JP4954200B2 - ヒストン脱アセチル化酵素阻害剤 - Google Patents
ヒストン脱アセチル化酵素阻害剤 Download PDFInfo
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- JP4954200B2 JP4954200B2 JP2008511780A JP2008511780A JP4954200B2 JP 4954200 B2 JP4954200 B2 JP 4954200B2 JP 2008511780 A JP2008511780 A JP 2008511780A JP 2008511780 A JP2008511780 A JP 2008511780A JP 4954200 B2 JP4954200 B2 JP 4954200B2
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- Prior art keywords
- alkyl
- amino
- hydroxy
- carboxamide
- pyrimidine
- Prior art date
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- 239000003276 histone deacetylase inhibitor Substances 0.000 title abstract description 8
- 229940121372 histone deacetylase inhibitor Drugs 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 137
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 9
- 239000012453 solvate Substances 0.000 claims abstract description 7
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 6
- 230000002062 proliferating effect Effects 0.000 claims abstract description 6
- 150000004677 hydrates Chemical class 0.000 claims abstract description 4
- 125000000165 tricyclic carbocycle group Chemical group 0.000 claims abstract description 3
- -1 -Methylamino Chemical group 0.000 claims description 208
- 125000000217 alkyl group Chemical group 0.000 claims description 137
- 239000000203 mixture Substances 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 41
- 125000005647 linker group Chemical group 0.000 claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- 102000003964 Histone deacetylase Human genes 0.000 claims description 20
- 108090000353 Histone deacetylase Proteins 0.000 claims description 20
- 125000002883 imidazolyl group Chemical group 0.000 claims description 20
- 125000004193 piperazinyl group Chemical group 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 230000000694 effects Effects 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 150000003857 carboxamides Chemical class 0.000 claims description 16
- 125000001425 triazolyl group Chemical group 0.000 claims description 16
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 14
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 14
- 125000002950 monocyclic group Chemical group 0.000 claims description 14
- 125000002757 morpholinyl group Chemical group 0.000 claims description 14
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 13
- 125000003386 piperidinyl group Chemical group 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 9
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 8
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 8
- 125000002619 bicyclic group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000006413 ring segment Chemical group 0.000 claims description 8
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 7
- 125000006603 (C1-C3) alkylaminosulfonyl group Chemical group 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 7
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 7
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 7
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 150000002825 nitriles Chemical class 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 4
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims description 4
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 claims description 4
- 150000001356 alkyl thiols Chemical class 0.000 claims description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 claims description 4
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 125000006261 methyl amino sulfonyl group Chemical group [H]N(C([H])([H])[H])S(*)(=O)=O 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 4
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000004014 thioethyl group Chemical group [H]SC([H])([H])C([H])([H])* 0.000 claims description 4
- 150000003573 thiols Chemical class 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 208000023105 Huntington disease Diseases 0.000 claims description 3
- 206010052779 Transplant rejections Diseases 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 230000009702 cancer cell proliferation Effects 0.000 claims description 3
- 125000005518 carboxamido group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 208000014951 hematologic disease Diseases 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 210000000056 organ Anatomy 0.000 claims description 3
- 229920000155 polyglutamine Polymers 0.000 claims description 3
- 108010040003 polyglutamine Proteins 0.000 claims description 3
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- 208000035473 Communicable disease Diseases 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 2
- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 claims description 2
- 150000003568 thioethers Chemical class 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 4
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims 3
- 125000006308 propyl amino group Chemical group 0.000 claims 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- 102100039996 Histone deacetylase 1 Human genes 0.000 claims 1
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- LOWILHBHMVLGAV-UHFFFAOYSA-N n-hydroxy-2-[5-(naphthalene-2-carbonyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]pyrimidine-5-carboxamide Chemical compound N1=CC(C(=O)NO)=CN=C1N1CC2CN(C(=O)C=3C=C4C=CC=CC4=CC=3)CC2C1 LOWILHBHMVLGAV-UHFFFAOYSA-N 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 129
- 238000005481 NMR spectroscopy Methods 0.000 description 125
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 105
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 86
- 239000011541 reaction mixture Substances 0.000 description 73
- 239000000243 solution Substances 0.000 description 60
- 239000007787 solid Substances 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 27
- 239000000047 product Substances 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
- 235000019439 ethyl acetate Nutrition 0.000 description 22
- 239000000725 suspension Substances 0.000 description 22
- 238000001914 filtration Methods 0.000 description 19
- 238000000746 purification Methods 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- 239000000284 extract Substances 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- 239000002244 precipitate Substances 0.000 description 15
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 13
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 0 C*[C@](C)(C=C)NC=C Chemical compound C*[C@](C)(C=C)NC=C 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
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- 239000000758 substrate Substances 0.000 description 7
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 238000004007 reversed phase HPLC Methods 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 108010077544 Chromatin Proteins 0.000 description 5
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- 108010033040 Histones Proteins 0.000 description 5
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- 125000002837 carbocyclic group Chemical group 0.000 description 5
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
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- 238000004458 analytical method Methods 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
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- 231100000673 dose–response relationship Toxicity 0.000 description 4
- JJAKMKPBJCWWIK-UHFFFAOYSA-N ethyl 2-(2,3,3a,4,6,6a-hexahydro-1h-pyrrolo[3,4-c]pyrrol-5-yl)pyrimidine-5-carboxylate Chemical compound N1=CC(C(=O)OCC)=CN=C1N1CC2CNCC2C1 JJAKMKPBJCWWIK-UHFFFAOYSA-N 0.000 description 4
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- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 4
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 3
- JOKLFPCQSFFDPZ-UHFFFAOYSA-N 4-[6-(naphthalen-2-ylmethylamino)-3-azabicyclo[3.1.0]hexan-3-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1N1CC(C2NCC=3C=C4C=CC=CC4=CC=3)C2C1 JOKLFPCQSFFDPZ-UHFFFAOYSA-N 0.000 description 3
