromo-2-(2-bromo-4-iodoanilino)-3,4-difluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC(Br)=C(F)C(F)=C1NC1=CC=C(I)C=C1Br RPWNJSYAWBWAFW-UHFFFAOYSA-N 0.000 claims description 2
- WBQVEORRHAMIPY-UHFFFAOYSA-N 5-bromo-n-(cyclobutylmethoxy)-3,4-difluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C(=O)NOCC1CCC1 WBQVEORRHAMIPY-UHFFFAOYSA-N 0.000 claims description 2
- MKRVIYRPNNYISB-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-3,4-difluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC(Cl)=C(F)C(F)=C1NC1=CC=C(I)C=C1Cl MKRVIYRPNNYISB-UHFFFAOYSA-N 0.000 claims description 2
- FVMKNRIUORTHMN-UHFFFAOYSA-N 5-chloro-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC(Cl)=C(F)C(F)=C1NC1=CC=C(I)C=C1F FVMKNRIUORTHMN-UHFFFAOYSA-N 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 208000006029 Cardiomegaly Diseases 0.000 claims description 2
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 2
- 206010019842 Hepatomegaly Diseases 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- IVKQAKIJQNIBIO-UHFFFAOYSA-N n-hydroxy-2-(4-iodo-2-methylanilino)-4-nitrobenzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC([N+]([O-])=O)=CC=C1C(=O)NO IVKQAKIJQNIBIO-UHFFFAOYSA-N 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 6
- ZSOPSNFTRFGERY-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-3,4-difluoro-n-(oxan-2-yloxy)benzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=C(F)C(F)=CC=C1C(=O)NOC1CCCCO1 ZSOPSNFTRFGERY-UHFFFAOYSA-N 0.000 claims 2
- UUQXUOKQBSWOHD-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-n-hydroxy-4-nitrobenzamide Chemical compound ONC(=O)C1=CC=C([N+]([O-])=O)C=C1NC1=CC=C(I)C=C1Cl UUQXUOKQBSWOHD-UHFFFAOYSA-N 0.000 claims 2
- AYEUPCJRNJQNQD-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-(oxan-2-yloxy)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOC1OCCCC1 AYEUPCJRNJQNQD-UHFFFAOYSA-N 0.000 claims 2
- ILYBIGUHBUIMMX-UHFFFAOYSA-N 3,4-difluoro-n-hydroxy-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NO ILYBIGUHBUIMMX-UHFFFAOYSA-N 0.000 claims 2
- HHLZFIBFGYVDRZ-UHFFFAOYSA-N 5-chloro-n-hydroxy-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC=C(Cl)C=C1C(=O)NO HHLZFIBFGYVDRZ-UHFFFAOYSA-N 0.000 claims 2
- UHAXDAKQGVISBZ-UHFFFAOYSA-N N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C(=O)NOCC1CC1 UHAXDAKQGVISBZ-UHFFFAOYSA-N 0.000 claims 2
- HPFQWCKXOZLYJQ-UHFFFAOYSA-N n-but-2-enoxy-3,4-difluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC=CCONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1C HPFQWCKXOZLYJQ-UHFFFAOYSA-N 0.000 claims 2
- KBJDNLWKCWKLMD-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-5-chloro-n-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C1CC1CONC(=O)C=1C=C(Cl)C(F)=C(F)C=1NC1=CC=C(I)C=C1Br KBJDNLWKCWKLMD-UHFFFAOYSA-N 0.000 claims 1
- BWOZEHCSZGOGER-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-n-(cyclopropylmethoxy)-3,4,5-trifluorobenzamide Chemical compound C=1C=C(I)C=C(Br)C=1NC=1C(F)=C(F)C(F)=CC=1C(=O)NOCC1CC1 BWOZEHCSZGOGER-UHFFFAOYSA-N 0.000 claims 1
- RDTSNRQFNRNSCU-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-n-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C=1C=C(I)C=C(Br)C=1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CC1 RDTSNRQFNRNSCU-UHFFFAOYSA-N 0.000 claims 1
- LZRKJVJJXDFWLG-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-n-(cyclopropylmethoxy)-4-fluorobenzamide Chemical compound C=1C=C(I)C=C(Br)C=1NC1=CC(F)=CC=C1C(=O)NOCC1CC1 LZRKJVJJXDFWLG-UHFFFAOYSA-N 0.000 claims 1
- LHZVMSNGGDZKFO-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-n-(cyclopropylmethoxy)-4-nitrobenzamide Chemical compound C=1C=C(I)C=C(Br)C=1NC1=CC([N+](=O)[O-])=CC=C1C(=O)NOCC1CC1 LHZVMSNGGDZKFO-UHFFFAOYSA-N 0.000 claims 1
- NMGPTKSLPIARAK-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-n-hydroxy-4-nitrobenzamide Chemical compound ONC(=O)C1=CC=C([N+]([O-])=O)C=C1NC1=CC=C(I)C=C1Br NMGPTKSLPIARAK-UHFFFAOYSA-N 0.000 claims 1
- IJCHFSDTDHLRIQ-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-(oxan-2-yloxy)benzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=CC(F)=CC=C1C(=O)NOC1CCCCO1 IJCHFSDTDHLRIQ-UHFFFAOYSA-N 0.000 claims 1
- YVSLCRVTJGUKSV-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-n-(cyclopropylmethoxy)-3,4,5-trifluorobenzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC=1C(F)=C(F)C(F)=CC=1C(=O)NOCC1CC1 YVSLCRVTJGUKSV-UHFFFAOYSA-N 0.000 claims 1
- DVENTWJICBBDAJ-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-n-(cyclopropylmethoxy)-4-fluorobenzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=CC(F)=CC=C1C(=O)NOCC1CC1 DVENTWJICBBDAJ-UHFFFAOYSA-N 0.000 claims 1
- BOWUZVRUZUWLAM-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-n-ethoxy-4-nitrobenzamide Chemical compound CCONC(=O)C1=CC=C([N+]([O-])=O)C=C1NC1=CC=C(I)C=C1Cl BOWUZVRUZUWLAM-UHFFFAOYSA-N 0.000 claims 1
- HDLXUSUTCIBXQZ-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-(2-methylprop-2-enoxy)benzamide Chemical compound CC(=C)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1C HDLXUSUTCIBXQZ-UHFFFAOYSA-N 0.000 claims 1
- HYIXUGDJHLKVGF-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-(2-phenoxyethoxy)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCCOC1=CC=CC=C1 HYIXUGDJHLKVGF-UHFFFAOYSA-N 0.000 claims 1
- ILKRGOONQZFQPI-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-(3-methyl-5-phenylpent-2-en-4-ynoxy)benzamide Chemical compound C=1C=CC=CC=1C#CC(C)=CCONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1C ILKRGOONQZFQPI-UHFFFAOYSA-N 0.000 claims 1
- RLUBNNSZZPDBIV-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-(3-phenylprop-2-ynoxy)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC#CC1=CC=CC=C1 RLUBNNSZZPDBIV-UHFFFAOYSA-N 0.000 claims 1
- HAONTWSXIVMMHV-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-(thiophen-2-ylmethoxy)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC1=CC=CS1 HAONTWSXIVMMHV-UHFFFAOYSA-N 0.000 claims 1
- ZWXXSMYLKXWUIM-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-prop-2-ynoxybenzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC#C ZWXXSMYLKXWUIM-UHFFFAOYSA-N 0.000 claims 1
- FUDMVYZZNQDLOV-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-propoxybenzamide Chemical compound CCCONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1C FUDMVYZZNQDLOV-UHFFFAOYSA-N 0.000 claims 1
- YPKLFSUXFMFTNP-UHFFFAOYSA-N 3,4-difluoro-n-(furan-3-ylmethoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC1=COC=C1 YPKLFSUXFMFTNP-UHFFFAOYSA-N 0.000 claims 1
- OEYRWOJRMOBKSM-UHFFFAOYSA-N 3,4-difluoro-n-[3-(2-fluorophenyl)prop-2-ynoxy]-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC#CC1=CC=CC=C1F OEYRWOJRMOBKSM-UHFFFAOYSA-N 0.000 claims 1
- XYPDOWBXGOOEOA-UHFFFAOYSA-N 4-fluoro-2-(4-iodo-2-methylanilino)-n-(2-phenoxyethoxy)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NOCCOC1=CC=CC=C1 XYPDOWBXGOOEOA-UHFFFAOYSA-N 0.000 claims 1
- PBAMOEUDSFIDGM-UHFFFAOYSA-N 4-fluoro-2-(4-iodo-2-methylanilino)-n-(thiophen-2-ylmethoxy)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NOCC1=CC=CS1 PBAMOEUDSFIDGM-UHFFFAOYSA-N 0.000 claims 1
- PEZQORQECWUYJA-UHFFFAOYSA-N 4-fluoro-2-(4-iodo-2-methylanilino)-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1C PEZQORQECWUYJA-UHFFFAOYSA-N 0.000 claims 1
- PFWAYQMMRCDJJX-UHFFFAOYSA-N 4-fluoro-2-(4-iodo-2-methylanilino)-n-prop-2-enoxybenzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NOCC=C PFWAYQMMRCDJJX-UHFFFAOYSA-N 0.000 claims 1
- VFLRZRPXLGMONP-UHFFFAOYSA-N 4-fluoro-2-(4-iodo-2-methylanilino)-n-prop-2-ynoxybenzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NOCC#C VFLRZRPXLGMONP-UHFFFAOYSA-N 0.000 claims 1
- TYSFIFCGLKBEJN-UHFFFAOYSA-N 4-fluoro-n-hydroxy-2-(4-iodo-2-methylanilino)-5-nitrobenzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C(=O)NO TYSFIFCGLKBEJN-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D307/42—Singly bound oxygen atoms
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- C07D309/10—Oxygen atoms
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Description
Područje izuma
Ovaj izum prikazuje neke derivate hidroksamske kiseline koji su derivati antranilne kiseline, a inhibiraju neke konaze dvojne specifičnosti, a koje su obuhvaćene u proliferativnim bolestima kao što je karcinom ili restenoza.
Dosadašnje spoznaje
Proliferativne bolesti su uzrokovane poremećajem unutrašnjeg sustava signalizacije ili mehanizam prijenosa signala. Karcinom je primjerice obično uzrokovan serijom poremećaja u tim signalnim proteinima, što nastaje zbog promjene u njihovoj unutarnjoj aktivnosti ili njihovoj celularnoj koncentraciji. Stanica može proizvoditi faktor rasta koji se veže na vlastite receptore, što rezultira krugom u kojem se kontinuirano stimulira proliferacija. Mutacije ili pojačana ekpresije intracelularnih signalnih proteina mogu voditi do mitogenog signala unutar stanice. Neke od najčešćih mutacija se primjećuju u genima koji kodiraju protein poznat kao Ras, a koji je G-protein i aktiviran je kad ima vezan GTP, a inaktiviran kada ima vezan GDP.