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- ZYUZLEUJKZZXNN-UHFFFAOYSA-N C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 Chemical group C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 ZYUZLEUJKZZXNN-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- 102000006947 Histones Human genes 0.000 description 3
- 229910010082 LiAlH Inorganic materials 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- IHSJTUOAJPVEGH-UHFFFAOYSA-N N-[6-(naphthalen-2-ylsulfonylamino)-3-azabicyclo[3.1.0]hexan-3-yl]-N-(oxan-2-yloxy)pyrimidine-5-carboxamide Chemical compound N1=CN=CC(=C1)C(=O)N(OC1OCCCC1)N1CC2C(C2C1)NS(=O)(=O)C1=CC2=CC=CC=C2C=C1 IHSJTUOAJPVEGH-UHFFFAOYSA-N 0.000 description 3
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Classifications
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Description
真核細胞内では、DNAはヒストンと共にパッケージされてクロマチンを形成する。約150塩基対のDNAが、ヒストンのオクタマー(ヒストン2A、2B、3および4がそれぞれ2つずつ)の周囲に2回巻きついて、クロマチンの基本単位であるヌクレオソームを形成する。クロマチンの規則正しい構造は、関連する遺伝子の転写を可能にするために改変される必要がある。転写調節は、分化、増殖およびアポトーシスの鍵であり、よって厳密に制御される。クロマチン構造の変化(よって転写)の制御は、ヒストン、最も顕著にはN-末端尾部への共有結合形の改変により媒介される。アミノ酸の側鎖の共有結合形の改変(例えばメチル化、アセチル化、リン酸化およびユビキチン化)は、酵素により媒介される(ヒストンの共有結合形の改変および転写調節におけるそれらの役割についての総説は、Berger SL 2001 Oncogene 20, 3007〜3013に見出される;ヒストンのアセチル化および転写の総説についてはGrunstein, M 1997 Nature 389, 349〜352; Wolffe AP 1996 Science 272, 371〜372;およびWade PAら 1997 Trends Biochem Sci 22, 128〜132を参照)。
を有するはずであることを示唆する。
この発明は、HDACの細胞内阻害により恩恵を受ける癌のような疾患の治療において医薬的な利用性を有する新規なクラスのHDAC阻害剤を入手可能にする。
から選択される2価の基であり;
Aは、任意に置換されていてもよい、単環式、2環式もしくは3環式の炭素環式基または複素環式基であり;そして
-[リンカー1]-および-[リンカー2]-は独立して、結合手、または2価のリンカー基を表す]。
水和物もしくは溶媒和物の使用を提供する。
本明細書において、用語「(Ca-Cb)アルキル」(ここで、aおよびbは整数である)は、a〜b個の炭素原子を有する直鎖または分枝鎖状アルキル基のことである。したがって、例えばaが1でありbが6である場合、この用語はメチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、t-ブチル、n-ペンチルおよびn-ヘキシルを含む。
本明細書において、用語「2価の(Ca-Cb)アルケニレン基」は、a〜b個の炭素原子、少なくとも一つの2重結合、および二つの不飽和原子価を有する炭化水素鎖を意味する。
本明細書において、用語「炭素環式基」は、全てが炭素である16個までの環原子を有する単環式、2環式または3環式の基のことであり、アリールおよびシクロアルキルを含む。
アミノC1-6アルキル(例えばアミノエチル)、C1-3アルキルアミノC1-6アルキル、C1-3ジアルキルアミノC1-6アルキル、ヒドロキシC1-6アルキル(例えばヒドロキシエチル)、C1-3アルコキシC1-6アルキル(例えばメトキシエチル)、メルカプトC1-3アルキル、C1-3アルキルメルカプトC1-6アルキル、カルボキサミドC1-6アルキル(例えば-CH2CONH2)、アミノスルホニルC1-6アルキル(例えば-CH2SO2NH2)、C1-3アルキルアミノスルホニルC1-6アルキル(例えば-CH2SO2NHMe)、C1-3ジアルキルアミノスルホニルC1-6アルキル(例えば-CH2SO2NMe2)、C1-6アルカノイル、C1-6アルキルスルホニル、アミノスルホニル(-SO2NH2)、C1-6アルキルアミノスルホニル(例えば-SO2NHMe)、C1-6ジアルキルアミノスルホニル(例えば-SO2NMe2)、任意に置換されていてもよいフェニルアミノスルホニル、カルボキサミド(-CONH2)、C1-6アルキルアミノカルボニル、C1-6ジアルキルアミノカルボニル、モルホリニルC1-6アルキル、イミダゾリル、トリアゾリルもしくはヘテロシクリルの環が任意に置換されていてもよい、イミダゾリルC1-6アルキル、トリアゾリルC1-6アルキルもしくは単環式のヘテロシクロアルキルC1-6アルキル(例えばピペリジニルC1-6アルキル、ピペラジニルC1-6
アルキルまたは4-(C1-6アルキル)ピペラジニルC1-6アルキルから選択される。
本発明の化合物、あらゆる共存できる組み合わせにおいて、化合物は600未満の分子量を有することが好ましいことが念頭に置かれる。
Q、VおよびWがそれぞれ-C=であり得るか、またはQ、VおよびWの少なくとも一つが-N=であり得るか、またはQが-C=であり、VおよびWがそれぞれ-N=であり得る;現在のところ、Qが-C=であり、VおよびWがそれぞれ-N=であり、HONHC(=O)-基が、得られるピリミジン-2-イル基の5-位に結合している場合が好ましい。
環A基は、例えば任意に置換されていてもよいフェニルおよびナフチルのような、任意に置換されていてもよい芳香族炭素環式基、または任意に置換されていてもよいピロリル、フリル、チエニル、イミダゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、ピラゾリル、1,2,3-トリアゾリル、1,2,4-トリアゾリル、1,3,4-トリアゾリル、1,2,5-トリアゾリル、1,2,3-オキサジアゾリル、1,2,4-オキサジアゾリル、1,2,5-オキサジアゾリル、1,3,4-オキサジアゾリル、1,3,4-チアジアゾリル、ピリジル、ピリミジニル、ピリダジニル、ピラジニル、1,3,5-トリアジニル、1,2,4-トリアジニル、1,2,3-トリアジニル、ベンゾフリル、[2,3-ジヒドロ]ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イソベンゾチエニル、インドリル、イソインドリル、インダニル、3H-インドリル、ベンズイミダゾリル、インダゾリル、イミダゾ[1,2-a]ピリジル、ベンゾチアゾリル、ベンズオキサゾリル、キノリジニル、キナゾリニル、フタラジニル、キノキサリニル、シンノリニル、ナフチリジニル、ピリド[3,4-b]ピリジル、ピリド[3,2-b]ピリジル、ピリド[4,3-b]ピリジル、キノリル、イソキノリル、テトラゾリル、5,6,7,8-テトラヒドロキノリル、5,6,7,8-テトラヒドロイソキノリル、プリニル、プテリジニル、カルバゾリル、キサンテニルまたはベンゾキノリル基のような、任意に置換されていてもよい芳香族複素環式基であり得る。
イミダゾリニル)、イミダゾリジニル、ピラゾリニル(例えば2-ピラゾリニル)、ピラゾリジニル、ピラニル(例えば2-または4-ピラニル)、ピペリジニル、1,4-ジオキサニル、モルホリニル、1,4-ジチアニル、チオモルホリニル、ピペラジニル、1,3,5-トリチアニル、オキサジニル(例えば2H-1,3-、6H-1,3-、H-1,2-、2H-1,2-または4H1,4-オキサジニル)、1,2,5-オキサチアジニル、イソキサジニル、オキサチアジニル(例えば1,2,5または1,2,6-オキサチアジニル)、または1,3,5-オキサジアジニル基のような、任意に置換されていてもよい非芳香族炭素環式基および複素環式基でもあり得る。
-[リンカー1]-および-[リンカー2]-は、2価のB基を環AならびにQ、VおよびWを含む環と結合させる役目をする。したがって、それらは独立して、次の例:
(i) 結合手;
(ii) -O-、-S-、-C(=O)-、-S(=O)2-、-NR1-、-C(=O)NR1-、-S(=O)2NR1-、-NR1C(=O)-、-NR1S(=O)2-、-NR1(CH2)m-、-NR1C(=O)(CH2)m-、-NR1S(=O)2(CH2)m、-NR2C(=O)NR1-、-NR1C(=O)(CH2)mAr-、または-NR1S(=O)2(CH2)mAr-
(ここで、R1およびR2は独立して、水素、C1-C4アルキルまたは窒素置換基であり、mは0、1、2、3、4または5であり、そしてArは2価のフェニル基または5〜13員環の単環式もしくは2環式の2価のヘテロアリール基である);および
(iii) 任意に置換されていてもよい、直鎖もしくは分枝鎖状C1-C6アルキレン、C2-C6アルケニレンまたはC2-C6アルキニレン基(これらはエーテル(-O-)、チオエーテル(-S-)またはアミノ(-NRA-)結合(ここで、RAは水素、C1-C3アルキルまたは窒素置換基である)を任意に含むかまたはこれらの結合が末端をなしていてもよい)
から選択され得る。
から選択される2価の基であり得る。例えば、-[リンカー1]-および-[リンカー2]-の一方に存在する場合、-Ar-は、1,4-フェニレンのような2価のフェニレン基であり得る。
現在のところ、本発明の化合物のいくつかの好ましい態様において、-[リンカー1]-は、Bが2価の基(IIA)、(IIB)、(IID)もしくは(IIE)である場合に結合手であるか、またはBが2価の基(IIC)である場合に-NH-である。
のものからなる。
N-ヒドロキシ 2-(5-ナフタレン-2-イルメチルヘキサヒドロピロロ[3,4-c]ピロール-2[1H]-イル)ピリミジン-5-カルボキサミド、
N-ヒドロキシ 2-{6-[(2-ナフチルスルホニル)アミノ]-3-アザビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド トリフルオロアセテート、
N-ヒドロキシ 2-{6-[(6-フルオロキノリン-2-イルメチル)アミノ]-3-アザ-ビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド、
N-ヒドロキシ 2-{6-[(2-ナフチルメチル)アミノ]-3-アザビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド、
N-ヒドロキシ 2-[6-(1,3-ジヒドロ-2H-イソインドール-2-イル)-3-アザビシクロ[3.1.0]ヘキシ-3-イル]ピリミジン-5-カルボキサミド 塩酸塩、
N-ヒドロキシ 2-{6-[(ナフタレン-2-スルホニル)-(2-ピペリジン-1-イルエチル)-アミノ]-3-アザ-ビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド、
N-ヒドロキシ 2-{6-[(キノリン-2-イルメチル)アミノ]-3-アザビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド トリフルオロアセテート、
N-ヒドロキシ 2-[5-(4-クロロベンジル)ヘキサヒドロピロロ[3,4-c]ピロール-2(1H)-イル]ピリミジン-5-カルボキサミド 四トリフルオロアセテート、
N-ヒドロキシ 2-[5-(ナフタレン-2-カルボニル)-ヘキサヒドロピロロ[3,4-c]ピロール-2-イル]ピリミジン-5-カルボキサミド
ならびにそれらのN-オキサイド、塩、水和物および溶媒和物を含む。
p-ヒドロキシベンゾエートまたはソルビン酸、および所望により慣用の着香剤もしくは着色剤を含み得る。
本発明が関係する化合物の合成のための複数の合成戦略があるが、全て、公知の化学を基にしており、有機合成化学者に公知である。したがって、式(I)の化合物は、標準的な文献に記載され、当業者に周知の方法により合成できる。典型的な文献源は、"Advanced organic chemistry", 第4版 (Wiley), J March、"Comprehensive Organic Transformation", 第2版 (Wiley), R.C. Larock、"Handbook of Heterocyclic Chemistry", 第2版 (Pergamon), A.R. Katritzky、 "Synthesis"、"Acc. Chem. Res."、"Chem. Rev"中に見出されるような総説論文、あるいは標準的な文献検索オンラインまたは"Chemical Abstracts"もしくは"Beilstein"のような二次情報源により特定される一次文献源である。以下の実施例の化合物の製造に用いられる合成ルートは、類似化合物の製造に適用され得る。
マイクロ波照射は、CEM Discover集束(focused)マイクロウェーブ反応器を用いて行った。溶媒は、加熱せずにGeneVac Series Iを用いるか、または30℃にてVacRampを備えるGenevac Series IIを用いるか、またはBuchiロータリーエバポレータを用いて除去した。フラッシュクロマトグラフィーカラムによる化合物の精製は、Silicycleから得た粒子サイズ40〜63μm (230〜400メッシュ)のシリカゲルを用いて行った。分取(preparative)HPLCによる化合物の精製は、逆相ThermoHypersil-Keystone Hyperprep HS C18カラム(12μm、100×21.2 mm)、9.5分でのグラジエント20〜100% B (A=水/0.1% TFA、B=アセトニトリル/0.1% TFA)、流速=30 ml/分、注入溶媒2:1 DMSO:アセトニトリル (1.6 ml)、215 nmでのUV検出を用いるGilsonシステムで行った。
MeOH = メタノール
EtOH = エタノール
EtOAc = 酢酸エチル
Boc = tert-ブトキシカルボニル
DCM = ジクロロメタン
DMF = ジメチルホルムアミド
DMSO = ジメチルスルホキシド
THF = テトラヒドロフラン
Na2CO3 = 炭酸ナトリウム
HCl = 塩化水素酸
DIPEA = ジイソプロピルエチルアミン
NaH = 水素化ナトリウム
NaOH = 水酸化ナトリウム
NaHCO3 = 炭酸水素ナトリウム
Pd/C = パラジウム炭素
TME = tert-ブチルメチルエーテル
N2 = 窒素
Na2SO4 = 硫酸ナトリウム
Et3N = トリエチルアミン
NH3 = アンモニア
TMSCl = トリメチルクロロシラン
NH4Cl = 塩化アンモニウム
LiAlH4 = 水素化リチウムアルミニウム
PyBrOP = ブロモ-トリピロリジノホスホニウムヘキサフルオロリン酸
MgSO4 = 硫酸マグネシウム
nBuLi = n-ブチルリチウム
EDCI = N-(3-ジメチルアミノプロピル)-N'-エチルカルボジイミド 塩酸塩
Et2O = ジエチルエーテル
LiOH = 水酸化リチウム
HOBt = 1-ヒドロキシベンゾトリアゾール
TLC = 薄層クロマトグラフィー
ml = ミリリットル
g = グラム
mg = ミリグラム
mol = モル
mmol = ミリモル
CMS = 高性能液体クロマトグラフィー/質量分析
NMR = 核磁気共鳴
r.t. = 室温
sat. = 飽和
h = 時間
min = 分
(5H, m).
m), 4.75 (1H, s), 9.50 (2H, br s).
(9H, s), 2.65 (2H, s), 3.50 (2H, d), 3.75 (2H, q), 4.10 (1H, t).
(300 MHz, d6-DMSO) δ: 2.11 (2H, m), 2.44 (1H, m), 2.50 (2H, d, J = 9.3 Hz), 3.07 (2H, d, J = 9.3 Hz), 3.64 (2H, s), 7.21-7.35 (5H, m), 9.31 (1H, d, J = 4.8 Hz).
(4H, m), 1.86 (1H, m), 2.29 (4H, d, J = 9 Hz), 2.50 (1H, m), 2.91 (4H, dd, J = 2.4, 9 Hz), 3.57 (4H, s), 6.05 (1H, d, J = 9 Hz), 6.96 (1H, d, J = 8.1 Hz), 7.21-7.34 (10H, m), 10.28 (1H, s), 10.59 (1H, s).
1H NMR (300 MHz, d6-DMSO) δ: 0.85 (6H, d), 1.15 (3H, d), 1.75 (1H, m), 3.18 (1H, dd), 3.42 (1H, dd), 4.53 (1H, q), 5.82 (2H, s).
実施例1:N-ヒドロキシ 2-{6-[(2-ナフチルスルホニル)アミノ]-3-アザビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド トリフルオロアセテート
s), 7.62-7.68 (2H, m), 7.85 (1H, m), 7.93 (1H, d), 7.99-8.02 (2H, m), 8.47 (1H,
m).
= 34.0g)。この生成物を、さらに精製することなく次の工程に用いた。1H NMR (400 MHz, d6-DMSO) δ: 1.86 (2H, s), 2.20 (1H, m), 3.22 (4H, m), 7.70-7.75 (2H, m), 7.83
(1H, dd), 8.08 (1H, d), 8.18-8.23 (3H, m), 8.33 (1H, br s), 8.48 (1H, s), 9.20 (1H, br s).
Eで洗浄し、風乾して標記の化合物を白色の固体として得た(25.40g, 85%)。LCMS純度 96%, m/z 439 [M+H]+, 1H NMR (400 MHz, d6-DMSO) δ: 1.26 (3H, t), 1.82 (2H, s), 1.90
(1H, m), 3.50-3.53 (2H, m), 3.67-3.70 (2H, m), 4.23 (2H, q), 7.67-7.71 (2H, m),
7.84 (1H, m), 8.04 (1H, d), 8.15-8.22 (3H, m), 8.50 (1H, m), 8.70 (2H, s).
(400 MHz, d6-DMSO)δ: 1.75 (2H, s), 1.80 (1H, s), 3.20 (1H, s), 3.45 (2H, d), 3
.65 (2H, d), 7.45 (2H, m), 7.65 (1H, d), 7.95-8.15 (4H, m), 8.40 (1H, s), 8.50 (2H, s), 11.0 (1H, br s). 元素分析 C21H26ClN5O6Sの計算値: C, 49.27; H, 5.12; Cl, 6.92; N, 13.68. 実測値: C, 49.70; H, 5.09; Cl, 7.10; N, 13.55.
実施例2:N-ヒドロキシ 2-{6-[(チエニ-2-イルスルホニル)アミノ]-3-アザビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド
(1H, br s), 3.45-3.55 (2H, m), 3.70 (2H, d, J = 11.7 Hz), 8.38 (2H, s), 8.47-8.52 (1H, m), 8.54-8.57 (1H, m), 8.62 (2H, s), 9.00 (1H, br s), 11.05 (1H, br s).
(1H, s), 3.51 (2H, d, J = 11.6 Hz), 3.68 (2H, d, J = 11.8 Hz), 7.64 (2H, d, J =
8.2 Hz), 7.97 (2H, d, J = 8.8 Hz), 8.24 (1H, br s), 8.62 (2H, s), 9.01 (1H, br s), 11.07 (1H, br s).
2.64-2.70 (1H, m), 3.60-3.70 (2H, m), 3.95 (2H, d, J = 11.6 Hz), 7.55-7.66 (2H,
m), 7.88-8.05 (4H, m), 8.43 (1H, br s), 8.69 (2H, s), 8.74 (1H, d, J = 3.9 Hz),
9.01 (1H, br s), 11.05 (1H, br s).
実施例6:N-ヒドロキシ 2-(6-{2-[4-(1,1-ジオキソイソチアゾリジン-2-イル)フェニル]アセチルアミノ}-3-アザビシクロ[3.1.0]ヘキシ-3-イル)ピリミジン-5-カルボキサミド
t, J = 6.8 Hz), 3.84 (2H, m), 7.14 (2H, d, J = 5.5 Hz), 7.24 (2H, d, J = 5.5 Hz), 8.28 (1H, d, J = 2.5 Hz), 8.64 (2H, s), 11.05 (1H, br s).
(4H, m), 1.75 (2H, br s), 2.02 (2H, t, J = 8.6 Hz), 2.33 (1H, m), 2.55 (2H, t, J = 9.1 Hz), 3.56 (2H, m), 3.83 (2H, m), 7.13-7.29 (5H, m), 7.97 (1H, d), 8.65 (2H, s), 11.03 (1H, br s).
11.07 (1H, br s).
2.55-2.63 (1H, m), 3.62 (2H, d, J = 11.7 Hz), 3.92 (2H, d, J = 11.7 Hz), 7.41-7.58 (3H, m), 7.83 (2H, m), 8.60 (1H, d, J = 3.9 Hz), 8.67 (2H, s), 8.95-9.05 (1H, br s), 11.08 (1H, s).
d, J = 7.9 Hz), 8.19 (1H, d, J = 3.7 Hz), 8.64 (2H, s), 8.98 (1H, br s), 11.01 (1H, br s).
1.86-1.98 (2H, m), 2.22 (2H, t, J = 7.5 Hz), 2.34-2.38 (1H, m), 3,52-3.61 (2H, m), 3.83 (1H, d, J = 11.7 Hz), 3.94 (2H, t, J = 6.3 Hz), 6.88-6.95 (3H, m), 7.28
(2H, dd, J = 8.3, 8.3 Hz), 8.07 (1H, d, J = 3.8 Hz), 8.65 (2H, s), 8.99 (1H, br
s), 11.06 (1H, br s).
Hz), 8.17 (1H, d, J = 1.8 Hz), 8.61 (1H, d, J = 3.9 Hz), 8.68 (2H, s), 9.00 (1H, br s), 11.07 (1H, br s).
= 5.4 Hz), 7.81 (1H, dd, J = 8.6, 1.5 Hz), 7.86 (1H, d, J = 5.4 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.37 (1H, d, J = 1.2 Hz), 8.68 (3H, m), 8.99 (1H, br s), 11.05 (1H, br s).
(1H, m), 3.57-3.66 (2H, m), 3.90 (2H, d, J = 11.6 Hz), 7.12-7.18 (1H, m), 7.72-7.78 (2H, m), 8.63-8.65 (1H, m), 8.67 (2H, m), 11.07 (1H, br s).
= 11.6 Hz), 7.34 (3H, m), 7.46 (2H, m), 7.62 (4H, m), 8.34 (1H, d, J = 4.1 Hz),
8.65 (2H, s), 9.00 (1H, br s), 11.07 (1H, br s).
M+H]+.
実施例21:N-ヒドロキシ 2-{6-[(4-メトキシベンジル)アミノ]-3-アザビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド
10.1 Hz), 3.68 (2H, dm, J = 10.8 Hz), 4.06 (2H, d, J = 10.8 Hz), 7.10 -7.30 (5H, m), 8.69 (2H, s).
d, J = 7.8 Hz), 7.05 (2H, d, J = 7.2 Hz), 7.18 (1H, t, J = 5.4 Hz), 7.42 (2H, td, J = 7.5, 2.1 Hz), 7.51 (2H, d, J = 8.4 Hz), 8.48 (2H, s), 9.23 (1H, br s), 11.05 (1H, br s).
(2H, dm, J = 12 Hz), 4.08 (2H, d, J = 12 Hz), 8.69 (2H, s).
(1H, br s).
Hz), 1.87 (2H, q, J = 7.8 Hz), 2.17 (2H, br s), 2.64 (1H, br s), 2.78 (2H, m), 2.98 (1H, m), 3.57 (2H, dm, J = 11.7 Hz), 3.86 (2H, d, J = 11.7 Hz), 7.19-7.35 (5H, m), 8.66 (2H, s), 8.82 (1H, br s), 9.01 (1H, m), 11.08 (1H, s).
s), 7.54 (4H, m), 8.67 (2H, s), 9.04 (1H, br s), 9.26 (1H, br s), 11.07 (1H, br
s).
s), 7.45 (2H, m), 7.97 (1H, s), 8.07 (2H, dd, J = 7.8, 0.9 Hz), 8.67 (2H, s), 9.04 (1H, br s), 9.32 (1H, br s), 11.10 (1H, br s).
s), 7.42-7.51 (5H, m), 8.67 (2H, s), 9.02 (1H, br s), 9.20 (1H, br s), 11.09 (1H, br s).
s), 7.25 (2H, d, J = 8.7 Hz), 7.64 (2H, d, J = 8.7 Hz), 8.67 (2H, s), 9.02 (1H,
br s), 9.28 (1H, br s), 11.07 (1H, br s).
s), 7.40 (1H, m), 7.47-7.54 (4H, m), 7.73 (2H, m), 7.93 (1H, s), 8.67 (2H, s), 9.75 (2H, br s), 11.10 (1H, br s).
J = 11.7 Hz), 7.27-7.38 (5H, m), 8.68 (2H, s).
(1H, m), 3.58 (2H, dm, J = 11.7 Hz), 3.84 (2H, d, J = 11.7 Hz), 4.30 (2H, m), 7.35 (2H, m), 7.68 (2H, m), 8.73 (2H, s), 9.83 (2H, m), 11.20 (1H, m).
(1H, m), 3.57 (2H, dm, J = 11.7 Hz), 3.80 (2H, d, J = 11.7 Hz), 4.59 (2H, m), 7.56 (2H, d, J = 8.1 Hz), 7.68 (2H, d, J = 8.1 Hz), 8.68 (2H, s), 10.01 (2H, m), 11.10 (1H, m).
7.87 (1H, d, J = 8.4 Hz), 8.01 (1H, d, J = 8.4 Hz), 8.30 (1H, d, J = 8.4 Hz), 8.57 (2H, s).
(1H, s), 3.60 (2H, dm, J = 11.7 Hz), 3.88 (2H, d, J = 11.7 Hz), 4.69 (2H, br s), 7.66 (1H, d, J = 8.4 Hz), 7.75 (1H, td, J = 8.7, 3.0 Hz), 7.88 (1H, dd, J = 9.3, 2.7 Hz), 8.48 (1H, d, J = 8.4 Hz), 8.67 (2H, s), 9.01 (1H, br s), 9.61 (1H, br s), 11.09 (1H, br s).
N-キャップされたスルホンアミドは、スキーム8に記載された方法にしたがって製造した。
s).
1H NMR (300 MHz, d6-DMSO) δ: 1.71 (1H, m), 1.82 (2H, m), 2.34 (3H, s), 3.43-3.55 (4H, m), 3.71 (2H, d, J = 11.9 Hz), 4.14 (2H, t, J = 6.5 Hz), 6.76 (1H, d, J = 1.2 Hz), 7.08 (1H, d, J = 1.2 Hz), 7.66-7.76 (2H, m), 7.88 (1H, dd, J = 1.8, 10.5 Hz), 8.06 (1H, dd, J = 2.0, 7.1 Hz), 8.18 (1H, d, J = 8.7 Hz), 8.25 (1H, dd,
J = 2.0, 8.9 Hz), 8.57-8.62 (3H, m), 8.98 (1H, br s), 11.02 (1H, br s).
3.52-3.59 (2H, m), 3.79 (2H, t, J = 11.8 Hz), 7.66-7.76 (2H, m), 7.83 (1H, dd, J = 1.8, 8.7 Hz), 8.04-8.09 (1H, m), 8.18 (1H, d, J = 8.8 Hz), 8.22-8.27 (1H, m), 8.53-8.56 (1H, m), 8.63 (2H, s), 8.99 (1H, br s), 11.03 (1H, br s).
実施例49(方法B):N-ヒドロキシ 2-{6-[(2-ヒドロキシエチル)(ナフタレン-2-スルホニル)アミノ]-3-アザビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド
(2H, m), 3.32 (2H, m), 3.50-3.65 (4H, m), 3.78 (2H, d, J = 11.9 Hz), 7.64-7.77 (2H, m), 7.85 (1H, dd, J = 1.8, 8.6 Hz), 8.05 (1H, dd, J = 2.1, 9.2 Hz), 8.16 (1H, d, J = 8.8 Hz), 8.28 (1H, dd, J = 1.9, 7.1 Hz), 8.53 (1H, m), 8.61 (2H, s), 9.00 (1H, br s), 11.02 (1H, br s).