Kada su gore spomenuti receptori faktora rasta i mnogi drugi mitogeni receptori aktivirani, vode tome da Ras bude preveden u GDP-vezanog stanja u GRP-vezano stanje. Taj signal je apsolutno nužan da bi došlo do proliferacije u mnogim tipovima stanica. Poremećaj u tom sustavu signaliziranja, posebice u deaktivaciji Ras.GTP kompleksa je čest u karcinomima, i vodi ka kroničnoj aktivaciji kaskade iza Ras.
Aktivirani Ras vodi aktivaciji kaskade serin/treonin kinaze. Jedna poznata skupina kinaza zahtjeva aktivni Ras.GTP za vlastitu aktivaciju je Raf obitelj. Ovi zatim aktiviraju MEK, koji zatim aktivira MAP kinazu. Aktivacija MAP kinaze mitogenima je nužna za proliferaciju i konsekutivna aktivacija te kinaze je dovoljna da inducira celularnu transformaciju. Blokadom nizvodno od Ras signalizacije, primjerice korištenjem dominantnog negativnog Ras-1 proteina, može se potpuno inhibirati mitogeneza, bez obzira je li inducirana receptorima iz površine stanice ili onkogenim Ras mutantima. Mada Ras nije po sebi protein kinaza, on sudjeluje u aktivaciji Raf i drugih kinaza, vjerojatno memhanizmom fosforilacije. kad je jedanput aktiviran, Raf i ostale kinaze fosforiliraju MEK na dva susjedna serinska ostatka, S218 i S222 u slučaju MEK-1 koji su potrebni za aktivaciju MEK kao kinaze. MEK zatim fosforilira MAP kinazu na tirozinskom Y85 i treoniskom ostatku, T183, koji su rastavljeni jednom aminokiselinom. Ova dvostruka fosforilacija aktivira MAP kinazu najmanje 100 puta i sada ona može katalizirati fosforilaciju velikog broja proteina, uključujući nekoliko transkripcijskih faktora i druge kinaze. Mnoge od ovih kinaza fosforilacijom postaju mitogeniski aktivirane prema ciljanom proteinu, koji može biti druga kinaza, transkripcijski faktor ili drugi stanični protein. MEK je također aktiviran nekim kinazama koje nisu Raf-1, uključujući MEKK, te se sam pojavljuje kao kinaza kojom je obuhvaćena signalizacija. Koliko je do sada poznato, MEK je visoko specifičan za fosforilaciju MAP kinaze. Zapravo, do danas nije poznat ni jedan supstrat za MEK osim MAP kinaza, pa MEK ne fosforilira peptide koji su prisutni u fosforilacijskoj sekvenciji MAP kinaze, čak niti ne fosforilira denaturiranu MAP kinazu. MEK je također jako povezan s MAP kinazom i prije fosforilacije, pokazujući da je za fosforilaciju potrebna jaka interakcija između ta dva proteina. Oba ova zahtjeva, kao i neobična specifičnost MEK pokazuju da se mehanizam djelovanja MEK dovoljno razlikuje u mehanizmu djelovanja drugih kinaza koje su selektivni inhibitor MEK, koji vjerojatno ide putem alosteričnih mehanizama, a ne putem uobičajene blokade mjesta vezivanja ATP.
Izum prikazuje spojeve koji su visoko specifični inhibitori kinazne aktivnosti MEK. U testu s enzimom i s cijelom stanicom, spojevi inhibiraju fosforilaciju MAP kinaze od MEK, pa tako sprečavaju aktivaciju MAP kinaze u stanicama u kojima su aktivirane Ras kaskade. Rezultat inhibicije tog enzima uključuje vraćanje nekih tipova transformiranog fenotipa u prvobitno stanje, a mjereno sposobnošću transormiranih stanica da rastu na neovisan način, te sposobnošću transformiranih staničnih linija da proliferiraju neovisno o eksternim mirogenima.
Spojevi prikazani u ovom izumu su derivati fenilaminohidroksamske kiseline u kojima je fenilni prsten supstituiran u položaju 4 s bromom ili jodom. U.S. patent br. 5,155,110 prikazuje veliki raspon derivata femanimske kiseline, uključujući neke derivate fenilamino-benzihidroksamske kiseline, kao protuupalna sredstva. Navedeni patent ne opisuje spoj iz ovog izuma, niti njegovu inhibitorsku aktivnost prema kinazi.
Sažetak izuma
Ovaj izum prikazuje 4-brom i 4-jod derivate fenilaminohidroksamske kiseline koji su inhibitori kinaze i kao takvi korisni su u tretmanu proliferativnih bolesti kao što je karcinom, psorijaza i restenoza. Spojevi su definirani formulom I
[image]
u kojoj
R1 jeste vodik, hidroksi, C1-C8 alkil, C1-C8-alkoksi, halogen, trifluormetil ili CN;
R2 jeste vodik;
R3, R4 i R5 neovisno jesu vodik, hidroksi, halogen, trifluormetil, C1-C8 alkil, C1-C8 alkoksi, nitro, CN ili (O ili NH)m-(CH2)n-R9, pri čemu R9 jeste vodik, hidroksi, CO2H ili NR10R11;
n jeste od 0 do 4;
m jeste 0 ili 1;
R10 i R11 neovisno jesu vodik, C1-C8 alkil, ili uzeti zajedno s dušikom na koji su vezani tvore tro- do deseteročlani prsten koji može sadržavati jedan, dva ili tri dodatna heteroatoma koji su odabrani od: O, S, NH, ili N-C1-C8 alkil;
R6 jeste vodik C1-C8 alkil, -CO-C1-C8 alkil, aril, aralkil ili C3-C10 cikloalkil,
R7 je vodik C1-C8 alkil, C2-C8 alkenil, C2-C8 alkinil, C3-C10 (cikloalkil ili ciikloalkil koji ima heteroatom koji je odabran od O, S ili NR9); ili R6 i R7 uzeti zajedno s N-O na koji su vezani, tvore petero- do deseteročlani prsten koji može sadržavati jedan, dva ili tri dodatna heteroatoma koji su odabrani od: O, S ili NR10R11;
pri čemu prethodne alkilne, alkenilne i alkinilne skupine mogu biti nesupstituirane ili supstituirane cikloalkilom (ili cikloalkilom koji može sadržavati heteroatom koji je odabran od O, S ili NR9), arilom, ariloksi, heteroarilom ili heteroariloksi.
Preferirani spojevi imaju formulu II
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u kojoj R1, R3, R4, R5, R6 i R7 jesu kao što su gore definirani. Posebno su preferirani spojevi u kojima R1 jeste metil ili halogen, R3, R4 i R5 jesu halogen kao što je fluor ili brom.
Slijedeća preferirana skupina spojeva ima formulu III
[image]
u kojoj R1, R3, R4, R5, R6 i R7 jesu kao što su gore definirani.
Najpreferiraniji spojevi su oni u kojima R1 jeste metil ili halogen, kao što je F, Cl i I, R3 jeste vodik ili halogen kao što je fluor, R4 halogen kao što je fluor, te R5 je vodik ili halogen kao što je fluor ili brom. Takvi spojevi imaju formule:
[image]
Specifični spojevi prikazani u izumu uključuju slijedeće:
3,4,5-trifluor-N-hidroksi-2-(4-jod-2-metil-feilamino)-benzamid,
5-klor-3,4-difluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-3,4-difluor-2-(2-fluor-4-jod-fenilamino)-N-hidroksi-benzamid,
N-hidroksi-2-(4-jod-2-metil-fenilamino)-4-nitro-benzamid,
3,4,5-trifluor-2-(2-fluor-4-jod-fenilamino)-N-hidroksi-benzamid,
5-klor-3,4-difluor-2-(2-fluor-4-jod-fenilamino)-N-hidroksi-benzamid,
5-brom-2-(2-flor-4-jod-fenilamino)-3,4-difluor-N-hidroksi-benzamid,
2-(2-flor-4-jod-fenilamino)-N-hidroksi-4-nitro-benzamid,
2-(2-klor-4-jod-fenilamino)-3,4,5-trifluor-N-hidroksi-benzamid,
5-klor-2-(2-klor-4-jod-fenilamino)-3,4-difluor-N-hidroksi-benzamid,
5-brom-2-(2-brom-4-jod-fenilamino)-3,4-difluor-N-hidroksi-benzamid,
2-(2-klor-4-jod-fenilamino)-N-hidroksi-4-metil-benzamid,
2-(2-brom-4-jod-fenilamino)-3,4,5-trifluor-N-hidroksi-benzamid,
2-(2-brom-4-jod-fenilamino)-5-klor-3,4-difluor-N-hidroksi-benzamid,
2-(2-brom-4-jod-fenilamino)-N-hidroksi-benzamid,
4-fluor-2-(2-fluor-4-jod-fenilamino)-N-hidroksi-benzamid,
2-(2-klor-4-jod-fenilamino)-4-fluor-N-hidroksi-benzamid,
2-(2-klor-4-jod-fenilamino)-3,4-difluor-N-hidroksi-benzamid,
2-(2-brom-4-jod-fenilamino)-4-fluor-N-hidroksi-benzamid,
2-(2-brom-4-jod-fenilamino)-3,4-difluor-N-hidroksi-benzamid,
3,4-difluor-2-(2-klor-4-jod-fenilamino)-N-ciklobutilmetoksi-benzamid,
5-brom-2-(2-klor-4-jod-fenilamino)-N-(2-dimetilamino-etoksi)-3,4-difluor-benzamid monohidroklorid,
5-brom-2-(2-klor-4-jod-fenilamino)-3,4-difluor-N-hidroksi-benzamid,
3,4-difluor-2-(2-klor-4-jod-fenilamino)-N-ciklopropilmetoksi-benzamid,
5-brom-2-(2-klor-4-jod-fenilamino)-N-ciklopropilmetoksi-3,4-difluor-benzamid,
5-brom-N-cikloheksilmetoksi-3,4-difluor-2-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-N-cikloheksilmetoksi-3,4-difluor-2-(4-jod-2-metil-fenilamino)-benzamid, te
5-brom-N-ciklobutilmetoksi-3,4-difluor-2-(4-jod-2-metil-fenilamino)-benzamid.
Ovaj izum također prikazuje farmaceutske pripravke koji sadrže spoj formule I skupa s farmaceutski prihvatljivim ekcipijensom, razrjeđivačem ili nosačem. Preferirane formualcije uključuju bilo koji od prethodno navedenih spojeva skupa s ekcipijensom, razrjeđivačem ili nosačem.
Spojevi formule I su selektivni inhibitori enzima kinaza, posebice MEK1 i MEK2. Oni su stoga korisni u tretmanu osoba koje pate od karcinoma i ostalih proliferativnih bolesti kao što je psorijaza, restenoza, autoimune bolesti i steroskleroza. Spojevi su posebice pogodni u tretmanu karcinoma kao što je karcinom dojke, karcinom debelog crijeva, karcinom prostate, karcinom kože i karcinom pankreasa. Spoejvi se također mogu koristiti u tretmanu moždanog udara, dijabetesa, hepatomegalije, kardiomegalije, Alzheimerove bolesti, cistične fibroze i virusnih oboljenja. Izum prikazuje metodu inhibicije MEK enzima i prethodno navedenih bolesti, a davanjem osobi učinkovite količine spoja Formule I.