1.76-1.80 (1H, m), 2.05 (6H, s), 2.16 (2H, t, J = 6.9 Hz), 2.22-2.29 (2H, m), 3.22-3.33 (2H, m), 3.55-3.64 (2H, m), 3.79 (2H, d, J = 11.8 Hz), 7.64-7.75 (2H, m), 7.83 (1H, dd, J = 1.8, 8.7 Hz), 8.03-8.08 (1H, m), 8.16 (1H, d, J = 8.7 Hz), 8.22-8.25 (1H, m), 8.52-8.54 (1H, m), 8.62 (2H, s), 9.00 (1H, br s), 11.02 (1H, br s).
2.26-2.39 (6H, m), 2.42-2.50 (2H, m), 3.33-3.42 (2H, m), 3.45-3.60 (6H, m), 3.78 (2H, d, J = 11.7 Hz), 7.65-7.75 (2H, m), 7.87 (1H, dd, J = 1.8, 8.6 Hz), 8.06 (1H, dd, J = 1.9, 7.0 Hz), 8.16 (1H, d, J = 8.7 Hz), 8.24 (1H, dd, J = 2.1, 6.8 Hz), 8.53-8.56 (1H, m), 8.58 (2H, s).
3.52-3.58 (2H, m), 3.76 (2H, d, J = 11.6 Hz), 7.65-7.75 (2H, m), 7.86 (1H, dd, J = 1.8, 8.7 Hz), 8.06 (1H, dd, J = 2.2, 6.5 Hz), 8.18 (1H, d, J = 8.7 Hz), 8.24
(1H, dd, J = 2.1, 6.8 Hz), 8.52-8.57 (1H, m), 8.56 (2H, s).
1.51-1.60 (4H, m), 1.92 (1H, t, J = 1.8 Hz), 2.30-2.35 (2H, m), 2.38-2.50 (4H, m), 2.59 (2H, t, J = 7.5 Hz), 3.46 (2H, t, J = 7 Hz), 3.59-3.69 (2H, m), 3.92 (2H, d, J = 12 Hz), 7.66-7.77 (2H, m), 7.87 (1H, dd, J = 1.7, 8.7 Hz), 8.00 (1H, dd, J = 2.4, 9.1 Hz), 8.07-8.15 (2H, m), 8.48-8.52 (1H, m), 8.63 (2H, s).
2.55-2.63 (2H, m), 3.46 (2H, t, J = 7.1 Hz), 3.92-4.0 (2H, m), 4.09 (2H, t, J =
7.1 Hz), 4.17 (2H, d, J = 11.8 Hz), 7.67-7.80 (2H, m), 8.08-8.17 (2H, m), 8.16-8.29 (2H, m), 8.48 (1H, dd, J = 1.4, 8.8 Hz), 8.58 (1H, d, J = 8.7 Hz), 8.66 (1H, dd, J = 1.4, 7.2 Hz), 8.92-8.99 (2H, m), 9.04 (2H, s), 9.40 (1H, br s), 11.46 (1H, br s).
2.18 (2H, t, J = 8.0 Hz), 2.22-2.24 (2H, m), 3.34-3.44 (6H, m), 3.55-3.62 (2H, m), 3.81 (2H, d, J = 11.9 Hz), 7.64 (2H, d, J = 8.4 Hz), 7.98 (2H, d, J = 8.8 Hz), 8.64 (2H, s), 8.99 (1H, br s), 11.04 (1H, br s).
br s), 7.61 (2H, m), 7.76 (1H, d, J = 8.4 Hz), 7.95-8.04 (3H, m), 8.20 (1H, s),
8.71 (2 H, s).
実施例57:N-ヒドロキシ 2-[6-(ビスナフタレン-2-イルメチルアミノ)-3-アザビシクロ[3.1.0]ヘキシ-3-イル]ピリミジン-5-カルボキサミド
(6H, m), 7.97-8.11 (8H, m), 8.66 (2H, s).
実施例60:N-ヒドロキシ 2-[6-(アセチルナフタレン-2-イルメチルアミノ)-3-アザビシクロ[3.1.0]ヘキシ-3-イル]ピリミジン-5-カルボキサミド
m), 7.98 (1H, m), 8.60-8.69 (4H, m), 8.85 (1H, br s).
100%, m/z 319 [M+H]+.
(1H, t, J = 2.1 Hz), 3.62 (2H, s), 3.71 (2H, d, J = 10.1 Hz), 4.10 (2H, d, J = 10.1 Hz), 4.60 (2H, s), 7.17-7.33 (4H, m), 8.68 (2H, s).
した。次いで、溶媒を真空下に除去し、残渣を高真空下で乾燥し、さらに精製することなく、次の工程に用いた。LCMS純度 91%, m/z 226 [M+H]+.
Hz), 8.09 (1H, d, J = 8.0Hz), 8.33 (1H, d, J = 8.8 Hz), 8.28 (2H, s), 10.24 (1H,
br s), 11.12 (1H, br s), 12.96 (1H, br s).
実施例68:N-ヒドロキシ 2-[6-(イソキノリン-1-イルアミノ)-3-アザビシクロ[3.1.0]ヘキシ-3-イル]ピリミジン-5-カルボキサミド
= 6.9 Hz), 7.74-7.82 (2H, m), 7.95-8.02 (2H, m), 8.73 (2H, s), 8.80 (1H, d, J =
8.4 Hz), 10.12 (1H, br s), 11.15 (1H, br s), 12.81 (1H, br s).
z 439 [M+H]+.
1.16mmol)およびK2CO3(481mg, 3.48mmol)に、中間体A(267mg, 1.16mmol)を加えた。得られた白色の懸濁液をr.t.で4時間撹拌した。反応混合物を水(50ml)で希釈し、EtOAc(3×50ml)で抽出した。合わせた有機相を水(2×50ml)、食塩水(50ml)で洗浄し、乾燥(MgSO4)し、真空下に濃縮して、標記の化合物を白色の固体として得た(323mg, 86%)。LCMS純度 100%, m/z 323 [M+H]+, 1H NMR (400 MHz, CDCl3) δ: 1.37 (3H, t), 1.46 (9H, s), 4.04 (2H, m), 4.34 (2H, q), 4.53 (2H, t), 4.64 (1H, br s), 5.02 (1H, br s), 8.84 (2 H, s).
CDCl3) δ: 1.32 (3H, t), 3.87 (2H, m), 4.29-4.38 (5H, m), 5.18 (1H, d), 7.65-7.70 (2H, m), 7.83 (1H, d), 7.93-8.02 (3H, m), 8.45 (1H, s), 8.76 (2H, s).
の固体として得た(162mg, 86%)。LCMS純度 93%, m/z 484 [M+H]+.
32.1mmol)と一緒に10分間撹拌した。次いで、中間体A(2.48g, 10.7mmol)を加え、反応混合物を30分間撹拌した。次いで、反応混合物をH2O(100ml)で希釈し、EtOAc(2×100ml)で抽出した。合わせた有機抽出液を乾燥(MgSO4)し、溶媒を真空下に除去した。残渣をDCM中0〜5% MeOHで溶出するカラムクロマトグラフィーで精製して、標記の化合物を白色の固体として得た(3.5g, 90%)。LCMS純度 97%, m/z 363 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 0.70 (1H, m), 1.28 (3H, t, J = 7.2 Hz), 1.38 (9H, s), 1.61 (2H, m), 2.93 (2H, m), 3.54 (2H, d, J = 11.7 Hz), 3.82 (2H, d, J = 11.7 Hz), 4.26 (2H, q, J = 7.2
Hz), 6.92 (1H, m), 8.76 (2H, s).
0.09mmol)をDCM(2ml)中で撹拌し、ジオキサン中の4M HCl(45μl, 0.18mmol)を加えた。すぐに固体の沈殿が生じた。反応混合物を10分間撹拌し、次いで溶媒を真空下に除去して、標記の化合物を白色の固体として得た(16mg, 50%)。LCMS純度 98%, m/z 390 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 1.91 (2H, m), 2.50 (1H, m), 2.99 (2H, m), 3.55 (2H, m), 3.88 (2H, d, J = 11.7 Hz), 4.34 (2H, m), 7.58 (2H, m), 7.68 (1H, m), 7.95 (2H, m), 8.03 (2H, m), 8.66 (2H, s), 9.11 (2H, br s), 11.07 (1H, br s).
実施例72:N-ヒドロキシ 2-{6-[(ベンジルアミノ)メチル]-3-アザビシクロ[3.1.0]ヘキ
シ-3-イル}ピリミジン-5-カルボキサミド
= 7.2 Hz), 7.99 (1H, d, J = 8.7 Hz), 8.12 (1H, d, J = 8.7 Hz), 8.41 (1H, d, J =
8.7 Hz), 8.67 (2H, s), MeODによりNH/NHOHのピ−クはない。
3.6, 5.4 Hz), 8.39 (1H, d, J = 8.4 Hz), 8.68 (2H, s), MeODによりNH/NHOHのピ−クはない。
g, 58%)。1H NMR (300 MHz, CDCl3) δ: 1.39 (3H, t), 1.47 (9H, s), 3.02 (2H, m), 3.22-3.41 (2H, m), 3.55-3.65 (4H, m), 3.80-3.97 (2H, m), 4.36 (2H, t), 8.88 (2H, s).
8mmol)を加えた。その混合物をr.t.で1時間撹拌し、次いで蒸発乾固した。残渣をメタノールに溶解し、SCX-2カートリッジに装填し、メタノール(100ml)で洗浄し、次いでメタノール中の2M アンモニアで溶出して、標記の化合物を得た(0.285g, 100%)。LCMS純度 >95%, m/z 263 [M+H]+.
= 3.9, 12.3 Hz), 3.59 (2H, dd, J = 7.2, 10.2 Hz), 4.35 (2H, q, J = 7.2 Hz), 7.58-7.75 (2H, m), 7.82 (1H, dd, J = 1.8, 8.7 Hz), 7.90-8.05 (2H, m), 8.40 (1H, s),
8.77 (2H, s).
CM(100ml)で抽出した。合わせた有機抽出液を乾燥(MgSO4)し、濃縮し、フラッシュカラムクロマトグラフィーで精製して、標記の化合物を得た(0.266g, 99%)。1H NMR (300 MHz, CDCl3) δ: 1.39 (3H, t, J = 6.9 Hz), 2.59 (2H, d, J = 6.9 Hz), 2.73-2.90 (2H, m), 2.94-3.10 (2H, m), 3.67 (2H, d, J = 11.7 Hz), 3.82 (2H, s), 3.90 (2H, dd, J = 8.1, 12 Hz), 4.37 (2H, q, J = 7.2 Hz), 7.41-7.43 (3H, m), 7.74 (1H, s), 7.76-7.89 (3H, m), 8.88 (2H, s).
2-[5-(ナフタレン-2-スルホニル)ヘキサヒドロピロロ[3,4-c]ピロール-2(1H)-イル]ピリミジン-5-カルボン酸
s).
実施例77:N-ヒドロキシ 2-[5-(ナフタレン-2-カルボニル)ヘキサヒドロピロロ[3,4-c]ピ
ロール-2(1H)-イル]ピリミジン-5-カルボキサミド
3.40-3.90 (8H, m), 4.57 (2H, s), 7.61 (2H, s), 7.90-8.13 (3H, m), 8.65-8.75 (2H, m), 9.04 (1H, br s), 10.09 (1H, br s), 11.12 (1H, br s).
3.20-3.28 (4H, m), 3.50 (2H, dd, J = 6.4, 9.8 Hz) 3.63 (2H, dd, J = 7.3, 11.9 Hz), 8.34 (2H, s), 8.52 (1H, s), 8.63 (2H, s), 8.99 (1H, br s), 11.06 (1H, br s).
3.13 (2H, dd, J = 3.6, 10.1 Hz), 3.21 (2H, dd, J = 3.5, 11.7 Hz), 3.33-3.46 (2H, dd, J = 7.0, 10.3 Hz), 3.65 (2H, dd, J = 6.9, 11.5 Hz), 7.60 (2H, d, J = 8.0 Hz), 7.95 (2H, d, J = 8.8 Hz), 8.64 (2H, s), 8.97 (1H, br s), 11.05 (1H, br s).
3.42-3.51 (2H, m), 3.53-3.65 (2H, m), 3.65-3.88 (4H, m), 4.42 (2H, s), 7.22-7.33 (2H, m), 7.39 (1H, t, J = 9.3 Hz), 8.70 (2H, s), 11.21 (1H, br s), 11.10 (1H, br s).
3.28-3.50 (2H, m), 3.52-3.71 (4H, m), 3.72-3.86 (2H, m), 4.36-4.45 (2H, m), 7.50-7.58 (4H, m), 8.66-8.75 (2H, m), 10.08 (1H, br s), 11.11 (1H, br s).
[M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 1.30 (4H, m), 1.58 (4H, m), 3.03 (4H, m),
3.70 (4H, m), 7.69 (1H, dd, J = 1.3, 6.9 Hz), 7.74 (1H, dd, J = 1.9, 8.1 Hz), 7.78 (1H, dd, J = 2.1, 8.7 Hz), 8.10 (2H, d, J = 7.8 Hz), 8.15 (1H, d, J = 8.7 Hz), 8.22 (2H, d, J = 5.2 Hz), 8.45 (2H, br s), 8.60 (2H, s).
ー(5% MeOH-DCM)で精製して、標記の化合物を得た(1.429g, 75%)。m/z 362.25 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 8.32 (1H, dd, J = 0.6, 2.1 Hz), 8.03 (1H, dd, J = 2.4, 9.0 Hz), 6.32 (1H, d, J = 8.7 Hz), 4.34 (2H, q, J = 6.9 Hz), 3.24-3.85 (8H, m), 3.03 (2H, m), 1.47 (9H, s), 1.38 (3H, t, J = 7.2 Hz).
40mmol)を加えた。その混合物を2時間撹拌し、次いで、Et2O(50ml)を加えた。生成物を濾過により回収し、さらなるEt2O(50ml)で洗浄し、標記の化合物を得た(1.19g, 定量的)。1H NMR (300 MHz, d6-DMSO) δ: 9.95 (1H, br s), 9.84 (1H, br s), 8.44 (1H, d, J
= 1.8 Hz), 8.20 (1H, dd, J = 2.1, 9.3 Hz), 7.01 (1H, d, J = 9.3 Hz), 4.31 (2H, q, J = 7.2 Hz), 3.0-4.05 (10H, m), 1.31 (3H, t, J = 7.2 Hz).
(300 MHz, d6-DMSO) δ: 8.63 (1H, d, J = 2.1 Hz), 7.92 (1H, dd, J = 2.4, 9.0 Hz), 7.75-7.89 (3H, m), 7.44-7.49 (3H, m), 6.53 (1H, d, J = 8.7 Hz), 4,25 (2H, q, J
= 7.2 Hz), 3.65-3.74 (4H, m), 3.35-3.41 (2H, m), 2.94 (2H, m), 2.57-2.64 (2H, m), 1.29 (3H, t, J = 7.2 Hz).
リウム(50ml)、水(50ml)および食塩水(50ml)で洗浄した。次いで、抽出液を乾燥(MgSO4)し、濃縮し、フラッシュカラムクロマトグラフィー(4% MeOH-DCM)で精製して、標記の化合物を得た(0.199g, 58%)。1H NMR (300 MHz, d6-DMSO) δ:11.17 (1H, br s), 8.50 (1H, d, J = 2.1 Hz), 7.81-7.90 (4H, m), 7.77 (1H, s), 7.42-7.50 (3H, m), 6.52 (1H, d, J = 8.8 Hz), 4.95 (2H, q, J = 7.0 Hz), 3.61-3.74 (6H, m), 2.88-2.99 (2H, m), 2.60-2.69 (2H, m), 1.72-1.84 (1H, m), 1.31 (3H, d, J = 5.1 Hz), 0.86 (6H, d, J =
6.6 Hz).
ヒストン脱アセチル化酵素活性
化合物がヒストン脱アセチル化酵素活性を阻害する能力を、Biomolから市販で入手可能なHDAC蛍光活性アッセイを用いて測定した。簡単に、Fluor de Lys (商標)基質、ε-アミノがアセチル化されたリジンを、ヒストン脱アセチル化酵素活性の源(HeLa核抽出物)と、阻害剤の存在下または非存在下でインキュベートする。基質の脱アセチル化は、基質をFluor de Lys (商標)デベロッパーに感作させ、これが蛍光体を発生する。よって、基質をHDAC活性の源とインキュベートすると、HDAC阻害剤の存在下で減少されるシグナルの増加をもたらす。
%活性 = ((Si − B) / (S0 − B)) × 100
(式中、Siは、基質、酵素および阻害剤の存在下でのシグナルであり、S0は基質、酵素および阻害剤を溶解するビヒクルの存在下でのシグナルであり、Bは、酵素の非存在下で測定されたバックグラウンドシグナルである)
範囲A:IC50<100nM;
範囲B:IC50が101nMから1000nMまで;および
範囲C:IC50>1000nM。
対数増殖している癌細胞系統(U937およびHUT)を回収し、1000〜2000細胞/ウェル(最終容量100μl)で96ウェル組織培養プレートに播種した。細胞増殖24時間後に、細胞を化合物で処理した。次いで、プレートをさらに72〜96時間インキュベートした後に、WST-1細胞生存アッセイを供給者(Roche Applied Science)の指示に従って行った。
%阻害 = 100−((Si/S0)×100)
(式中、Siは阻害剤の存在下でのシグナルであり、S0はDMSOの存在下でのシグナルである)
IC50値は、Graphpad Prismソフトウェアを用いて、8個のデータ点の結果を可変の傾きを有するシグモイドの用量応答の等式に適合させた後に(化合物のlog濃度に対する%活性)、非線形回帰分析により決定した。
範囲A:IC50<330nM;
範囲B:IC50が331nMから3300nMまで;および
範囲C:IC50>3300nM。
対数増殖しているHeLa細胞を回収し、1000細胞/ウェル(最終容量200μl)で96ウェル組織培養プレートに播種した。細胞増殖24時間後に、細胞を化合物(最終濃度20μM)で処理した。次いで、プレートをさらに72時間インキュベートした後に、スルホローダミンB (SRB)細胞生存アッセイをSkehan 1990 J Natl Canc Inst 82, 1107〜1112に従って行った。
ジ阻害として表した。
%阻害 = 100−((Si/S0)×100)
(式中、Siは阻害剤の存在下でのシグナルであり、S0はDMSOの存在下でのシグナルである)
範囲A:IC50<330nM;
範囲B:IC50が331nMから3300nMまで;および
範囲C:IC50>3300nM。
Claims (19)
- 式(I):
Q、VおよびWは独立して、-N=または-C=を表し;
Bは、(IIB)、(IIC)、(IID)、および(IIE):
から選択される2価の基であり;
Aは、
− メチル、エチル、n-プロピル、イソプロピル、フッ素、塩素、臭素もしくはヨウ素原子、
− メチルアミノ、エチルアミノ、ヒドロキシメチル、ヒドロキシエチル、メチルチオール、エチルチオール、メトキシ、エトキシ、n-プロポキシ、2-ヒドロキシエトキシ、3-ヒドロキシプロポキシ、2-アミノエトキシ、3-アミノプロポキシ、2-(メチルアミノ)エトキシ、2-(ジメチルアミノ)エトキシ、3-(ジメチルアミノ)プロポキシ、シクロペンチル、シクロヘキシル、シクロヘキシルアミノ、トリフルオロメチル、トリフルオロメトキシ、アミノ(-NH 2 )、アミノメチル、アミノエチル、ジメチルアミノ、ジエチルアミノ、エチル(メチル)アミノ、プロピル(メチル)アミノ、2-ヒドロキシエチルアミノ、3-ヒドロキシプロピルアミノ、2-アミノエチルアミノ、3-アミノプロピルアミノ、2-(メチルアミノ)エチルアミノ、2-(エチルアミノ)エチルアミノ、2-(イソプロピルアミノ)エチルアミノ、3-(イソプロピルアミノ)プロピルアミノ、2-(ジメチルアミノ)エチルアミノ、2-(ジエチルアミノ)エチルアミノ、2-(メチルアミノ)エチル(メチル)アミノ、3-(メチルアミノ)プロピル(メチル)アミノ、ニトロ、シアノ、ヒドロキシ、ホルミル、カルボキシ(-CO 2 H)、-CH 2 CO 2 H、-OCH 2 CO 2 H、-CO 2 CH 3 、-CO 2 CH 2 CH 3 、-CH 2 CO 2 CH 2 CH 3 、-CH 2 CO 2 CH 2 Ph、t-ブトキシカルボニルメトキシ、アセチル、フェナシル、チオ、チオメチル、チオエチル、スルホニル、メチルスルホニル、メチルアミノスルホニル、エチルアミノスルホニル、ジメチルアミノスルホニル、カルボキサミド、メチルアミノカルボニル、エチルアミノカルボニル、ジメチルアミノカルボニル、ジエチルアミノカルボニル、メチルアミノカルボニルメチル、-NHC(S)NH 2 、スルホニルアミノ(-NHSO 2 H)、メチルスルホニルアミノ、ジメチルスルホニルアミノ、アミノスルホニルアミノ(-NHSO 2 NH 2 )、メチルアミノスルホニルアミノ、ジメチルアミノスルホニルアミノ、メチルアミノカルボニルアミノ、ジメチルアミノカルボニルアミノ、アセチルアミノ、フェニルカルボニルアミノ、アミノメチルカルボニルアミノ、アセチルアミノメチル、メトキシカルボニルアミノ、t-ブトキシカルボニルアミノ、ピロリジニル、ピペリジニル、ピペラジニル、4-メチルピペラジニル、ホモピペラジニル、モルホリニル、イミダゾリル、1,2,4-トリアゾリル、1.2.3-トリアゾリル、1,3,4-トリアゾリル、1,2,5-トリアゾリル、C 1-6 直鎖もしくは分枝鎖状アルキル、アミノC 1-6 アルキル、C 1-3 アルキルアミノC 1-6 アルキル、C 1-3 ジアルキルアミノC 1-6 アルキル、ヒドロキシC 1-6 アルキル、C 1-3 アルコキシC 1-6 アルキル、メトキシエチル、チオールC 1-3 アルキル、C 1-3 アルキルチオールC 1-6 アルキル、C 1-6 アルカノイル、C 1-6 アルキルスルホニル、アミノスルホニル(-SO 2 NH 2 )、C 1-6 アルキルアミノスルホニル、-SO 2 NHMe、C 1-6 ジアルキルアミノスルホニル、-SO 2 NMe 2 、カルボキサミド(-CONH 2 )、カルボキサミドC 1-6 アルキル、CH 2 CONH 2 、C 1-6 アルキルアミノカルボニル、C 1-6 ジアルキルアミノカルボニル、アミノスルホニルC 1-6 アルキル、CH 2 SO 2 NH 2 、C 1-3 アルキルアミノスルホニルC 1-6 アルキル、CH 2 SO 2 NHMe、C 1-3 ジアルキルアミノスルホニルC 1-6 アルキル、CH 2 SO 2 NMe 2 、C 1-6 モルホリニルC 1-6 アルキル、ピペリジニルC 1-6 アルキル、ピペラジニルC 1-6 アルキル、および4-(C 1-6 アルキル)ピペラジニルC 1-6 アルキル基、および