Detaljan opis izuma
Termin “aril” označuje ciklični, biciklični ili triciklični aromatski prsten koji ima pet do dvanaest atoma ugljika. Primjeri tipičnih aroilnih skupina uključuju fenil, naftil i fluorenil. Aril može biti supstituiran jednom, dvjema ili trima skupinama koje su odabrane od: fluor, klor, brom, jod, alkil, hidroksi, alkoksi, nitro ili amino. Tipične supstituirane arilne skupine uključuju 3-fluorfenil, 3,5-dimetoksifenil, 4-nitronaftil, 2-metil-4-klor-7-aminofluorfenil i slično.
Termin “ariloksi” označuje arilnu skupinu vezanu preko atoma kisika, primjerice fenoksi, 3-bromfenoksi, naftiloksi i 4-metil-1-fluoreniloksi.
“Heteroaril” označuje ciklični, biciklični ili triciklični aromatski prsten koji ima od četiri do jedanaest atoma ugljika i jedan, dva ili tri heteroatoma koji su odabrani od O, S ili N. Primjeri uključuju furil, tienil, pirolil, pirazolil, tiazolil, ksantenil, pironil, indolil, pirimidil, naftiridil, piridil i triazinil. Heteroatilne skupine mogu biti nesupstituirane ili supstituirane jednom, dvjema ili trima skupinama koje su odabrane od: fluor, brom, jod, alkil, hidroksi, alkoksi, nitro ili amino. Primjeri supstituiranih heteroarilnih skupina uključuju klorpropanil, metiltienil, fluorpiridil, amino-1,4- benziz oksazil, nitroizokinolinil i hidroksiindolil.
Heteroarilne skupine mogu biti vezane preko kisika, pri čemu čine heteroariloksi skupine, primjerice tieniloksi, izotiazoliloksi, benzofuraniloksi, piridiloksi i 4-metilizokinoliniloksi.
Termin “C1-C8 alkil” označuje ravni ili razgranati lanac alfatskih skupina koje imaju od jedan do osam atoma ugljika. Tipična C1-C8 alkilne skupine uključuje metil, etil, izopropil, tert-butil. 2,3-dimetilheksil i 1,1-dimetilpentil. Alkilne skupine mogu biti nesupstituirane ili supstituirane s cikloalkilom, cikloalkilom koji sadrži heteroatom koji je odabran od O, S ili NR9, arilom, ariloksi, heteroarilom ili heteroariloksi, a koje jesu kao što je gore definirano. Primjeri arilom i heteroarilom supstituiranih alkilnih skupina uključuju fenilmetil,2-feniletil, 3-klorfenilmetil, 1,1-dimetil- 3-(2- nitro fenoksi)butil i 3,4,5-trifluornaftilmetil. Primjeri alkilnih skupina supstituiranih heteroarilom ili heteroariloksi skupinom uključuju tienilmetil, 2-furiletil, 6-furiloksioktil, 4-metilkinoliloksimetil i 6-izotiazolilheksil. Cikloalkilom supstituirane alkilne skupine uključuju ciklopropilmeitl, 2-ciklopentilmetil, 2-piperidin-1-iletil, 3-(tetrahidropiran-2-il)-propil i ciklobutilmetil.
Termini “C2-C8 alkenil” označuje ravni ili razgranati lanac koji ima jednu ili više dvostrukih veza. Primjeri uključuju but-2-enil, 2-metil-prop-2-enil, 1,1-dimetil-heks-4-enil, 3-etil-4-metil-pent-2-enil i 3-izopropil-pent-4-enil. Alkenilne skupine mogu biti supstituirane s aril, ariloksi, heteroaril ili heteroariloksi, primjerice 3-fenilprop-2-enil, 6-tienil- heks-2- enil, 2-furiloksi-but-2-enil i 4-naftil-oski-heks-2-enil.
Termini “C2-C8 alkinil” označuje ravni ili razgranati lanac od dva do osam atoma ugljika, koji ima najmanje jednu trostruku vezu. Tipične alkilne skupine uključuju prop-2-inil, 2-metil-heks-5-inil, 3,4-dimetil-heks-5-inil i 2-etil-but-3-inil. Alkilne skupine mogu biti supstituirane s arilom, ariloksi, heteroaril ili heteroariloksi, primjerice 4-(2-fluorfenil)-but-3-inil, 3-metil-5-tienil-4-inil, 3-fenoksi-heks-4-inil i 2-fluoriloksi-3-metil-heks-4-inil.
Alkenilne i alkinilne skupine mogu imati jednu ili više dvostrukih veza ili trostrukih veza, ili kombinaciju dvostrukih i trostrukih veza. Primjerice, tipične skupine koje imaju dvostruke i trostruke veze uključuju heks-2-en-4-inil, 3- metil- 5- fenilpent-2-en-4-inil i 3-tieniloksi-heks-3-en-5-inil.
Termini “C3-C10 cikloalkil” označuje nearomatski prsten ili fuzionirane prstene koji sadrže od tri do deset atoma ugljika. Primjeri uključuju ciklopropil, ciklobutil, ciklopentil, ciklooktil, bicikloheptil, adamantil ili cikloheksil, Prsten može sadržavati heteroatom koji je odabran od O, S ili NR9. Takve skupine uključuju tetrahidrofuril, tetrahidropirolil, oktahidrobenzofuranil, oktahidroindolil i okrahidrobenzotiofuranil.
R3, R4 i R5 uključuju skupine definirane terminom (O ili NH)m-(CH2-R9. Primjeri takovih skupina uključuju aminometil, 2-aminoetil, 2-aminoetilamino, 3-aminopropoksi, N,N-dietilamino, 3-(N-metil-N-izopropilamino)-propilamino, 2-(N- acetilamino)-etoksi, 4-(N-dimetilaminokarbonilamino)-butoksi, te 3-(N-ciklopropilaino)-propoksi.
Derivati 4-brom i 4-klorfenilamino-benzhidroksamske kiseline Formule I se mogu pripraviti iz komercijalno pristupačnih polaznih spojeva a korištenjem sintetskih metodologija dobro poznatih stručnjacima u organskoj kemiji. Tipična sinteza je izvedena reakcijom 4-brom ili 4-jodanilina i benzojeve kiseline koja ima odlazeću skupinu u položaju 2, pri čemu nastaje fenilaminobenzojeva kiselina, te reakcijom derivata fenilaminobenzojeve kiseline s derivatom hidroksilamina. Postupak je prikazan u Shemi 1.
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u kojoj je L odlazeća skupina, primjerice halogen kao što je fluor, klor, brom ili jod, ili aktivirana hidroksilna skupina, kao što je dietilfosfat, trimetilsililoksi, p-nitrofenoksi ili fenilsulfonoksi.
Reakcija derivata anilina i derivata benzojeve kiseline je općenito završena miješanjem benzojeve kiseline s ekvimolarnom količinom ili suviškom anilina u nereaktivnom organskom otapalu kao što je tetrahidrofuran ili toluen, u prisutnosti baze kao što je litijev izopropoksid, n-butil-litij, natrijev hidrid ili natrijev amid. Reakcija se općenito izvodi pri temperaturama od oko -78°C do oko 25°C, a obično je završena unutar 2 sata i 4 dana. Produkt se može izolirati uklanjanjem otapala, primjerice uparavanjem pod sniženim tlakom, te daljnjim čišćenjem po želji, standardnim metodama kao što je kromatografija, kristalizacija ili destilacija.
Fenilaminobenzojeva kiselina zatim reagira s derivatom hidroksilamina HNR6OR7 u prisutnosti sredstva za kondenzaciju peptida. Derivat hidroksilamino koji se može koristiti uključuje metoksiamin, N-etil-izopropoksiamin i tetrahidro-oksazin. Tipično sredstvo za kondenzaciju uključuje 2-etoksi-1-etoksikarbonil-1,2-dihidrokinolin (EEDQ), 1,3- diciklo heksilkarbodiimid (DCC), brom-tris(pirolidino)-fosfonij-heksafluorfosfat (PyBrOP) i (benzotriazoliloksi) pirolidino- fosfonij-heksafluorfosfat (PyBOP). Fenilaminobenzojeva kiselina i derivat hidroksilamina se normalno miješaju u približno ekvimolarnim količinama u nereaktivnom organskom otapalu kao što je diklormetan, tetrahidrofuran, kloroform ili ksilen, te se dodaje ekvimolarna količina sredstva za kondenzaciju. Može se dodati trietilamin ili diizopropiletilamin da djeluje kao sredstvo za vezivanje. Reakcija kondenzacijeje obično završena nakon od 10 minuta do 2 sata, a produkt se lako izolira uklanjanjem otapala, primjerice uparavanjem pod sniženim tlakom, te čišćenjem produkta standardnim metodama kao što je kromatografija, kristalizacija iz otapala kao što je aceton, dietil-eter ili etanol.
Alternativna metoda priprave spojeva iz izuma uključuje pretvorbu benzojeve kiseline u derivat hidroksamske kiseline, a zatim reakciju hidroksamske kiseline s derivatom anilina. Ta sintetska sekvencija prikazana je u Shemi 2.
[image]
u kojoj je L odlazeća skupina. Općeniti reakcijski uvjeti za oba koraka u Shemi 2 su siti kao što su opisani u Shemi 1.
Slijedeća metoda priprave spojeva iz izuma sastoji se od reakcije benzhidroksamske kiseline s eterom, kao što je prikazano u Shemi 3.
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u kojoj je L odlazeća skupina kao što je halogen a baza je trietilamin ili diizopropilamin.
Sinteza spojeva formule I je nadalje ilustrirana slijedećim detaljnim primjerima.
Primjer 1
4-fluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-benzamid
(a) Priprava 4-fluor-2-(4-jod-2-metil-fenilamino)-benzojeve kiseline
U otopinu 3.16 g (0.0133 mol) 2-amino-5-jodtoluena u 5 ml tetrahidrofurana je pri -78°C dodano 10 ml (0.020 mmol) 2.0 M litij-diizopropamida u otopini tetrahidrofuran/hepotan/etilbenzena (Aldrich). Nastala zelena suspenzija je miješana intenzivno 15 minuta, nakon čega je dodana otopina 1.00 g (0.00632 mol) 2,4-difluorbenzojeve kiseline u 10 ml tetrahidrofurna. Reakcijska temperatura je ostavljena da polako poraste do sobne temperature, pri kojoj je smjesa miješana 2 dana. Otapalo reakcijske smjese je upareno pod sniženim tlakom. Ostatku je dodana vodena HCl (10%) i otopina je ekstrahirana diklormetanom, Organska faza je sušena (MgSO4), te je uparena u parnoj kupelji na mali volumen (10 ml) i ohlađena je na sobnu temperaturu. Obojena vlakna koja su nastala su izdvojena filtracijom, isparena heksanom i sušena u vakuum sušioniku (76°C, cca 10 mmHg), pri čemu je dobiveno 1.10 g (47%) željenog materijala, talište 224-229.5°C.