− フェニルアミノスルホニル、イミダゾリルC 1-6 アルキル、トリアゾリルC 1-6 アルキルおよびヘテロC 3-6 シクロアルキルC 1-6 アルキル基[ここで、前記フェニルアミノスルホニル、イミダゾリルC 1-6 アルキル、トリアゾリルC 1-6 アルキルおよびヘテロC 3-6 シクロアルキルC 1-6 アルキル基は、(C 1 -C 6 )アルキル、(C 1 -C 6 )アルコキシ、ヒドロキシ、ヒドロキシ(C 1 -C 6 )アルキル、メルカプト、メルカプト(C 1 -C 6 )アルキル、(C 1 -C 6 )アルキルチオ、フェニル、ハロ(フルオロ、ブロモおよびクロロを含む)、トリフルオロメチル、トリフルオロメトキシ、ニトロ、ニトリル(-CN)、オキソ、-COOH、-COOR C 、-COR C 、-SO 2 R C 、-CONH 2 、-SO 2 NH 2 、-CONHR C 、-SO 2 NHR C 、-CONR C R D 、-SO 2 NR C R D 、-NH 2 、-NHR C 、-NR C R D 、-OCONH 2 、-OCONHR C 、-OCONR C R D 、-NHCOR C 、-NHCOOR C 、-NR D COOR C 、-NHSO 2 OR C 、-NR D SO 2 OH、-NR D SO 2 OR C 、-NHCONH 2 、-NR C CONH 2 、-NHCONHR D 、-NR C CONHR D 、-NHCONR C R D または-NR C CONR C R D (ここで、R C およびR D は独立して(C 1 -C 6 )アルキル、(C 3 -C 6 )シクロアルキル、フェニルまたは5もしくは6の環原子を有する単環式ヘテロアリールである)から独立して選択される四つまでの置換基で置換されていてもよい]
から独立して選択される四つまでの置換基で置換されていてもよい単環式、2環式もしくは3環式の炭素環式基または複素環式基であり;そして
-[リンカー1]-および-[リンカー2]-は独立して、
(i) 結合手;
(ii) -O-、-S-、-C(=O)-、-S(=O)2-、-NR1-、-C(=O)NR1-、-S(=O)2NR1-、-NR1C(=O)-、-NR1S(=O)2-、-NR1(CH2)m-、-NR1C(=O)(CH2)m-、-NR1S(=O)2(CH2)m、-NR2C(=O)NR1-、-NR1C(=O)(CH2)mAr-、または-NR1S(=O)2(CH2)mAr-
(ここで、R1およびR2は独立して、水素、C1-C4アルキルまたは窒素置換基であり、mは1、2、3、4または5であり、Arは2価のフェニル基または5〜13員環の単環式もしくは2環式の2価のヘテロアリール基である);および
(iii) − (C 1 -C 6 )アルキル、(C 1 -C 6 )アルコキシ、ヒドロキシ、ヒドロキシ(C 1 -C 6 )アルキル、メルカプト、メルカプト(C 1 -C 6 )アルキル、(C 1 -C 6 )アルキルチオ、フェニル、ハロ(フルオロ、ブロモおよびクロロを含む)、トリフルオロメチル、トリフルオロメトキシ、ニトロ、ニトリル(-CN)、オキソ、-COOH、-COOR C 、-COR C 、-SO 2 R C 、-CONH 2 、-SO 2 NH 2 、-CONHR C 、-SO 2 NHR C 、-CONR C R D 、-SO 2 NR C R D 、-NH 2 、-NHR C 、-NR C R D 、-OCONH 2 、-OCONHR C 、-OCONR C R D 、-NHCOR C 、-NHCOOR C 、-NR D COOR C 、-NHSO 2 OR C 、-NR D SO 2 OH、-NR D SO 2 OR C 、-NHCONH 2 、-NR C CONH 2 、-NHCONHR D 、-NR C CONHR D 、-NHCONR C R D または-NR C CONR C R D (ここで、R C およびR D は、独立して(C 1 -C 6 )アルキル、(C 3 -C 6 )シクロアルキル、フェニルまたは5もしくは6の環原子を有する単環式ヘテロアリールである)から独立して選択される四つまでの置換基で置換されていてもよい、直鎖もしくは分枝鎖状C1-C6アルキレン、C2-C6アルケニレンまたはC2-C6アルキニレン基[これらはエーテル(-O-)、チオエーテル(-S-)またはアミノ(-NRA-)結合を含むかまたはこれらの結合を末端に有していてもよい(ここで、RAは水素、C1-C3アルキル、または
アミノC 1-6 アルキル、アミノエチル、C 1-3 アルキルアミノC 1-6 アルキル、C 1-3 ジアルキルアミノC 1-6 アルキル、ヒドロキシC 1-6 アルキル、ヒドロキシエチル、C 1-3 アルコキシC 1-6 アルキル、メトキシエチル、メルカプトC 1-3 アルキル、C 1-3 アルキルメルカプトC 1-6 アルキル、カルボキサミドC 1-6 アルキル、-CH 2 CONH 2 、アミノスルホニルC 1-6 アルキル、-CH 2 SO 2 NH 2 、C 1-3 アルキルアミノスルホニルC 1-6 アルキル、-CH 2 SO 2 NHMe、C 1-3 ジアルキルアミノスルホニルC 1-6 アルキル、-CH 2 SO 2 NMe 2 、C 1-6 アルカノイル、C 1-6 アルキルスルホニル、アミノスルホニル(-SO 2 NH 2 )、C 1-6 アルキルアミノスルホニル、-SO 2 NHMe、C 1-6 ジアルキルアミノスルホニル、-SO 2 NMe 2 、フェニルアミノスルホニル、カルボキサミド(-CONH 2 )、C 1-6 アルキルアミノカルボニル、C 1-6 ジアルキルアミノカルボニル、モルホリニルC 1-6 アルキル、イミダゾリルC 1-6 アルキル、トリアゾリルC 1-6 アルキルもしくは単環式のヘテロシクロアルキルC 1-6 アルキル、ピペリジニルC 1-6 アルキル、ピペラジニルC 1-6 アルキルまたは4-(C 1-6 アルキル)ピペラジニルC 1-6 アルキルから選択される窒素置換基であり、
前記のフェニルアミノスルホニルおよび前記のイミダゾリルC 1-6 アルキル、トリアゾリルC 1-6 アルキルもしくは単環式のヘテロシクロアルキルC 1-6 アルキルのイミダゾリル、トリアゾリルもしくはヘテロシクロアルキル環は、(C 1 -C 6 )アルキル、(C 1 -C 6 )アルコキシ、ヒドロキシ、ヒドロキシ(C 1 -C 6 )アルキル、メルカプト、メルカプト(C 1 -C 6 )アルキル、(C 1 -C 6 )アルキルチオ、フェニル、ハロ(フルオロ、ブロモおよびクロロを含む)、トリフルオロメチル、トリフルオロメトキシ、ニトロ、ニトリル(-CN)、オキソ、-COOH、-COOR C 、-COR C 、-SO 2 R C 、-CONH 2 、-SO 2 NH 2 、-CONHR C 、-SO 2 NHR C 、-CONR C R D 、-SO 2 NR C R D 、-NH 2 、-NHR C 、-NR C R D 、-OCONH 2 、-OCONHR C 、-OCONR C R D 、-NHCOR C 、-NHCOOR C 、-NR D COOR C 、-NHSO 2 OR C 、-NR D SO 2 OH、-NR D SO 2 OR C 、-NHCONH 2 、-NR C CONH 2 、-NHCONHR D 、-NR C CONHR D 、-NHCONR C R D または-NR C CONR C R D (ここで、R C およびR D は独立して(C 1 -C 6 )アルキル、(C 3 -C 6 )シクロアルキル、フェニルまたは5もしくは6の環原子を有する単環式ヘテロアリールである)から独立して選択される四つまでの置換基で置換されていてもよい)]
から選択される]
の化合物、またはその塩、N-オキサイド、水和物もしくは溶媒和物。 - Qが-C=であり、VおよびWがそれぞれ-N=である、請求項1に記載の化合物。
- Aが、次の環の一つである請求項1または2に記載の化合物:
前記の環は、− メチル、エチル、n-プロピル、イソプロピル、フッ素、塩素、臭素もしくはヨウ素原子、
− メチルアミノ、エチルアミノ、ヒドロキシメチル、ヒドロキシエチル、メチルチオール、エチルチオール、メトキシ、エトキシ、n-プロポキシ、2-ヒドロキシエトキシ、3-ヒドロキシプロポキシ、2-アミノエトキシ、3-アミノプロポキシ、2-(メチルアミノ)エトキシ、2-(ジメチルアミノ)エトキシ、3-(ジメチルアミノ)プロポキシ、シクロペンチル、シクロヘキシル、シクロヘキシルアミノ、トリフルオロメチル、トリフルオロメトキシ、アミノ(-NH 2 )、アミノメチル、アミノエチル、ジメチルアミノ、ジエチルアミノ、エチル(メチル)アミノ、プロピル(メチル)アミノ、2-ヒドロキシエチルアミノ、3-ヒドロキシプロピルアミノ、2-アミノエチルアミノ、3-アミノプロピルアミノ、2-(メチルアミノ)エチルアミノ、2-(エチルアミノ)エチルアミノ、2-(イソプロピルアミノ)エチルアミノ、3-(イソプロピルアミノ)プロピルアミノ、2-(ジメチルアミノ)エチルアミノ、2-(ジエチルアミノ)エチルアミノ、2-(メチルアミノ)エチル(メチル)アミノ、3-(メチルアミノ)プロピル(メチル)アミノ、ニトロ、シアノ、ヒドロキシ、ホルミル、カルボキシ(-CO 2 H)、-CH 2 CO 2 H、-OCH 2 CO 2 H、-CO 2 CH 3 、-CO 2 CH 2 CH 3 、-CH 2 CO 2 CH 2 CH 3 、-CH 2 CO 2 CH 2 Ph、t-ブトキシカルボニルメトキシ、アセチル、フェナシル、チオ、チオメチル、チオエチル、スルホニル、メチルスルホニル、メチルアミノスルホニル、エチルアミノスルホニル、ジメチルアミノスルホニル、カルボキサミド、メチルアミノカルボニル、エチルアミノカルボニル、ジメチルアミノカルボニル、ジエチルアミノカルボニル、メチルアミノカルボニルメチル、-NHC(S)NH 2 、スルホニルアミノ(-NHSO 2 H)、メチルスルホニルアミノ、ジメチルスルホニルアミノ、アミノスルホニルアミノ(-NHSO 2 NH 2 )、メチルアミノスルホニルアミノ、ジメチルアミノスルホニルアミノ、メチルアミノカルボニルアミノ、ジメチルアミノカルボニルアミノ、アセチルアミノ、フェニルカルボニルアミノ、アミノメチルカルボニルアミノ、アセチルアミノメチル、メトキシカルボニルアミノ、t-ブトキシカルボニルアミノ、ピロリジニル、ピペリジニル、ピペラジニル、4-メチルピペラジニル、ホモピペラジニル、モルホリニル、イミダゾリル、1,2,4-トリアゾリル、1.2.3-トリアゾリル、1,3,4-トリアゾリル、1,2,5-トリアゾリル、C 1-6 直鎖もしくは分枝鎖状アルキル、アミノC 1-6 アルキル、C 1-3 アルキルアミノC 1-6 アルキル、C 1-3 ジアルキルアミノC 1-6 アルキル、ヒドロキシC 1-6 アルキル、C 1-3 アルコキシC 1-6 アルキル、メトキシエチル、チオールC 1-3 アルキル、C 1-3 アルキルチオールC 1-6 アルキル、C 1-6 アルカノイル、C 1-6 アルキルスルホニル、アミノスルホニル(-SO 2 NH 2 )、C 1-6 アルキルアミノスルホニル、-SO 2 NHMe、C 1-6 ジアルキルアミノスルホニル、-SO 2 NMe 2 、カルボキサミド(-CONH 2 )、カルボキサミドC 1-6 アルキル、CH 2 CONH 2 、C 1-6 アルキルアミノカルボニル、C 1-6 ジアルキルアミノカルボニル、アミノスルホニルC 1-6 アルキル、CH 2 SO 2 NH 2 、C 1-3 アルキルアミノスルホニルC 1-6 アルキル、CH 2 SO 2 NHMe、C 1-3 ジアルキルアミノスルホニルC 1-6 アルキル、CH 2 SO 2 NMe 2 、C 1-6 モルホリニルC 1-6 アルキル、ピペリジニルC 1-6 アルキル、ピペラジニルC 1-6 アルキル、および4-(C 1-6 アルキル)ピペラジニルC 1-6 アルキル基、および
− フェニルアミノスルホニル、イミダゾリルC 1-6 アルキル、トリアゾリルC 1-6 アルキルおよびヘテロC 3-6 シクロアルキルC 1-6 アルキル基から独立して選択される四つまでの置換基で置換されていてもよく、前記のフェニルアミノスルホニル、イミダゾリルC 1-6 アルキル、トリアゾリルC 1-6 アルキルおよびヘテロC 3-6 シクロアルキルC 1-6 アルキル基は、(C 1 -C 6 )アルキル、(C 1 -C 6 )アルコキシ、ヒドロキシ、ヒドロキシ(C 1 -C 6 )アルキル、メルカプト、メルカプト(C 1 -C 6 )アルキル、(C 1 -C 6 )アルキルチオ、フェニル、ハロ(フルオロ、ブロモおよびクロロを含む)、トリフルオロメチル、トリフルオロメトキシ、ニトロ、ニトリル(-CN)、オキソ、-COOH、-COOR C 、-COR C 、-SO 2 R C 、-CONH 2 、-SO 2 NH 2 、-CONHR C 、-SO 2 NHR C 、-CONR C R D 、-SO 2 NR C R D 、-NH 2 、-NHR C 、-NR C R D 、-OCONH 2 、-OCONHR C 、-OCONR C R D 、-NHCOR C 、-NHCOOR C 、-NR D COOR C 、-NHSO 2 OR C 、-NR D SO 2 OH、-NR D SO 2 OR C 、-NHCONH 2 、-NR C CONH 2 、-NHCONHR D 、-NR C CONHR D 、-NHCONR C R D または-NR C CONR C R D (ここで、R C およびR D は独立して(C 1 -C 6 )アルキル、(C 3 -C 6 )シクロアルキル、フェニルまたは5もしくは6の環原子を有する単環式ヘテロアリールである)から独立して選択される四つまでの置換基で置換されていてもよい]。 - 環Aが、フェニル、ナフチル、キノリン-2-イルおよび1,3-ジヒドロ-イソインドール-2-イルから選択される請求項1または2に記載の化合物:
[ここで、フェニル、ナフチル、キノリン-2-イルおよび1,3-ジヒドロ-イソインドール-2-イルは、
− メチル、エチル、n-プロピル、イソプロピル、フッ素、塩素、臭素もしくはヨウ素原子、
− メチルアミノ、エチルアミノ、ヒドロキシメチル、ヒドロキシエチル、メチルチオール、エチルチオール、メトキシ、エトキシ、n-プロポキシ、2-ヒドロキシエトキシ、3-ヒドロキシプロポキシ、2-アミノエトキシ、3-アミノプロポキシ、2-(メチルアミノ)エトキシ、2-(ジメチルアミノ)エトキシ、3-(ジメチルアミノ)プロポキシ、シクロペンチル、シクロヘキシル、シクロヘキシルアミノ、トリフルオロメチル、トリフルオロメトキシ、アミノ(-NH 2 )、アミノメチル、アミノエチル、ジメチルアミノ、ジエチルアミノ、エチル(メチル)アミノ、プロピル(メチル)アミノ、2-ヒドロキシエチルアミノ、3-ヒドロキシプロピルアミノ、2-アミノエチルアミノ、3-アミノプロピルアミノ、2-(メチルアミノ)エチルアミノ、2-(エチルアミノ)エチルアミノ、2-(イソプロピルアミノ)エチルアミノ、3-(イソプロピルアミノ)プロピルアミノ、2-(ジメチルアミノ)エチルアミノ、2-(ジエチルアミノ)エチルアミノ、2-(メチルアミノ)エチル(メチル)アミノ、3-(メチルアミノ)プロピル(メチル)アミノ、ニトロ、シアノ、ヒドロキシ、ホルミル、カルボキシ(-CO 2 H)、-CH 2 CO 2 H、-OCH 2 CO 2 H、-CO 2 CH 3 、-CO 2 CH 2 CH 3 、-CH 2 CO 2 CH 2 CH 3 、-CH 2 CO 2 CH 2 Ph、t-ブトキシカルボニルメトキシ、アセチル、フェナシル、チオ、チオメチル、チオエチル、スルホニル、メチルスルホニル、メチルアミノスルホニル、エチルアミノスルホニル、ジメチルアミノスルホニル、カルボキサミド、メチルアミノカルボニル、エチルアミノカルボニル、ジメチルアミノカルボニル、ジエチルアミノカルボニル、メチルアミノカルボニルメチル、-NHC(S)NH 2 、スルホニルアミノ(-NHSO 2 H)、メチルスルホニルアミノ、ジメチルスルホニルアミノ、アミノスルホニルアミノ(-NHSO 2 NH 2 )、メチルアミノスルホニルアミノ、ジメチルアミノスルホニルアミノ、メチルアミノカルボニルアミノ、ジメチルアミノカルボニルアミノ、アセチルアミノ、フェニルカルボニルアミノ、アミノメチルカルボニルアミノ、アセチルアミノメチル、メトキシカルボニルアミノ、t-ブトキシカルボニルアミノ、ピロリジニル、ピペリジニル、ピペラジニル、4-メチルピペラジニル、ホモピペラジニル、モルホリニル、イミダゾリル、1,2,4-トリアゾリル、1.2.3-トリアゾリル、1,3,4-トリアゾリル、1,2,5-トリアゾリル、C 1-6 直鎖もしくは分枝鎖状アルキル、アミノC 1-6 アルキル、C 1-3 アルキルアミノC 1-6 アルキル、C 1-3 ジアルキルアミノC 1-6 アルキル、ヒドロキシC 1-6 アルキル、C 1-3 アルコキシC 1-6 アルキル、メトキシエチル、チオールC 1-3 アルキル、C 1-3 アルキルチオールC 1-6 アルキル、C 1-6 アルカノイル、C 1-6 アルキルスルホニル、アミノスルホニル(-SO 2 NH 2 )、C 1-6 アルキルアミノスルホニル、-SO 2 NHMe、C 1-6 ジアルキルアミノスルホニル、-SO 2 NMe 2 、カルボキサミド(-CONH 2 )、カルボキサミドC 1-6 アルキル、CH 2 CONH 2 、C 1-6 アルキルアミノカルボニル、C 1-6 ジアルキルアミノカルボニル、アミノスルホニルC 1-6 アルキル、CH 2 SO 2 NH 2 、C 1-3 アルキルアミノスルホニルC 1-6 アルキル、CH 2 SO 2 NHMe、C 1-3 ジアルキルアミノスルホニルC 1-6 アルキル、CH 2 SO 2 NMe 2 、C 1-6 モルホリニルC 1-6 アルキル、ピペリジニルC 1-6 アルキル、ピペラジニルC 1-6 アルキル、および4-(C 1-6 アルキル)ピペラジニルC 1-6 アルキル基、および
− フェニルアミノスルホニル、イミダゾリルC 1-6 アルキル、トリアゾリルC 1-6 アルキルおよびヘテロC 3-6 シクロアルキルC 1-6 アルキル基から独立して選択される四つまでの置換基で置換されていてもよく、
前記のフェニルアミノスルホニル、イミダゾリルC 1-6 アルキル、トリアゾリルC 1-6 アルキルおよびヘテロC 3-6 シクロアルキルC 1-6 アルキル基は、(C 1 -C 6 )アルキル、(C 1 -C 6 )アルコキシ、ヒドロキシ、ヒドロキシ(C 1 -C 6 )アルキル、メルカプト、メルカプト(C 1 -C 6 )アルキル、(C 1 -C 6 )アルキルチオ、フェニル、ハロ(フルオロ、ブロモおよびクロロを含む)、トリフルオロメチル、トリフルオロメトキシ、ニトロ、ニトリル(-CN)、オキソ、-COOH、-COOR C 、-COR C 、-SO 2 R C 、-CONH 2 、-SO 2 NH 2 、-CONHR C 、-SO 2 NHR C 、-CONR C R D 、-SO 2 NR C R D 、-NH 2 、-NHR C 、-NR C R D 、-OCONH 2 、-OCONHR C 、-OCONR C R D 、-NHCOR C 、-NHCOOR C 、-NR D COOR C 、-NHSO 2 OR C 、-NR D SO 2 OH、-NR D SO 2 OR C 、-NHCONH 2 、-NR C CONH 2 、-NHCONHR D 、-NR C CONHR D 、-NHCONR C R D または-NR C CONR C R D (ここで、R C およびR D は独立して(C 1 -C 6 )アルキル、(C 3 -C 6 )シクロアルキル、フェニルまたは5もしくは6の環原子を有する単環式ヘテロアリールである)から独立して選択される四つまでの置換基で置換されていてもよい]。 - 環Aの置換基がフルオロおよびクロロから選択される、請求項4に記載の化合物。
- -Ar-が、-[リンカー1]-および-[リンカー2]-の一方に存在し、2価のフェニレン基である、請求項1〜5のいずれか一つに記載の化合物。
- -[リンカー1]-が、Bが2価の基(IIB)、(IID)もしくは(IIE)であるときに結合手であるか、またはBが2価の基(IIC)であるときに-NH-である、請求項1〜5のいずれか一つに記載の化合物。
- -[リンカー2]-が、-NHS(=O)2-、-NHC(=O)-、-NHC(=O)(CH2)m-、-NHS(=O)2(CH2)m -または-NH(CH2)m-である、請求項8に記載の化合物:[ここで、mは1、2、3、4または5であり、そして窒素原子上の水素は窒素置換基で置き換えられていてもよく、
該窒素置換基は、アミノC 1-6 アルキル、アミノエチル、C 1-3 アルキルアミノC 1-6 アルキル、C 1-3 ジアルキルアミノC 1-6 アルキル、ヒドロキシC 1-6 アルキル、ヒドロキシエチル、C 1-3 アルコキシC 1-6 アルキル、メトキシエチル、メルカプトC 1-3 アルキル、C 1-3 アルキルメルカプトC 1-6 アルキル、カルボキサミドC 1-6 アルキル、-CH 2 CONH 2 、アミノスルホニルC 1-6 アルキル、-CH 2 SO 2 NH 2 、C 1-3 アルキルアミノスルホニルC 1-6 アルキル、-CH 2 SO 2 NHMe、C 1-3 ジアルキルアミノスルホニルC 1-6 アルキル、-CH 2 SO 2 NMe 2 、C 1-6 アルカノイル、C 1-6 アルキルスルホニル、アミノスルホニル(-SO 2 NH 2 )、C 1-6 アルキルアミノスルホニル、-SO 2 NHMe、C 1-6 ジアルキルアミノスルホニル、-SO 2 NMe 2 、フェニルアミノスルホニル、カルボキサミド(-CONH 2 )、C 1-6 アルキルアミノカルボニル、C 1-6 ジアルキルアミノカルボニル、モルホリニルC 1-6 アルキル、イミダゾリルC 1-6 アルキル、トリアゾリルC 1-6 アルキルもしくは単環式のヘテロシクロアルキルC 1-6 アルキル、ピペリジニルC 1-6 アルキル、ピペラジニルC 1-6 アルキルまたは4-(C 1-6 アルキル)ピペラジニルC 1-6 アルキルから選択される窒素原子上の置換基であり、