1H NMR (400 MHz, DMSO): δ 9.72 (s, 1H), 7.97 (dd, 1H, J=7.0, 8.7 Hz) 7.70 (d, 1H, J=1.5 Hz), 7.57 (dd, 1H, J=8.4, 1.7 Hz), 7.17 (d, 1H, J=8.2 Hz) 6.61-6.53 (m, 2H), 2.18 (s, 3H);
13C NMR (100 Hz, DMSO):169,87, 166.36 (d, JC-F=249.4 Hz), 150.11 (d, JC-F=11.4 Hz),139.83, 138.49, 136.26 (d, JC-F=11.5 Hz) 135.07, 125.60, 109.32, 104.98 (d, JC-F=21.1 Hz) 99.54 (d, JC-F=26.0 Hz), 89.43, 17.52;
19F NMR (376 MHz, DMSO): -104.00 do - 104.07 (m);
IR(KBr) 1670 (C=O istezanje) cm-1.
MS (CI (M+1=372.
Analiza izračunata za C14H11FIBO2:
C, 45.31; H, 2.99; N,3.77;
Nađeno: C, 45.21; H, 2.77; N, 3.64.
(b) Priprava 4-fluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-benzamida
U otopinu 4-fluor-2-(4-jod-2-metil-fenilamino)-benzojeve kiseline (0.6495 g, 0.001750 mol), O-(tetrahidro- 2H-piran- 2-il)-hidroksilamina (0.2590 g, 0.002211 mol) i diizopropletilamina (0.40 ml, 0.0023 mol) u 31 ml ekvimolarne smejse tetrahidrofuran/dikloretana je izravno dodano 1.18 g (0.00227 mol) čvrstog PyBOP ([benzo triazolil oksi] tripiridino-fosfonijev heksafluorfosfat, Advanced Chem Tech). Reakcijska smjesa je miješana 30 minuta, nakon čega je uparena u vakuumu. Smeđem ulju je dodana 10% vodena klorovodična kiselina. Suspenzija je ekstrahirana eterom. Organski ekstrakt je pran 10% natrijevim hidroksidom, a zatim slijedećom količinom 10% klorovodične kiseline, te je sušen (MgSO4) i uparen u vakuumu, pri čemu je dobiveno 1.0 g svjetlosmeđe pjene. Ovaj međuprodukt je otopljen u 25 ml etanolnog klorovodika i otopina je ostavljena da stoji pri sobnoj temperaturi 15 minuta. Reakcijska smjesa je uparena u vakuumu, a smeđe ulje je čišćeno flash kromatografijom na silikagelu. Eluiranjem s diklormetanom → diklormetan /me-tanolom (166:1) dobiveno je 0.2284 g svjetlosmeđeg viskoznog ulja. Obradom s pentan/heksanom i sušenjem pri visokom vakuumu dobiveno je 0.1541 g (23%) obojene pjene, talište 61-75°C.
1H NMR (400 MHz, DMSO): δ 11.34 (s, 1H), 9.68 (s, 1H), 9.18 (s, 1H), 7.65 (d, 1H, J=1.5 Hz), 7.58 (dd, 1H, J=8.7, 6.8 Hz), 7.52 (dd, 1H, J=8.4, 1.9 Hz), 7.15 (d, 1H, J=8.4 Hz), 6.74 (dd, 1H, J=11.8, 2.4 Hz), 6.62 (ddd, 1H, J=8.4, 8.4, 2.7 Hz), 2.18 (s, 3H);
13C NMR (100 MHz, DMSO): 165.91, 164.36 (d, JC-F=247.1 Hz), 146.78, 139.18, 138,77, 135.43, 132.64, 130.60 (d, JC-F=11.5 Hz), 122,23, 112.52, 104.72 (d, JC-F=22.1 Hz), 100.45 (d, JC-F=21.1 Hz), 99.54 (d, JC-F=25.2 Hz), 86.77, 17.03;
19F NMR (376 MHz, DMSO): -107.20 do - 107.27 (m);
IR(KBr) 3307 široka vrpca, O-H istezanje), 1636 (C=O istezanje) cm-1.
MS (Cl (M+1=387.
Analiza izračunata za C14H12FIN2O2:
C, 43.54; H, 3.13; N, 7.25;
Nađeno: C, 43.62; H, 3.24; N, 6.98.
Primjer 2
4-Brom-3,4-difluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-benzamid
(a) Priprava 4-brom-2,3,4-trifluorbenzojeve kiseline
Otopina 1-brom-2,3,4-trifluorbenzena (Aldrich, 99.9%; 5.30 g, 0.0249 mol) u 95 ml bezvodnog tetrahidrofurana je ohlađena na -78°C i dodano je 12.5 ml 2.0 M litij-diizopropamida u otopini heptan/tetrahidrofuran/etilbenezena (Aldrich).Smjesa je miješana 1 sat i prenošena je pomoću kanule u 700 ml i eterske otopine ugljičnog dioksida koja je ohlađena na -78°C. Ledena kupelj je uklonjena, reakcijska smjesa je miješana 18 sati pri sobnoj temperaturi. U reakcijsku smjesu je ulivena razrijeđena (10%) vodena otopina klorovodične kiseline (oko 500 ml) i smjesa je zatim uparena u uparivaču do krutine. Čvrsti produkt je razdijeljen između dietil-etera (150 ml) i aq. HCl (330 ml, pH 0). Vodena faza je ekstrahirana drugim obrokom (100 ml) dietil-etera i spojeni eterski ekstrakti su prani 5% vodenom otopinom natrijevog hidroksida (200 ml) i vodom (100 ml, pH 12). Spojeni alkilni vodeni ekstrakti su zakiseljeni do pH 0 koncentriranom klorovodičinom kiselinom. Nastala suspenzija je ekstrahirana eterom (2x200 ml). Spojeni organski ekstrakti su sušeni (MgSO4), upareni u vakuumu i podvrgnuti visokom vakuumu do postizanja konstantne mase, pri čemu je dobiveno 5.60 g (iskorištenje 88%) obojenog praška, talište 139-142.5°C.
1H NMR (400 MHz, DMSO): δ 13.97 (širok s, 1H), 8.00-796 (m, 1H);
13C NMR (100 MHz, DMSO): δ 162.96, 129.34, 118,47 104.54 (d, JC-F=22.9 Hz);
19F NMR (376 MHz, DMSO): -120.20 do - 120.31 (m); -131.75 - 131.86 (m); -154.95 - 155.07 (m);
IR(KBr) 1696 (C=O istezanje) cm-1.
MS (Cl (M+1=255.
Analiza izračunata za C14H21BrF2O2:
C, 32.97; H, 0.79; N, 0.00; Br, 31.34; F, 22.35;
Nađeno: C, 33.18; H, 0.64; N, 0.01; Br, 30.14; F, 22.75;
(b) Priprava 5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)benzojeve kiseline
U otopinu 1.88 g (0.00791 mol) 2-amino-2-jodtoluena u 10 ml tetrahidrofurana je pri -78°C uz miješanje dodano 6 ml (0.012 mol) 2.0 M litijevog diizopropoksida u otopini tetrahidrofuran/heptan/etoilbenzena (Aldrich). Nastala zelena suspenzija je miješana intenzivno 10 minuta, nakon čega je dodana otopina 1.00 g (0.00392 mol) 5-brom-2,3,4-trifluorbenzojeve kiseline u 15 ml tetrahidrofurana. Ledena kupelj je zatim uklonjena, i reakcijska smjesa je miješana 18 sati. Smjesa je uparena, a ostatku je dodano 100 ml razrijeđene (10%) vodena klorovodične kiseline. Nastala suspenzija je ekstrahirana eterom (2x150 ml) i spojeni organski ekstrakti su sušeni (MgSO4), i upareni u vakuumu, pri čemu je dobivena narančasta krutina. Krutina je razmuljena u vrijućem diklormetanu, ohlađena je na sobnu temperaturu i izolirana je filtracijom. Krutina je isparena diklormetanom i sušena u vakuum sušioniku (80°C), pri čemu je dobiveno 1.39 g (76%) žutozelenog praška, talište 259.5-262°C).
1H NMR (400 MHz, DMSO): 9.03 (s, 1H), 7.99 (dd, 1H, J=7.5, 1.9 Hz), 7.57 (dd, 1H, J=1.5 Hz), 7.42 (dd, 1H, J=8.4, 1.7 Hz), 6.70 (dd, 1H, J=8.4, 6.0 Hz, 2.24 (s, 3H);
19F NMR (376 MHz, DMSO): -123.40 do - 123.47 (m); -139.00 do - 139.14 (m);
IR(KBr) 1667 (C=O istezanje) cm-1.
MS (Cl (M+1=469.
Analiza izračunata za C14H9F2INO2:
C, 35.93; H, 1.94; N, 2.99; Br, 17.07; F, 8.12; I, 27,11;
Nađeno: C, 35.15; H, 1.91; N, 2.70; Br, 16.40; F, 8.46; I, 26.05
(b) Priprava 4-brom-3,4-difluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)benzamida
U otopinu 5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)benzojeve kiseline (0.51 g, 0.0011 mol), O-(tetrahidro- 2H- piran-2-il)hidroksilamina (0.15 g, 0.0013 mol) i diizopropletilamina (0.25 ml, 0.0014 mol) u 20 ml ekvimolarne smjese tetrahidrofuran/dikloretan je izravno dodano 0.06794 g (0.001306 mol) čvrstog PyBOP Advanced Chem Tech). Reakcijska smjesa je miješana 10 minuta pri 24°C, a zatim je uparena u vakuumu. Ostatak je suspendiran u 100 ml 10% vodene otopine klorovodične kiseline. Suspenzija je ekstrahirana s 125 ml dietil-etera. Eterski sloj je odvojen, pran sa 75 ml 10% vodene otopine natrijevog hidroksida, a zatim sa 100 ml razrijeđene kiseline. Eterska otopina je sušena (MgSO4) i uparena u vakuumu, pri čemu je dobiveno 0.62 g (100%) obojene pjene.
Pjena je otopljena u oko 15 ml metalnog klorovodika. Nakon 5 minuta je otopina uparena u vakuumu do ulja, a ulje je čišćeno flash kromatogradijom na silikagelu. Eluiranjem s diklormetanom → diklormetan/metanolom (99:1) dobiveno je 0.2233 g (42%) žutog praška. Prašak je otopljen u dietil-eteru i pran razriješenom otopinom klorovodične kisleine. Organska faza je sušena (MgSO4) i upareno je u vakuumu, pri čemu je dobiveno 0.2000 g pjene. Ovaj produkt je razmuljen u pentanu, pri čemu je dobiveno 0.1525 g praška koji je ponovo čišćen flash kromatografijom. Eluiranjem s diklormetanom dobiveno je 0.0783 (15%) analitički čistog spoja iz naslova, talište 80-90°.
1H NMR (400 MHz, DMSO): δ 11.53 (s, 1H), 9.38 (s, 1H), 8.82 (s, 1H), 7.70 (dd, 1H, J=7.0, 1.9 Hz), 7.53 (s, 1H), 7.37 (dd, 1H, J=8.4, 1.9 Hz), 6.55 (dd, 1H, J=8.2, 6.5 Hz), 2.22 (s, 3H);
19F NMR (376 MHz, DMSO): -126.24 do - 126.29 (m), -137.71 do 137.77 (m);
IR(KBr) 3346 široka vrpca, O-H istezanje), 1651 (C=O istezanje) cm-1.
MS (Cl (M+1=484.
Analiza izračunata za C14H120F2IN2O2:
C, 34.814; H, 2.09; N, 5.80;
Nađeno: C, 34.53; H, 1.73; N, 5.52.
Primjeri od 3 do 12, te od 78 do 102 u donjoj tablici pripravljeni su p općim postupcima iz Primjera 1 i 2.
Primjeri 13 - 77
Primjeri od 13 do 77 koriste kombinacijsku sintetsku metodologiju, a reakcijom odgovarajuće supstituirane fenio amino benzojeve kiseline (npr. kao što je prikazano u Shemi 1) i hidroksilamina (npr. R6-NH-O-R7). Opće metode su slijedeće:
U 0.8 ml “autosampler” posudice u metalnom bloku je dodano 40 μL 0.5 M otopine kiseline u DMF i 40 μL hidroksilamina (2M otopina u Hunigovoj bazi u 1M amin u DMF). U posudicu je dodano 50μL svježe pripravljene 0.5M otopine PyBrop. Reakcija je ostavljena da stoji 14 sati.
Reakcijska smjesa je prenešena u posudicu od 2 drama i razrijeđena je 2 ml etil-acetata. Organski sloj je pran s 3 ml destilirane vode i vodeni sloj je pran ponovo s 2 ml etil-acetata. Spojeni organski slojevi su upareni do suha u digestoru.
Ostatak je obrađen s 2 ml 50%acetonitrila u vodi injektiran je na smipreparativnu kolonu reverzne faze (10 mm x 25 cm, 5 μM sferični silikagel, veličina pora 115A derivatizirana s C-18 kolone, uzorak je eluiran pri protoku od 4.7 ml/min s linearnim porastom acetonitrila do 100% kroz 8.5 minuta). Frakcije su sakupljene nakon promatranja kod 214 nM. Željene frakcije su uparene korištenjem Zymark Turbovap. Produkt je otopljen u kloroformu i prenešen je u prethodno izvaganu posudu, otapalo je upareno i vagano je ponovo da se odredi iskorištenje. Strukture su potvrđene spektroskopski.
Primjeri 3-102
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Spojevi iz izuma su korisni u tretmanu karcinoma i ostalih proliferativnih bolesti zbog njihove selektivne inhibicije proteina MEK1 i MEK2 kiznaza koje imaju dvojnu specifičnost. Spoj iz izuma je procijenjen u brojnim biološkim testovima koji se normalno koriste za utvrđivanje inhibicije proteina i kinaze, te za mjerenje mitogenog odgovora na takvu inhibiciju.
Enzimski testovi
Kaskadni test za inhibitore puta MAP kinaze
Ugradnja 32P u mielinski bazični (MBP) je testirana u prisutnosti proteina fuzioniranog na glutation S-transferazu koji sadrži p45MAP (GST-MAPK) i proteina fuzioniranog na glutation S-transferazu koji sadrži p45MEK (GST-MEK). Otopina za test je sadržavala 20 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM MnCl2, 1 1mM EGTA, 50 mM [γ32P]ATP, 10 μm GST-MEK, 0.5 μg GST-MAPK i 40 μg MBP u konačnom volumenu od 100 μL. Reakcija je prekinuta nakon 20 minuta dodatkom tilkloroctene kiseline i filtrirana je preko GF/C filtera. 32P zaostao na filteru je određen korištenjem 1205 Betaplate. Sposobnost spojeva da inhibiraju ugradnju 32 P je procijenjena pri 10 μM.
Da bi se pokazalo inhibiraju li spojevi GST-MEK ili GST-MAPK, korištena su dva dodatna protokola. U prvom protokolu, spojevi su dodani u epruvete koje sadrže GST-MEK, a zatim je dodan GST-MAPK, MBP i [γ32P]ATP. Spojevi koji su pokazali aktivnost u oba protokola su označeni kao MAP inhibitori, dok su spojevi koji su pokazali aktivnost samo u prvom protokolu označeni kao MEK inhibitori.
In vitro test za MAP kinazu
Inhibitorska aktivnost je također dokazana izravnim testom. Za MAP kinazu je 1 μg GST-MAPK inkubiran 15 minuta s 40 μg MPB pri 30°C u konačnom volumenu od 50 μl koji sadrži 50 mM Tris (pH 7.5) 10 μM 10 MgCl2, 1 μM EGTA, i 10 μM [γ32P]ATP. Reakcija je prekinuta dodatkom Laemmli SDS uzorka pufera i fosforilirani MBP je razdvojen elektroforezom na 10% poliakrilamidnom gelu. Radioaktivnost ugrađena u MBP je određena autoradiografijom, a zatim izrezivanjem vrpci, te scintilacijskim brojanjem.
In vitro test za MEK
Za procjenu izravne MEK aktivnosti, 10 μg GST-MEK1 je inkubiran s 5 μg proteina fuzioniranog na glutation S-transferazu koji sadrži p44MAP kinazu s mutacijom alanina u lizin u položaju 71 (GST-MAPK-KA). Ova mutacija eliminira aktivnost kinaze prema MAPK, tako da aktivnost kinaze potječe samo od MEK. Inkubirano je 15 minuta pri 30°C u konačnom volumenu od 50 μl koji sadrži 50 mM Tris (pH 7.5), 10 μM 10 MgCl2, 2 μM EGTA, i 10 μM [γ32P]ATP. Reakcija je prekinuta dodatkom Laemmli SDS uzorka pufera i fosforilirani GST-MAPK-KA je razdvojen elektroforezom na 10% poliakrilamidnom gelu. Radioaktivnost ugrađena u GST-MAPK-KA je određena autoradiografijom, a zatim izrezivanjem vrpci, te scintilacijskim brojanjem. Nadalje korišten je umjetno aktivirani MEK mutacijom serina umjesto glutamata u položaju 218 i 222 (GST-MEK-2E). Kada su ta mjesta fisforilirana, aktivnost MEK je povećana. Fosforilacijom tih mjesta se može imitirati mutacija serinski ostatak glutamatom. Za ovaj test inkubirano je 5 μg GST-MEK-2E s 5 μg GST-MAPK-KA 15 minuta pri 30°C u istom reakcijskom puferu kao što je gore opisano. Reakcija je prekinuta i analizirana kao gore.
Test za MAP kinaze u cijelim stanicama
Da bi se odredilo jesu li spojevi sposobno blokirani aktivaciju MAp kinaze u cijelim stanicama, korišten je slijedeći protokol: Stanice su uzgajane na ploči s jažicama od konfluencije. Stanicama je zatim odstranjen serum preko noći. Stanice su izložene željenoj koncentraciji spoja ili vehikula (DMSO) kroz 30 minuta, nakon čega slijedi dodatak faktora rasta, npr. PDGE (100 ng/ml). Nakon 5 minuta tretmana s faktorom rasta, stanice su prane PBS, te su lizirane u puferu koji se sastojao od 70 mM NaCl, 10 mM HEPESE (pH 7.4), 50 mM glicerol-fosfata i 1% Triton X-100. Lizat je pročišćen centrifugiranjem pri 13000xg kroz 10 minuta. Pet mikrograma nastalog supernatanta je inkubirano s 10 μg proteina-2-vezanom uz mikrotubule (Map2) kroz 15 minuta pri 30°C u konačnom volumenu od 25 μl koji sadrži 50 mM Tris (pH 7.4), 10 mM MgCl2, 2mM EGTA i 30 μM [γ32P]ATP. Reakcije su zaustavljene dodatkom Laemmli uzorka pufera. Fosforiliranom Map2 koji je razdvojen elektroforezom na 7.5% akrilamidnom gelu je ugrađena radioaktivnost određena atoradiografijom, a zatim izrezivanjem vrpci, te scintilacijskim brojanjem.
Imunoprecipitacija i imunoblotiranje pomoću antitijela na antifosfotirozin
Da se odredi stupanj fosforilacije tirozina celularne MAp kinaze, stanice su lizirane, endogena MAP kinaza je imunoprecipirtirana specifičnim antitijelima i nastala imunoprecipitat je analiziran na prisustvo fosfotirozina na slijedeći način: konfluentnim stanicama je uklonjen serum preko noći i djelovano je na njih spojevima i faktorom rasta, kao što je gore opisano. Stanice su zatim ostrugane u taložene pri 13000xg kroz 2 minute. Nastali stanični talog je ponovo suspendiran i otopljen u 100 μ 1% SDS koji sadrži 1 mM NaVO4. Nakon naizmjeničnog zagrijavanja do vrijenja i vrtloženja, a da se denaturira stanični protein, dodano je 900 μl RIPA pufera (50 mM Tris (pH 7.4), 150 mM NaCl, 1% Triton X-100, 0.1% deoksikolata i 10 mM EDTA). Toj smjesi je dodan 60 μl Pansorin stanica, a da očiste lizat od nespecifično vezanih proteina. Smjesa je inkubirana 15 minuta pri 4°C, te je centrifugirana pri 30000xg kroz 10 minuta. Nastali supernatant prenešen je novu epruvetu i inkubiran je s 10 μl poliklonalnog antiseruma na fragemt MAP kinaze najmanje 1 sat pri 4°C. Sedamdeset mikrolitara smjese proteina G vezanog na aragozu i protein A su dodani, te je inkubacija nastavljena dodatnih 30 minuta pri 4°C. Načinjene su kuglice centrifugiranjem pri 13000xg kroz 5 minuta i prane su tri puta s 1 ml RIPA pufera. Leammli pufer za uzorak je dodan talogu. Smjesa je prokuhana 5 minuta, te otopljena u 10% akrilnom gelu. Proteini na gelu su prenešeni na nitroceluloznu membranu i nespecifična mjesta vezivanja na membrani su blokirana inkubacijom s 1% ovalbuminom i 1% albuminom goveđeg seruma u TBST (150 mM NaCl, 10 mM i Tris (pH 7.4) i 0.05% Tween 20). Membrane su inkubirane s komercijalno pristupačnim antitijelom specifičnim za fosfotiozin. Antitijelo vezano na membranu je detektirano inkubacijom s 125I-proteinom A, nakon čega slijedi autoradigrafija.