前記のフェニルアミノスルホニルおよび前記イミダゾリルC 1-6 アルキル、トリアゾリルC 1-6 アルキルもしくは単環式のヘテロシクロアルキルC 1-6 アルキルのイミダゾリル、トリアゾリルもしくはヘテロシクロアルキル環は、(C 1 -C 6 )アルキル、(C 1 -C 6 )アルコキシ、ヒドロキシ、ヒドロキシ(C 1 -C 6 )アルキル、メルカプト、メルカプト(C 1 -C 6 )アルキル、(C 1 -C 6 )アルキルチオ、フェニル、ハロ(フルオロ、ブロモおよびクロロを含む)、トリフルオロメチル、トリフルオロメトキシ、ニトロ、ニトリル(-CN)、オキソ、-COOH、-COOR C 、-COR C 、-SO 2 R C 、-CONH 2 、-SO 2 NH 2 、-CONHR C 、-SO 2 NHR C 、-CONR C R D 、-SO 2 NR C R D 、-NH 2 、-NHR C 、-NR C R D 、-OCONH 2 、-OCONHR C 、-OCONR C R D 、-NHCOR C 、-NHCOOR C 、-NR D COOR C 、-NHSO 2 OR C 、-NR D SO 2 OH、-NR D SO 2 OR C 、-NHCONH 2 、-NR C CONH 2 、-NHCONHR D 、-NR C CONHR D 、-NHCONR C R D または-NR C CONR C R D (ここで、R C およびR D は独立して(C 1 -C 6 )アルキル、(C 3 -C 6 )シクロアルキル、フェニルまたは5もしくは6の環原子を有する単環式ヘテロアリールである)から独立して選択される四つまでの置換基で置換されていてもよい]。 - Aが請求項3〜5のいずれか一つで定義されたとおりである、請求項10に記載の化合物。
- 次の:
N-ヒドロキシ 2-(5-ナフタレン-2-イルメチル-ヘキサヒドロ-ピロロ[3,4-c]ピロール-2-イル)ピリミジン-5-カルボキサミド、
N-ヒドロキシ 2-{6-[(2-ナフチルスルホニル)アミノ]-3-アザビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド トリフルオロアセテート、
N-ヒドロキシ 2-{6-[(ナフタレン-2-イルメチル)-アミノ]-3-アザ-ビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド、
N-ヒドロキシ 2-[6-(1,3-ジヒドロ-イソインドール-2-イル)-3-アザ-ビシクロ[3.1.0]ヘキシ-3-イル]ピリミジン-5-カルボキサミド、
N-ヒドロキシ 2-[6-(4-クロロ-ベンジルアミノ)-3-アザ-ビシクロ[3.1.0]ヘキシ-3-イル]ピリミジン-5-カルボキサミド、
N-ヒドロキシ 2-{6-[(ナフタレン-2-スルホニル)-(2-ピペリジン-1-イル-エチル)-アミノ]-3-アザ-ビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド、
N-ヒドロキシ 2-{6-[(キノリン-2-イルメチル)-アミノ]-3-アザ-ビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド、
N-ヒドロキシ 2-[5-(4-クロロ-ベンジル)-ヘキサヒドロ-ピロロ[3,4-c]ピロール-2-イル]ピリミジン-5-カルボキサミド、および
N-ヒドロキシ 2-[5-(ナフタレン-2-カルボニル)-ヘキサヒドロ-ピロロ[3,4-c]ピロール-2-イル]-ピリミジン-5-カルボキサミド
からなる群から選択される、請求項1に記載の化合物、またはそれらのN-オキサイド、塩、水和物もしくは溶媒和物。 - N-ヒドロキシ 2-{6-[(6-フルオロ-キノリン-2-イルメチル)-アミノ]-3-アザ-ビシクロ[3.1.0]ヘキシ-3-イル}ピリミジン-5-カルボキサミド、またはそのN-オキサイド、塩、水和物もしくは溶媒和物である、請求項1に記載の化合物。
- 請求項1〜13のいずれか一つに記載の化合物を医薬的に許容される担体とともに含む医薬組成物。
- HDAC酵素の活性を阻害するための組成物の製造における、請求項1〜13のいずれか一つに記載の式(I)の化合物の使用。
- エキスビボまたはインビボでHDAC1活性を阻害するための、請求項15に記載の使用。
- 細胞増殖性疾患、ポリグルタミン病、神経変性疾患、自己免疫疾患、炎症性疾患、臓器移植拒絶、糖尿病、血液学的疾患または感染症の治療のための、請求項14に記載の医薬組成物。
- 癌細胞増殖、ハンチントン病またはアルツハイマー病の治療のための、請求項17に記載の医薬組成物。
- リウマチ性関節炎の治療のための、請求項17に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0510204.1 | 2005-05-19 | ||
GBGB0510204.1A GB0510204D0 (en) | 2005-05-19 | 2005-05-19 | Enzyme inhibitors |
PCT/GB2006/001779 WO2006123121A1 (en) | 2005-05-19 | 2006-05-15 | Histone deacetylase inhibitors |
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JP2008540623A JP2008540623A (ja) | 2008-11-20 |
JP2008540623A5 JP2008540623A5 (ja) | 2009-06-18 |
JP4954200B2 true JP4954200B2 (ja) | 2012-06-13 |
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JP2008511780A Active JP4954200B2 (ja) | 2005-05-19 | 2006-05-15 | ヒストン脱アセチル化酵素阻害剤 |
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US (1) | US7932246B2 (ja) |
EP (1) | EP1881977B1 (ja) |
JP (1) | JP4954200B2 (ja) |
KR (1) | KR20080016539A (ja) |
CN (1) | CN101163696B (ja) |
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AU (1) | AU2006248788B2 (ja) |
BR (1) | BRPI0611522B1 (ja) |
CA (1) | CA2605050C (ja) |
DE (1) | DE602006019410D1 (ja) |
DK (1) | DK1881977T3 (ja) |
ES (1) | ES2358604T3 (ja) |
GB (2) | GB0510204D0 (ja) |
IL (1) | IL186362A (ja) |
MX (1) | MX2007013066A (ja) |
NZ (1) | NZ562519A (ja) |
PL (1) | PL1881977T3 (ja) |
PT (1) | PT1881977E (ja) |
WO (1) | WO2006123121A1 (ja) |
ZA (1) | ZA200709608B (ja) |
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AU2008338631A1 (en) | 2007-12-14 | 2009-06-25 | Georgetown University | Histone deacetylase inhibitors |
GB0803747D0 (en) | 2008-02-29 | 2008-04-09 | Martin | Enzyme and receptor modulation |
JP5564033B2 (ja) * | 2008-03-27 | 2014-07-30 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ヒストンデアセチラーゼの新規インヒビターとしてのアザ−ビシクロヘキシル置換インドリルアルキルアミノ誘導体 |
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GB2429707A (en) | 2007-03-07 |
BRPI0611522A2 (pt) | 2010-09-21 |
MX2007013066A (es) | 2008-01-11 |
CA2605050C (en) | 2014-01-21 |
ES2358604T3 (es) | 2011-05-12 |
US20100152155A1 (en) | 2010-06-17 |
DK1881977T3 (da) | 2011-04-04 |
GB2429707B (en) | 2007-06-13 |
JP2008540623A (ja) | 2008-11-20 |
AU2006248788B2 (en) | 2011-05-26 |
KR20080016539A (ko) | 2008-02-21 |
US7932246B2 (en) | 2011-04-26 |
EP1881977B1 (en) | 2011-01-05 |
IL186362A0 (en) | 2008-01-20 |
ATE494283T1 (de) | 2011-01-15 |
ZA200709608B (en) | 2008-12-31 |
CN101163696A (zh) | 2008-04-16 |
DE602006019410D1 (de) | 2011-02-17 |
PL1881977T3 (pl) | 2011-07-29 |
EP1881977A1 (en) | 2008-01-30 |
NZ562519A (en) | 2010-11-26 |
GB0618717D0 (en) | 2006-11-01 |
CA2605050A1 (en) | 2006-11-23 |
CN101163696B (zh) | 2011-09-14 |
PT1881977E (pt) | 2011-04-11 |
WO2006123121A1 (en) | 2006-11-23 |
BRPI0611522B1 (pt) | 2021-08-03 |
GB0510204D0 (en) | 2005-06-22 |
IL186362A (en) | 2012-01-31 |
AU2006248788A1 (en) | 2006-11-23 |
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