Testovi rasta stanica
Ugradnja 3H-timidina
Stanice su nanešene na ploče s jaživama i ostavljene rasti do blizu konfluencije. Medij je uklonjen i zamijenjen medijem rasta koji sadrži 1% albumina goveđeg seruma. Nakon 24 sata uklanjanja seruma, dodani su spojevi i specifični faktori rasta, te je inkubacija nastavljena dodatnih 24 sata. Tijekom zadnjih 2 sata 3H-timidin je dodan u medij. Da bi se zaustavila inkubacija, medij je uklonjen u stanični slojevi su prani dva puta ledenim fosfatnim puferom u fiziološkoj otopini. Nakon zadnjeg ispiranja, dodana je ledena 5% trikloroctena kiselina i stanice su inkubirane 15 minuta pri sobnoj temperaturi. Otopina trikloroctene kiseline je zatim uklonjena i stanični sloj je pran tri puta destiliranom vodom. Nakon zadnjeg ispiranja, stanice su otopljene dodatkom 2% dodecilsulfata. Radioaktivnost te otopine je određena scintilacijskim brojanjem.
U 3T3-L1 adipocitne stanice u kojima inhibicija blokira aktivaciju MAPK inzulinom s IC50 do 3μM, nije imao učinka na inzulinom stimulirano unošenje radioobilježenog 2-deoksiglukoze ili na inzulinom simuliranu sintezu lipida ili glikogena pri 10 μM koncentraciji. Ovim je prikazano da inhibitor pokazuje selektivnost između mitogenog i metaboličnog efekta inzulina i pokazuje da će inhibitor pokazati manju toksičnost nego inhibitor koji ne pokazuje tu iznenađujuću selektivnost.
Rast jednostaničnog sloja
Stanice su nanešene na ploče s jažicama pri 10 do 20000 stanica/ml. Četrdeset osam sati nakon nanošenja, dodani su spojevi u medij rasta i inkubacija je nastavljena 2 slijedeća dana. Stanice su zatim uklonjene iz jažica inkubacijom s tripsinom i brojane su Coulter brojačem.
Rast u mekom agaru
Stanice su nanešene u posude od 35 mm pri 5 do 10000 stanica/posudi korištenjem medij rasta koji sadrži 03% agar. Nakon hlađenja da se agar stvrdne, stanice su prenešene u inkubator pri 37°C. Nakon 7 do 10 dana rasta, vidljive kolonije su ručno brojane pomoću mikroskopa za seciranje. Dodatni eksperiment je pokazao da spojevi iz izuma inhibiraju MEK a ne MAP kinaze. Eksperimenti u kojima se promatra fosforilacija kinaze u mutantima koji su defektni na MAP kinazu kao supstrat (tako da ne može doći do autofosforilacije MAP kinaze, što bi kompliciralo interpertaciju), dokazuju da inhibitor inhibira MEK s IC50 koji je u suštini identičan onom koji je dobiven u kastkadnom testu.
Kinetička analiza pokazuje da spojevi iz izuma nisu kompetitivni s ATP. Stoga se oni ne vežu na mjesto vezivanja ATP enzima, što je vjerojatno objašnjenje zašto ovi spojevi ne pokazuju nespecifilnu inhibiciju aktivnosti kinaze koja je tipična za većinu inhibitora kinaze, a koji se vežu na mjesto vezivanja ATP, pa su stoga ATP kompetitivni.
In vitro i in vivo biološka aktivnost nekih predstavnika spoja formule I po prethodnim testovima je prikazana u Tablici 1. Podaci za nekoliko poznatih spojeva su također prikazani.
Tablica 1.
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Slijedeći spojevi, a koji su prikazani u U.S. Patentu br. 5,155,110 su procijenjeni u prethodnim testovima, i svaki spoj pokazuje malu ili nikakvu inhibitorsku vrijednost.
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Primjer 103
Spoj iz primjera 95, 2-(2-klor-4-jod-fenilamino)-N-ciklopropilmetoksi-3,4-difluor-benzamid, je procijenjen u životinjama u koje je implementiran tomor crijeva glodavaca 26/klon 10. Ženskama CD2F1 miševi (NCl: Charles River, Kingston) s subkutalno implementirani tumorski fragmenti (približno 30 mg) u podruju desne aksile dana 0. Spoj j+iz Primjera 95 je dan intraperitonalno (IP) ili otalno (PO) dana 1 do 14 naon inplementacije, a ukupno 14 dana (6 miševa po skupini). Vehikuli za testirani spoj za kontrolne životinje su bili 10% EtOH010% Cremophor-EL (Sigma)/80% H2O, pH 5.0. Volumeni tumora su bilježen tri puta tjedno mjerenjem duljine i pirine pojedinog tumora i izračunavanjem mase u miligramima prema formuli (axb2)/2, pri čemu su a i be duljina i širina tumora. Postotak tretirane/kontrolnoj skupini (T/C) je izračunat na bazi omjera medijalnog volumena tumora tretiranih tumora u usporedbi s medijalnim volumenom kontoliranih životinja na određene dane mjerenja.
U procjeni u kojoj je spoj iz Primjera 95 dan IP, doze su bile 200, 124, 77 i 48 mg/kg/danu. Spoj iz izuma inhibira rast tumora 59% do 100%, a kako je izmjereno dana 15. Medijalna veličina kontroliranih tumora dana 15 je bila 1594 mg. Tablica 2 pokazuje broj smrti kod životinja u svakoj tretiranoj skupini, primjenu tjelesne težine prema kontrolnoj skupni i postotak inhibicije.
Tablica 2
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U testu u kojem je spoj iz Primjera 95 dan oralno, doze su bile 300, 186, 115 i 71 mg/kg/danu. Spoj iz izuma inhibira rast tumora 64% do 83%, a kako je izmjereno dana 17. Medijalna veličina kontroliranih tumora dana 17 je bila 1664 mg. Tablica 3 pokazuje broj smrti kod životinja u svakoj tretiranoj skupini, primjenu tjelesne težine prema kontroliranoj skupini, postotak medijalnog volumena tumora tretiranje skupine prema kontrolnoj i postotak inhibicije.
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Prethodni test pokazuje da su spojevi iz izuma Formule I posebno korisni u tretmanu karcinoma kao što je karcinom debelog crijeva. Spojevi su posebice pogodni za korištenje u kombinaciji s radijacijom, a za tretman i kontrolu karcinoma.
Spojevi iz izuma će biti korišteni u tretmanu osoba koje pate od karcinoma i ostalih proliferativnih bolesti, pa im je tretman potreban. Spojevi su idealni a tretman psorijaze, restenoze, autoimunih bolesti i ateroskleroze. Spojevi će se općenito koristiti kao farmaceutske formulacije u kojima je spoj Formule I prisutan u koncentraciji od oko 5% do oko 95% po masi. Spojevi mogu biti formulirani za uobičajeno oralno, parenteralno, topičko, rektalni ili slično davanje. Spojevi će biti furmulirani s uobičajenim razrjeđivačima, ekcipijensima i nosačima koji se obično koriste u medicini, primjerice s poliolima kao što je glicerol, etilen-glikolom, sorbitolom 70; mono- i desterima masnih kiselina i etilen-glikola. Škrobovi i šećeri kao što je kukuruzni škrob, saharoza, laktoza i slično se mogu koristiti za čvrste pripravke. Takve čvrste formulacije mogu biti u obliku tableta, vrećica, pilula, kapsula i slično. Mogu biti ugrađena sredstva za poboljšanje okusa kao što je pepermint i slično.
Tipične doze aktivnog spoja su one koje su učinkovite kod sisavaca u tretmanu karcinoma ili ostalih proliferativnih bolesti. Doze su općenito od oko 0,.1 mg po kilogramu tjelesne težine do oko 500 mg po kilogramu tjelesne težine. Takve doze će biti dane odjedanput do četiri puta na dan, ili koliko puta je potrebno za učinkovitost tretmana karcinoma, psorijaze ili ostalih proliferativnih bolesti.
Preferirana metoda davanja spoja iz izuma je oralna putem tableta kapsula, otopina ili sirupa. Druga metoda je parenteralno davanje, posebice putem intavenoznih otopina benzopirana u izotoničnoj fiziološkoj otopini ili 5% vodenoj glukozi.
Slijede tipične formulacije prikazane u izumu.
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Benzhidroksmska kiselina, laktoza i kukuruzni škrob (za miješanje) su pomiješani do homogenosti. Dodan je kukuruzni škrob (za pastu) suspendiran u 600 ml vode i zagrijavano je uz miješanje da se stvori pasta. Pasta je korištena da se dobiju granule od pomiješanih prašaka. Granule su propuštene kroz sito br. 8 sušene pri 120°C. Suhe granule su propuštane kroz sito br. 16. Smjesa je lubricirana s 1% magnezijevim stearatom i komprimirana u tablete. Tablete se daju sisavcima za inhibiciju MEK enzima i za tretman restenoze, ateroskleroze i psorijaze.
Primjer 105
Priprava oralnih suspenzija
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Otopina sorbitola je dodana u 40 ml destilirane vode u čemu je suspendiran derivat benzhidroksamske kiseline. Dodani su i otopljeni saharin, natrijev benzoat, okus i boja. Volumen je podešen na 100 ml destiliranom vodom. Svaki milimetar sirupa sadrži 5 mg spoja iz izuma. Sirup se daje sisavcima za tretman proliferativnih bolesti, posebice karcinoma dojke i karcinoma kože.
Primjer 106
Priprava parenteralnih otopina
U otopinu 100 ml propilen-glikola i 200 ml vode za injekciju dodano je 20.0 g 4-fluor-N-hidroksi- 2-(4-jod- 2- metil-fenilamino)-benzamida. Volumen otopine je podešen na 1000 ml dodatkom vode za injekciju. Formulacija je sterilizirana zagrijavanjem, punjena u ampule od 50 ml, a svaka sadrži 1.0 ml (40 mg 4-fluor-N- hidroksi- 2- (4- jod- 2- metil-fenilamino)-benzamida), te su zataljene pod dušikom.
Spojevi iz izuma tako formulirani će biti dani sisavcima koji imaju potrebu za tretmanom proliferativnih poremećaja, kao što je karcinom, psorijaza, restenozam ateroskleroza i autoimune bolesti, a u dozi učinkovitoj za tretman tih uvjeta. "Autoproliferativna količina" spoja iz izuma je ona količina spoja koja inhibira ili smanjuje stupanj proliferacije promatranih stanica. Tipični karcinomi koji se mogu tretirati su prema ovom izumu karcinom dojke, karcinom debelog crijeva, karcinom prostate, karcinom kože i slično. Spojevi su pogodni u tretmanu psorijaze, restenoze i ateroskleroze, te za inhibiciju MEK enzima, posebice MEK1 i MEK2.
Sve što je potrebno je dati sisavcu količinu spoja iz izuma koja inhibira MEK. "Količinu koja inhibira MEK" spoja iz izuma je količina koja kad je dana sisavcima uzrokuje mjerljivu inhibiciju MEK enzima. Tipična količina koja inhibira MEK će biti od oko 0.1 μg do oko 500 mg aktivne tvari po kilogramu tjelesne težine. Za tretman gore spomenutih proliferativnih bolesti, tipične doze će biti od oko 0.1 do oko 50 mg/kg, normalno dane od jedanput do četiri puta na dan.
Claims (32)
1. Spojevi definirani formulom I
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naznačeno time da:
R1 jeste vodik, hidroksi, C1-C8 alkil, C1-C8-alkoksi, halogen, trifluormetil ili CN;
R2 jeste vodik;
R3, R4 i R5 neovisno jesu vodik, hidroksi, halogen, trifluormetil, C1-C8 alkil, C1-C8 alkoksi, nitro, CN ili (O ili NH)m-(CH2)n-R9, pri čemu R9 jeste vodik, hidroksi, CO2H ili NR10R11;
n jeste od 0 do 4;
m jeste 0 ili 1;
R10 i R11 neovisno jesu vodik, C1-C8 alkil, ili uzeti zajedno s dušikom na koji su vezani tvore tro- do deseteročlani prsten koji može sadržavati jedan, dva ili tri dodatna heteroatoma koji su odabrani od: O, S, NH, ili N-C1-C8 alkil;
R6 jeste vodik C1-C8 alkil, -CO-C1-C8 alkil, aril, aralkil ili C3-C10 cikloalkil,
R7 je vodik C1-C8 alkil, C2-C8 alkenil, C2-C8 alkinil, C3-C10 (cikloalkil ili ciikloalkil koji ima heteroatom koji je odabran od O, S ili NR9); ili R6 i R7 uzeti zajedno s N-O na koji su vezani, tvore petero- do deseteročlani prsten koji može sadržavati jedan, dva ili tri dodatna heteroatoma koji su odabrani od: O, S ili NR10R11;
2. Spoj prema patentnom zahtjevu 1, naznačeno time da R1 jeste C1-C8 alkil ili halogen.
3. Spoj prema patentnom zahtjevu 2, naznačeno time da R6 jeste vodik.
4. Spoj prema patentnom zahtjevu 3, naznačeno time da R1 jeste metil.
5. Spoj prema patentnom zahtjevu 4, naznačeno time da ima formulu.
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6. Spoj prema patentnom zahtjevu 5, naznačeno time da R4 jeste fluor, a R3 i R5 jesu vodici.
7. Spoj prema patentnom zahtjevu 6, naznačeno time da jeste:
4-fluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-benzamid,
4-fluor-2-(4-jod-2-metil-fenilamino)-N-(metoksi)- benzamid,
4-fluor-2-(4-jod-2-metil-fenilamino)-N-(prop-2-iniloksi)-benzamid,
4-fluor-2-(4-jod-2-metil-fenilamino)-N-(2-fenoksietoksi)-benzamid,
4-fluor-2-(4-jod-2-metil-fenilamino)-N-(2-tienilmetoksi)-benzamid,
4-fluor-2-(4-jod-2-metil-fenilamino)-N-(prop-2-eniloksi)-benzamid,
4-fluor-2-(4-jod-2-metil-fenilamino)-N-(ciklopropilmetoksi)-benzamid,
4-fluor-2-(4-jod-2-metil-fenilamino)-N-(ciklopentiloksi)-benzamid ,
4-fluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-N-izopropil-benzamid te
4-fluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-N-ilmetil-benzamid.
8. Spoj prema patentnom zahtjevu 5, naznačeno time da R3 i R4 jesu fluor, a R5 jeste vodik.
9. Spoj prema patentnom zahtjevu 8, naznačeno time da jeste:
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(3-furilmetoksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-etoksi-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(but-2-eniloksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(ciklopropilmetoksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(1-metilprop-2-iniloksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(3-fenilprop-2-iniloksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(3-metil-5-fenilpent-2-en-4-iniloksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(prop-2-iniloksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(propoksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(ciklobutiloksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(2-tienilmetoksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(2-metil-prop-2-eniloksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(feniloksietoksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(but-2-eniloksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(but-3-iniloksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(ciklopentiloksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(3-(2-fluorfenil)-prop-2-iniloksi)-benzamid,
3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(tetrahidropiran-2-iloksi)-benzamid,
3,4-difluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-benzamid,
3,4-difluor-2-(2-klor-4-jod-fenilamino)-N-ciklobutilmetoksi-benzamid,
3,4-difluor-2-(2-klor-4-jod-fenilamino)-N-(tetrahidro-piran-2-iloksi)-benzamid, te
3,4-difluor-2-(2-klor-4-jod-fenilamino)-N-ciklopropilmetoksi-benzamid.
10. Spoj prema patentnom zahtjevu 5, naznačeno time da R3 i R4 jesu fluor, a R5 jeste brom.
11. Spoj prema patentnom zahtjevu 8, naznačeno time da jeste:
5-brom-3,4-difluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-3,4-difluor-(4-jod-2-metil-fenilamino)-N-(n-propoksi)-benzamid,
5-brom-3,4-difluor-N-(furan-3-ilmetoksi-2-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-N-(but-2-eniloksi)-3,4-difluor-2-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-N-butoksi-3,4-difluor-2-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(3-metil-but-2-eniloksi)-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(3-metil-pent-2-en-4-iniloksi)benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-[5-(3-metoksi-fenil)-3-metil-pent-2-en-4-iniloksi]-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(prop-2-iniloksi)-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-[3-(3-metil-fenil)-prop-2-iniloksi]-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-tiofen-2-ilmetoksi)-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(piridin-3-ilmetoksi)-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(t3-(2-fluorfenil)-prop-2-iniloksi)-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(etoksi)-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(ciklopropil-metoksi)-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(but-3-iniloksi)-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-2-piperidin-1-iletoksi)-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(tetrahidro-piran-2-iloksi)-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-(2-morfolin-4-iletoksi)-benzamid,
5-brom-N-(2-dietilamino-etoksi)-3,4-difluor-2-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-3,4-difluor-2-(4-jod-2-metil-fenilamino)-N-izobutoksi-benzamid,
5-brom-N-cikloheksilmetoksi-3,4-difluor-2-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-N-ciklopentilmetoksi-3,4-difluor-2-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-N-ciklobutilmetoksi-3,4-difluor-2-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-2-(2-klor-4-jod-fenilamino)-N-(2-dimetilamino-etoksi)-3,4-difluor-benzamid monohidroklorid,
5-brom-N-(2-dimetilamino-propoksi-3,4-difluor-2-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-2-(2-klor-4-jod-fenilamino)-3,4-difluor-2-N-hidroksi-benzamid monohidroklorid,
5-brom-2-(2-klor-4-jod-fenilamino)-3,4-difluor-2-N-(tetrahidro-piran-2-iloksi)-benzamid, te
5-brom-2-(2-klor-4-jod-fenilamino)-N-ciklopropilmetoksi-3,4-difluor-benzamid.
12. Spoj prema patentnom zahtjevu 5, naznačeno time da R3 i R4 jesu vodici, a R5 jeste halogen.
13. Spoj prema patentnom zahtjevu 12, naznačeno time da jeste:
5-klor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-benzamid,
5-klor-2-(4-jod-2-metil-fenilamino)-N-(tetrahidro-piran-2-iloksi)-benzamid,
5-klor-2-(4-jod-2-metil-fenilamino)-N-metoksi-benzamid,
5-klor-2-(4-jod-2-metil-fenilamino)-N-fenilmetoksi-benzamid,
5-fluor-2-(4-jod-2-metil-fenilamino)-N-fenilmetoksi-benzamid,
5-klor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-benzamid,
5-jod-2-(4-jod-2-metil-fenilamino)-N-fenilmetoksi-benzamid, te
5-jod-2-(4-jod-2-metil-fenilamino)-N-tetrahidro-piran-2-iloksi)-benzamid,
14. Spoj prema patentnom zahtjevu 4, naznačeno time da ima formulu.
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15. Spoj prema patentnom zahtjevu 14, naznačeno time da R3 i R4 jesu fluor, a R5 jeste vodik.
16. Spoj prema patentnom zahtjevu 15, naznačeno time da jeste:
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(3-fenil-prop-2-iniloksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(3-furilmetoksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(2-tienilmetoksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(but-3-iniloksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(2-metil-prop-2-eniloksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(but-2-eniloksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(metoksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(etoksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(ciklobutoksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(izopropoksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(2-fenoksietoksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(ciklopropil-metoksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(n-propoksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(1-metil-prop-2-iniloksi)-benzamid,
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(4,4-dimetilpent-2-iniloksi)-benzamid, te
3,4-difluor-2-(4-brom-2metil-fenilamino-N-(ciklopentoksi)-benzamid,
17. Spoj prema patentnom zahtjevu 1, naznačeno time da jeste:
3,4,5-trifluor-N-hidroksi-2-(4-jod-metil-fenilamino)-benzamid,
5-klor-3,4-difluor-N-hidroksi-2-(4-jod-metil-fenilamino-benzamid,
5-brom-3,4-difluor-2-(2-fluor-4-jod-fenilamino)-N-hidroksi-benzamid,
N-hidroksi-2-(4-jod-2-metil-fenilamino)-4-nitro-benzamid,
3,4,5-trifluor-2-(2-fluor-4-jod-fenilamino)-N-hidroksi-benzamid,
5-klor-3,4-difluor-2-(2-fluor-4-jod-fenilamino)-N-hidroksi-benzamid,
5-brom-2-(2-fluor-4-jod-fenilamino)-3,4-difluor-N-hidroksi-benzamid,
2-(2-fluor-4-jod-fenilamino)-N-hidroksi-4-nitro-benzamid,
2-(2-klor-4-jod-fenilamino)-3,4,5-trifluor-N-hidroksi-benzamid,
4-fluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-5-nitro-benzamid,
2-(2-klor-4-jod-fenilamino)-N-hidroksi-4-nitro-benzamid,
5-klor-2-(2-klor-4-jod-fenilamino)-3,4-difluor-N-hidroksi-benzamid,
5-brom-2-(2-brom-4-jod-fenilamino)-3,4-difluor-N-hidroksi-benzamid,
2-(2-klor-4-jod-fenilamino)-N-hidroksi-4-metil-benzamid,
2-(2-brom-4-jod-fenilamino)-3,4-trifluor-N-hidroksi-benzamid,
2-(2-brom-4-jod-fenilamino)-5-klor-3,4-difluor-N-hidroksi-benzamid,
2-(2-brom-4-jod-fenilamino)-N-hidroksi-4-nitro-benzamid,
4-fluor-2-(2-fluor-4-jod-fenilamino)-N-hidroksi-benzamid,
3,4,-difluor-2-(2-fluor-4-jod-fenilamino)-N-hidroksi-benzamid,
2-(2-klor-4-jod-fenilamino)-4-fluor-N-hidroksi-benzamid,
2-(2-klor-4-jod-fenilamino)-3,4-difluor-N-hidroksi-benzamid,
2-(2-brom-4-jod-fenilamino)-4-fluor-N-hidroksi-benzamid,
2-(2-brom-4-jod-fenilamino)-3,4-difluor-N-hidroksi-benzamid,
N-ciklopropilmetoksi-3,4,5-trifluor-2-(4-jod-2-metil-fenilamino)-benzamid,
5-klor-N-ciklopropilmetoksi-3,4-difluor-2-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-N-ciklopropilmetoksi-3,4-difluor-2-(2-fluor-4-jod-fenilamino)-benzamid,
N-ciklopropilmetoksi-2-(4-jod-2-metil-fenilamino)-4-nitro-benzamid,
N-ciklopropilmetoksi-3,4,5-trifluor-2-(2-fluor-4-jod-fenilamino)-4-benzamid,
5-klor-N-ciklopropilmetoksi-3,4-difluor-2-(2-fluor-4-jod-fenilamino)-4-benzamid,
5-brom-2-(2-klor-4-jod-fenilamino)-N-ciklopropilmetoksi-3,4-difluor-benzamid,
N-ciklopropilmetoksi-2-(2-fluor-4-jod-fenilamino)-4-nitro-benzamid,
2-(2-klor-4-jod-fenilamino)-N-ciklopropilmetoksi-3,4,5-trifluor-benzamid,
5-klor-2-(2-klor-4-jod-fenilamino)-N-ciklopropilmetoksi-3,4-difluor-benzamid,
5-brom-2-(2-brom-4-jod-fenilamino)-N-etoksi-3,4-difluor-benzamid,
2-(2-klor-4-jod-fenilamino)-N-etoksi-4-nitro-benzamid,
2-(2-brom-4-jod-fenilamino)-N-ciklopropilmetoksi-3,4,5-trifluor-benzamid,
2-(2-brom-4-jod-fenilamino)-5-klor-N-ciklopropilmetoksi-3,4-difluor-benzamid,
2-(2-brom-4-jod-fenilamino)-N-ciklopropilmetoksi-4-nitro-benzamid,
N-ciklopropilmetoksi-4-fluor-2-(2-fluor-4-jod-fenilamino)-benzamid,
2-(2-klor-4-jod-fenilamino)-N-ciklopropilmetoksi-4-fluor-benzamid,
2-(2-klor-4-jod-fenilamino)-N-ciklopropilmetoksi-3,4-difluor-benzamid,
2-(2-brom-4-jod-fenilamino)-N-ciklopropilmetoksi-4-fluor-benzamid,
2-(2-brom-4-jod-fenilamino)-N-ciklopropilmetoksi-3,4-difluor-benzamid,
N-ciklopropilmetoksi-3,4,5-trifluor-2-(4-jod-2-metil-fenilamino)-benzamid,
4-fluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-N-metil-benzamid,
2-(2-klor-4-jod-fenilamino)-N-hidroksi-4-nitro-benzamid,
3,4-difluor-(4-jod-2-metil-fenilamino)-N-(tetrahidro-piran-2-iloksi)-benzamid,
3,4-difluor-N-hidroksi-2-(4-jod-2-metil-fenilamino)-benzamid,
2-(2-klor-4-jod-fenilamino)-4-fluor-N-hidroksi-benzamid,
2-(2-klor-4-jod-fenilamino)-4-fluor-N-(tetrahidro-piran-2-iloksi)-benzamid,
2-(2-klor-4-jod-fenilamino)-N-ciklobutilamtoksi-3,4-difluor-benzamid,
2-(2-klor-4-jod-fenilamino)-3,4-difluor-N-(tetrahidro-piran-2-iloksi)-benzamid,
5-brom-2-(2-klor-4-jod-fenilamino)-N-(2-dimetilamino-etoksi)-3,4-difluor-benzamid monohidroklorid,
5-brom-2-N-(2-dimetilamino-propoksi)-3,4-difluor-(4-jod-2-metil-fenilamino)-benzamid,
5-brom-2-(2-klor-4-jod-fenilamino)-3,4,-difluor-N-hidroksi-benzamid,
5-brom-2-(2-klor-4-jod-fenilamino)-3,4,-N-(tetrahidro-piran-2-iloksi)-benzamid,
2-(2-klor-4-jod-fenilamino)-N-ciklopropilmetoksi-3,4,-difluor-benzamid,
18. Farmaceutska formulacija, naznačeno time da sadrži spoj iz patentnog zahtjeva 1, u smjesi s farmaceutski prihvatljivim ekcipijensom, razrjeđivačem ili nosačem.
19. Farmaceutska formulacija prema patentnom zahtjevu 18, naznačeno time da sadrži spoj formule
[image]
20. Farmaceutska formulacija prema patentnom zahtjevu 18, naznačeno time da sadrži spoj formule
[image]
21. Metoda inhibicije MEK enzima u sisavcima, naznačeno time da sadrži davanje spoja iz patentnog zahtjeva 1 u količini koja inhibira MEK.
22. Metoda tretmana sisavaca koji pate od proliferativne bolesti i imaju potrebu za tretomanom, naznačeno time da sadrži davanje spoja iz patentnog zahtjeva 1 u antiproliferativnoj količini.
23. Metoda prema patentnom zahtjevu 21, naznačeno time da je proliferativna bolest psorijaza, restenoza, autimuna bolest ili ateroskleroza.
24. Metoda prema patentnom zahtjevu 21, naznačeno time da je proliferativna bolest karcinom.
25. Metoda tretmana sisavaca koji pate od moždanog udara i imaju potrebu za tretmanom, naznačeno time da sadrži davanje učinkovite količine spoja iz patentnog zahtjeva 1.
26. Metoda tretmana sisavaca koji pate od zatajenja srca i imaju potrebu za tretmanom, naznačeno time da sadrži davanje učinkovite količine spoja iz patentnog zahtjeva 1.
27. Metoda tretmana sisavaca koji pate od hepatomegalije i imaju potrebu za tretmanom, naznačeno time da sadrži davanje učinkovite količine spoja iz patentnog zahtjeva 1.
28. Metoda tretmana sisavaca koji pate od kardiomegalije i imaju potrebu za tretmanom, naznačeno time da sadrži davanje učinkovite količine spoja iz patentnog zahtjeva 1.
29. Metoda tretmana sisavaca koji pate od dijabetesa i imaju potrebu za tretmanom, naznačeno time da sadrži davanje učinkovite količine spoja iz patentnog zahtjeva 1.
30. Metoda tretmana sisavaca koji pate od Alzheimerove bolesti i imaju potrebu za tretmanom, naznačeno time da sadrži davanje učinkovite količine spoja iz patentnog zahtjeva 1.
31. Metoda tretmana sisavaca koji pate od karcinoma i imaju potrebu za tretmanom, naznačeno time da sadrži davanje učinkovite količine spoja iz patentnog zahtjeva 1.
32. Metoda tretmana sisavaca koji pate od cistične fibroze i imaju potrebu za tretmanom, naznačeno time da sadrži davanje učinkovite količine spoja iz patentnog zahtjeva 1.
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CA3010236A1 (en) | 2016-01-20 | 2017-07-27 | Fate Therapeutics, Inc. | Compositions and methods for immune cell modulation in adoptive immunotherapies |
ES2878060T3 (es) * | 2016-07-28 | 2021-11-18 | Univ Johns Hopkins | Acidos hidroxámicos O-sustituidos |
WO2018106595A1 (en) | 2016-12-05 | 2018-06-14 | Fate Therapeutics, Inc. | Compositions and methods for immune cell modulation in adoptive immunotherapies |
CN107556201B (zh) * | 2017-09-08 | 2020-10-27 | 山西智创药研科技有限公司 | 一种制备间氨基苯酚的工艺方法 |
JP2022513089A (ja) * | 2018-11-20 | 2022-02-07 | エヌフレクション セラピューティクス インコーポレイテッド | 皮膚癌の処置のためのアリールアニリンおよびヘテロアリールアニリン化合物 |
JP2022510586A (ja) * | 2018-11-20 | 2022-01-27 | エヌフレクション セラピューティクス インコーポレイテッド | 皮膚障害の処置のためのチエニル-アニリン化合物 |
US20220143049A1 (en) | 2019-03-21 | 2022-05-12 | Onxeo | A dbait molecule in combination with kinase inhibitor for the treatment of cancer |
EP4054579A1 (en) | 2019-11-08 | 2022-09-14 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Methods for the treatment of cancers that have acquired resistance to kinase inhibitors |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
TW202342018A (zh) | 2022-03-04 | 2023-11-01 | 美商奇奈特生物製藥公司 | Mek激酶抑制劑 |
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US5525625A (en) * | 1995-01-24 | 1996-06-11 | Warner-Lambert Company | 2-(2-Amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran for treating proliferative disorders |
US6251943B1 (en) * | 1997-02-28 | 2001-06-26 | Warner-Lambert Company | Method of treating or preventing septic shock by administering a MEK inhibitor |
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1998
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HUP0003731A3 (en) | 2002-11-28 |
CO4940442A1 (es) | 2000-07-24 |
NO996491D0 (no) | 1999-12-27 |
CA2290506A1 (en) | 1999-01-14 |
PE97999A1 (es) | 1999-11-05 |
IS5256A (is) | 1999-11-19 |
AU8262798A (en) | 1999-01-25 |
CN1261877A (zh) | 2000-08-02 |
ES2229515T3 (es) | 2005-04-16 |
ATE277895T1 (de) | 2004-10-15 |
NO315271B1 (no) | 2003-08-11 |
CA2290506C (en) | 2005-12-27 |
UY25076A1 (es) | 1998-12-01 |
PL337698A1 (en) | 2000-08-28 |
IL132840A0 (en) | 2001-03-19 |
AU757046B2 (en) | 2003-01-30 |
DE69826662T2 (de) | 2005-02-17 |
JP2002511092A (ja) | 2002-04-09 |
WO1999001426A1 (en) | 1999-01-14 |
NZ501276A (en) | 2000-10-27 |
CN1163475C (zh) | 2004-08-25 |
TW396149B (en) | 2000-07-01 |
BR9810366A (pt) | 2000-08-29 |
AR016762A1 (es) | 2001-08-01 |
PT993439E (pt) | 2004-12-31 |
ZA985728B (en) | 1999-01-27 |
KR20010014362A (ko) | 2001-02-26 |
NO996491L (no) | 1999-12-29 |
HUP0003731A2 (hu) | 2001-04-28 |
EP0993439A1 (en) | 2000-04-19 |
EP0993439B1 (en) | 2004-09-29 |
DE69826662D1 (de) | 2004-11-04 |
MY120994A (en) | 2005-12-30 |
IL132840A (en) | 2004-12-15 |
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